Solubility Enhancement with

BASF Pharma Polymers

Solubilizer Compendium
Thomas Reintjes (Editor)
Pharma Ingredients & Services.
Welcome to more opportunities.
Solubility Enhancement with
BASF Pharma Polymers
Solubilizer Compendium
Thomas Reintjes (Editor)
October 2011
BASF SE
Pharma Ingredients & Services
68623 Lampertheim, Germany
1 Formulation of problem drugs and they are
all problem drugs
2 Preparation of solid solutions and dispersions
3 Investigation of solubilization efcacy using
a high-throughput robot
4 Overview chart: BASF pharma polymers for
solubility enhancement
5 Soluplus

6 Kolliphor TPGS
7 Kolliphor HS 15
8 Kolliphor RH 40
9 Kolliphor EL / ELP
10 Kolliphor P grades (Poloxamers)
11 Soluble Kollidon

grades
12 Alphabetical index
1
2
3
4
5
6
11
12
7
8
9
10
4
Contents
Sebastian Koltzenburg
1 Formulation of problem drugs and they are 9
all problem drugs
1.1 Introduction 9
1.1.1 Classication of poorly soluble drugs: The Biopharmaceutical 9
Classication System (BCS)
1.1.2 Poorly soluble drugs: The thermodynamics behind the problem 12
1.2 Approaches to overcome this issue 13
1.2.1 Surfactants 14
1.2.2 Complex formation with polymers 20
1.2.3 Nanotechnology: The kinetic approach 22
1.3 Summary and outlook 26
Matthias Karl, Michael Schnherr
2 Preparation of solid solutions and dispersions 27
2.1 Solid solutions and dispersions 27
2.1.1 Introduction and general aspects 27
2.1.2 Types of solid dispersions 27
2.1.3 Manufacturing of solid dispersions 28
2.1.4 Analytical investigations of solid dispersions 29
2.2 Hot-melt extrusion 31
2.2.1 Introduction to hot-melt extrusion 31
2.2.2 The hot-melt extrusion process 32
2.2.3 Polymers for hot-melt extrusion 36
2.3 Spray drying as a preparation technique for solid solutions 38
2.3.1 Introduction 38
2.3.2 Spray drying: theory and practice 39
2.3.3 Preparation of solid solutions using spray drying 45
Michael G. Herting, Viet Nguyen-Kim, Ann-Kathrin Marguerre
3 Investigation of solubilization efcacy 53
using a high-throughput robot
3.1 Introduction 53
3.2 Kinetic and thermodynamic solubility 53
3.3 Set-up of the Solu-HTS robot 55
3.3.1 Overview 55
3.3.2 Preparation of samples 57
3.3.3 Analysis of dissolved API 57
3.4 Proof of concept: Manual vs. HTS experiments 60
3.4.1 Materials 60
3.4.2 Determination of dissolved carbamazepine 60
3.4.3 Results and discussion 61
3.5 Conclusion 62
5
Thomas Reintjes
4 Overview chart: BASF pharma polymers for 64
solubility enhancement
Dejan Djuric
5 Soluplus

67
5.1 Composition 67
5.2 Properties 67
5.3 Applications 68
Jochen Dressler
6 Kolliphor TPGS 73
6.1 Composition 73
6.2 Properties 74
6.3 Applications 76
Shaukat Ali
7 Kolliphor HS 15 79
7.1 Composition 79
7.2 Properties 81
7.3 Applications 83
Shaukat Ali
8 Kolliphor RH 40 89
8.1 Composition 89
8.2 Properties 90
8.3 Applications 90
Shaukat Ali
9 Kolliphor EL / ELP 95
9.1 Composition 95
9.2 Properties 96
9.3 Applications 98
Thomas Reintjes
10 Kolliphor P grades (Poloxamers) 103
10.1 Composition 103
10.2 Properties 105
10.3 Applications 109
Thomas Reintjes
11 Soluble Kollidon

grades 112
11.1 Composition 112
11.2 Properties 113
11.3 Applications 117
12 Alphabetical index 119
6
7
Acknowledgements
First of all, I would like to thank all those authors who contributed to this compendium.
The authors are current or former BASF and Cognis employees who have essentially
devoted their free time to completing the chapters. In addition to their written contribu-
tions, they have given their input in many discussions on the nal concept of this book.
My special thanks go to Ulf Matussek and Hans-Jrgen Doelger for their support
and ideas in creating the cover picture and to James Brawley for his professional
language editing.
Furthermore, I would like to thank all those colleagues who helped in proofreading
and for providing many valuable comments for improving the quality and compre-
hensibility of the texts and diagrams.
Finally I would like to acknowledge the work of my colleagues from the Service-
center Medien und Kommunikation who transferred the drafts into the nal lay-
out, continuously introduced changes and who gave this compendium its visually
attractive design.
October 2011
Thomas Reintjes (Editor)
8
9
Sebastian Koltzenburg
1 Formulation of problem drugs and they are
all problem drugs
1.1 Introduction
About 90 % of all compounds in todays pharmaceutical drug delivery pipelines are
reported to be poorly soluble in water [1]. This poses enormous problems for the
industry; for an active pharmaceutical ingredient cannot reach its molecular target in
the body if the drug remains undissolved in the gastrointestinal tract (GIT) and is even-
tually excreted. The message is simple: drugs that dont dissolve will not heal you.
Therefore, poor solubility is a critical factor if the molecule is to survive the pharmaceu-
tical development process. Even those molecules that would have a highly benecial
effect on their physiological target would not be further developed if their bioavailability
is limited by their solubility in water. Thus, solubilization technologies that overcome
this issue by increasing the solubility of such drug candidates are becoming more and
more important to the pharmaceutical industry by opening up pathways to prepare
effective and marketable drugs from actives that would otherwise be useless. This
chapter will explain the thermodynamics behind the problem of poor solubility and
depict approaches to overcome it.
Since poor solubility and issues related to this are not specic to pharmaceuticals,
this chapter will follow an out-of-the box approach and show where solutions es-
tablished in other applications can help us overcome solubility problems in medicinal
applications.
1.1.1 Classication of poorly soluble drugs:
The Biopharmaceutical Classication System (BCS)
From a very rough perspective, drug candidates can suffer from two main problems
(apart from an almost innite number of further problems when it comes to details):
solubility and permeability. These represent the basis used to classify drug candida-
tes into four fundamental classes, a methodology known as the Biopharmaceutical
Classication System (BCS), introduced by Amidon et al. [2]. Figure 1.1 illustrates
this classication, complemented by an assessment of the percentage of new drug
candidates in the four classes:
Class I: In this class, we nd drugs (or rather: drug candidates) with both high
solubility and high permeability. They dissolve fast and quantitatively and are readily
taken up by the intestine, eventually reaching their target in the body.
Class II: These are drugs which would easily penetrate the relevant physio-
logical barriers but suffer from poor solubility in the aqueous body uids. Their share
1
1 10 100 1000 10000 100000 1000000
Volume needed to dissolve anticipated dose [mL]
Class I
~5%
Class II
~70%
Class III
~5%
Class IV
~20% C
e
l
l

P
e
r
m
e
a
b
i
l
i
t
y

[
x
1
0

6
c
m
/
s
e
c
]
100
10
1
10
Figure 1.1 The Biopharmaceutical classication system and percentage of new chemi-
cal entities in the individual classes [1,2]; for further explanations see text.
All these drugs pose particular problems in the development cycle. Class I drugs
do not normally have bioavailability problems (unless other problems such as fast
metabolism or the like occur). However, in some cases, their pharmacokinetics can
be compared to a military airplane: they appear extremely fast out of nowhere, and
they disappear just as quickly. In other words: we observe a very fast increase in
blood plasma levels, although, from a pharmacokinetic perspective, sometimes a
slower but longer lasting action would be desirable. In such cases, one option is
to work with a polymer-based formulation that deliberately retards drug dissolution
and thus drives the kinetics in the direction of a slow release system.
Actives in class II represent the majority of new chemical entities in pharmaceutical
development pipelines. However, if it proves possible to increase their solubility in
the GIT, they can be formulated into marketable products. This book aims to give
an overview of the tools that are currently available for this purpose. Class III drugs
represent a real challenge. In the scientic literature, there are continuous discussions
of the modern drug delivery pipeline is continuously growing.
Class III: Such actives are soluble in the GIT, but they are not taken up by the
body. Like class II actives, they risk being excreted without exercising any physio-
logical effect.
Class IV: This is the nightmare for the medicinal chemist: drugs that neither dis-
solve nor penetrate physiological barriers.
11
about the use of penetration enhancers, and there are denitely mechanisms that
increase the permeation of molecules through the gastrointestinal wall. However, the
intestine is usually full of substances that the body does not want to penetrate into the
portal vein for good reasons and unselective enhancement of penetration of this
fundamental membrane implies the risk of signicant side effects.
Class IV actives are usually outside of what is called the drugable space. This space
is indicated by the green line in Fig. 1.1. They combine the problems of class II and
class III drugs, and often the best way to get out of such a situation is to send the
candidate back to the pharmaceutical chemist and ask for chemical alternatives. If
there are reasons to believe that this active will have an excellent performance at the
target, e. g. based on in-silico modeling, prodrugs with enhanced dissolution and
permeability that will be converted into active agents under physiological conditions
are certainly an option to consider.
As mentioned above, class II actives represent the largest class of substances in
todays drug delivery pipelines. In some cases, this is due to a large portion of hydro-
phobic moieties in the molecules. Evidently, molecules that consist of carbon and
hydrogen only will be so non-polar that miscibility with water will be extremely low.
Let us take a well-known example from the vitamin family, -carotene (Fig. 1.2), to
show that such effects are not specic to active pharmaceutical ingredients. This
hydrocarbon has a water solubility clearly below 1 mg / L. Oral administration of
crystalline -carotene will not result in effective drug levels in the blood plasma.
Such molecules can have quite signicant solubility in hydrophobic solvents and are
sometimes referred to as grease balls.
Figure 1.2 Chemical structure of -carotene as an example of a very hydrophobic,
poorly water-soluble molecule.
However, in some cases we can also observe poor water solubility with molecules
that are composed of quite a signicant number of polar moieties, such as itracona-
zole (Fig. 1.3). Such molecules usually have a high molar mass and dissolve neither in
aqueous nor in non-polar solvents. To understand the reason behind this behavior, let
us briey consider the thermodynamics of the matter.
1
O
O
Cl
Cl
N
N
N
O N N N
N
N
O
12
Figure 1.3 Chemical structure of itraconazole as an example of
a polar but nevertheless poorly soluble molecule.
1.1.2 Poorly soluble drugs: The thermodynamics behind
the problem
Without wanting to go too deeply into theory, let us consider the thermodynamic
driving force behind dissolution processes. This driving force, characterized by Gibbs
free energy G, is composed of two fundamental contributions, enthalpy H and
entropy S, according to equation 1.1, known as the Gibbs-Helmholtz equation.
G = H T S (1.1)
When two substances of equal molecular size (i. e. molecular volume) are mixed in
a so-called regular mixture, this driving force is represented by
G =
1
ln
1
+
2
ln
2
+
1

2
(1.2)
entropy term enthalpy term
where

i
= the volume fraction of component i (i. e. the volume of component i relative
to the total volume). Index 1 refers to the solvent, index 2 to the solute.
= the interaction parameter between the two substances (see text).
The interaction parameter quanties the interaction between the two compounds in
the mixture. The larger (i. e. more positive) this parameter is, the higher (more positive)
is the interaction enthalpy of the two compounds. Please recall that a positive en-
thalpy is indicative of an endothermal process that consumes heat (rather than
releasing it), so this is an enthalpically unfavorable process. Many mixing processes
are endothermal unless there are specic interactions between the components
constituting the mixture, such as acid-base interactions.
If you look at the entropy contribution to the total Gibbs free energy in equation 1.2, it be-
comes clear that this term is always positive (since volume fractions in mixtures are always
smaller than unity, the logarithm is negative, which compensates for the minus preceding
the terms. Positive S values characterize processes that are entropically favorable.
13
From these simple considerations, it becomes clear that entropy always favors
mixing
1
, whereas a typically positive mixing enthalpy often counteracts it. For a
typical grease ball, it becomes clear immediately that the interaction of a pure
hydrocarbon with water is enthalpically so unfavorable that its contribution to the
overall Gibbs free energy over-compensates for the favorable mixing entropy. As a
result, grease balls are water-insoluble.
However, what is the problem with molecules such as itraconazole? The molecule
comprises a signicant number of polar rings that could interact quite well with water.
To understand this, we must consider the molar volume of the compounds, which
correlates (to a rst approximation) to its molar mass. Please remember that equation
(1.2) is valid only if the size of the solvent molecules matches that of the solute. If the
molar volume of the compound to be dissolved exceeds the molar volume of the
solvent, equation (1.2) needs to be modied and becomes
G =
1
ln
1
+ ln
2
+
1

2
(1.3)

2
X
n
entropy term enthalpy term
X
n
in this equation is the ratio of the two molar volumes ( 1).
As can be clearly seen in equation 1.3, this additional factor has a large impact on
the mixing entropy. Since X
n
is always greater than (or equal to) unity, the favorable
mixing entropy is reduced in such cases, and, consequently, the mixing process is
energetically less favorable. A favorable mixing entropy is easier to compensate for by
the usually unfavorable mixing enthalpy.
This is a very typical situation encountered when working with large active ingredients
in contact with water. Please note that the water molecule is one of the smallest mol-
ecules of all it is basically one oxygen atom with ears so this effect is particularly
pronounced for aqueous solutions of large molecules.
Due to the high throughput of todays drug development pipelines, more and more
complex molecules can be screened and identied as potential new drug candidates.
Therefore, the number of high molar mass candidates is increasing steadily, thus in-
creasing the proportion of class II actives. The three relatively simple thermodynamic
equations thus explain why poor solubility is also a constantly increasing challenge to
the pharmaceutical industry of the third millennium.
1.2 Approaches to overcome this issue
So, what can we do to solve this problem? From the formulation point of view, there
are three main approaches:
Surfactants Complex formation Nanotechnology.
1
There are exceptions. But lets keep this simple.
1
O
S
O

O O
Na
+
O
OH HO
OH
O
O
O
S
O

O O
Na
+
O
OH HO
OH
O
O
14
The individual approaches differ in their applicability to grease balls vs. brick dust,
as will be explained in detail in the following chapters.
1.2.1 Surfactants
Surfactants are amphiphilic molecules, i. e. molecules with a polar, hydrophilic moiety
(the so-called the head) and an non-polar, hydrophobic part usually called the
tail. The head group can be ionic or non-ionic, and the resulting structures are
correspondingly referred to as ionic and non-ionic surfactants respectively. Typical
representatives of these two classes are shown in Figure 1.4.
Figure 1.4 Chemical structures of sodium dodecyl sulfate (SDS), a typical ionic surfac-
tant (top), and sorbitan monostearate (Span 60), a non-ionic surfactant.
Due to the relatively large hydrophobic part, these molecules are not very water-
soluble either. In aqueous solution they exist as individual molecules only at very low
concentrations. However, due to the existence of two (or sometimes more) unlike,
incompatible molecule parts, they show unusual behavior when they reach their
solubility limit. In contrast to normal (i. e. non-amphiphilic) substances that simply
precipitate or form a new, relatively pure phase when they exceed their solubility
limit, these substances agglomerate and form so-called supramolecular structures
of well-dened size and shape. Due to the amphiphilic nature of the molecules, the
hydrophobic parts gather and try to aggregate into a hydrophobic domain; however,
the polar head groups do not have any reason to precipitate they are happy in
the aqueous phase, and they want to stay there. So, what is formed is an often
spherical superstructure with a sort of core-shell structure. Here, the hydrophobic
parts are in the core surrounded by the polar head groups, all of which keeps the
whole structure well dispersed in the aqueous phase. Such structures are referred
to as micelles (see Fig. 1.5), and the concentration at which they are formed is the
so-called critical micelle concentration (CMC). Therefore, in contrast to conventional
precipitation processes, we do not observe the formation of a macroscopic, sepa-
rate phase. These micelles are usually extremely small; typical diameters are in the
order of 5 nanometers. Thus, the system remains optically transparent and clear.
E D C B A
Hydrophilic
head
Hydrophobic
tail
Concentration
15
To make the story complete, we should mention that a further increase in surfactant
concentration will lead to the formation of additional, so-called liquid crystalline phases,
as indicated in Fig. 1.5. These phases comprise, among others, tube-like and laminar
arrangements of surfactant molecules as well as particular arrangements of micelles.
However, a detailed discussion of these phases would go far beyond the scope of this
chapter. For a more comprehensive review on surfactants, see e.g. reference [3].
Figure 1.5 Schematic sketch of different surfactant phases formed from individual
surfactant molecules at increasing concentration.
Usually, the CMC for most surfactants is very low. For non-ionic surfactants, it is in the
order of 10
-5
mol / L. For ionic surfactants, micelle formation is slightly more difcult
due to the electrostatic repulsion between the ionic head groups; therefore, typical
CMC values are in the order of 10
-3
mol / L.
It is important to understand the driving force behind micelle formation. Often, people
tend to argue that micelle formation is caused by the tendency of the hydrophobic
tails to attract each other and thus to agglomerate. This point of view is misleading.
In fact, the hydrophobic moieties do not care about their environment. They do not
interact with their surrounding molecules anyway. In contrast, it is the water mol-
ecules with their well-known tendency to form extensive (and relatively strong) hydrogen
bonds that expel the hydrophobic molecule parts. They strongly interact with their
neighbors, and they are very selective as to which molecules they like and which they
dont. And evidently, they dont like hydrophobes.
At rst glance, one might tend to believe that from the point of view of the Gibbs-
Helmholtz equation the driving force is enthalpy. However, like in the discussion of
the poor solubility of large molecules, it is the entropy that makes the difference
2
. To
understand this, we need to clearly understand that before micelle formation, i. e. in a
state in which the surfactants were molecularly dissolved in the aqueous phase, the
hydrophobic surfactant tails were naturally surrounded by water molecules. Although
2
This coincides with my personal feeling that the impact of entropy is notoriously underestimated in
discussions about solubilization and supramolecular effects in general.
1
16
there is an unfavorable interaction of these water molecules with the hydrophobic
molecules, they are bound to them. Micelle formation releases these molecules,
and the release of such a high number of small molecules is always favorable with
respect to system entropy. The entropy of the system does not necessarily support
this process. On the contrary, micelle formation can even be an endothermal (!)
process
3
driven by entropic forces.
One key aspect of these micelles is the existence of a hydrophobic domain in their
core. The situation can be characterized as an aqueous phase with hydrophobic, non-
polar holes in it; and these domains can be used to solubilize non-polar molecules.
The core of a micelle feels like a non-polar solvent; thus, if the solubility of the drug
in non-polar solvents is high which is particularly true for grease balls they will
dissolve in the core of the micellar phase. This has several important implications:
(a) The drug molecules do not separate from the aqueous phase (i. e. they do not
precipitate), but they are still dispersed in the medium, which could be a gastro-
intestinal uid.
(b) In the micellar core, the drug is stable in the form of individual, dissolved mol-
ecules and not as a crystalline phase. This is extremely important if bioavailability
issues are to be overcome, since it has been known for quite some time that
breaking the crystallinity of active ingredients is a key step in rendering a given
compound more bioavailable.
Nature also uses this highly effective principle in the form of surfactant-like bio-
molecules, e. g. bile salts.
Besides their solubilizing capacity, surfactants also act as dispersants. This means
that they can stabilize small particles of insoluble substances (usually of a size around
or below 1 m) in a liquid, which is usually water. Again, the amphiphilic character of
the surfactant is utilized: The hydrophobic tail moiety will adsorb onto the hydrophobic
surface of the water-insoluble particle, whereas the hydrophilic head will point away
from it into the aqueous phase. The use of ionic surfactants will lead to electrostati-
cally charged particles, which will be repelled by other particles in the system because
they are equally charged. This helps to disperse the particles in the aqueous phase.
If non-ionic surfactants are used, the hydrophilic parts of the molecule form a sort of
hydrophilic layer around the particle that also prevents particle-particle attraction and
likewise stabilizes an aqueous dispersion.
Similar to the tendency of surfactants to adsorb onto surfaces, they also exhibit a high
afnity to liquid-liquid interfaces (leading to the stabilization of emulsions, i. e. dispersions
of small droplets of one liquid in another) and to liquid-gas interfaces. The latter effect
leads to an accumulation of surfactant molecules at the surfaces of aqueous surfactant
solutions. The hydrophilic parts of the molecule stay in the aqueous phase, whereas
the hydrophobic tails point out of the water into the air. This may sound surprising.
3
An alternative explanation proposes that the structure of the water molecules in vicinity of the
hydrophobic tail is severely disturbed, and that they take on a structure similar to ice. Upon micelle
formation, this structure is destroyed. The melting of ice is known to be an endothermal process
leading to an increase of entropy due to increased mobility of the individual water molecules.
Surfactant concentration (log)
S
u
r
f
a
c
e

t
e
n
s
i
o
n

[
m
N
/
m
]
60
55
50
45
40
35
30
25
20
17
However, please remember that hydrophobic molecules or molecule moieties do not
care about their molecular environment just like air. In this sense, gases can be
considered as hydrophobic media.
The accumulation of surfactant molecules leads to a decrease of the energy of the
water-gas interface. Usually, when two media of different polarity meet (such as it is
the case here), the interface has a relatively high energy level due to the incompatibility
of the two media. Surfactant molecules have the ability to bridge this gap. Their polar
head is in the polar uid, whereas their non-polar tails are in the non-polar gas; thus,
the high energy level of the interface is decreased. This impact of surfactants on the
surface tension (the surface energy per unit area) can be used to determine the critical
micelle concentration (CMC). Starting with pure water with an interfacial tension of
72 mN / m, the addition of surfactants leads to a steady decrease of surface tension
until the surface is completely covered with surfactant molecules. Evidently, at this
point, surface tension reaches a plateau (see Fig. 1.6). As no additional surfactant
molecules can be positioned at the water-air interface, a further increase in surfactant
concentration will force the surfactant molecules to agglomerate and to form micelles.
Therefore, a measurement of the surface tension as a function of surfactant concen-
tration according to Figure 1.6 can be used to determine the CMC of the surfactant.
Alternatively, the CMC can be measured by direct measurement of the presence (or
absence) of micelles at a given concentration, e. g. by light scattering
4
.
4
Again, I must refer to specialized literature for a detailed discussion of methods to determine the
CMC of surfactant solutions.
Figure 1.6 Schematic diagram of surface tension as a function of surfactant concentration.
Please note that the driving force G for micelle formation depends on temperature,
according to equation (1.1). The higher the driving force for micelle formation, the lower
the CMC. Therefore, the CMC is also a function of temperature. As a consequence,
the phase behavior of surfactants is both a function of concentration and temperature,
1
Gastric
fluid
Capsule filled with:
oil, API and surfactant
(and co-solvent)
Surfactant
molecule
API
Oil droplet
18
and in analogy to the critical micelle concentration at a given temperature, one can
also dene a critical micelle temperature at a given surfactant concentration. From all
this, it becomes clear that surfactants are a fascinating (and very well investigated)
class of molecules that exert a signicant impact on the properties of pure water, go-
ing far beyond its usual properties. Micelles can act as nano-sinks for poorly soluble
drugs, provided that they dissolve in the hydrophobic core of these micelles. There-
fore, they present an attractive potential solution to overcome poor water solubility of
BCS class II actives, and in particular for the grease ball fraction among them.
Figure 1.7 Principle of a self-emulsifying drug delivery system (SEDDS)
(for explanations see text).
In the previous section, the use of surfactants to decrease the crystallinity of a drug
and to improve its oral bioavailability was discussed. However, more than 80 % of
all pharmaceutical dosage forms marketed today are solids, so the question arises
as to how to prepare a formulation that forms emulsions in the GIT. So-called Self-
Emulsifying Drug Delivery Systems (SEDDS) can achieve this.
SEDDS formulations consist of hard or soft gelatine capsules lled with a liquid. This
liquid contains the active pharmaceutical ingredient, oil that dissolves the active and
at least one surfactant. Optionally, other inactive ingredients such as co-solvents are
added
5
. The system is homogeneous and isotropic. If this dosage form is swallowed,
the gelatine capsule will dissolve in the stomach and the liquid comes into contact
with the gastric uid. Due to the presence of the surfactants and the agitation provided
by the stomach, the oil phase will spontaneously emulsify in the gastric uid and form
an emulsion containing the lipophilic active (Fig. 1.7).
The advantages of SEDDS are obvious: The active is provided in a dissolved, non-
crystalline state and it is nely dispersed in the GIT. Usually, emulsions produced
5
Often, solubility of an active in a solvent mixture can be higher than its solubility in the pure solvent.
Therefore, so-called co-solvents can be added to the formulation. Likewise, mixtures of surfactants
can be superior to pure surfactants, in particular for the formulation of microemulsions. However, a
detailed discussion of these effects would go far beyond the scope of this chapter.
19
from SEDDS develop a droplet size of 100 to 300 nm. More recently, so-called Self-
Microemulsifying Drug Delivery Systems (SMEDDS) have been successfully intro-
duced into the market. These systems are characterized by an even smaller droplet
diameter produced under physiological conditions (below 100 nm).
The idea of dissolving an active ingredient in a suitable oil and emulsifying the oil
phase in water has been used for quite some time in the eld of crop protection for-
mulations. Usually, these formulations can develop high bioavailability for the same
reasons as pharmaceutical formulations (reduced crystallinity, ne dispersion of the
drug), although for crop protection products the solvent content may be an issue
due to VOC problems
6
. However, the successful development of a pharmaceutically
acceptable SEDDS is far from being trivial. Many surfactants used in SEDDS are lipid-
based, and these surfactants strongly interact with lipases in the GIT uids. Naturally,
this signicantly affects the stability of the emulsion droplets over time. This is a seri-
ous obstacle to the development of in-vitro test assays for such formulations, and it
makes it difcult to predict how the formulation will behave in-vivo. Moreover, the ratio
of oil(s), lipid(s), co-solvent(s) relative to the active has to be tailored very carefully. The
oral bioavailability of the active in the SEDDS depends on many parameters, such as
surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and
charge. All the factors impact the self-emulsication ability. Only selected combina-
tions of these excipients result in the desired emulsication behavior.
Additionally, SEDDS are limited to lipophilic drugs. As discussed above, poor water
solubility of a drug does not necessarily mean that the drug dissolves well in hydro-
phobic solvents. Therefore, an SEDDS formulation approach can only be applied if
the drug readily dissolves in a pharmaceutically acceptable oil, such as olive oil, and
if it is incorporated chemically in this solvent. As a consequence, many grease ball
drugs are candidates for development in an SEDDS, but the typical brick dust frac-
tion that dissolves neither in oil nor in water can not be administered this way.
Although much effort has been put into studies on SEDDS, only three actives have
been successfully introduced into the market in this form. At present, there are four
products on the market, namely Sandimmune

and Neoral

(cyclosporine A), Norvir

(ritonavir), and Fortovase

(saquinavir).
Sandimmune

and Neoral

are both marketed by Novartis. However, the formulati-

ons differ in that Sandimmune

is an SEDDS whereas Neoral

is an SMEDDS. Cyclo-
sporin A is a cyclic peptide comprising 11 amino acids with a molar mass of about
1,200 g / mol. Water solubility is very low, but the drug exhibits fair solubility in oils. It
can be formulated as a conventional SEDDS as is the case in Sandimmune

; how-
ever, strong inter-patient variability of the bioavailability of the emulsion formed from
the SEDDS ranging from 10 60 % has been observed. Neoral

as a microemulsion
preconcentrate based on corn oil,-mono-, di-, and triglycerides, polyoxyl 40-hydrog-
enated castor oil, DL-()-tocopherol and propylene glycol turned out to be less sensi-
tive to such uctuations. Furthermore, the AUC of this microemulsion-based approach
6
VOC = volatile organic compound
1
20
turned out to be substantially higher, probably due to the smaller droplet size, leading
to a better distribution of the drug in the GIT.
All in all, SEDDS and SMEDDS are promising but highly complex ways to overcome
solubility issues with class II actives, at least for the grease ball fraction within this
class. It needs to be assessed over time whether the undoubted benets and the
potentially high bioavailability of such formulations will compensate for the extra
effort required for development.
1.2.2 Complex formation with polymers
One approach, which is more widely applicable and which also addresses the prob-
lem of the brick dust fraction of class II actives, is the use of polymeric solubilizers.
Polymeric solubilizers are water-soluble polymers with the ability to form complexes
with other molecules in the system. The idea as such is not new and has been ap-
plied in detergents for some time to avoid the unwanted transfer of dyes from colored
clothes onto white ones. During the washing process, colored textiles often lose a
certain fraction of their dyes that may be only loosely bound to the textile surface.
These dyes may then re-deposit onto other textiles, and they usually select your most
expensive favorite garments for doing so So-called dye transfer inhibitors can pre-
vent this by formation of a stable complex with the dye molecules; this stabilizes the
dye in the dissolved form and therefore keeps it from depositing onto other textile
surfaces. Such a complex is shown in Figure 1.8.
Figure 1.8 Complex formed by poly(vinylpyrrolidone) and a dye (direct blue 71).
Such interactions have been widely investigated and can be determined quantitatively
(see Table 1.1).
Time [min]
S
u
l
f
a
t
h
i
a
z
o
l
e
,

d
i
s
s
o
l
v
e
d

[
m
g
/
m
L
]
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
0 50 100 150 200 250 300 350
1 + 3
1 + 1
3 + 1
21
Table 1.1 Binding constants, binding enthalpy and relative
dye transfer inhibition performance of selected
polymers with a given dye (direct red 80) [4].
Polymer Binding constants
K
p
[L / mol]
(dye / polymer = 10
-2
)
Enthalpy of
reaction H
r

[kJ / mol]
DTI-
Performance
[%]
PVCap 700 +11.0 0
PVP 1500 -13.2 39
PVI 5500 -29.3 79
PVIVP 60000 -26.2 84
PVCap: poly(vinyl caprolactam)
PVP: poly(vinyl pyrrolidone)
PVI: poly(vinyl imidazole)
PVIVP: poly(vinyl pyrrolidone-
co-vinyl imidazole)
In a very analogous fashion, water-soluble polymers can also stabilize active pharmaceu-
tical ingredients in an aqueous phase, which increases their water solubility (Fig. 1.9).
Figure 1.9 In-vitro measurement of the solubility of sulfathiazole for different drug:
PVP ratios [5].
1
22
Poly(vinylpyrrolidone) or simply PVP, also known as Kollidon

, is a well-known ex-
ample of a pharmaceutically acceptable polymer that solubilizes poorly water-soluble
actives. In a way similar to surfactants, the molecules solubilized by such polymers
are present in the aqueous phase as individual, non-crystalline molecules with a usu-
ally high bioavailability. The mode of action of PVP relies on the large dipole moment
of the polymer side groups that strongly interact with any other dipole present in the
system. However, for some drugs, such a dipole-dipole interaction, this is not suf-
cient to enable complex formation with the drug, in particular if the drug does not have
any polar molecules. In such cases, amphiphilic polymers with hydrophobic pockets
to attract the non-polar drug can be used. One example of such solubilizing polymers
that was introduced only recently is a graft copolymer referred to as Soluplus

(see
chapter 5).
Due to the presence of both hydrophilic and hydrophobic groups, the polymer can
both interact with the poorly soluble drug and still be water-soluble. Again, complex
formation is driven by entropy due to the release of water molecules previously bound
to the polymer; however, molecular interactions between the polymer and the active
resulting in a favorable enthalpy term are usually required for good performance.
The use of polymers such as PVP or Soluplus

brings about two important advan-

tages for the formulation of poorly soluble drugs. This is because the polymer can fulll
two functions: It can act as a matrix material for the tablet and often forms so-called
solid solutions with the drug (see chapter 2), and it enhances oral bioavailability once
the tablet has been administered. Solubilizers such as Soluplus

present a major
advantage on the way towards new technologies to bring such difcult-to-formulate
drugs effectively to the patient. Details will be discussed in the following chapters, in
particular chapter 5.
1.2.3 Nanotechnology: The kinetic approach
The idea of solubilizing a poorly soluble drug by inuencing thermodynamic properties
such as solubility or binding constants basically relies on increasing its concentra-
tion in the GI tract. Precisely speaking, solubilization increases the concentration of
bioavailable (= solubilized) species in the GI tract. This is due to the generally accepted
view that coarse, crystalline particles usually do not permeate through the gut wall.
An increased concentration of such molecular species will increase the driving force
to permeate through the intestinal wall according to Ficks laws of diffusion. However,
increasing the concentration of a species above its equilibrium concentration always
carries the risk of recrystallization of this species under physiological conditions.
Assuming that the transport of the dissolved species out of the gut and into the
rest of the body is fast enough
7
, oversaturation can in principle be avoided. Re-
member that the dissolution process is always an equilibrium process between the
dissolved and the undissolved species. As long as the solubility limit is not reached,
7
This assumption is valid for most class II actives. Otherwise, they would be in class IV.
23
8
Please note that these two approaches, namely increasing the equilibrium solubility and the
dissolution rate, do not exclude each other. Ideally, they are combined.
9
A comprehensive review on organic nanoparticles, including their impact on oral bioavailability,
can be found in reference [6].
r RT
molecules dissolve as individual molecules out of the solid form and into the liquid phase.
Whenever we decrease the concentration of drug molecules in the liquid phase,
e. g. the GIT uid, some fraction of the solid drug will dissolve until the solubility limit
is reached again. If we continuously remove the dissolved drug from the uid e. g.
by allowing it to diffuse through the intestine wall eventually the whole amount of
drug that has been administered will dissolve and be taken up quantitatively.
Unfortunately, most class II actives are characterized by both low equilibrium solubility
and a low dissolution rate at which this is established. This is due to the high stability
of the drug in the crystalline form. Intuitively, it can be understood that dissolution will
not be a fast process if the drug molecules are energetically happy where they are.
Therefore, to make complete dissolution possible within the time frame of digestion
(which is approximately 24 hours), this requires that the dissolution process is fast,
i. e. that the equilibrium between the solid and the dissolved states of the drug is es-
tablished at a high rate. If this can be achieved, the absorption of the dissolved form
leading to its removal from this equilibrium will (in principle) make it possible that even
drugs with a low equilibrium solubility will eventually dissolve.
As a consequence, increasing the dissolution rate rather than the absolute equilibrium
solubility is an effective way to increase the uptake of a poorly soluble drug into the
body and, thus, to increase its bioavailability
8
. This is where nanotechnological drug
formulations come into play
9
.
If a poorly soluble drug is presented to the body in the form of nanoparticles, two
important impacts on its solubility can be observed: Firstly, if the particles are very
small (i. e. < 100 nm), solubility is a function of particle size according to the Kelvin
equation (eq. 1.4):
S(r) = S

exp ( ) (1.4)
In this equation, S(r) is the solubility as a function of the radius r, S

is the solubility
of a coarse, crystalline particle with at, even surfaces, is the interfacial tension
between drug and solvent, V
M
is the molar volume of the drug, R is the gas con-
stant and T is the temperature. This equation clearly shows that solubility increases
enormously when the particle size decreases. The effect becomes drastic at particle
sizes below approx. 100 nm, depending on the drug, as shown in Fig. 1.10.
2 V
M
1
Particle diameter [nm]
S
o
l
u
b
i
l
i
t
y

i
n
c
r
e
a
s
e
1000
100
10
1
0 10 100 1000
24
Figure 1.10: Solubility increase (solubility according to eq. 1.4 divided by the solubility
of the crystalline material) as a function of particle radius for typical
organic compounds.
Secondly, there is an additional effect contributing to the high bioavailability of nano-
particular drug formulations. This is related to the surface area that naturally in-
creases strongly as the drug particles decrease in size. This is expressed by the
Noyes-Whitney equation (eq. 1.5):
= (c(r) c) (1.5)
This equation describes how fast the concentration in a given medium c increases
with time t as a function of the diffusion coefcient of the drug D, its surface area A,
the thickness of the diffusion layer around the particle h (i. e. the distance the drug
needs to diffuse out of the region of high drug concentration c(r) immediately close to
the particle surface into the bulk medium where the concentration of the drug is c),
and the difference between drug solubility and drug concentration in the medium. In
other words, drug particles will dissolve fast when:
(a) The solubility of the drug is higher than the concentration in the solvent this can
be achieved by setting the particles size according to equation 1.4.
(b) The drug particles have a high surface area.
As an example, Fig. 1.11 shows the oral bioavailability of a nanotechnological for-
mulation of -carotene. As can be clearly seen, bioavailability is greatly accelerated
compared to the coarse crystalline material.
dc D A
h dt
Days after oral administration

-
c
a
r
o
t
e
n
e

b
l
o
o
d

l
e
v
e
l

[

g
/
m
L
]
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12
Hydrosol, d = 160 nm
Hydrosol, d = 350 nm
Cristallizate, d = 5 m
25
Figure 1.11 Graph of the -carotene blood level as a function of time after single oral
administration of -carotene to calves with minimal -carotene status.
Comparison of nanodispersed formulations with a microdispersed crystal-
lizate as described by Horn and Rieger in [6].
Naturally, nanoparticles have a higher specic surface area than coarse crystals.
Therefore, small particle sizes will increase both drug solubility (eq. 1.4) and drug
dissolution rate (eq. 1.5). Both effects potentially increase bioavailability.
Moreover, oral uptake of nanoparticles is enhanced even when particle sizes are so
large (i. e. signicantly above 100 nm) that the effects cannot be explained by eqs.
(1.4) or (1.5). Additional effects such as increased adhesion to the intestinal wall
have been discussed to account for these ndings.
All in all, nanotechnology has been intensively discussed as a new route to increase
solubility and, thus, bioavailability of poorly soluble drugs. First products have al-
ready been successfully introduced into the market. The rst solid-dose formulation
with this technology was the immunosuppressant Rapamune

(sirolimus). Emend

(antiemetic, aprepitant) was approved by the FDA in March 2003. TriCor

(feno-
brate) was approved by the FDA in 2004, and more nanomedicinal products are
likely to follow.
1
26
1.3 Summary and outlook
Summing it all up, poor solubility is a major issue for todays pharmaceutical industry,
leading to a high attrition rate in the development of new drugs. Therefore, effective
ways to increase solubility of new chemical entities, in particular those classied as
BCS class II, are invaluable tools for extending the drugable space and bringing these
new molecules to the market.
Consequently, a lot of effort has been put into this eld. Most approaches can be
classied as being based on one or more of the following principles:
Solubilization through surfactants
Solubilizing polymers, and / or
Nanotechnology.
For all these elds, the rst products have already been launched. More will follow.
The following chapters will give additional details on formulation requirements for
poorly soluble actives and in particular present concrete examples of excipients
that will help pharmaceutical formulators to dissolve their drugs and solve their
problems!
References
[1] S. R. Page, Presentation at CRS Meeting July 12.-16., 2008.
[2] G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison, A Theoretical Basis
for a Biopharmaceutic Drug Classication: The Correlation of in Vitro Drug
Product Dissolution and in Vivo Bioavailability, Pharmaceutical Research, 12
(1995), 413-420.
[3] T. F. Tadros, Applied Surfactants, Wiley, Weinheim 2005.
[4] F. Runge, J. +. Detering, G. Zwissler, D. Boeckh, and C. Schade, Binding
Equilibria of Multiazo Dyes with Polymeric Dye Transfer Inhibitors, Berichte der
Bunsengesellschaft fr physikalische Chemie, 100 (1996), 661-670.
[5] V. Bhler, Kollidon

: Polyvinylpyrrolidone excipients for the pharmaceutical

industry, BASF SE, Ludwigshafen 2009.
[6] D. Horn and J. Rieger, Organic Nanoparticles in the Aqueous Phase-Theory,
Experiment, and Use, Angewandte Chemie International Edition, 40 (2001),
4330-4361.
27
Matthias Karl, Michael Schnherr
2 Preparation of solid solutions and dispersions
2.1 Solid solutions and dispersions
2.1.1 Introduction and general aspects
In this area, pharmaceutical research focuses on improving the oral bioavailability of
poorly water-soluble drugs by enhancing the solubility and drug release of the APIs.
This challenge is currently becoming more and more important as the percentage
of poorly water-soluble new chemical entities in drug development is constantly in-
creasing (detailed information on this topic is given in chapter 1) [7].
Approaches to overcome poor solubility of the drug substance include salt formation,
solvation and particle size reduction. Other methods such as the solubilization of
drugs in solvents, complexation (e. g. cyclodextrin) and the use of surfactants and
cosolvents have also been used to improve the dissolution properties of poorly water-
soluble drugs. However, although there are substantial limitations associated with
each of these techniques, the formulation of drugs as solid dispersions offers a variety
of processing and excipient options that allow for exibility when formulating oral de-
livery systems for such drugs [8].
2.1.2 Types of solid dispersions
Solid dispersion refers to a group of solid products consisting of at least two different
components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can
be either crystalline or amorphous.
Of the various types of solid dispersions, three are relevant for pharmaceutical applica-
tions since the polymers used are usually amorphous. Principally, the drug can be either
dissolved or dispersed whilst in an amorphous or crystalline state. A thermodynamically
stable formulation (Figure 2.1) is achieved when the drug is completely dissolved below
its saturation solubility in the polymer, resulting in a solid solution (formulation is illustrated
on the right). When the drug concentration exceeds its saturation solubility, the whole
system is only kinetically controlled (formulation in the center) since the drug may crys-
tallize or precipitate out of the polymer during storage. This is because the amorphous
drug is dispersed in an amorphous polymer and as the drug may crystallize, hence
changing its dissolution and biopharmaceutical properties. The system on the left is
quite stable. In this case, the polymer contains crystalline drug because only Ostwald
ripening can occur and this leads to the formation of larger crystals. However, this is
not very pronounced due to the low diffusivity of the drug in a solid polymer [9].
1
2
Polymer
Thermo-
dynamic
stability
Drug Crystalline Amorphous
Molecularly
dissolved
Amorphous Amorphous Amorphous
Almost stable
Unstable
(kinetically controlled)
Stable
(drug below
saturation solubility)
28
Figure 2.1 Relevant types of solid dispersions
Various preparation techniques for solid dispersions deal with the challenge of mixing
a matrix and a drug, preferably on a molecular level, where both matrix and drug are
generally poorly miscible. During many of the preparation methods, de-mixing and
the formation of different phases can be observed. Phase separations like crystalli-
zation or the formation of amorphous drug clusters are difcult to control and should
therefore be avoided. Generally, phase separation can be prevented by maintaining
low molecular mobility of the matrix and the drug during preparation. Additionally,
phase separation is prevented by maintaining the driving force for phase separation
at a low level, for example by keeping the mixture at an elevated temperature, thereby
retaining sufcient miscibility for as long as possible [8].
2.1.3 Manufacturing of solid dispersions
The melt method (e. g. hot-melt extrusion, spray congealing and melt granulation),
solvent procedure (e. g. spray drying, solvent casting and freeze drying) and other
technologies (e. g. milling) are the usual manufacturing methods for solid dispersions.
The most popular techniques are hot-melt extrusion and spray drying, which are
described in detail in subsequent chapters.
The lm casting technique is very suitable for predicting the solubility of a certain API
in a polymer matrix. This can be carried out prior to HME or spray drying experiments
since it is much less time- and material consuming. In the lm casting procedure, an
appropriate solvent that dissolves the API and the polymer (or polymer-plasticizer)
should be selected. When the substances are dissolved after stirring, the solution can
be cast on a glass plate, resulting in a thin lm. A scraper that produces a lm of 120 m
Solvent
Dried polymer film
Active
Polymer or
Polymer / plasticizer combinations
29
thickness is recommended as casting device. The thin lm (thickness of the dry lm
< 120 m) enables fast drying and avoids the recrystallization of the poorly soluble
drug that can occur when high drug concentrations are used over a longer period,
as happens in case of thick lms. Drying should be performed for 30 minutes under
ambient conditions (ue) and then in a vacuum drying cabinet (50 C, 10 mbar for
30 minutes) to ensure fast and complete drying of the lm. To analyze the extent of
solubilization capacity of the polymer or of the polymer-plasticizer combination for a
specic drug, increasing amounts of API should be used (25, 33 and 50 %). The high-
er the clearly dissolved drug concentration, the greater the solubilization capacity. A
solid solution results in clear and smooth lms. Drug crystals can easily be recognized
as can amorphous precipitation (opaque lms). Visual inspection of the lms was
performed 7 days after open storage at 23 C / 54 % r. h. The lm casting procedure
is shown in Figure 2.2 [9].
Figure 2.2 Film casting procedure
Preparation of lms with 25 %,
33 % and 50 % drug content
Observation of lm stability
drug must not re-crystallize
Blank
sample
Crystalline
sample
2.1.4 Analytical investigation of solid dispersions
Different molecular structures (crystalline, amorphous and molecularly dissolved) of
the drug in the matrix can be encountered in solid dispersions.
Many methods are available that can contribute information regarding the physical
nature of a solid dispersion system. In many instances, a combination of two or more
methods is required to obtain a complete picture.
Generally, Powder X-Ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC)
techniques are important methods for determining the physical state of the incorpo-
rated drug. The XRD technique is illustrated in Figure 2.3. Sharper diffraction peaks
indicate more crystalline material.
2
L
i
n

[
c
o
u
n
t
s
]
4614
2 10 20 30
2-Theta-Scale
Amorphous system
Crystalline system
Itraconazole
0
500
1000
1500
2000
2500
3000
3500
4000
30
Figure 2.3 XRD examples of extrudates of Kollidon

VA 64 with the active pharmaceutical

ingredient (API) itraconazole
In DSC, solid dispersions are heated at a constant heating rate and the amount
of energy required is determined. With DSC, the temperatures at which thermal
events (e. g. glass transition, (re)crystallization, melting or degradation) occur can
be detected and determined.
Both techniques provide information concerning the crystallinity or amorphicity of the
API and the matrix. However, they can usually not distinguish between molecularly
dispersed drug and amorphous drug material. An innovative method is the use of
13 C solid state NMR to meet this need [10].
Currently, additional techniques are available to detect the crystals in solid dispersions:
infrared spectroscopy (IR), dissolution calorimetry which measures the energy of
dissolution of the sample vapor sorption and macroscopic techniques that measure
mechanical properties that are different for amorphous and crystalline samples [7].
The solid dispersion appears to be a suitable formulation for increasing the dissolution
and absorption rates of poorly soluble drugs. However, the result of aging or storage
under various conditions and the effects on the drug release characteristics and
chemical stabilities of the formulations still have to be shown [11].
The biopharmaceutical properties of a solid dispersion are highly affected by the uni-
formity of the distribution of the drug in the polymer matrix. The stability and disso-
lution behavior could be different for solid dispersions that incorporate the drug in
different states [8].
31
2.2 Hot-melt extrusion
2.2.1 Introduction to hot-melt extrusion
Interest in hot-melt extrusion (HME) techniques for pharmaceutical applications has
grown signicantly in recent years. Hot-melt extrusion is an established manufacturing
process that has been used in the plastics and food industries since the 1930s. In the
1980s, BASF SE was the rst to apply the melt extrusion process based on polymers
with a high glass transition temperature (such as polyvinylpyrrolidones) to pharmaceu-
ticals [7]. Later on, Soliqs, the drug delivery business unit of Abbott GmbH & Co KG,
commercialized the technology and subsequently launched several drugs [12]. A num-
ber of research groups have demonstrated HME processes as being viable techniques
for the preparation of pharmaceutical drug delivery systems, including granules [13,
14], pellets [15, 16], sustained release tablets [17-21], transdermal and transmucosal
drug delivery systems [22-30] and implants [31-34]. The HME technique is an attractive
alternative to traditional processing methods [35]. Examples for solving pharmaceuti-
cal challenges using HME are given in Table 2.1.
Table 2.1 Advantages of hot-melt extrusion
Problem
Poor (low / unreliable) bioavailability due to
poor API solubility
Use of Hot-Melt Extrusion to prepare solid solution /
dispersion or SEDDS (enhanced dissolution)
Poor API stability during processing caused by
hydrolysis
Use of Hot-Melt Extrusion as alternative to wet
agglomeration (no hydrolytic stress)
Unreliable sustained release action
Use of Hot-Melt Extrusion to prepare sustained
release dosage form (single / multiple units)
Poor stability or tolerability of API in the stomach
Use of Hot-Melt Extrusion to prepare enteric
dosage forms (single / multiple units)
Poor taste of the API
Use of Hot-Melt Extrusion to prepare taste-masked
dosage forms
Manufacturing of lms
Use of Hot-Melt Extrusion to prepare oral strips or
dermal patches
Solution by HME
Hot-melt extrusion technology is a popular technique in the pharmaceutical industry.
It is of particular interest for dispersing APIs in a matrix at the molecular level, thus
forming solid solutions. This technique is currently becoming more and more impor-
tant as the percentage of poorly soluble new chemical entities in drug development
is constantly increasing [7]. For BCS class II compounds in particular, improved ab-
sorption and therapeutic efcacy can be realized by enhancing API solubility [12]. An
2
32
additional benet of the HME technique is a robust and continuous manufacturing
process which can be run in practically any pharmaceutical plant. However, as with
other breakthrough innovations, numerous obstacles had to be overcome before the
technology and resulting dosage forms could be commercially exploited. Compared
with other pharmaceutical technologies such as granulation and compression, hot-
melt extrusion is still an emerging technology and its potential has not yet been fully
exploited. The technology itself can be described as a process in which a material
melts or softens under elevated temperature and pressure and is forced through an
orice by screws. A prerequisite of the polymer to be used in hot-melt extrusion is
appropriate thermoplastic behavior. However, the number of such polymers approved
for pharmaceutical use is limited.
2.2.2 The hot-melt extrusion process
Extruders for pharmaceutical use have been designed and adapted for mixing drugs
with carriers in various dosage forms. The signicant difference between extruders
for thermoplastics and pharmaceutical applications is the equipment used, where,
for pharmaceuticals, the contact surface must meet regulatory requirements. Those
parts of extruders used in pharmaceuticals that have contact with product must not
be reactive nor may they release components into the product. Extruder equipment
is specially congured to fulll all cleaning and validation standards applicable to the
pharmaceutical industry.
In principle, an extruder consists of barrels enclosing single-, twin- or multi-screws
which transport and subsequently force the melt through a die, thus giving it a parti-
cular shape. The barrel can be heated to the desired temperature. Due to the external
heat and shear provided by the screws, the polymer is plasticized and hence its visco-
sity reduced. Since the extruder is fed at one side and the extruded material exits from
the other side, it is a typical continuous process; this makes it even more attractive
for pharmaceutical applications [36]. The hot-melt extrusion process comprises the
steps melting, mixing and shaping (see Figure 2.4).
The purpose of the feeding section is to transfer the materials from the feeder to the
barrel. The polymer mixture typically begins to soften in the melting zone. The melt
moves in a circulatory manner in a helical path by means of transverse ow, drag ow,
pressure ow and leakages [35]. Thermoplastic polymers primarily exist in a molten
state when entering the shaping section. The function of this zone is to reduce the
pulsation ow and ensure a uniform delivery rate through the die. At the end of the
barrel, the attached die determines the shape of the extrudates.
Powder
Die Tempering Cylinder Screw
Engine Extrudate
33
Figure 2.4 Principle of hot-melt extrusion
Modied according to: M. Thommes, Systematische Untersuchungen zur Eignung von kappa-Carrageenan als
Pelletierhilfsstoff in der Feuchtextrusion / Sphronisation, Ph. D. Thesis, University of Dsseldorf, 2006.
Shaping Mixing Melting
Temperature: above T
g
of polymer (60 180 C)
Residence time: variable (0.5 5 min)
The complete extrusion set-up consists of three distinct parts:
Screws with a conveying and kneading system for material transport and mixing
A die system for forming the extrudates
Downstream auxiliary equipment (cooling, pelletizing and collecting)
The components of the extruder are:
The feed hopper (gravimetric or volumetric feeding)
Temperature-controlled barrels (heating and / or cooling)
Die (different die congurations are available)
Additional equipment:
Process analytical technology (e. g. spectroscopic systems)
Vacuum pumps for degassing extrudates
Pelletizer equipment
Calendering equipment
In-process control parameters can be e. g.:
Zone and die temperatures
Screw speed
Torque or power consumption
Pressure
Melt viscosity
Feed rate
2
34
Extruders are available as single- or multi-screw versions. Twin-screw extruders utilize
two screws usually arranged side by side. The use of two screws allows a number of
different congurations to be obtained and imposes different conditions on all zones
of the extruder. In the twin-screw extruder, the screws can either rotate in the same
(co-rotating) or in the opposite (counter-rotating) direction [35].
Co-rotating extruders are the most important types for industrial applications.
They can be operated at high screw speeds and high output and provide good
mixing and conveying characteristics as well as more exibility in screw design. The
co-rotating and counter-rotating twin-screw extruders can be classied as either
non-intermeshing or intermeshing. In most cases, co-rotating intermeshing twin-
screw extruders are used. The main advantages of single- and twin-screw extruders
are listed below.
Advantages of twin-screw compared to single-screw extruders [35]:
Easier material feeding
High kneading potential
High dispersing capacity
Less tendency to overheat (important for sensitive APIs)
Shorter and constant residence times
Advantages of single-screw compared to twin-screw extruders:
Mechanical simplicity
Low cost of investment
The major advantages of the twin-screw extruders are in their conveying and trans-
port mechanisms and in their mixing abilities compared to the single-screw extruders.
This is why applications are continuing to expand within the pharmaceutical eld.
Conveying and kneading elements
Most extruders have a modular design to facilitate different screw congurations. The
conguration of the screw has a signicant impact on the extrusion process and
can be designed to achieve either a high or a low shear. In the extrusion process
the screws are specied in terms of the L / D ratio (length of the screw divided by
the screw diameter) [37, 38]. The conguration of the screws can be varied by the
number and arrangement of conveying and kneading elements [39].
The design of the kneading elements has an inuence on the mixing behavior within
the extrusion process. The advance angle also determines the conveying abil-
ity of the element ranging from forwards (30 and 60) to neutral (90) to reverse
(30) mode. Neutral elements (90) push material neither forwards nor backwards.
Irrespective of the reverse-ighted element, the ability for mixing and shearing of the
material increases the higher the advance angle. Reverse-ighted kneading blocks
have a retaining character and are usually used when substantial mechanical stress
has to be exerted upon the material [14].
35
Process variables of twin-screw extrusion
Process variables in twin-screw extrusion can be divided into step- and continuous
changes. Continuous changes include modications during the running process and
step changes require off-line modications (Table 2.2).
Table 2.2 Variables in twin-screw extrusion
Step changes:
Screw design
Die design
Barrel layout
Continuous changes:
Screw speed
Feed rate
Barrel temperature
Screw speed, feed rate and barrel temperature are the most relevant process para-
meters in twin-screw extrusion. These parameters in particular inuence the system
parameters mechanical energy, residence time and the temperature of the material.
On increasing feed rate and screw speed, the residence time of the material decreases
and the torque of the machine increases for the feed rate used; it is also constant for
the screw speed in question. At higher temperatures, the torque decreases due to a
lowering of the melt viscosity of the polymer (Figure 2.5).
Figure 2.5 Effect of feed rate, screw speed and temperature on HME
Feed rate [kg / h]
Screw speed [rpm]
Temperature [C]
Torque Residence time
Extrudability is mainly determined by the glass transition (T
g
) or melting temperature
(T
m
) and melt viscosity [40]. Materials of high molecular weight generate a high melt
viscosity and are difcult to extrude. A high glass transition or melting temperature
requires high processing temperatures, which can affect sensitive drugs. As a general
rule, extrusion processes can be run at temperatures 20 40 C above the glass tran-
sition temperature. Most polymers demonstrate thixotropic behavior, which means
that the viscosity reduces as a function of increasing shear stress.
2
36
2.2.3 Polymers for hot-melt extrusion
The polymer used in HME must exhibit thermoplastic characteristics in order to enable
the hot-melt extrusion process to be carried out and it must be thermally stable at the
extrusion temperatures employed. Other relevant characteristics are: suitable T
g
or T
m

(50 180 C), low hygroscopicity and no toxicity since larger amounts of polymer are
used (Figure 2.6). Polymers with a high solubilization capacity are particularly suitable
because large quantities of drugs can be dissolved [41].
Figure 2.6 Basic requirements for polymers used in HME
Thermoplastic behavior deformability is essential
Suitable T
g
50 180 C
High thermal stability 50 180 C
Low hygroscopicity prevents crystallization
No toxicity application of large
amounts
High or no solubilization thermodynamically stable
capability formulation
Some features like lipophilicity, hydrogen bonding acceptors or donors [42] and amide
groups are basic prerequisites for a high solubilization capacity; the same applies to or-
ganic solvents. This explains why povidone (Kollidon

), copovidone (Kollidon

VA 64)
and Soluplus

are highly suitable for hot-melt extrusion. Kollidon

VA 64 and Soluplus

in particular are much more lipophilic than many other water-soluble polymers con-
taining hydroxyl groups and, therefore, are best suited to the lipophilicity of poorly
soluble drugs. In addition, the solubility parameter (see Extrusion Compendium [41]
pages 53 55) can be used to determine whether actives and polymers are com-
patible [43, 44]. Regarding the topics solubilization / extrusion and bioavailability en-
hancement of poorly soluble drugs, some examples of Soluplus

formulations are
described in chapter 5.
The solubilization capacity of a certain excipient can also be determined using hot-
melt extrusion [41]. Figure 2.7 clearly illustrates how the appearance of a Soluplus

extrudate changes with increasing amounts of API: While the extrudates containing
25 % fenobrate appear almost transparent, they change to more and whiter extru-
dates when the concentration of drug is increased in 5 % steps. This white color is
attributed to undissolved, crystalline drug and indicates that the solubility of feno-
brate in Soluplus

is around 25 30 %. However, it is advisable to perform some

solvent casting trials with a certain API / excipient ratio, as previously described, to
obtain a rst impression of the API solubility within the polymer matrix.
37
Figure 2.7 Appearance of Soluplus

with increasing drug concentration of fenobrate

Increasing drug concentration [% (w / w)]
25 % 30 % 35 % 40 % 45 % 50 %
2
Spray tower
Filter
Feed tank
Feed pump
Spray nozzle
Inlet filter
Pressure fan
Heat exchanger
Suction fan
Product
1
2
3
4
5
6
7
8
9
10
9
1
2
3
4
5
6 7 8
10
38
2.3 Spray drying as a preparation technique for
solid solutions
2.3.1. Introduction
In spray drying, liquids are converted into powdered solids. The process functions
by atomizing the liquid and vaporizing off the solvent used. The heat required for the
process is provided by a drying gas; this gives off its heat and takes up the solvent
vapor. The drying gas also becomes colder and moister during the drying process.
The widespread use of spray drying has led to the development of numerous differ-
ent types of processes. Below, a standard conguration, as shown in Figure 2.8, is
described.
Figure 2.8 Standard spraying tower
In this chapter, we will concentrate on the core process of spray drying using a
pressure nozzle. Further information on the technique can be obtained for example
from Masters "Spray Drying Handbook" [45] and Lefebres "Atomization and Sprays"
[46].
39
In the manufacture of solid solutions, spray drying offers a number of
advantages:
It is a widespread technique and is readily available.
In one process step, it is possible to manufacture a powder for producing tablets
starting from a liquid.
It is a gentle process with respect to temperature as the individual process steps
require seconds only and the maximum product temperature is only as high as the
gas exit temperature of the spray drier (approx. 50 100 C).
Due to the short drying times involved, amorphous solids with good solubility pro-
perties are frequently formed.
2.3.2 Spray drying: theory and practice
In general, a spray drying process involves the following steps:
I. Manufacture and atomization of the liquid.
II. Drying and formation of particle morphology within the spray tower.
III. Filtration, post drying, cooling and packaging of the powder.
Below, we will have a closer look at these steps as illustrated in Figure 2.8.
I. Manufacture and atomization of the liquid
For the spray drying process, one decisive factor is whether water or organic solvent
is used. The active ingredients and excipients normally used in the manufacture of
solid solutions are mostly more readily soluble in organic solvents than in water. How-
ever, spray drying with organic solvents requires an explosion-proof spray tower. This
in turn involves high investment and also requires higher operating costs due to the
necessary use of inert gas (e. g. nitrogen). The residual solvent content in the spray
powder after drying must be so low that there is no risk of explosion in the gas space
above the powder. Often, it is required that the solvent concentration should be a
maximum of 40 % of the lower explosion limit.
When using organic solvents, higher throughputs can be achieved due to the sub-
stantially lower heat of evaporation required in comparison to water. In many cases
higher solid concentrations in the liquid can be achieved as the viscosity in organic
solvents is lower. These inuences can be of considerable advantage if organic sol-
vents are preferred to water. Thus, when developing formulations, the advantages
and disadvantages of organic solvents compared to water should be taken into ac-
count at an early stage. It can thus be benecial to develop alternative formulations in
parallel until concrete data have been gathered on the performance and economics
of the planned manufacturing process.
The solid content of the liquid should be as high as possible (
>
20 %). This is because,
on the one hand, it improves the economics of the process as a spray drying plant is
based on liquid evaporation and low solid content means that the plant can be smaller
2
40
and the cost of cleaning and service also lower. On the other hand, liquids with low
concentrations of solid generally produce ne powders of low bulk density and poor
ow properties, both of which tend to have a negative effect on subsequent process
steps.
The solid content also determines the viscosity and hence the ability of the liquid to
be atomized. The process of atomization creates the large liquid surface area that is
necessary for the heat- and mass transfer required for the liquid to be dried within a
few seconds in the spray tower. Atomization should be carried out to produce a spray
with a controlled and dense drop size distribution. As large drops require longer to dry
than small drops, these determine the dimensions of the spray tower. Drops that are
too large and still moist and sticky can reach the walls of the spray tower where they
can form coatings. It is thus of importance that the atomization system is properly
dimensioned and that it operates smoothly.
Hollow cone pressure nozzles are frequently used for atomization, as illustrated by the
example of a Schlick nozzle in Figure 2.9. In such a case, the viscosity should not be
higher than 50 100 mPa*s. Such hollow cone pressure nozzles are normally used for
the pressure range of 20 200 bar. The maximum throughput per nozzle is approx.
500 kg liquid per hour. For higher throughputs, several nozzles can be employed. The
size of the drops can be set via the atomization pressure.
Figure 2.9 Hollow cone pressure nozzle (Schlick)
Nozzle cap Orice Swirl chamber Pressure spring Nozzle end-piece
The spray pattern of a pressure nozzle is illustrated in Figure 2.10.
41
Figure 2.10 Spray pattern of a
pressure nozzle
II. Drying and formation of particle
morphology within the spray tower
For a liquid to be suitable for spray drying
and hence for the manufacture of a solid
solution, two parameters must be taken
into account: the drying kinetics and the
achievable moisture equilibrium.
Under suitable drying kinetics, a thin
liquid lm can be converted into a man-
ageable solid within a few seconds. For
this to be achieved, a minimum process
temperature is required dependent on
the boiling point of the solvent and the af-
nity of the solid to the solvent. At such a
temperature (roughly, one corresponding
to the outlet temperature of the spray
drier), the solid should not be sticky.
In most cases, the drying kinetics would be assessed by drying small amounts in a
laboratory scale spray tower. Due to the smaller dimensions of such an apparatus,
the powder produced should be very ne (approx. 10 20 m). For this reason, the
samples obtained are not representative in their powder properties with respect to the
product to be obtained later; however, it provides an indication of expected behavior
within the spray tower, e. g. the tendency to form coatings on the walls of the tower.
The moisture equilibrium is characterized by the sorptive behavior of solvent with
respect to the solid. For each amount of humidity in the gas phase there should be
a moist equilibrium on the part of the solid; this is characterized by the sorption iso-
therm. In this way, depending on the humidity in the exhaust of the spray tower, there
will be a minimal residual moisture in the powder. However, the residual moisture that
is practically achievable is higher than the equilibrium value due to the short process
time and can only be determined in scale-up experiments.
In the case of spray drying plants operated with air in the open mode, the humidity of
the exhaust air is not only dependent on the amount of water vaporized in the spray
tower, but also by the humidity of the inlet air. This dependence has a stronger effect
on the residual moisture of the powder the more hygroscopic the solid is. In order to
reduce the effect of inlet moisture on the residual moisture of the product, the inlet air
is usually dehumidied to a maximum dew point of approx. 10 C.
One of the most interesting questions regarding the development of a spray dried
powder is what powder properties can be achieved and how these can be inuenced
by the formulation and the process. The key to understanding this is to be found in the
particle morphology. Many of the application properties of the spray powder such
2
42
d
1
d
2
Suspension
Dissolved
excipients
Ideal shrinking
as ow-, dust-, dissolution- and tableting behavior can be explained by physical pro-
perties such as particle size distribution, bulk density and REM imaging, all of which
illustrate the particle structure. Figure 2.11 shows, on the left, a compact particle that
has resulted from a slaked lime suspension and, on the right, particles that have been
produced by spray drying a polymer solution of hollow beads.
Figure 2.11 Forms of spray dried particles
100 m 10 m
The Bttiker model shown in Figure 2.12 assumes hollow bead formation due to the
proportion of dissolved components. Pure suspensions of solid particles in the liquid
shrink ideally and give rise to compact particles which in turn result in a powder of
high bulk density. With increasing proportion of dissolved solid, the greater the chance
of producing hollow bead formation.
Figure 2.12 Inuence of dissolved solid on particle morphology during spray drying
(Bttiker model)
a) b) c)
1
1
1
1
2
2
2
2
3
3
4
4
3 4
3
4
Hot air inlet
Feed
Exhaust air
Product
43
Apart from the composition of the liquid, the properties of the spray powder are deter-
mined principally by the process conditions in the spray tower. Some of these condi-
tions are determined by the construction of the spray drier. Variants of spray driers
are shown in Figure 2.13. Variant a) is a co-current ow nozzle tower. Here, the drying
gas and the spray are led through the tower in co-current mode. In this way, the
efuent liquid comes into contact with the warm air and shows a high drying speed
during the rst few seconds of the process. This drying speed can be increased by
inserting a rotary atomizer as shown in variant b). The rotational atomizer, due to its
circumferential speed of over 100 m / s, creates excellent heat- and mass transfer
within its immediate atomization area. Variant c) also involves a nozzle tower. In this
case, however, it is operated in counter-current mode. Here, the spray rst comes into
contact with the cool exhaust gas; it thus has a signicantly lower initial drying speed
than variant a) due to the lower temperature increment.
Figure 2.13 Variants of spray driers: a) co-current nozzle tower, b) disc tower, c)
counter-current nozzle tower. See text above for explanation.
The bulk density of spray powder is strongly dependent on the initial drying speed in
the spraying tower due to the formation of hollow beads. Thus, it is obvious that the
lowest bulk density can be attained with variant b) whilst the highest can be attained
with variant c). Apart from these primary effects there are, however, some secondary
effects that do not occur directly in the spray tower but which also have to be taken
into account. For example, large hollow beads with very thin shells are more likely
to rupture than smaller beads with thicker shells; they are also more likely to be de-
stroyed during the process, which of course alters the properties of the powder.
In addition to atomization, the most important process parameters in spray drying
are the inlet- and outlet air temperatures and the gas speed in the spray tower.
2
44
III. Filtration, post drying, cooling and packaging of the powder
After drying in the spraying tower, the powder must be separated from the drying gas.
Cyclones, bag lters and absolute lters can be used for this purpose. Cyclones are
simple and economically priced devices; they are also easy to clean. Their disadvan-
tage is that they have a limited degree of ltration; very small particles are simply not
ltered out. Typical ltration rates are around 99 %, i. e. 1% of the solid is lost in the
exhaust. The particles remain in the cyclone for a few seconds only. Bag lters form a
lter cake on the lter material; this is then cleaned up with compressed air. Very high
degrees of ltration can be achieved with such lters; the dust remaining is usually
less than 1 to 10 mg / m
3
. The particle residence time in the bag lter is dependent
on the cleaning cycles and can be up to several minutes. The bag lter can also be
used for post drying of the particles. The disadvantages of bag lters are the high
purchase price, the complex cleaning process and the ber impurities caused by the
lter material.
If very clean exhaust air is required, as is the case with biologically active substances,
only an absolute lter can achieve this. These are usually in the form of lter cassettes
graded according to the degree of cleanliness required and lled with appropriate lter
material. They are normally connected in series and disposed of after use.
Typical lter systems can be e. g.: bag lter + absolute lter or cyclone + bag lter +
absolute lter.
In some cases, post drying and / or cooling of the powder is necessary once it has
left the spray tower. Fluid-bed driers are frequently used for this purpose; they often
combine drying and cooling. However, contact driers or coolers can also be used.
This becomes meaningful e. g. when starting with continuous spray drying and then
changing to batch processing. In such a case, a mixer can be inserted to dene
the batch size. When packaging, the selection of suitable containers is of particular
importance. The package must be resistant to humidity and the inherent weight of the
powder must not lead to the formation of lumps.
2a
2a
Feed tank
Heat exchanger
Heating system
Spray nozzle
Spray tower
Product
1
1
2
2
3
3
4
4
5
5
45
2.3.3 Preparation of solid solutions using spray drying
Spray driers as described above can be used for the preparation of solid solutions
from active ingredients. In this case, the liquid is a mixture of solvent (water, organic
solvent or a mixture of both), active ingredient and suitable excipients. The excipients
help to improve the dissolution of the active ingredient or to stabilize it within the spray
powder; they also prevent recrystallization during storage subsequent to spray drying.
Should the active ingredient be poorly soluble, this can be improved by wet milling,
a process that aids dispersion. If the solubility is still not adequate for economic pro-
duction, it can be further improved (e. g. by briey overheating the liquid according to
BASF submission PF 56790 GD "Herstellung von festen Lsungen schwerlslicher
Wirkstoffe durch Kurzzeitberhitzung und schnelle Trocknung" Manufacture of solid
solutions of poorly soluble active substances by briey overheating and rapid drying).
The process principle is illustrated in Figure 2.14.
Figure 2.14 Manufacture of a solid solution by briey overheating and subsequent
spray drying
The mixture of water, active ingredient and excipients is subjected to wet milling and
placed in feed tank 1. The active ingredient, depending on its solubility, may not be
completely dissolved. On its way to the spray nozzle (3), the liquid passes through a
heat exchanger (2) which, aided by a heating system (2a), is brought to a tempera-
ture above the boiling point of the liquid at ambient pressure. For example, the liquid
can be exposed to a temperature of 150 C for 15 seconds at a pressure of 100 bar.
During this time the nely milled active ingredient can be fully dissolved in the aqueous
polymer solution. The solution prepared in this way is then dried in the spray tower
(4) and the powder-formed solid solution of the active ingredient is collected in the
collection vessel (5).
2
H
e
a
t

f
l
o
w

[
W
/
g
]
6
5
4
3
2
1
Min.
C 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
5 0 10 15 20 25 30 35 40 45 50 55 60
0
46
The residual moisture of the spray powder, which should not be greater than 5 %
(m / m), has an inuence on the storage stability of the formulation and should thus be
determined by appropriate experiments.
The process involved is illustrated below using the example of the spray drying of
theophylline with Kollidon

30:
Pure theophylline is a crystalline active ingredient with a melting point of approx.
270 C (see Figure 2.15).
Figure 2.15 REM image and DSC of pure theophylline
50 m Theophylline
H
e
a
t

f
l
o
w

[
W
/
g
]
0.6
0.4
0.2
0.4
0.2
0.8
0.6
Min.
C 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
5 0 10 15 20 25 30 35 40 45 50 55 60
0.8
0.0
47
Pure Kollidon

30 on the other hand is an amorphous polymeric excipient which

forms hollow beads during spray drying. Apart from the vaporization of residual water
in the area of 100 C, no further energy aspects can be observed in the course of DSC
(see Figure 2.16).
Figure 2.16 REM image and DSC of pure Kollidon

30line
50 m Kollidon

30, 20 %
(with heating) V3
In a pilot plant spray drying apparatus as shown in Figure 2.14, a mixture of Kolli-
don

30 and theophylline were spray dried together. The mixture, comprising 10 %

theophylline, 20 % Kollidon

30 and 70 % water, was milled prior to spray drying in

a stirred mixer mill and the particle size of the theophylline reduced to smaller than
5 m. This suspension was then fed into the heat exchanger using a 3-stage piston
membrane pump at a mass ow of 50 kg / h. The heat exchanger was heated with
steam at 13 bar so that, after overheating, a temperature of 150 C set in. The liquid
was then atomized in a spray tower using a hollow cone pressure nozzle (bore dia-
meter 0.6 mm) at a pressure of 100 bar. The spray tower was operated with nitrogen
at an inlet temperature of 140 C and an outlet temperature of approx. 100 C. The
spray dried powder was subsequently ltered using a tube lter.
2
48
By using this spray drying process, a powder was obtained that was very similar in
appearance to pure Kollidon

30 and that, in spite of a proportion of 1 / 3 theophylline,

showed no crystalline melting peak in DSC (Figure 2.17).
H
e
a
t

f
l
o
w

[
W
/
g
]
0.6
0.4
0.2
0.4
0.2
0.0
0.8
0.6
Min.
C 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
5 0 10 15 20 25 30 35 40 45 50 55 60
0.8
50 m Kollidon

30, 20 % +
Theophylline
(with heating) V4
Figure 2.17 REM image and DSC of a spray dried mixture
(1 / 3 theophylline, 2 / 3 Kollidon

30)
The crystallinity of the pure theophylline (dark blue) is also shown in the x-ray
structural analysis (XRD) (see Figure 2.18) while neither pure Kollidion 30 (red and
yellow) nor the spray dried mixture (light blue) show crystalline structures. The
combination of results from DSC and XRD clearly indicate the existence of a solid
solution of theophylline in Kollidon

30.
L
i
n

[
c
o
u
n
t
s
]
1400
1200
1000
800
600
400
200
0
1 10 20
2-Theta Scale
30 40
Theophylline
Kollidon

30, 20% (without heating) V1

Kollidon

30, 20% (with heating) V3

Kollidon

30, 20% + Theophyllin (with heating) V4

49
Figure 2.18 X-ray structural analysis of theophylline, Kollidon

30 and a solid solution

of both
Even after lengthy storage the powder remained amorphous and no recrystallization
of the theophylline occurred. This illustrates the high degree of suitability of the
method for the manufacture of solid solutions.
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solid dispersions, Eur. J. Pharm. Biopharm. 50 (2000), 47 60.
[37] Verein Deutscher Ingenieure (VDI) Kunststofftechnik, Optimierung des Com-
poundierprozesses durch Rezeptur- und Verfahrensverstndnis, VDI-Verlag
GmbH, Dsseldorf (1997).
[38] K. Nakamichi, S. Izumi, H. Yasuura, Method of Manufacturing Solid Dispersion,
EP 580860 and US 5456923.
[39] I. Ghebre-Sellassie, C. Martin, Pharmaceutical Extrusion Technology, Drugs
and the Pharmaceutical Sciences, Volume 133 (2007).
[40] E. Karavas, G. Ktistis, A. Xenakis, E. Georgarakis, Effect of hydrogen bonding
interactions on the release mechanism of felodipine from nanodispersions with
polyvinylpyrrolidone, Eur. J. of Pharm. Biopharm. 63 (2006), 103 114.
[41] K. Kolter, M. Karl, S. Nalawade, N. Rottmann, Extrusion Compendium: Hot-
melt extrusion with BASF pharma polymers, BASF SE (2010).
[42] A. Forster, J. Hempenstall, T. Rades, Characterization of glass solutions of
poorly water-soluble drugs produced by melt extrusion with hydrophilic amor-
phous polymers, J. Pharm. Pharmacology 53 (2001), 303 315.
[43] A. Forster, J. Hempenstall, I. Tucker, T. Rades, Selection of excipients for melt
extrusion with two poorly water-soluble drugs by solubility parameter calcula-
tion and thermal analysis, Int. J. Pharm. 226 (2001), 147 161.
[44] J. E. Patterson, M. B. James, A. H. Forster, T. Rades, Melt extrusion and spray
drying of carbamazepine and dipyridamole with polyvinylpyrrolidone / vinyl-
acetate copolymers; Drug Dev. Ind. Pharm 34 (2008), 95 106.
[45] K. Masters, Spray Drying Handbook, George Godwin Limited, London, (1979).
[46] Athur H. Lefebvre, Atomization and Sprays, Hemisphere Publishing Corpo-
ration, (1989).
2
52
53
Michael G. Herting, Viet Nguyen-Kim, Ann-Kathrin Marguerre
3 Investigation of solubilization efcacy using a
high-throughput robot
3.1 Introduction
Pharmaceutical scientists are increasingly facing the challenge of formulating active
pharmaceutical ingredients (APIs) that are poorly soluble in water. Such APIs are
usually associated with low oral bioavailability. Four out of ten development candi-
dates are discontinued due to insufcient biopharmaceutical tness [47]. This trend
is likely to continue: new APIs in pharmaceutical research are becoming more and
more lipophilic and complex, given that combinatorial chemistry and pharmaco-
logical high-throughput screening (HTS) have become standard methods in the in-
dustry [48] and new drug targets are requiring more lipophilic API structures. Because
of their problematic physico-chemical properties such as poor water solubility or low
permeability, a large number of new chemical entities show poor bioavailability and
consequently fail during the development phase [49-51]. Therefore, scientists around
the world are currently trying to tackle the issue of bioavailability by developing novel
strategies for increasing "biopharmaceutical tness during drug formulation. Such
formulation strategies include pH adjustment, solid dispersions, particle size reduc-
tion, salts, co-solvents, SEDDS, micellar solutions and emulsions.
However, to date, scientists have still not been able to relate compound structures
to the solubilizing activity of excipients. Thus, within the pharmaceutical industry, the
solubilization effect is being examined more by the trial and error principle during early
drug development. In conventional screening, this consumes large amounts of material,
leads to long development times and consequently results in high development costs.
The type and number of tested formulations is limited by the available time and the
compounds on hand. However, the time required for experiments can be signicantly
reduced by applying HTS. The use of HTS provides absolutely reproducible and well-
documented screening of the solubilization capacity of different solubilizers for various
compounds [52, 53]. Moreover, it appears to be the only way of generating a sufciently
reliable database that allows the general structure-property relationships to be deter-
mined for deducing the solubilizing efcacy of solubilizer-compound combinations.
3.2 Kinetic and thermodynamic solubility
Many methods have been described on how to measure the solubility of compounds.
Depending on the experimental set-up, the kinetic- or thermodynamic solubility of the
compound in question can be measured.
For the determination of kinetic (non-thermodynamic) solubility, the compound
is initially dissolved in an organic solvent (e. g. DMSO) and, in a second step, the
3
54
resulting stock solution is diluted in a well-stirred aqueous medium. Using the kinetic
solubility approach, however, it is not possible to determine the possible inuences of
various polymorphic forms or the crystal lattice energy; this is because the compound
has been pre-dissolved. Thus, the measured kinetic solubilities present the maximum
solubility of the fastest precipitating modication of the compound. The kinetics of the
compound therefore determine its solubility level.
The structure of this precipitating compound is unclear. It can be a crystal or amor-
phous form, a salt or co-crystal or even combinations of various possibilities [49].
Furthermore, as the process is time-dependant and supersaturation may occur, the
obtained values lack reproducibility [54].
In addition, the kinetic method usually leads to a higher aqueous solubility compared
to thermodynamic solubility. One reason for this is the presence of organic solvent,
which acts as a co-solvent even at low concentrations (0.5 5 %) during measure-
ment. Another reason for the higher aqueous solubility levels is the fact that the pre-
dissolved compound is in a high energy state. This enhances the apparent solubility
of the compound.
Figure 3.1 HTS robot at BASF for the determination of thermodynamic solubility
55
The determination of thermodynamic solubility (equilibrium solubility) is carried out by
dosing a solid compound (in excess) into an aqueous medium. The measured solu-
bility is the saturation solubility of the examined compound over the non-dissolved
compound (equilibrium). Measurement of equilibrium solubility is commonly a single
measurement after a dened time (24 72 h) for rst assessments. Following these
rst screening experiments, it makes sense to verify the ndings by determining the
equilibrium solubility at different time points.
In contrast to the determination of kinetic solubility, the breakage of the crystal lattice
plays an important role in thermodynamic solubility. Therefore, compounds in an
amorphous state will have higher solubilities than compounds in the crystalline state.
In solubility measurements, kinetic solubility is frequently determined using HTS [48].
The application of a compound dissolved in an organic liquid is faster and easier to
handle. Furthermore, the quantity of compound required for a single test is lower
(g range) compared to a solid (mg range).
However, as the thermodynamic solubility measurement includes the dissolution step of
the compound, this approach was used for setting up the HTS robot at BASF (Fig. 3.1).
3.3 Set-up of the Solu-HTS robot
3.3.1 Overview
The three-axes system moves either the needle or the dosing unit for powders to the
different stations of preparation and analytics: Solid is weighed in the sample rack on
the balance and solubilizer solutions are added to each sample. After incubation, the
samples are diluted in the dilution rack and the amount of solubilized active ingredient
determined by UV / VIS spectroscopy. The general set-up of the multi purpose HTS
is shown in Fig. 3.2.
3
UV/VIS spectrometer
Dilution rack
Sample rack
Balance
Solubilizer rack
Sample rack
Dosing unit
Needle
Three-axes system
0
0.1
0.2
0.3
0.4
0.5
0.6
250 270 290 310 330 350 370 390 410 430 450
Wavelength [nm]
A
b
so
rb
a
n
c
e
Total absorption
API absorption
Solubilizer Absorption
56
Figure 3.2 Set-up of the multi-purpose HTS Robot at BASF
The process can be divided into two parts:
Sample preparation
Sample analysis
Sample preparation is carried out by dosing solid active and liquid solubilizer solution
into each well. For thermodynamic solubility, stirring bars are added and the samples
incubated for 72 hours. Separation of the dissolved active and its solid form are per-
formed by ltration and the amount of solubilized active determined via UV / VIS spec-
troscopy. The different processes performed by the robot are illustrated in Fig. 3.3.
Figure 3.3 Workow of the multi-purpose HTS Robot
Solid actives
Liquid solubilizer
solution
Dosing
Agitation
Stirring
Dissolution Filtration
UV / VIS
HPLC
Analysis
Data elaboration
Evaluation of
results
Data Processing
57
3.3.2 Preparation of samples
The set-up of the multi-purpose HTS robot allows for the dispensing of liquids and solids.
Solubilizer solutions and API powders are dispensed into vials (Fig. 3.4). The amount
of API to be added is set to 10 mg and the actual amount added is controlled using
a balance (X404S DeltaRange, Mettler Toledo, Germany) and recorded. 0.5 mL of the
solubilizer solution in phosphate buffer pH 7.0 is dispensed from a 1 % and 5 % (w / w)
aqueous stock solution. Thermodynamic solubility measurement was used for setting
up the HTS robot at BASF because it includes the dissolution step of the compound.
The 1.0 mL vials have standard dimensions and are placed on a standard tray to pro-
vide high operational freedom with regard to analytics such as UV / VIS spectroscopy
or HPLC.
Figure 3.4 Preparation set-up showing the 3-axis robot arm and balance with vials
3.3.3 Analysis of dissolved API
After ltration of the saturated API solutions, each sample is analyzed by UV / VIS
spectroscopy. For this purpose, the absorption spectra of pure active ingredient in
terms of calibration curves as well as the absorption spectra of the pure solubilizers
are measured during the same run (Fig. 3.5). Later, they are employed in the tting
procedure.
3
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
180 230 280 330
Wavelength [nm]
A
b
s
o
r
b
a
n
c
e
Soluplus

Tween 20
Tween 80
Kolliphor EL
Kolliphor RH 40
Kolliphor TPGS
Kolliphor HS 15
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
180 190 200 210 220 230 240 250
Wavelength [nm]
A
b
s
o
r
b
a
n
c
e
Kolliphor P 124
Kolliphor P 188
Kolliphor P 237
Kolliphor P 338
Kolliphor P 407
58
Soluplus

> 260 nm
Tween 20 > 260 nm
Tween 80 > 270 nm
Kolliphor EL > 270 nm
Kolliphor RH 40 > 210 nm
Kolliphor TPGS > 300 nm
Kolliphor HS 15 > 210 nm
Kolliphor P grades > 210 nm
Figure 3.5 Absorption
spectra of solubilizers
0
0.1
0.2
0.3
0.4
0.5
0.6
250 270 290 310 330 350 370 390 410 430 450
Wavelength [nm]
A
b
s
o
r
b
a
n
c
e
Total absorption
API absorption
Solubilizer Absorption
59
The diode array monochromator covers a broad wavelength range (200 700 nm)
and measures one full spectrum per second, usually over 100 seconds. The chroma-
togram (time / intensity graph) for the API-specic wavelength acts as a quality check
for optimal performance of the robot. Overall, this leads to ~ 2 mill. data points per
sample, which makes an automated data analysis a prerequisite. In the next step,
the mean intensity value for each wavelength over 100 seconds and for each sample
are generated and the active content calculated. This is performed by employing two
different tting procedures. The Peakt method adds up the spectra of active and
solubilizers and stores them in the database until the deviation from the measured
spectrum is minimal (Fig. 3.6). With the area-over-baseline-method, a baseline is ma-
nually generated and the area over this baseline is compared to that of the pure API.
Figure 3.6 Absorption spectra of solubilizer, active and measured sample
3
N
Carbamazepine
O NH
2
60
3.4 Proof of concept: Manual vs. HTS experiments
The purpose of this study was to set up an HTS robot for the solubilization of poorly
soluble APIs. Carbamazepine was used as a model API and the solubilization capac-
ity of various solubilizers for this API was determined. Screenings obtained with the
help of the robot benet from automation, miniaturization and parallelization. It can
be used to accelerate research projects and to scan various inuencing parameters
simultaneously. For proof of the concept, the results obtained were compared to the
data from manual experiments in the lab.
3.4.1 Materials
Name Chemistry Supplier
Kolliphor RH 40 Polyoxyl 40 hydrogenated castor oil
Macrogolglycerol hydroxystearate
Polyoxyl 35 castor oil
BASF SE
Kolliphor EL / ELP Macrogolglycerol ricinoleate BASF SE
Kolliphor HS 15 Macrogol 15 hydroxystearate BASF SE
Kolliphor P 188 Poloxamer 188 BASF SE
Kolliphor P 407 Poloxamer 407 BASF SE
Tween 20 Polysorbate 20 Croda Plc
Tween 80 Polysorbate 80 Croda Plc
Kolliphor TPGS D- -Tocopheryl polyethylene glycol
1000 succinate
BASF SE
Table 3.1 Overview of solubilizers tested:
3.4.2 Determination of dissolved carbamazepine
Following incubation and a ltration step, a 1:10 dilution with a phosphate buffer /
methanol 1:1 (v / v) mixture was carried out to avoid precipitation of the API. 0.1 mL
of the diluted sample was then analyzed automatically using the incorporated UV
spectrometer (DDT3200, Duratec, Germany) at a wavelength of 286 nm. In the case
0
100
200
300
400
500
600
700
800
B
u
f
f
e
r
K
o
l
l
i
p
h
o
r

E
L
K
o
l
l
i
p
h
o
r

R
H

4
0
K
o
l
l
i
p
h
o
r

P

1
8
8
K
o
l
l
i
p
h
o
r

P

4
0
7
T
w
e
e
n

2
0
T
w
e
e
n

8
0
K
o
l
l
i
p
h
o
r

H
S

1
5
K
o
l
l
i
p
h
o
r

T
P
G
S
S
o
l
u
b
i
l
i
z
e
d

c
a
r
b
a
m
a
z
e
p
i
n
e

[
p
p
m
]
Solu-HTS
Manual
61
of maximal absorbance being higher than 1.0, an appropriate second dilution step
was automatically performed. In the manual trials, all steps were performed by a
Ph. D. student. Evaluation of solubilized carbamazepine for the manually prepared
samples was carried out using a Hewlett Packard HP8452A Diode Array UV / VIS
spectrometer.
3.4.3 Results and discussion
The use of solubilizers resulted in an improvement in the saturation solubility of carb-
amazepine in all cases. The saturation solubility achieved for the different solubilizers
tested ranged from approximately 190 ppm using Kolliphor P 188 to 610 ppm for
Kolliphor TPGS at 1 % solubilizer concentration as detected by the UV / VIS spec-
trometer built into the HTS robot.
Kolliphor TPGS proved to be the most efcient solubilizer for carbamazepine and
resulted in the highest saturation solubility.
Figure 3.7 Comparison of the saturation solubility of carbamazepine obtained by two
different methods at a solubilizer concentration of 1 % (w / w)
3
62
The experiments showed that the use of an HTS robot for screening trials can help to
save development time. The trials with the HTS robot took two days while the manu-
ally performed experiments by one operator took three times as long. As these were
the rst test trials using the robot, it can be expected that the analyzing speed in future
trials can be increased due to optimization of the processes.
An additional benet compared to manual work is perfect reproducibility of the dis-
pensing steps and the automated documentation of parameters and results in a
database. This data can be used in the evaluation step for data mining and statistical
analysis to extract correlations and structure-property relationships.
3.5 Conclusion
The HTS robot was successfully used for the fast screening of different solubilizers
with carbamazepine as a model API. The data obtained were comparable to the
manually obtained results. The use of the HTS robot allowed for a large number
of data and increased the information output signicantly due to the built-in soft-
ware. Therefore, this approach helps to reduce development time. The benets are
summarized in Table 3.2.
Manual HTS
Number of screened solubilizers * Low High
Amount of work High Low
Time requirement High Low
Repeatability Medium High
Documentation Unknown Full
Table 3.2 Comparison of manual screening and screening with an HTS robot:
* In a given time
It is to be expected that, using the HTS robot, a comprehensive database will be
obtained, allowing for the correlation of the API structure and solubilization capacity
of different solubilizers for specic APIs.
63
References
[47] R.A. Prentis, Y. Lis and S.R. Walker, Pharmaceutical innovation by the seven
UK-owned pharmaceutical companies, Br. J. Clin. Pharmacol, 25 (1988),
387 396.
[48] E. H. Kerns, High Throughput Physicochemical Proling for Drug Discovery,
J. Pharm. Sci., 90 (1) (2001), 1838 1858.
[49] J. Alsenz and M. Kansy, High throughput solubility measurement in drug
discovery and development, Adv. Drug Deliv. Rev. 59 (2007), pp. 546 56.
[50] C. Lipinski, F. Lombardo, B. Dominy and P. Feeney, Experimental and compu-
tational approaches to estimate solubility and permeability in drug discovery
and development settings, Adv. Drug Del. Rev. 46 (1 3) (2001), pp. 3 26.
[51] T. I. Oprea, Current trends in lead discovery: are we looking for the appropriate
properties?, J. Comput. Aided Mol. Des. 16 (5 / 6) (2002), pp. 325 334.
[52] W.-G. Dai, C. Pollock-Dove, L.C. Dong and S. Li, Advanced screening assays
to rapidly identify solubility-enhancing formulations: high-throughput, mini-
aturization and automation, Adv. Drug Deliv. Rev. 60 (2008), pp. 657 672.
[53] W.-G. Dai, L. C. Dong, S. Li, C. Pollock-Dove, J. Chen, P. Mansky and
G. Eichenbaum, Parallel screening approach to identify solubility-enhancing
formulations for improved bioavailability of a poorly water-soluble compound
using milligram quantities of material, Int. J. Pharm. 336 (2007), pp. 111.
[54] M. Stuart and K. Box, Chasing equilibrium: measuring the intrinsic solubility of
weak acids and bases, Anal. Chem. 77 (2005), pp. 983 990.
3
64
Thomas Reintjes
4 Overview chart: BASF pharma polymers for
solubility enhancement
4.1 General notes
The chart below gives an overview of the pharmaceutical excipients that are pre-
sented in detail in the next chapters. Besides their mode of action and state at room
temperature (RT), at least one recommended application (dosage form or process) is
given for each excipient. And while both mode of action and state are quite clear for
most of the substances listed, a specic application is sometimes difcult to dene.
Some of the excipients have already been used for decades in various applications;
others are quite new and little experience has been gathered to date. The same is
true for the different applications: processes such as hot-melt extrusion (HME) for
example are still relatively new to the pharmaceutical industry and thus not all the
excipients have been extensively investigated for this specic process. Consequently,
the recommendation of an excipient for a certain application should not exclude it
from any other applications.
4.2 Chart legend
The mode of action is separated into:
Micellization M and complex formation C or a combination of both MC .
The second column divides the substances according to their state at room
temperature into:
Solid S pasty P and liquid L .
The suitability of a certain substance for a specic application or process is
expressed by:
++
if it is strongly recommended or by
+
if it is recommended but other sub-
stances are expected to perform even better. However, even if neither "strongly
recommended", nor "recommended" is stated for a particular substance, it does not
mean that this substance cannot be used for this specic process / application at all,
but that possibly no convincing experiments have been performed to date.
65
Substance
Recommended application
Soluplus

Kolliphor TPGS
Kolliphor HS 15
Kolliphor RH 40
Kolliphor EL
ELP
Kollisolv P 124
Kolliphor P 188
micro
Kolliphor P 237
Kolliphor P 338
Kolliphor P 407
micro
Kollidon

12 PF
Kollidon

17 PF
Kollidon

25 / 30
Kollidon

VA 64 / Fine
4.3 Application chart
M
o
d
e

o
f

a
c
t
i
o
n
S
t
a
t
e

(
R
T
)
T
o
p
i
c
a
l

f
o
r
m
u
l
a
t
i
o
n

(
o
i
n
t
m
e
n
t

/

g
e
l
)
O
r
a
l

s
o
l
u
t
i
o
n
P
a
r
e
n
t
e
r
a
l

s
o
l
u
t
i
o
n
M
a
t
r
i
x

i
n

s
o
f
t

g
e
l

c
a
p
s
u
l
e
s
M
a
t
r
i
x

f
o
r

H
M
E
P
l
a
s
t
i
c
i
z
e
r

f
o
r

H
M
E
M
a
t
r
i
x

f
o
r

s
p
r
a
y

d
r
y
i
n
g
M
M
M
M
M
M
M
M
M
M
M
M
C
C
C
C
MC S
S
S
S
S
S
S
S
S
S
S
S
P
P
P
L
L
++ ++
++
++
++ ++
++
++
++
++
++
++
++
++
++
++ ++
++
++
+ +
+ + +
+
+ +
+
+
+ +
+ +
+
+
+
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+
4
66
N
O
O
O
HO
O
O
HO
O
l

m

n
67
Dejan Djuric
5 Soluplus

5.1 Composition
Soluplus

is a polymeric solubilizer with

an amphiphilic chemical structure, which
was particularly developed for solid solu-
tions. Due to its bifunctional character, it
is able to act as a matrix polymer for solid
solutions on the one hand, while being
capable of solubilizing poorly soluble
drugs in aqueous media on the other.
Soluplus

is a polyvinyl caprolactam
polyvinyl acetate polyethylene glycol
graft copolymer (13 % PEG 6000 / 57 %
vinyl caprolactam / 30 % vinyl acetate). It
has a PEG 6000 backbone with one or
two side chains consisting of vinyl ace-
tate randomly copolymerized with vinyl
caprolactam (Fig. 5.1).
5.2 Properties
Soluplus

is available as free-owing
white to slightly yellowish granules with
a faint characteristic odor and practically
no taste. The spherically shaped gran-
ules (Fig. 5.2) have a mean particle size
of approximately 340 m (determined by
laser diffraction); this ensures proper feed-
ing of the extruder during processing.
The molecular weight of the polymer was
determined by means of gel permeation
chromatography (reference: polymethyl
methacrylate) and has an average value
of 118,000 g / mol (Fig. 5.3).
Figure 5.1 Chemical structure of
Soluplus

Figure 5.2 SEM picture of Soluplus

granules
200 m
5
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
100 1.000 10.000 100.000 1.000.000 10.000.000
Molecular weight [Da]
S
i
g
n
a
l

i
n
t
e
n
s
i
t
y
68
Figure 5.3 Molecular weight distribution of Soluplus

Since it was primarily developed for solid solutions, i. e. by means of hot-melt ex-
trusion, the glass transition temperature (T
g
) of the polymer was adjusted to approxi-
mately 70 C in order to enable extrudability at lower temperatures compared to
already known polymers. Moreover, the T
g
is still high enough to provide sufcient
rigidness for proper storage stability of the nal solid solution.
Having an amphiphilic structure, Soluplus

also has a detectable critical micelle con-

centration (CMC = 7.6 mg / L) which is much lower than can be found with classical
low-molecular weight surfactants.
5.3 Applications
Solubilization
Soluplus

can be used as a solubilizer in aqueous media for oral purposes. This

can be realized for example when using it as a binder or in a simple suspension
respectively. In order to conrm this, solubilization capacity was determined in duplicate
by means of saturation solubility. A 10 % solution (w / w) of solubilizer in buffer media
was oversaturated with active and stirred for 72 h at room temperature. The resulting
suspension was ltered through a 0.45 m lter. The amount of dissolved active was
detected by UV spectroscopy (Hewlett Packard 8452A). Saturation solubility was
expressed as a mean value in g / 100 mL as shown in Fig. 5.4.
69
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
E
s
t
r
a
d
i
o
l
P
i
r
o
x
i
c
a
m
C
l
o
t
r
i
m
a
z
o
l
e
C
a
r
b
a
m
a
z
e
p
i
n
e
G
r
i
s
e
o
f
u
l
v
i
n
K
e
t
o
c
o
n
a
z
o
l
e
C
i
n
n
a
r
i
z
i
n
e
F
e
n
o
f
i
b
r
a
t
e
I
t
r
a
c
o
n
a
z
o
l
e
D
a
n
a
z
o
l
S
a
t
u
r
a
t
i
o
n

s
o
l
u
b
i
l
i
t
y

[
g
/
1
0
0
m
L
]
Soluplus

Pure API
~
0
.
0
0
1
~
0
.
0
2
6
~
0
.
0
0
1
~
0
.
0
1
3
~
0
.
0
8
0
~
0
.
0
0
1
~
0
.
0
0
0
1
~
0
.
0
0
0
1
~
0
.
0
0
0
1
~
0
.
0
0
1
10% solubilizer solution, saturation solubility in phosphate buffer pH 7.0 detected after 72 h stirring
Figure 5.4 Solubilization capacity of Soluplus

for poorly soluble actives

The use of Soluplus

resulted in increased solubility for all tested actives. The 10 %

solubilizer solution enabled saturation solubilities ranging from 0.013 g / 100 mL for
itraconazole to 0.35 g / 100 mL for carbamazepine. The saturation solubilities that
were detected for the pure actives were all below 0.08 g / 100 mL. With the use of
Soluplus

, these values could be increased more than one hundredfold, e. g. in the

case of estradiol, danazol or fenobrate. A preference for solubilization of Soluplus

for discrete chemical structures could not be detected since a variety of different
actives were solubilized successfully.
Extrusion and bioavailability enhancement
For formulation scientists, it has always been a challenge to overcome the issue of
low bioavailability [55]. A popular technique for increasing the solubility and bioavail-
ability is the formation of solid solutions prepared by hot-melt extrusion [56]. The
effect of solubility enhancement can be shown by drug release studies; however, it
can be veried more successfully by conducting bioavailability tests. Itraconazole
as a poorly water-soluble drug was chosen to prove bioavailability enhancement
when forming solid solutions with Soluplus

. A solid solution was prepared by hot-

melt extrusion and administered to dogs. For comparison, in vitro drug release tests
were performed as well.
Extrudates with 15 % itraconazole and 85 % Soluplus

were prepared using a 16 mm

twin-screw extruder (Polylab, ThermoFisher, Germany) at 1 kg / h powder feed rate
and 200 rpm screw speed at 150 C.
5
0
20
40
60
80
100
120
0 30 60 90 120
t [min]
D
r
u
g

r
e
l
e
a
s
e

[
%
]
Soluplus

itraconazole
Crystalline itraconazole
0
20
40
60
80
100
120
0 30 60 90 120
t [min]
D
r
u
g

r
e
l
e
a
s
e

[
%
]
Soluplus

itraconazole
Soluplus

itraconazole 3 months
40C/75% rh
70
XRD analysis revealed that no crystalline substance could be detected within the
freshly extruded solid solution. In vitro dissolution testing of crystalline itraconazole led
to ~4 % drug release of the tested 100 mg, which approximately equals the saturation
solubility of the active in the applied 700 mL HCl (Fig. 5.6).
Figure 5.5 Drug release of itraconazole from extrudates with Soluplus

compared to
crystalline substance
Figure 5.6 Drug release of itraconazole from fresh extrudates and after storage at
40 C / 75 % for 3 months
0
50
100
150
200
250
300
350
400
450
0 5 10 15 20
t [h]
B
l
o
o
d

c
o
n
c
e
n
t
r
a
t
i
o
n

[
n
g
/
m
L
]
Soluplus

itraconazole
Crystalline itraconazole
71
In comparison, the solid solution of Soluplus

and itraconazole showed complete

drug release, itraconazole achieving oversaturation in the dissolution medium. After
storage for 3 months under accelerated conditions in closed glass bottles, drug
release was comparable and the extrudates were XRD-amorphous (Fig. 5.7).
The in vivo tests were performed on beagles (n = 5) over 21 days (3 administrations at
intervals of 7 days). 10 mg API / kg bodyweight and day were administered orally at
fasted state. Blood sampling was performed before the administration of drug sub-
stances and then at 0.5, 1, 2, 4, 6, 8 and 24 h after administration. For the dog formu-
lations, the extruded strands were milled with an analytical mill (A 10, IKA, Germany)
for 15 seconds and then sieved through a 500 m sieve. For comparison, crystalline
itraconazole was also administered. The results are shown in Fig. 5.8.
Figure 5.7 Blood concentration of itraconazole formulations in dogs (mean, n=5)
In contrast to the slight drug release in vitro, crystalline itraconazole was not absor-
bed by the dogs. The blood concentrations were below the detection limit. However,
administration of solid solutions with itraconazole resulted in high blood concentration
levels with a maximum blood concentration after 4 h.
Finally, with the use of Soluplus

, complete drug release of poorly soluble itraconazole

could be realized in vitro as well as bioavailability enhancement in vivo.
5
72
References
[55] P. Buch et al., IVIVC in oral absorption for fenobrate immediate release tablets
using a dissolution / permeation system, Journal of Pharmaceutical Sciences,
98 (2008), 2001 2009
[56] MM. Crowley et al., Pharmaceutical applications of hot-melt extrusion: Part 1.
Drug Development and Industrial Pharmacy, 33 (2007), 909 926
HO
n = 2022
O
O
O
n
O
O
73
Jochen Dressler
6 Kolliphor TPGS
6.1 Composition
Kolliphor TPGS (d--tocopheryl polyethylene glycol 1000 succinate) is a D-alpha
vitamin E ester derived from natural vitamin E. TPGS is manufactured by esterication
of natural d--tocopheryl succinate with polyethylene glycol 1000.
The resulting product is a mixture containing mainly monoester (Fig. 6.1), a certain
amount of diester and residual free PEG 1000. The empirical formula of TPGS is
C
33
O
5
H
54
(CH
2
CH
2
O)
2022
(molecular weight: ~ 1513 g / mol).
Figure 6.1 Chemical structure of Kolliphor TPGS
Table 6.1 Monograph listing, names and declaration
USP / NF Monograph Name Vitamin E polyethylene glycol succinate
INCI Name
Tocophersolan
CAS Number
9002-96-4
EINECS Number
Polymer
5
6
74
6.2 Properties
Kolliphor TPGS is a non-ionic surfactant with amphiphilic character: The tocopheryl
succinate moiety acts as the lipophilic part while the polyethylene glycol structure can
be seen as the hydrophilic part. Further properties are summarized in Table 6.2.
Table 6.2 Overview of the physical and chemical properties of TPGS [57]
Molecular weight approx. 1513 g / mol
Physical form
waxy solid
Specic gravity at 45 C
approx. 1.06
Melting Point
37 41 C
Appearance
white to light brown
Gardner color
max. 10
Vitamin E content
260 300 mg / g as d-alpha-tocopherol
Potency
387 447 I.U. / g
Solubility in water
miscible in all parts
HLB value
approx. 13
Stability
stable in air and in solutions between a pH range of
4.5 to 7.5
Critical micelle concentration (CMC)
approx. 0.02 wt%
(determination of surface tension at 37 C; [1])
Dynamic viscosity (5 % sol. in water)
approx. 1.5 mPa*s at 22 C [10]
Kolliphor TPGS can be dissolved in water and is preferably used in aqueous con-
centrations from 0.5 to 20 %. TPGS mainly improves the bioavailability of poorly soluble
drugs by enhancing drug solubility as well as by modulating P-glycoprotein-dependent
drug efux mechanisms [58, 59, 60]. Due to its amphiphilic character, TPGS exhibits
emulsifying properties and allows the formulation of O / W emulsions. TPGS has been
used as a water-soluble source of natural vitamin E with high bioavailability, especially
for patients suffering from vitamin E malabsorption. Although TPGS lacks the free hyd-
roxyl group of vitamin E, it can still be used successfully as an antioxidant. A summary
of the different elds of application is given in Table 6.3.
75
Table 6.3 Typical elds of application of Kolliphor TPGS:
Solubilizer for poorly soluble drugs
Bioavailability enhancer for BCS Class II, III, IV drugs
Stabilizer for amorphous drugs or nanocrystal suspensions
Drug permeability enhancer by inhibition of P-glycoprotein
Emulsion vehicle (SEDDS; SMEDDS)
Thermal binder for hot-melt granulation and hot-melt extrusion
Water-soluble source of vitamin E
Antioxidant
Reduction of tissue and skin sensitivity to certain drugs
Carrier for dermal applications
Prior to application, TPGS is melted, preferably by heating the whole container up to
60 C, and by gently mixing the molten mass to obtain a uniform melt which is then
dosed for further processing. Kolliphor TPGS can be molten and cooled in cycles
several times without affecting the quality. The product can be sterilized and is ther-
mally stable up to 200 C. Thermal decomposition is observed at 215 C during DSC
analysis. If TPGS is melted using a water bath heating assembly, it is recommended
to ensure that TPGS has no contact with water vapor for any length of time, even if
TPGS is not hygroscopic.
The viscosity of aqueous TPGS solutions rises with increasing concentration. Addi-
tionally, during the heating of highly concentrated TPGS solutions, further viscosity
increases can be observed above 70 C (Table 6.4). Temperature-dependent viscosity
increase is a reversible phenomenon which is observed for aqueous concentrations
above 10 %.
Table 6.4 Inuence of heat and concentration on solution viscosity (Brookeld)
Temperature [C] / Viscosity [mPa*s]
TPGS concentration wt % 20 60 70 80
10
< 10 mPa*s < 10 mPa*s < 10 mPa*s 50 mPa*s
20
< 10 mPa*s 10 mPa*s 530 mPa*s 5620 mPa*s
Kolliphor TPGS remains stable for several years under ambient storage conditions
in closed containers . Aqueous solutions of TPGS are stable at a pH range between
pH 4.5 and 7.5. Hydrolysis of the TPGS ester can occur under acidic conditions
below pH 1.8 and under alkaline conditions above pH 10.
6
76
Kolliphor TPGS is compatible with many commonly used pharmaceutical excipients;
some examples are given in Table 6.5.
Table 6.5 Examples of the compatibility of TPGS with common excipients:
TPGS is compatible with:
TPGS is incompatible with:
Calcium carbonate
Citric acid, sodium bicarbonate
Fumed silica
Lactose
Microcrystalline cellulose (MCC)
Polysorbate 20
Polysorbate 80
Cellulose derivatives (HPMC)
Sodium lauryl sulfate (at high concentrations)
Glycerin
Magnesium stearate
Polyethylene glycol, propylene glycol
Polysorbate 60
Polyvinylpyrrolidone
6.3 Applications
Kolliphor TPGS can be used to improve the solubility of poorly soluble drugs in tab-
lets or capsules [61]. For tableting or lling hard capsules, hot-melt granulation can be
performed using TPGS as a binder for granulation. Active ingredients can be admixed
to the binder in the molten state if they are not heat-sensitive. The following applica-
tion example is the formulation of vitamin E tablets (Table 6.6) that can be used as a
dietary supplement if normal vitamin E cannot be absorbed by patients with vitamin E
malabsorption [62].
Table 6.6 Examples of tablet formulation as a vitamin E supplement:
Substance name Function Amount [%]
Kolliphor TPGS Active pharmaceutical ingredient
API
15.68
Fujicalin SG Filler / binder 54.05
Ethanol 96 % Solvent 30.27
Total 100
77
Fujicalin (highly porous dibasic calcium phosphate, anhydrous; Fuji Chemical Industry
Co., Ltd) is granulated / wetted with a solution of Kolliphor TPGS in ethanol using
a high shear mixer that can be operated with organic solvents. Granulation is carried
out for 15 minutes at low speed to allow uniform incorporation of TPGS into the po-
rous particles. The powder is gently dried under reduced atmospheric pressure or
in a uidized bed dryer to remove residual ethanol while the product temperature is
maintained below 35 C. The granules are compressed into tablets of 1.2 g. Due to
the self-lubricating properties of TPGS, it might not be necessary to use additional
lubricant. In this example, one tablet contains about 100 I. U. of natural vitamin E.
To enhance the solubility of poorly soluble drugs, it is recommended to melt the drug
together with TPGS and eventually together with additional co-solvents such as
polyethylene glycol 400. The melt can be liquid-lled into hard capsules where it
solidies, added to water to form an emulsion that can be further used for nasal and
pulmonary applications [63] or spray dried together with additional excipients [64]
(e. g. mannitol, lactose, hypromellose) to obtain a solid dispersion or solid solution.
Instead of formulating a melt, TPGS and the active can also be dissolved in an appro-
priate organic solvent and if necessary a co-solvent (e. g. PEG 400 or propylene
glycol) can be added. In this context it is recommended to dissolve the active in TPGS
rst before further diluting in the aqueous phase since this order is relevant for proper
micelle formation and for good solubilization results.
Kolliphor TPGS has been widely investigated for the solubility enhancement of poorly
soluble drugs. Using the Solu-HTS screening system, different concentrations of
Kolliphor TPGS have been successfully tested as solubilizers for selected active
ingredients. The solubility of carbamazepine, which is used as an anticonvulsant, can
be markedly increased using TPGS (Fig. 6.2). This nding was also conrmed in dis-
solution studies [65].
6
118
< 5 < 5 < 5 < 5
0
500
1000
1500
2000
2500
3000
Carbamazepine Danazol Piroxicam Fenofibrate Cinnarizine
S
o
l
u
b
i
l
i
t
y

[
p
p
m
]
Buffer
1%
5%
10%
78
Figure 6.2 TPGS increases drug solubility in a concentration-dependent manner during
Solu-HTS screening experiments
References
[57] Wu, S. H.-W. and Hopkins, W. K., Characteristics of D--Tocopheryl PEG
1000 Succinate for Applications as an Absorption Enhancer in Drug Delivery
Systems, Pharmaceutical Technology (1999)
[58] Dintaman, J. M., Silverman, J. A., Inhibition of P-Glycoprotein by D--Tocopheryl Poly-
ethylene Glycol 1000 Succinate (TPGS), Pharm. Res. 16 (10), (1999), 1550 1556
[59] Yu, L. et al.,Vitamin E-TPGS Increases Absorption Flux of an HIV Protease Inhibitor by
Enhancing its Solubility and Permeability, Pharm. Res. 16 (12), (1999), 1812 1817
[60] Varma, V. S. M. and Panchagnula, R., Enhanced oral paclitaxel absorption with
vitamin E-TPGS: Effect on solubility and permeability in vitro, in situ and in vivo,
Eur. J. Pharm. Sci. 25 (2005), 445 453
[61] Strickley, R. G., Solubilizing Excipients in Oral and Injectable Formulations,
Phar, Res. 21 (2), (2004), 201 230
[62] Papas, K., Kalbeisch, J. and Mohon, R., Bioavailability of a Novel, water-So-
luble Vitamin E Formulation in Malabsorbing Patients, Dig. Dis. Sci. 52 (2006),
347 352, DOI: 10.1007 / s10620-006-9489-2
[63] Saidi, Z., Klyashchitsky, B., Patent EP1089715B1 (2001)
[64] Goddeeris, C., Willems, T., Van den Mooter, G., Formulation of fast disinteg-
rating tablets of ternary solid dispersions consisting of TPGS 1000 and HPMC
2910 or PVPVA 64 to improve the dissolution of the anti-HIVdrug UC 78, Eur.
J. Pharm. Sci. 34 (2008), 293 302
[65] Charkoftaki, G. et al., Supersaturated dissolution data and their interpretation: the
TPGScarbamazepine model case, J. Pharm. Pharmacol. 63 (2011), 352 361
H(O-CH
2
-CH
2
)
x
H(O-CH
2
-CH
2
)
y
O
O
O
O
OH
OH
O
A
B
O
79
Shaukat Ali
7 Kolliphor HS 15
7.1 Composition
Kolliphor HS 15 is a non-ionic solubilizer and emulsifying agent. It is comprised of
15 moles of ethylene oxide and 1 mole of 12-hydroxy stearic acid. The ethoxylation
reaction can take place on the carboxylic group or the hydroxyl group of the fatty
acid, or on both functional groups. Thus, Kolliphor HS 15 is a mixture of polyglycol
mono- and di-esters of 12-hydroxystearic acid derivatives (Fig. 7.1, A and B), and
about 30 % of free polyethylene glycol.
Figure 7.1 Chemical structures of the main components in Kolliphor HS 15
The synthesis of Kolliphor HS 15 is shown in Fig. 7.2: Reaction of hydrogenated
fatty acid (I) with ethylene oxide (II) in the presence of an alkaline catalyst yields the
polyethoxylated major components III and V. Other minor components such as free
polyethylene glycol (VII) and (IV and VI) are also formed. The 12-C atoms of the
fatty acid chains in Kolliphor HS 15 are non-chiral and the product is a racemic
mixture. The stereo conguration of C-12 atoms does not affect the functionality of
Kolliphor HS 15 as a solubilizer.
6
7
H
3
C(CH
2
)
5
(CH
2
)
10
CH COOH
OH
KOH
(II)
(I)
(VII)
(III) (IV)
H
2
C
CH
3
COOH
H
2
O
CH
2
O
H
3
C(CH
2
)
5
R
1
= H, (CH
2
CH
2
-O)
y
H, CO CH
O
R
2
(CH
2
)
10
(CH
2
)
5
CH
3
(CH
2
)
10
CH O
O
(CH
2
CH
2
O)
X
H + HO(CH
2
CH
2
-O)
Z
H
O
R
1
(V) (VI)
R
2
= H, (CH
2
CH
2
-O)
y
H
80
Figure 7.2 Reaction scheme for the synthesis of Kolliphor HS 15
(for explanations please see text).
No metallic catalysts are used in the manufacture of Kolliphor HS 15 and the
manufacturing process does not require any purication steps except for the re-
moval of water and volatile components under reduced pressure and at elevated
temperatures.
Kolliphor HS 15 is also known by the chemical names, polyethylene glycol 15-hy-
droxy stearate and polyoxyl 15-hydroxystearate. The compendial names are: Mac-
rogol 15 Hydroxystearate (Ph. Eur.) and Polyoxyl 15 Hydroxystearate (USP).
81
7.2 Properties
An overview of the different properties of Kolliphor HS 15 is given in Table 7.1; a
summary of the complete specications is available upon request.
Property Observation
Appearance Yellowish white paste, waxy
Melting point ~ 30 C
Solubility Freely soluble in water, ethanol, 2-propanol;
insoluble in liquid parafn
Viscosity (30 % solution) 20 mPas (20 C)
pH 6 7
Hydrophilic lipophilic balance (HLB) [1,3] 14 16
Critical micelle concentration (CMC)
[66, 67]
0.005 % 0.02 %
Table 7.1 Properties of Kolliphor HS 15
The micelle sizes of pure Kolliphor HS 15 and with 0.1 % solubilizate in water are
shown in Fig. 7.3 as a function of temperature. Photon correlation data suggests that
the micelle size of 1 % Kolliphor HS 15 is about 10 nm, increasing to about 20 nm
when 0.1 % solubilizate is incorporated. As the temperature increases to > 50 C, the
micelle size also increases with and without solubilizate (Fig. 7.3).
7
Pure surfactant 1 %
Solubilizate 0.1 %
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80
Temperature [C]
M
i
c
e
l
l
e

d
i
a
m
e
t
e
r

[
n
m
]
82
Figure 7.3 Micelle size as a function of temperature
Stability testing indicates that Kolliphor HS 15 is stable for at least 24 months if stored
in the unopened original containers at room temperature (max. 25 C). Additionally,
Kolliphor HS 15 is stable over the ICH conditions for steam sterilization at 121 C and
20 min. Tables 7.2 and 7.3 show the products stability in pure and in solution before
and after sterilization. The data indicates that Kolliphor HS 15 is stable under those
conditions as no obvious changes are observed following steam sterilization. The pH
may drop slightly during heating and this should be taken into account. Separation
into phases may also occur, but this can be reversed by agitation. Aqueous solutions
can be stabilized with the usual preservatives used in pharmaceuticals
Parameter Untreated Sterilization 121 C; 20 Min.
Acid value (mg / g KOH) 0.2 0.2
Saponication value (mg / g KOH) 60 60
Hydroxyl value (mg / g KOH) 99 99
Table 7.2 Stability of Kolliphor HS 15 as a raw material on autoclaving
83
Parameter Untreated Sterilization 121 C; 20 Min.
Acid value (mg / g KOH) 0.1 0.2
Saponication value (mg / g KOH) 13 13.2
pH value 6.0 5.5
Micelle diameter (nm) 13 13
Table 7.3 Stability of 20 % Kolliphor HS 15 solution on autoclaving
The safety of Kolliphor HS 15 was evaluated in beagles (n = 8) with reference to
known solubilizers at a single dose level of 100 mg / kg. Table 7.4 shows the histamine
release effects. Kolliphor HS 15 showed signicantly less or no histamine release
compared to Kolliphor EL and Polysorbate 80. No incidence of histamine reaction
was observed with Kolliphor HS 15, but Kolliphor EL and Polysorbate 80 showed
reactions in all the dogs.
Table 7.4 Effects of solubilizers on histamine release in dogs.
Solubilizer
Serum Histamine Level
Histamine level
(ng / mL)
Incidence of histamine
reaction
Polysorbate 80
400 8 / 8
Kolliphor EL
115 8 / 8
Kolliphor HS 15
< 10 0 / 8
7.3 Applications
A number of fat-soluble vitamins can be solubilized in Kolliphor HS 15 aqueous
solutions for parenteral preparations; these include vitamins A, D, E and K, and sev-
eral other lipophilic pharmaceutical active agents, such as propanidid, miconazole,
alfadolone, alfaxalone, nifedipine and piroxicam amongst others.
A simple formulation of a fat-soluble vitamin is illustrated in Table 7.5, where Kolliphor
HS 15 is used for the preparation of an aqueous solution of vitamin A. The prepa-
ration requires the slow addition and mixing of vitamin A palmitate in Kolliphor HS
15 at 60 65 C. The mixture is then added slowly to water already heated to 60 C.
The solution turns cloudy, and thickening may occur initially due to hydration but the
solution turns clear as viscosity decreases with further dilution with water.
7
40
30
20
10
0
0 50000 100000 150000 200000
Vitamin A [I. U. /mL]
K
o
l
l
i
p
h
o
r

H
S

1
5

[
%
]
84
Table 7.5 Aqueous formulation of vitamin A palmitate
Material Amount
Vitamin A palmitate 1.7 million I. U. / g 8.3 g
Kolliphor HS 15 25.0 g
Water, dist. ad 100.0 mL
The solubilization capacity of such a formulation is presented in Fig. 7.4. Here it is
obvious that the above mentioned formulation can solubilize about 100,000 inter-
national units (I. U.) of vitamin A per mL solution.
Figure 7.4 Solubilization of vitamin A palmitate 1.7 million I. U. / g
0
500
1000
1500
2000
C
l
o
t
r
i
m
a
z
o
l
e
C
a
r
b
a
m
a
z
e
p
i
n
e
K
e
t
o
c
o
n
a
z
o
l
e
D
a
n
a
z
o
l
P
i
r
o
x
i
c
a
m
F
e
n
o
f
i
b
r
a
t
e
C
i
n
n
a
r
i
z
i
n
e
S
o
l
u
b
i
l
i
t
y

[
p
p
m
]
Buffer
1%
5%
10%
85
Figure 7.5 illustrates the results of the robotic high-throughput screening (HTS) of
poorly soluble drugs in buffer of pH 7.0 and solutions containing Kolliphor HS 15
at 1 %, 5 % and 10 % (w / v). Increasing the amounts of Kolliphor HS 15 from 1 % to
10 % increased the solubilization of all the drugs investigated. Thus, Kolliphor HS 15
successfully increased the solubility for a very broad range of different poorly soluble
active pharmaceutical ingredients (APIs).
Figure 7.5 HTS solubilization screening of poorly soluble drugs in Kolliphor HS 15 solutions
The bioavailability of vitamin A was evaluated in broilers following intramuscular
(IM) administration. The drug was dosed in Kolliphor HS 15 emulsions, organic
solution and oily solution. Figure 7.6 shows the data from in vivo studies. The bio-
distribution of drug in the liver was monitored by analyzing vitamin A acetate after
7 days of dosing. Kolliphor HS 15 emulsions improved liver uptake > 1.5-fold as
compared to other vehicles.
7
V
i
t
a
m
i
n

A
,

f
o
u
n
d

i
n

t
h
e

l
i
v
e
r

[
%
]
70
60
50
40
30
20
10
0
Aqueous Emulsion
(with Kolliphor HS 15)
Organic solution Oily solution
Comparison: Vitamin A in injectables
(Intramuscular application in broilers)
Measurement after 7 days
86
Figure 7.6 Liver uptake of vitamin A after intramuscular (IM) administration
Another method for delivering poorly soluble drugs with the help of Kolliphor HS 15
is the preparation of self-emulsifying and nano-emulsifying drug delivery systems
(SEDDS and SNEDDS) with co-surfactants and / or co-solvents as has been reported
in many studies [68 72]. Additionally, Kolliphor HS 15 has also demonstrated its
ability to be used as a self-emulsier in pellets [73 75].
Kolliphor HS 15 remains one of the most commonly used solubilizers in the phar-
maceutical industry as the preferred choice for in vitro screening and in vivo evalua-
tion of new chemical entities (NCEs). Progress has been made in recent years and
many of the products are commercially available. Especially in parenteral formu-
lations, Kolliphor HS 15 is used to increase the solubility of poorly soluble drugs
such as propofol and colchicine among others [76 78].
87
References
[66] Solutol

HS15: Technical brochure (2010)

[67] Gonzalez et al., In vitro investigation on the impact of Solutol HS 15 on the
uptake of colchicine into rat hepatocytes, Int. J. Pharm., 279 (2004), 27 31
[68] Garcion et al., A new generation of anticancer, drug-loaded, colloidal vectors
reverses multidrug resistance in glioma and reduces tumor progression in rats,
Mol. Cancer Ther., 5 (2006), 1710 1721
[69] Zhao et al., Synthesis of ibuprofen eugenol ester and its microemulsion formu-
lation for parenteral delivery, Chem. Pharm. Bull., 53 (2005), 1246 1250
[70] Gonzalez et al., Improved oral bioavailability of cyclosporin A in male Wistar
rats comparison of a Solutol

HS 15 containing self-dispersing formulation

and a microsuspension, Int. J. Pharm., 245 (2002), 143 151
[71] Buszello et al., The inuence of alkali fatty acids on the properties and the
stability of parenteral O / W emulsions modied with Solutol HS 15

, Eur. J.
Pharm. Biopharm., 49 (2000), 143 149
[72] Ku and Velagaleti, Solutol HS 15 as a novel excipient: Identication of the need for
an implementation of a US regulatory strategy, Pharm. Tech., 34 (2010), 1 4.
[73] Abdalla et al., A new self-emulsifying drug delivery system (SEDDS) for poorly
soluble drugs: Characterization, dissolution, in vitro digestion and incorporati-
on into solid pellets, Eur. J. Pharm. Sci., 35 (2008), 457 464;
[74] Abdalla and Mader, Preparation and characterization of a self-emulsifying
pellet formulation, Eur. J. Pharm. Biopharm., 66 (2007), 220 226
[75] Abdalla and Mader, ESR studies on the inuence of physiological dissolution
and digestion media on the lipid phase characteristics of SEDDS and SEDDS
pellets, Int. J. Pharm., 367 (2009), 29 36.
[76] Ryoo et al., Development of propofol-loaded microemulsion systems for
parenteral delivery, Arch. Pharm. Res., 28 (2005), 1400 1404
[77] Li et al., Preparation and evaluation of novel mixed micelles as nanocarriers for
intravenous delivery of propofol, Nanoscale Res. Lett., 6 (2011), 275 284
[78] Bittner et al., Impact of Solutol HS 15 on the pharmacokinetic behaviour of
colchicine upon intravenous administration to male Wistar rats, Biopharm.
Drug Dispos., 24 (2003), 173 181
7
88
H
2
C O CH
2
CH
2 l
CH
2
CH
OR
(CH
2
)
7
(CH
2
)
5
CH
2
CH
2
CH
3
O C
O
H
2
C O CH
2
CH
2 n
CH
2
CH
OR
(CH
2
)
7
(CH
2
)
5
CH
2
CH
2
CH
3
O C
O
HC O CH
2
CH
2 m
CH
2
CH
OR
(CH
2
)
7
(CH
2
)
5
CH
2
CH
2
CH
3
O C
O
89
Shaukat Ali
8 Kolliphor RH 40
8.1 Composition
Kolliphor RH 40 is a non-ionic solubilizer and emulsifying agent obtained by reac-
ting 1 mole of hydrogenated castor oil with about 40 45 moles of ethylene oxide. It
contains mainly the tri-hydroxystearate ester of ethoxylated glycerol (Figure 8.1), with
smaller amounts of polyethylene glycol tri-hydroxystearate and the corresponding free
glycols. The main component is therefore an amphiphilic molecule, with fatty acid
esters forming the lipophilic part and glycerol polyethylene glycol ethers acting as the
hydrophilic part. The molecular weight of the main component is around 2,900 g / mol.
Figure 8.1 Chemical structure of the main component in Kolliphor RH 40
where, l + m + n = 40-45; R = H of polyethylene glycol residue
The 12-C atoms of the fatty acid chains are achiral (racemic), which avoids potential
isomerization of the hydroxyl group on the fatty acid chain. Changes in the ratios of
enantiomers are not expected to affect the functionality of Kolliphor RH 40.
Kolliphor RH 40 (RH, hydrogenated ricinoleic acid) is also known by the chemical
name, PEG 40 Hydrogenated Castor Oil, and the compendial names, MacrogoI
Glycerol Hydroxystearate (Ph. Eur.), and Polyoxyl 40 Hydrogenated Castor Oil (USP).
8
90
Property Observation
Appearance White yellowish paste, odorless
Melting point ~ 25 C
Solubility Water, ethanol, propanol, 2-propanol, ethyl acetate,
chloroform, carbon tetrachloride, toluene and xylene
Viscosity (30 % solution) 20 mPas (20 C)
pH (10 % water) 6 7
Relative density 1.023 1.026 g / mL (25 C, 30 % water).
Hydrophilic lipophilic balance (HLB) 14 16
Critical micelle concentration (CMC) 0.02 %
Table 8.1 Properties of Kolliphor RH 40
Pure Kolliphor RH 40 is chemically very stable. Prolonged exposure to elevated tem-
peratures can cause physical separation into a liquid and a solid phase on cooling but the
product can be restored to its original form by homogenization. Kolliphor RH 40 is stable
in aqueous alcohol and purely aqueous solutions. However, it must be noted that strong
bases or acids should not be added to avoid saponication of the ester components.
Aqueous Kolliphor RH 40 solutions can be sterilized by heating to 120 C. Con-
sideration must be given to the fact that this can cause a slight decrease in the pH
value. The phases may also separate during sterilization, but this can be remedied
by agitating the solution while it is still hot. The preservatives normally used in the
pharmaceutical industry may be added to the aqueous solutions.
8.3 Applications
Aqueous solutions of fat-soluble vitamins A, D, E and K for oral and topical admin-
istration can be prepared with Kolliphor RH 40. For a clear aqueous solution, the
fat-soluble vitamins must be thoroughly mixed with the solubilizer. For vitamin A pre-
parations with Kolliphor RH 40, vitamin A palmitate 1.7 million I. U. / g, or vitamin A
propionate 2.5 million I. U. / g should be used, while for vitamin K, vitamin K 1 phyto-
menedione should be preferred.
8.2 Properties
Kolliphor RH 40 is a waxy material, with almost no taste and which melts at
20 25 C; thus, the question of polymorphism does not arise. Further properties
are listed in Table 8.1.
40
30
20
10
0
0 50000 100000 150000 200000
Vitamin A [I. U. /mL]
K
o
l
l
i
p
h
o
r

R
H

4
0

[
%
]
91
Figure 8.2 Solubilization of vitamin A palmitate 1.7 million I. U. / g
The method for preparing the solubilizate is very important. The production of a
150,000 I. U. / mL aqueous vitamin A palmitate solution is described in detail below as
a typical example:
Vitamin A palmitate 8.8 g
(1.7 million I. U. / g)
Kolliphor RH 40 25.0 g
Water ad. 100.0 mL
The vitamin is mixed with Kolliphor RH 40 and heated to 60 65 C. The liquid
is then added slowly to water heated to 60 C and mixed. As mixing continues, the
solution viscosity increases as the solution turns opalescent and then decreases
as it clears up. Fig. 8.2 illustrates the solubilization capacity of Kolliphor RH 40
in highly concentrated aqueous solutions of vitamin A palmitate. Kolliphor HS 15
also behaves very similarly to Kolliphor RH 40 for the solubilization of vitamin A
palmitate (see chapter 7).
8
Vitamin D2
Vitamin D3
Vitamin D [I. U. /mL]
10
8
6
4
2
0
300000 200000 100000 0
K
o
l
l
i
p
h
o
r

R
H

4
0

[
%
]
92
Figure 8.3 Solubilization capacity of Kolliphor RH 40 for Vitamins D 2 and D 3
Fig. 8.4 shows the results of high-throughput solubilization screening of a number
of poorly soluble drugs in buffer and in solutions with Kolliphor RH 40 at 1 %, 5 %
and 10 %. It is obvious that the solubilization of drugs increased with increasing
amounts of Kolliphor RH 40 in the solutions. A similar trend is also observed with
Kolliphor HS 15.
Fig. 8.3 illustrates the solubilization capacity of Kolliphor RH 40 for different types
of D vitamins. Relatively low concentrations of Kolliphor RH 40 (about 5 %) can si-
gnicantly increase the solubility of vitamin D 2 and D 3. At a concentration of 5 % of
Kolliphor RH 40 in solution, vitamin D 2 and D 3 were solubilized at 300,000 I. U.
and 180,000 I. U. respectively.
0
500
1000
1500
2000
2500
3000
C
l
o
t
r
i
m
a
z
o
l
e
C
a
r
b
a
m
a
z
e
p
i
n
e
K
e
t
o
c
o
n
a
z
o
l
e
D
a
n
a
z
o
l
P
i
r
o
x
i
c
a
m
F
e
n
o
f
i
b
r
a
t
e
C
i
n
n
a
r
i
z
i
n
e
S
o
l
u
b
i
l
i
t
y

[
p
p
m
]
Buffer
1%
5%
10%
93
Figure 8.4 Solubilization of drugs in buffer and Kolliphor RH 40 solutions
Kolliphor RH 40 is widely used as a solubilizer in combination with a co-solubili-
zer and / or co-solvent in self-emulsifying drug delivery systems (SEDDS) or micro-
emulsifying systems (SMEDDS) [79 83]. A recent study by Cuine et al. suggests
that Kolliphor RH 40 is stable in the solution and less subjected to lipolysis in the
gastrointestinal tract compared to many ester-linked short and long unsaturated fatty
acids [84]. An example is Neoral

, a soft gelatine capsule formulation of cyclosporine,

which contains Kolliphor RH 40 in combination with ethanol, propylene glycol and
glycerol (see also chapter 1).
Kolliphor RH 40 is used in concentrations of about 2 % as a taste masking agent
for caffeine [85]. Though the mechanism of the taste masking effect of Kolliphor
RH 40 remains to be investigated, the author suggests that it is the coating of taste
bud receptors in the mouth that mimics the taste of bitter drugs. In combination with
the aforementioned features, stability with regard to digestion and its self- emulsifying
properties, Kolliphor RH 40 is especially suitable for oral applications. However,
many alternative elds of application exist: Kolliphor RH 40 is also useful for examp-
le in melt extrusion, where it can act as a plasticizer for different polymers [86].
8
94
References
[79] Mullertz et al., New perspectives on lipid and surfactants based drug delivery
systems for oral delivery of poorly soluble drugs, J. Pharm. Pharmacol., 62
(2010), 1622 1636.
[80] Rhee et al., Transdermal delivery of ketoprofen using microemulsions, Int. J.
Pharm., 228 (2001), 161 170.
[81] Seir et al., Bioavailability of probucol from lipid and surfactant based formu-
lations in minipigs: Inuence of droplet size and dietary state, Eur. J. Pharm.
Biopharm., 69 (2008), 553 562.
[82] Fatouros, et al., Structural development of self nano emulsifying drug delive-
ry systems (SNEDDS) during in vitro lipid digestion monitored by small-angle
X-ray scattering, Pharm. Res., 24 (2007), 1844 1853.
[83] Zhang et al., Preparation of nimodipine-loaded microemulsion for intranasal
delivery and evaluation on the targeting efciency to the brain, Int. J. Pharm.,
275 (2004), 85 96.
[84] Cuine et al., Evaluation of the impact of surfactant digestion on the bioavaila-
bility of danazol after oral administration of lipidic self-emulsifying formulations
to dogs, J. Pharm. Sci., 97 (2008), 995 1012.
[85] R. Stier, Masking bitter taste of pharmaceutical actives, Drug Deliv. Tech., 4(2),
(2004), 54 57.
[86] K. Kolter et al., Hot-melt extrusion with BASF pharma polymers, Extrusion
Compendium (2010).
H
2
C O CH
2
CH
2 l
CH CH
OR
(CH
2
)
7
(CH
2
)
5
CH CH
2
CH
3
O C
O
H
2
C O CH
2
CH
2 n
CH CH
OR
(CH
2
)
7
(CH
2
)
5
CH CH
2
CH
3
O C
O
HC O CH
2
CH
2 m
CH CH
OR
(CH
2
)
7
(CH
2
)
5
CH CH
2
CH
3
O C
O
R
1
O CH
2
CH
2 x
CH CH
O-R
2
(CH
2
)
7
(CH
2
)
5
CH CH
2
CH
3
O C
O
95
Shaukat Ali
9 Kolliphor EL / ELP
9.1 Composition
Kolliphor EL (or ELP) is synthesized by reacting castor oil (glycerol triricinoleate) with
ethylene oxide. The main components of Kolliphor EL are: (A) triricinoleate esters of
ethoxylated glycerol, (B) polyethylene glycol ricinoleates and derivatives of these with
polyethoxylated 12-hydroxy ricinoleic acid residues. Thus, Kolliphor EL is a non-
uniform product lacking a single well-dened formula or structure.
(A) l + m + n = 35 (nominal value); R = H or polyethylene glycol residue
(B) x = 040; R
1
= H or ricinoleate, R
2
= H or polyethylene glycol /
polyethylene glycol ricinoelate
The relative molar masses (Mr) of the entities A (C
127
H
244
O
44
with l + m + n = 35
and R = H) and B (C
58
H
114
O
23
with for x = 20 and R
1
= R
2
= H) are approximately
2,500 g / mol and 1,200 g / mol, respectively.
The conguration of the double bond at C-9 is cis, as is the case in the starting
material, castor oil. The C-12 atoms of the fatty acid chains are achiral or racemic,
which means that both (R) and (S) enantiomers are present in equal proportions.
Kolliphor EL is known by its chemical name polyoxyl castor oil and PEG 35 castor
oil. The compendial names of Kolliphor EL / ELP (emulsifying liquid, puried) are
Macrogolglycerol Ricinoleate (Ph. Eur.), Polyoxyl 35 Castor Oil (USP), and Polyoxyl
Castor Oil.
8
9
96
9.2 Properties
Kolliphor EL is an oily liquid whereas Kolliphor ELP is a waxy paste; thus, the
question of polymorphism does not arise. The Kolliphor RH 40 grade provides
better taste masking than Kolliphor EL / P, presumably due to the creamy mouth
feel. Further properties of Kolliphor EL and Kolliphor ELP are summarized in
Table 9.1.
Property Observation
Appearance Kolliphor EL
Kolliphor ELP
Clear, yellow viscous liquid
White-yellowish paste
Solubility Freely soluble in water, dichloromethane, ethanol
Melting point Kolliphor ELP 26 C
pH 6 8 (10 % water)
Relative density 1.05 1.06 g / mL (25 C)
HLB 12 14
CMC* 0.02 %
Viscosity Kolliphor EL 700 800 mPa.s (25 C)
Kolliphor ELP 600 750 mPa.s (25 C)
Table 9.1 Properties of Kolliphor EL and Kolliphor ELP
* Determined by surface tension measurement (Herting, unpublished work)
Fig. 9.1 illustrates the viscosity of 5 35 % Kolliphor EL solutions as a function of
temperature. As can be seen, the viscosity of Kolliphor EL solution increased with
increasing amounts of solubilizer. With 5 % Kolliphor EL, the viscosity was about
5 mPa.s and was unchanged at temperatures between 5 C 80 C. On increasing
the amount of Kolliphor EL to 10 35%, the viscosity decreased as the temperature
increased but it showed an increase as the temperature increased to 50 C or higher,
depending upon the amounts of Kolliphor EL in the solutions.
1000
100
10
1
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
Temperature [C]
D
y
n
a
m
i
c

v
i
s
c
o
s
i
t
y

[
m
P
a
s
]
35% Kolliphor EL
30% Kolliphor EL
25% Kolliphor EL
20% Kolliphor EL
10% Kolliphor EL
5% Kolliphor EL
97
Figure 9.1 Viscosity of Kolliphor EL solutions as a function of temperature
Some of the key specications of Kolliphor EL and Kolliphor ELP are shown in
Table 9.2. The ELP grade has a controlled, low content of potassium and free fatty
acids, while these parameters are not specied for the EL grade.
Parameter Kolliphor EL Kolliphor ELP
Water
<
2.8 %
<
0.5 %
Potassium n. d.
<
15 ppm
Ricinoleic acid n. d.
<
0.2 %
Oleic acid n. d.
<
0.1 %
Palmitic acid n. d.
<
0.1 %
Free fatty acids C
12
-C
18
n. d.
<
1.0 %
Table 9.2 Main differences between the two grades
n. d. not determined
9
40
30
20
10
0
0 50000 100000 150000 200000
Vitamin A [I. U. /mL]
K
o
l
l
i
p
h
o
r

E
L

[
%
]
98
Stability studies showed that Kolliphor EL and ELP are stable for at least 48 months
under standard conditions (25 C / 60 % RH), and 6 months under accelerated con-
ditions (40 C / 75 % RH). Therefore, Kolliphor EL / ELP should be stored in tight
containers at < 25 C or room temperature, and should be protected from light.
9.3 Applications
Kolliphor ELP is recommended primarily for parenterals but is also suitable for oral
and other dosage formulations. Its preferential use in parenteral formulations is due
to its controlled free acid and potassium content and lower moisture level, which can
prevent hydrolysis of the drug.
Kolliphor EL or ELP emulsies the fat-soluble vitamins A, D, E and K in aqueous so-
lution for oral and topical administration. In aqueous alcoholic solutions, it very readily
solubilizes essential oils. Aqueous solutions of hydrophobic drugs (e. g. Miconazole,
Hexedetine, Clotrimazole, Benzocaine) can also be prepared with Kolliphor EL.
Fig. 9.2 illustrates the solubilization of vitamin A palmitate. As shown, the solubilization
characteristics of Kolliphor EL are in many ways identical to Kolliphor RH 40 or
Kolliphor HS 15 for vitamin A palmitate.
Figure 9.2 Solubilization of vitamin A palmitate with Kolliphor EL
99
Typical compositions of multivitamin formulations are shown in Table 9.3. The com-
bination of the fat-soluble vitamins A, D 3 and E is formulated with the use of Kolli-
phor EL as solubilizing agent and glycerol as co-solvent. These aqueous solutions
can deliver about 12 mill. I. U. / mL of vitamin A and about 6 mill. I. U. / mL of vitamin
D 3, respectively.
Component Amount (g)
Vitamin A palmitate (1,700,000 I. U. / g) 7.10 4.80
Vitamin A propionate (2,600,000 I. U. / g) 4.80
Vitamin D 3 (40,000,000 I. U. / g) 0.15 0.15
Vitamin E acetate 4.20 4.20
BHT 0.06 0.06
Kolliphor EL 30.0 30.0
Glycerol 6.50 6.50
Preservative As necessary As necessary
Water ad 100 mL ad 100 mL
Table 9.3 Typical formulations of vitamins
Fig. 9.3 illustrates the solubilization capacity of Kolliphor EL and Polysorbate 80
for vitamin E acetate. In smaller solubilizer concentrations (up to 15 %), the solubili-
zation capacity for vitamin E seems to be more efcient for Polysorbate 80. However,
gure 9.3 also indicates that the solubilization efcacy of Polysorbate 80 is limited in
the case of vitamin E. For higher solubilizer concentrations (> 20 %), the solubilization
capacity is much better for Kolliphor EL: for example, 30 % aqueous solution of
Polysorbate 80 dissolved about 100 mg / mL, whereas, 30 % Kolliphor EL dissolved
about 150 mg / mL (+ 50 %) vitamin E acetate.
9
S
o
l
u
b
i
l
i
z
e
r

[
%
]
30
20
10
0
30 50 100 150
Vitamin E acetate [mg/mL]
Polysorbate 80
Kolliphor EL
0
500
1000
1500
2000
2500
3000
3500
C
l
o
t
r
i
m
a
z
o
l
e
*
C
a
r
b
a
m
a
z
e
p
i
n
e
K
e
t
o
c
o
n
a
z
o
l
e
*
D
a
n
a
z
o
l
P
i
r
o
x
i
c
a
m
F
e
n
o
f
i
b
r
a
t
e
C
i
n
n
a
r
i
z
i
n
e
S
o
l
u
b
i
l
i
t
y

[
p
p
m
]
Buffer
1%
5%
10%
100
Figure 9.3 Solubilization of Vitamin E acetate in Kolliphor EL and Polysorbate 80
The enhanced solubilization capacity of Kolliphor EL is presumably due to its ri-
cinoleic fatty acid content; this allows the formation of relatively larger micelles than
oleic fatty acids in Polysorbate 80.
The in vitro high-throughput screening of a number of poorly soluble drugs was
investigated in Kolliphor EL solutions at 1 %, 5 % and 10 %, as shown in Fig. 9.4.
Increasing amounts of Kolliphor EL led to an increase in the solubilization of all
the drugs investigated. A similar trend was also observed with Kolliphor RH 40
and Kolliphor HS 15.
Figure 9.4 In vitro solubilization of model drugs (* evaluation not possible)
101
Numerous studies are cited in the literature about the application of Kolliphor EL
in the formation of self-emulsication systems, SEDDS and SNEDDS, with co-sur-
factants and / or co-solvents [87 91]. For example, Cremophor EL has been used
as a self-emulsifying system in Kaletra

soft gel capsules with oleic acid as a co-

solvent. The effects of Kolliphor EL and other non-ionic solubilizers on the inhibition
of transport membrane protein, or P glycoprotein (P
gp
) have been studied extensively
[92 94], but the actual mechanism of P
gp
inhibition by Kolliphor EL is not clear.
Kolliphor EL has been approved for use in several oral, parenteral, and ophthalmic
drug products.
References
[87] Bali et al., Nanocarrier for the enhanced bioavailability of a cardiovascular
agent: In vitro, pharmacodynamic, pharmacokinetic and stability assessment,
Int. J. Pharm., 403 (2011), 46 56.
[88] Sadurni et al., Studies on the formation of O / W nano-emulsions, by low-ener-
gy emulsication methods, suitable for pharmaceutical applications, Eur. J.
Pharm. Sci., 26 (2005), 438 445.
[89] Chen et al., Self-microemulsifying drug delivery system (SMEDDS) of vinpoce-
tine: Formulation development and in vivo assessment, Biol. Pharm. Bull., 31
(2008), 118 125.
[90] Cuine et al., Evaluation of the impact of surfactant digestion on the bioavail-
ability of danazol after oral administration of lipidic self-emulsifying formulations
to dogs, J. Pharm. Sci., 97 (2008), 995 1012.
[91] Gao et al., Development of a supersaturable SEDDS (S-SEDDS) formulation
of paclitaxel with improved oral bioavailability, J. Pharm. Sci., 92 (2003),
2386 2398.
[92] Seelig and Gerebtzoff, Enhancement of drug absorption by noncharged
detergents through membrane and P-glycoprotein binding, Expert Opin.
Drug Metab. Toxicol., 2 (2006), 733 752.
[93] Wang et al., Determination of P-glycoprotein inhibition by excipients and their
combinations using an integrated high-throughput process, J. Pharm. Sci., 93
(2004), 2755 2767.
[94] Constantinides and Wasan, Lipid formulation strategies for enhancing in-
testinal transport and absorption of P-glycoprotein (P
gp
) substrate drugs: In
vitro / In vivo case studies, J. Pharm. Sci., 96 (2007), 235 248.
9
102
HO
HO
HO
OH
OH
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
O
O
O
O
n n
O
x
KOH
3 2 1
I
II
n
HO
OH
OH
CH
3
CH
3
CH
3
o o m
O
O
O
O
O
KOH
y
4 5
+
+
103
Thomas Reintjes
10 Kolliphor P grades (Poloxamers)
10.1 Composition
Poloxamers are ABA-type copolymers of poly (ethylene oxide) (PEO = A) and poly (pro-
pylene oxide) (PPO = B). The synthesis of poloxamers was rst described in the 1950s
[95] and since then they have become widely known as Pluronics. The pharmaceu-
tical grade poloxamers that are manufactured by BASF are commercially available
for all compendial poloxamers and are distributed as Kolliphor P and Kollisolv P
grades (formerly Lutrol

L and F grades).
In general, the synthesis of poloxamers comprises two steps: In a rst step (Fig. 10.1 I),
propylene oxide (2) is reacted with a suitable starting material such as propylene
glycol (1) to form PPO (3). In a second step (II), PPO reacts with ethylene oxide (4)
to form the PEO-PPO-PEO block-copolymer poloxamer (5). Both of these steps are
usually base-catalyzed with potassium hydroxide; this then requires neutralization of
the product after synthesis.
Figure 10.1 Two-step synthesis schematic for poloxamers (for explanations see text).
where x = 2n + 2
where y = 20 + 1 and m = n + 1
For all compendial poloxamers (USP / NF), the number of unsaturations is specied
and lies typically within the range 0.02 0.05 meq / g (usually increasing with in-
creasing length of the PPO chain). These unsaturations result from a side reaction
that occurs during the synthesis of the PPO [96, 97] (Fig. 10.2): During reaction (I),
an alkoxylate anion (1) is formed. In an intra-molecular reaction (II), the negative
charge is transferred, resulting in the formation of a terminally unsaturated PPO
(2). This terminal unsaturation persists during the subsequent reaction with ethy-
lene oxide (III) and leads to the formation of a PEO-PPO-diblock copolymer.
10
III
HO
HO
HO
HO
+
+
OH
KOH
1
2
3
n
n
n
n
n
m
m
O
O
O
O
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
2
CH
2
CH
2
OH

O
O
O
O
O
HO
I
II
+
O
100,000 10,000 1,000 100
5
4
3
2
1
0
S
i
g
n
a
l

i
n
t
e
n
s
i
t
y
Molecular weight [g/mol]
Triblock
copolymer
Diblock
copolymer
104
Figure 10.2 Side reaction leading to unsaturation and consequently to the formation of
a diblock copolymer
The existence of these diblock copolymers becomes visible during gel permeation
chromatography (GPC) for determination of the molecular weight distribution, where
a second peak of a smaller fraction can be observed (Fig. 10.3).
Figure 10.3 Example of bimodal molecular weight distribution (GPC) in Kolliphor P 407
Increase of T
hydrophobic
PPO-part
hydrophilic
PEO-part
Increase of c
and/or
105
10.2 Properties
The block composition of poloxamers with both hydrophilic PEO blocks and more
hydrophobic PPO blocks enables poloxamers to form micelles in aqueous solution.
There are two methods involved in inducing micelle formation in a poloxamer solution:
The poloxamer concentration can be increased until the critical micelle concentration
(CMC) is reached, or the temperature can be increased, which leads to a subsequent
decrease of the CMC [98] (Fig. 10.4).
Figure 10.4 Schematic of micelle formation in an aqueous poloxamer solution
Poloxamers are liquid, pasty or solid at room temperature; this is closely related
to their molecular weight and their chemical composition. These two key features
are directly displayed in the nomenclature of the poloxamers: The last of the three
numbers that characterize every poloxamer grade is linked to the PEO content
(188 = 80 % m / m PEO) while the prepending numbers multiplied by 100 give an idea
of the average molecular weight of the PPO part (188 = molecular weight of the PPO
part: 1800). The different poloxamer grades are usually arranged in a grid system,
in which areas of liquid, pasty and solid poloxamer grades can be observed (Fig.
10.5 top). Most commercial grades of poloxamers have a slightly different nomen-
clature, but can be displayed within the same grid system (Fig. 10.5 bottom). For
the Pluronic and former Lutrol grades, a letter and number combination was used
as nomenclature: The letter is dened by the aggregate state (L = liquid; P = paste;
F = flakes), while the last number represents the PEO content (F 68 = 80 % m / m
PEO) and the prepending numbers are again related to the molecular weight of the
PPO part. Here a factor of approximately 300 can be used for an estimation of the
PPO parts molecular weight (F 68 = molecular weight of PPO part: 1800). However,
use of the grid system is recommended for molecular weight estimation to ensure
that all poloxamer grades conform.
10
0 10
4000
3625
3250
2750
2250
2050
1800
1450
1200
950
20 30 40 50 60 70 80
Percentage PEO-part [%(m/m)]
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

o
f

P
P
O
-
p
a
r
t

[
g
/
m
o
l
]
0 10
4000
3625
3250
2750
2250
2050
1800
1450
1200
950
20 30 40 50 60 70 80
Percentage PEO-part [%(m/m)]
M
o
l
e
c
u
l
a
r

w
e
i
g
h
t

o
f

P
P
O
-
p
a
r
t

[
g
/
m
o
l
]
101
L121
L101
L92
L122
L81
L72
L61 L62 L63 L64
L42
L31
L43 L44
L35
F68
F88 F87
F77
F98
F108
F127 P123
P103 P104 P105
P85
P75
P65
P84
122 123 124
105
184 183 182 181
202
231
272
331
401 402 407
338
278
238 237
207
188 185
205
234 235
335 334 333
403
liquid
pasty
solid
106
Figure 10.5 Grid system displaying the systematic nomenclature of poloxamer grades
(top) and of the corresponding Pluronic / Lutrol grades (bottom)
107
There are ve compendial poloxamer grades, one liquid (124) and four solid grades
(188, 237, 338 and 407). For each of these compendial grades BASF supplies a
commercial grade in pharmaceutical quality (Kolliphor P, Kollisolv P) that meets
the requirements of the USP, Ph.Eur. and JPE. Some of the specications and pro-
perties of the compendial poloxamers are given in Table 10.1 below; a complete
overview of the specications can be provided for each grade on request.
Poloxamer * Mw (g / mol) PEO (% m / m) CMC (mol / l) **
124 2.090 2.360 44.8 48.6 3.6 10
-3
188 7.680 9.510 79.9 83.7 4.8 10
-4
237 6.840 8.830 70.5 74.3 9.1 10
-5
338 12.700 17.400 81.4 84.8 2.2 10
-5
407 9.840 14.600 71.5 74.9 2.8 10
-6
Table 10.1 Properties of compendial poloxamers
* For translation of poloxamer / Lutrol nomenclature please see Figure 10.5
** CMCs were determined at 37 C, pH 7.4 using the pyrene solubilization technique as described in [99, 100]
The solid Kolliphor P grades are prepared by a so-called prilling process that leads
to the formation of spherical granules with excellent owability and a mean particle
size of about 600 800 m (Fig. 10.6 A). In addition to the standard grades, a micro-
prilled grade was recently introduced for the two Kolliphor P grades 188 and 407.
These two grades are available as Kolliphor P micro and exhibit much smaller mean
particle sizes of around 50 m only (Fig. 10.6 B). However, since the material is not micro-
nized, but micro-prilled, dust formation is still very low. The smaller particle size is
especially favorable in the case of powder blends, since more homogeneous particle
sizes will cause less segregation. Additionally, the increased surface area of the smal-
ler particles will lead to faster dissolution and faster melting in HME applications.
10
V
o
l
u
m
e

[
%
]
13
12
11
10
9
8
7
6
5
4
3
2
1
100
90
80
70
60
50
40
30
20
10
0.1 1 10 100 1000 3000
Particle size [m] A
V
o
l
u
m
e

[
%
]
10
9
8
7
6
5
4
3
2
1
100
90
80
70
60
50
40
30
20
10
0.1 1 10 100 1000 3000
Particle size [m] B
108
Figure 10.6 Particle size distribution and SEM images of Kolliphor P 188 (A) and
of the corresponding micro-prilled grade (B)
200 m P 188
20 m P 188 micro
109
10.3 Applications
Due to their good solubility in water and their ability to form micelles, poloxamers are
generally suitable for use as solubilizers. However, under the conditions of testing with
the Solu-HTS (see chapter 3), Kollisolv P 124, Kolliphor P 188 and P 237 showed
a remarkable enhancement of the saturation solubility for only two of the seven APIs
tested (Fig. 10.7). The saturation solubility of piroxicam, which in buffer is not higher than
5 ppm, was increased to more than 200 ppm for solutions containing 1 % poloxamer
and to more than 1,000 ppm with 10 % poloxamer. For carbamazepine, which has a
saturation solubility of about 120 ppm in buffer, the solubility was signicantly increased
for solutions containing 5 % solubilizer and more. The two Kolliphor P grades, with a
mean molecular weight of higher than 10,000 Da (P 338 and P 407), showed a massively
enhanced solubilization efcacy. For solutions with 10 % P 338, an increase of the
saturation solubility was observed for all seven APIs tested. This effect was even more
pronounced for P 407 solutions, where a concentration of 5 % was already sufcient
to increase the saturation solubility of all APIs, and a concentration of 10 % massively
enhanced the solubility.
Since Kolliphor P 188 and P 407 both show thermoreversible gelation in solutions
with a content of about 15 % and higher already at room temperature [101], they are
very suitable for use in hydrogel drug delivery systems were they can additionally act
as solubilizers for poorly soluble drugs. Liquid Kollisolv P 124 is very suitable as
a lling matrix for soft gelatine capsules, where P 124 can be used as a water-free
solvent.
Micro-prilled grades of Kolliphor P 188 and P 407 have a particle size compatible
with most actives or other excipients; this makes them very suitable for applications
in direct compression, roller compaction or melt granulation, where they can improve
the wetting and dissolution of poorly soluble drugs.
10
C
l
o
t
r
i
m
a
z
o
l
e
C
a
r
b
a
m
a
z
e
p
i
n
e
K
e
t
o
c
o
n
a
z
o
l
e
D
a
n
a
z
o
l
P
i
r
o
x
i
c
a
m
F
e
n
o
f
i
b
r
a
t
e
C
i
n
n
a
r
i
z
i
n
e
1400
1200
1000
800
600
400
200
0
S
a
t
u
r
a
t
i
o
n

s
o
l
u
b
i
l
i
t
y

[
p
p
m
]
C
l
o
t
r
i
m
a
z
o
l
e
C
a
r
b
a
m
a
z
e
p
i
n
e
K
e
t
o
c
o
n
a
z
o
l
e
D
a
n
a
z
o
l
P
i
r
o
x
i
c
a
m
F
e
n
o
f
i
b
r
a
t
e
C
i
n
n
a
r
i
z
i
n
e
1400
1200
1000
800
600
400
200
0
S
a
t
u
r
a
t
i
o
n

s
o
l
u
b
i
l
i
t
y

[
p
p
m
]
C
l
o
t
r
i
m
a
z
o
l
e
C
a
r
b
a
m
a
z
e
p
i
n
e
K
e
t
o
c
o
n
a
z
o
l
e
D
a
n
a
z
o
l
P
i
r
o
x
i
c
a
m
F
e
n
o
f
i
b
r
a
t
e
C
i
n
n
a
r
i
z
i
n
e
1400
1200
1000
800
600
400
200
0
S
a
t
u
r
a
t
i
o
n

s
o
l
u
b
i
l
i
t
y

[
p
p
m
]
Control
P 124
P 188
P 237
P 338
P 407
1% solubilizer
5% solubilizer
10% solubilizer
110
Figure 10.7 Solubilization efcacy of poloxamers as tested with the Solu-HTS System. All
poloxamer grades signicantly enhance the solubility of piroxicam and, in higher
concentrations (5 % and more), also of carbamazepine; however, only P 407 shows
good solubilization efcacy for all tested APIs in concentrations of 5 % and higher.
111
In the case of hot-melt extrusion applications, the micro-prilled grades are very suit-
able plasticizers in combination with other excipients, since they enable processing
over a wider temperature range and mix very homogeneously. However, due to their
high molecular weight compared with classical plasticizers such as PEG 1,000, they
are not readily soluble in many polymers and will often form crystalline regions within
the solid dispersions. Shah et al. also report on a melt formulation using Poloxamer
188 as matrix and show an increased dissolution of rofecoxib from the prepared solid
dispersion [102]. Nevertheless, due to their crystallinity and very low melt viscosity,
pure polymers are not recommended for melt extrusion since the downstreaming of
the extrudate is extremely difcult.
To summarize: The compendial poloxamer grades do not demonstrate the best
solubilization capacity; however, they are easy to handle at room temperature due
to their solid state. They thus have a very broad application range. The liquid grade
extends the application range even more, for example as a liquid matrix in soft gela-
tine capsules.
References
[95] Lundsted, Lester G. Polyoxyalkylene compounds. WYANDOTTE CHEMICALS
CORP. [2674619]. 6-4-1954. United States. Ref Type: Patent
[96] G. J. Dege, R. L. Harris, and J. S. MacKenzie, Terminal Unsaturation in
Polypropylene Glycol, Journal of the American Chemical Society, 81 (1959),
3374 3379.
[97] L. E. St. Pierre and C. C. Price, The Room Temperature Polymerization
of Propylene Oxide, Journal of the American Chemical Society, 78 (1956),
3432 3436.
[98] Z. Zhou and B. Chu, Light-scattering study on the association behavior of
triblock polymers of ethylene oxide and propylene oxide in aqueous solution,
Journal of Colloid and Interface Science, 126 (1988), 171 180.
[99] E. Batrakova, S. Lee, S. Li, A. Venne, V. Alakhov, and A. Kabanov, Funda-
mental Relationships Between the Composition of Pluronic Block Copoly-
mers and Their Hypersensitization Effect in MDR Cancer Cells, Pharmaceu-
tical Research, 16 (1999), 1373 1379.
[100] A. V. Kabanov, I. R. Nazarova, I. V. Astaeva, E. V. Batrakova, V. Y. Alakhov,
A. A. Yaroslavov, and V. A. Kabanov, Micelle Formation and Solubilization of
Fluorescent Probes in Poly(oxyethylene-b-oxypropylene-b-oxyethylene) So-
lutions, Macromolecules, 28 (1995), 2303 2314.
[101] G. Dumortier, J. Grossiord, F. Agnely, and J. Chaumeil, A Review of Poloxamer
407 Pharmaceutical and Pharmacological Characteristics, Pharmaceutical
Research, 23 (2006), 2709 2728.
[102] T. J. Shah, A. F. Amin, J. R. Parikh, and R. H. Parikh, Process Optimization
and Characterization of Poloxamer Solid Dispersions of a Poorly Water-soluble
Drug, AAPS PharmSciTech, 8 (2010), article 29.
10
III
CH
CH
OH
n n
n
C
H
2
C
H
C
H
CH
2
C
H

1 2 3
4
5
I
II
O
N N N N
N N
N N
N N
+
+
+ + R
R
R C
H
2
C
H
2
C
H
2
C
H
2
C
H
2
C
H
2
C
H
2
H
2
C
H
2
C CH
CH
CH
CH
R
R
R R
R O O
O
O
O
O
O
O
O
O O
O
O
n
O
O
O
112
Thomas Reintjes
11 Soluble Kollidon

grades
11.1 Composition
Although not typical solubilizers due to their lack of an amphiphilic structure, Kollidon

grades can also increase the solubility of poorly soluble substances. From the range of
Kollidon

grades, the soluble Kollidons

of low molecular weight such as Kollidon

12 PF
and Kollidon

17 PF and of medium molecular weight such as Kollidon

25 and Kol-
lidon

30 especially are very suitable. In addition to these pure polyvinyl pyrrolidone

(PVP) grades, the copovidone grade, Kollidon

VA 64 is also very important in the

group of solubilizing agents.
PVPs are usually produced by radical polymerization (Fig. 11.1), a process that can
be divided into 3 steps: activation (I), propagation (II) and termination (III). In the
rst step, vinylpyrrolidone (2) is activated by a radical (1) to form the vinylpyrrolidone
radical (3). In the propagation step, this radical then reacts with a certain amount of
vinylpyrrolidone to form a polyvinyl pyrrolidone radical (4). In the nal termination step
this then transfers its radical to another molecule such as a tertiary alcohol, to form
the nal PVP (5).
Figure 11.1 Synthesis of PVP by radical polymerization
m
CH C
H
C
H
O
O
6 7
O
O
N N
n + m
n
R O C
H
2
H
2
C
H
2
C CH
CH CH R
O
O
O
N
O
+
N II
O C
H
2
C
H
2
C
H
2
CH
3
CH
3
113
For the copovidone grades, the synthesis is almost the same as for the PVP, the
only difference being that in the propagation step (Fig. 11.2) a certain amount of vinyl
acetate (6) is added. This leads to the formation of a randomly structured copolymer
of vinylpyrrolidone and vinylacetate (7).
Figure 11.2 Propagation reaction for the synthesis of vinylpyrrolidone-vinyl acetate
copolymers (copovidone)
11.2 Properties
The soluble Kollidon

grades, including Kollidon

VA 64, appear as almost white,

free-owing powders with a characteristic odor. Particle sizes of the standard grades
are usually within the range 50 250 m and are of a medium particle size of around
100 m. The ne fraction (< 50 m) of the standard grade comprises typically 10 20 %
(Fig. 11.3 A). In addition to the standard grade of Kollidon

VA 64 a Fine grade is
also offered. This Fine grade has much smaller particle sizes, about 90 % < 50 m
(Fig. 11.3 B), and also differs in particle shape. The Kollidon

grades discussed in
this chapter are all produced by a spray drying process, which usually generates
particles with a typical, spherical, hollow structure (see also chapter 2.3). However,
in the case of the standard grade of Kollidon

VA 64, these hollow particles are

almost completely disintegrated so that irregularly shaped fragments and debris can
be observed in the SEM image (Fig. 11.3 A). The Fine grade in contrast consists of
very homogeneous, spherical particles (Fig. 11.3 B) that are also typical for the PVP
grade Kollidons

.
11
V
o
l
u
m
e

[
%
]
8
7
6
5
4
3
2
1
0
100
80
60
40
20
0
0.1 1 10 100 1000 3000
Particle size [m] B
V
o
l
u
m
e

[
%
]
12
10
8
6
4
2
0
100
80
60
40
20
0
0.1 1 10 100 1000 3000
Particle size [m] A
V
o
l
u
m
e

[
%
]
8
7
6
5
4
3
2
1
0
100
80
60
40
20
0
0.1 1 10 100 1000 3000
Particle size [m] B
V
o
l
u
m
e

[
%
]
12
10
8
6
4
2
0
100
80
60
40
20
0
0.1 1 10 100 1000 3000
Particle size [m] A
114
Figure 11.3 Particle shape (SEM) and particle size distribution of Kollidon

VA 64 (A)
and of Kollidon

VA 64 Fine (B)
100 m
100 m
115
The characteristic 'soluble' of this group of polymers is attributed to their high solubility
in almost any hydrophilic solvent. However, the soluble Kollidon

grades are not only

readily soluble in water and different alcohols such as methanol, ethanol and iso-
propanol but also dissolve in methylene chloride and chloroform. While the solubility of
the PVP grades and copovidone is almost the same for both groups, they show strong
differences with regard to hygroscopicity. The hygroscopicity of the PVP grades is typi-
cally very high and shows hardly any difference between the individual grades. Kollidon

VA 64 and the corresponding Fine grade in contrast show a much lower hygrosco-
picity and adsorb only about one third of the quantity of water adsorbed by the povidone
grades (details are given in the technical brochures that are available on request).
Table 11.1 Molecular weights of the different Kollidon

grades
Kollidon

grade K-value Mw
12 PF 10.2 13.8 2,000 3,000
17 PF 15.3 18.4 7,000 11,000
25 22.5 27.0 28,000 34,000
30 27.0 32.4 44,000 54,000
VA 64 25.5 30.8 45,000 70,000
One parameter that differentiates the Kollidon

grades is molecular weight. Like most

polymers, the molecular weight of the Kollidons

has a certain molecular weight dis-

tribution; thus, the determination of a certain molecular weight is difcult and not very
distinctive. Consequently, instead of a molecular weight range, the viscosity of a poly-
mer solution (typically the inherent viscosity) is usually used to characterize a polymer.
A dimensionless number that is closely related to the viscosity is the so called K-value,
which is used to characterize the Kollidon

grades. The equation for calculation of the

K-value from the relative viscosity of a certain polymer solution can be found in [104].
This K-value is also part of the nomenclature of the PVP grade Kollidons

, followed
by the letters PF for pyrogen free in case of Kollidon

12 PF and 17 PF. For the co-

povidone grade VA (vinyl acetate) 64 the nomenclature is different: Here, the number
does not display the K-value, which is in the range of 25 30, but gives the ratio of
vinylpyrrolidone to vinyl acetate (6 to 4). An overview of the corresponding molecular
weights (weight average) for the different Kollidon

grades is given in Table 11.1.

The key feature of the different Kollidon

grades, which makes them suitable for

increasing the solubility of various APIs and other substances, is their ability to form
water-soluble complexes. Probably the best-known Kollidon

-based complex is the

PVP-iodine complex (Fig. 11.4), in which a triiodide anion is ionically bound to a pro-
ton that is xed by short hydrogen bonds between two carbonyl groups [104]. This
11
CH
N
I
3

n
N
+
O O H
R R CH CH
2
CH
2
101
149
90
138
225
175
175
230
250
200
150
100
50
0
Kollidon

12 PF Kollidon

17 PF Kollidon

30 Kollidon

VA 64
T
e
m
p
e
r
a
t
u
r
e

[

C
]
T
g
T
degr
116
complex is typically used in formulations
for wound disinfection, where the solu-
bility of iodine is increased approximately
17-fold for solutions that contain 1 % of
PVP only [105]. In addition to the PVP-
iodine complex, complexes with various
APIs such as sulfathiazole, nifedipine or
phenobarbital have also been described
[103]. However, the stability of these
complexes is pH-dependent: In general,
the complexes are formed under acidic
conditions but decompose again in the
alkaline pH range.
Figure 11.4 Chemical structure of the
PVP-iodine complex
Since the Kollidons

(PVP and the copovidone grades) are amorphous polymers,

they show a glass transition temperature (T
g
) which increases with increasing mo-
lecular weight. Figure 11.5 clearly illustrates how the T
g
increases for different PVP
grades with increasing K-value. For the copovidone grade VA 64, the T
g
is signi-
cantly reduced compared to the PVP grade (Kollidon

30) of similar molecular

weight (149 C 101 C). For applications such as melt extrusion, the degradation
temperature of the polymers is also of great interest. However, the degradation
temperature does not show the same similar trend as was observed for the T
g
: For
Kollidon

30 and Kollidon

17 PF, the degradation temperature is about 50 C lower

than that for the Kollidon

12 PF and VA 64 grades.
Figure 11.5 Glass transition temperature (T
g
) and temperature of degradation (T
degr
)
for different Kollidon

grades.
35
30
25
20
15
10
5
0
120 100 80 60 40 20 0
Time [min]
D
i
s
s
o
l
v
e
d

A
P
I

[
m
g
]
Itraconazole/VA 64 extrudate
Pure Itraconazole 100 mg
117
11.3 Applications
Due to their low molecular weight and pyrogen-free quality, the Kollidon

12 PF and 17 PF
grades are especially suitable for use in parenteral formulations, since the molecular
weight below 35,000 Da allows fast clearance from the blood stream. In oral and
topical formulations, the low molecular weight grades can also be used; however, for
this purpose, the medium molecular weight grades Kollidon

25 and 30 are typically

used. If binding properties are required in a certain formulation such as granules or
tablets, the Kollidon

25, 30 or VA 64 grades are preferably used; this is because

the binding efcacy increases with increasing K-value and is especially high for the
copovidone grade. Investigations of the T
g
and temperature of degradation revealed
that Kollidon

12 PF and VA 64 are particularly suitable for hot-melt extrusion (HME)

applications. Due to the fact that the polymers are usually processed about 30 50 C
above their T
g
, they should exhibit a high difference between T
g
and temperature of
degradation. For Kollidon

30 and 17 PF, this difference is only about 30 C (Fig. 11.5),

which makes processing of the pure polymers extremely difcult, if not impossible.
Kollidon

VA 64 showed very good processability in the HME application and was

used to formulate the poorly water-soluble API itraconazole in a solid dispersion. In-
vestigation of the drug release from the extrudates showed that the solubility of itra-
conazole was signicantly increased (Fig. 11.6). While only 3 4 mg of the crystalline
API were dissolved in the dissolution buffer (700 ml 0.1 M HCl), the amount of soluble
API was about 10-fold from the extrudates after two hours of dissolution.
Figure 11.6 Increased solubility of itraconazole as observed during a dissolution study
from Kollidon

VA 64 extrudates. (USP II, 700 mL 0.1 M HCl).

11
118
The use of Kollidon

VA 64 as a matrix for melt extrudates has already found its way

into commercial products. In 2005, Abbott launched a tablet formulation of the API
combination ritonavir and lopinavir (Kaletra

), which is used for the treatment of HIV

infections. A major advantage of this formulation is that the daily intake of six cap-
sules of the former soft gelatine capsule formulation could be reduced to four tablets.
Additional benets of the melt-extruded formulation are that these tablets show no
food interaction and therefore can be taken with or without food and that there is no
need to keep the tablets refrigerated [106, 107].
At the moment, the melt extrusion process is still the exception in the pharmaceutical
industry; however, more melt-extruded formulations are expected in the near future.
Reference List
[103] V. Bhler, Kollidon

: Polyvinylpyrrolidone excipients for the pharmaceutical

industry, BASF SE, Ludwigshafen (2009).
[104] H. U. Schenck, P. Simak, and E. Haedicke, Structure of polyvinylpyrrolidone-
iodine (povidone-iodine), J. Pharm. Sci., 68 (1979), 1505 1509.
[105] S. Siggia, The chemistry of polyvinylpyrrolidone-iodine, Journal of the Ameri-
can Pharmaceutical Association, 46 (1957), 201 204.
[106] C. E. Klein, Y. L. Chiu, W. Awni, T. Zhu, R. S. Heuser, T. Doan, J. Breitenbach,
J. B. Morris, S. C. Brun, and G. J. Hanna, The Tablet Formulation of Lopinavir /
Ritonavir Provides Similar Bioavailability to the Soft-Gelatin Capsule Formula-
tion With Less Pharmacokinetic Variability and Diminished Food Effect, JAIDS
Journal of Acquired Immune Deciency Syndromes, 44 (2007).
[107] M. Olmo, E. Ferrer, J. Curto, P. Barragan, M. Saumoy, N. Perulero, and
D. Podzamczer, Improved tolerability and quality of life with the new lopinavir /
ritonavir tablet formulation, Journal of Infection, 57 (2008), 503 505.
119
12 Alphabetical index
A absolute lters 44
absorption spectra (solubilizers) 58
advance angle 34
antioxidant (TPGS) 74
application chart (solubilizers) 65
aprepitant 25
area-over-baseline-method 59
atomization 39
B bag lters 44
bile salts 16
bimodal molecular weight distribution 104
binding constants 21
biomolecules 16
biopharmaceutical classication system (BCS) 9 10
biopharmaceutical tness 53
brick dust 14, 19
briey overheating 45
Bttiker model 42
C caffeine 93
calendering 33
carbamazepine 60 61, 69, 77, 85, 93
casting device 29
chemical stability 30
cinnarizine 69, 78, 85, 93
clotrimazole 69, 85, 93
co-current nozzle tower 43
compendial poloxamers 103, 107
complex formation 20 22, 64, 115
continuous changes 35
continuous manufacturing process 32
conveying 33 34
copovidone 112 117
-particle size distribution 113 114
core-shell structure 14
co-rotating 34
co-solvents 18, 53, 77, 86, 101
counter-current nozzle tower 43
counter-rotating 34
critical micelle concentration (CMC) 14, 17 18
-determination 17
-ionic surfactant 15
11
12
120
C critical micelle concentratio (CMC) -non-ionic surfactant 15
-Kolliphor EL / ELP 96
-Kolliphor HS 15 81
-Kolliphor RH 40 90
-poloxamers 105, 107
-Soluplus

68
critical micelle temperature 18
crop protection 19
crystal lattice energy 54
cyclones 44
cyclosporine A 19, 93
D danazol 69, 78, 85, 93
degassing 33
degradation temperature (Kollidon

) 116
differential scanning calorimetry (DSC) 29 30
-Kolliphor TPGS 75
-theophylline 46 48
diffusion coefcient 24
diffusion layer 24
diode array monochromator 59
dipole moment 22
dipole-dipole interaction 22
direct blue 71 20
direct red 80 21
disc tower 43
dispersants 16
dissolution calorimetry 30
dissolution rate 23
downstream auxiliary equipment 33
drop size distribution 40
drugable space 11
drying gas 38
drying kinetics 41
dye transfer inhibitors 20
E electrostatic repulsion 15
Emend

25
emulsion stabilization 16
enthalpy 12
entropy 12
equilibrium solubility 23, 55
estradiol 69
extrudability 35
extrudate shape 32
121
E extrusion temperature 36
F fat-soluble vitamins 83, 90, 98
feed hopper 33
feeding section 32 33
fenobrate 69, 72, 85, 93
-extrudates 36 37
-nanoparticle formulation 25
Fick's law 22
lm casting 28
uid-bed driers 44
Fortovase

19
freeze drying 28
G gel permeation chromatography (GPC) 67, 104
Gibbs free energy 12
Gibbs-Helmholtz equation 12
glass transition temperature (T
g
) 30, 31, 35
-Kollidon

116
-Soluplus

68
granules 31
grease balls 11, 13, 18
grid system (poloxamer nomenclature) 105 106
griseofulvin 69
H head-tail structure 14
high-throughput robot (Solu-HTS) 53 62
histamine release 83
hollow beads 42
hollow cone pressure nozzles 40
hot-melt extrusion (HME) 31 36
-advantages 31
-equipment 32
hydrogen bonding acceptors / donors 36
hydrophobic pockets 22
hygroscopicity 36
-Kollidon

115
I implants 31
infrared spectroscopy 30
interaction parameter 12
interface energy 17
interfacial tension 23
intermeshing 34
itraconazole 69
12
122
I itraconazole -bioavailability enhancement 71
-extrudates (Kollidon

VA 64) 117
-extrudates (Soluplus

) 69 71
-structure 12
K Kaletra

101, 118
Kelvin equation 23
ketoconazole 69, 85, 93
kinetic solubility 54 57
kneading 33
Kollidon

(soluble grades) 112 118

-molecular weights 115
Kolliphor EL / ELP 95 101
-chemical structures 95
-properties 96
Kolliphor HS 15 79 86
-chemical structures 79
-properties 81
-Solu-HTS 85
-synthesis 80
Kolliphor P grades 103 111
-synthesis 103
Kolliphor RH 40 89 94
-chemical structure 89
-properties 90
-Solu-HTS 93
Kolliphor TPGS 73 78
-chemical structure 73
-properties 74
-Solu-HTS 77
K-value 115
L L / D ratio 34
laminar arrangements 15
light scattering 17
liquid crystalline phases 15
Lutrol

103, 105, 106

M matrix material 22
mechanical energy 35
mechanical properties 30
melt granulation 28, 75, 109
melt viscosity 33, 35
micelle size 14
-Kolliphor HS 15 81 82
123
M micelles 14
micro-prilled poloxamers 108 109
mixing enthalpy 13
mixing entropy 13
mixing step 33
modular screw design 34
moisture equilibrium 41
molar mass 13
molar volume 13
molecular mobility 28
N nanoparticles 25
nano-sinks 18
nanotechnology 22 25
Neoral

19, 93
neutral elements 34
Norvir

19
Noyes-Whitney equation 24
O O / W emulsion 74
off-line modications 35
olive oil 19
Ostwald ripening 27
oversaturation 22
overview chart (solubilizers) 64 65
P particle morphology 41 42
particle size distribution (poloxamers) 108
peakt method 59
pelletizer 33
pellets 31
penetration enhancer 10
P-glycoprotein inhibition 74 75, 101
pharmacokinetic 10
piroxicam 69, 78, 85, 93, 109
Pluronic

103, 105, 106

poloxamers 103 111
polymeric solubilizers 20
polymorphic forms 54
prilling 107
process analytical technology 33
process variables 35
prodrugs 11
proof of concept (HTS robot) 60 62
PVP 112 118
12
124
P PVP -mode of action 22
-synthesis 112
-iodine complex 115 116
R Rapamune

25
residence time 35
reverse-ighted kneading blocks 34
ritonavir 19
rofecoxib 111
S Sandimmune

19
saquinavir 19
saturation solubility -carbamazepine 61
Schlick nozzle 40
screw design 34
self-emulsifying drug delivery systems (SEDDS) 18 19, 75, 86, 101
self-microemulsifying drug delivery systems (SMEDDS) 19
self-nanoemulsifying drug delivery systems (SNEDDS) 86, 101
shaping section 33
shear stress 35
single-screw extruder 34
sirolimus 25
solid content 39
solid dispersions 27 30
solid solutions 22, 27 30
solid state NMR 30
Soliqs 31
solubility parameter 36
solubilization capacity 36
-Soluplus

68 69
Soluplus

67 72
-gel permeation chromatography (GPC) 67 68
-molecular weight distribution 67
solution viscosity (TPGS) 75
-Kolliphor EL 97
solvent casting 28, 36
sorption isotherm 41
spray congealing 28
spray drying 38 49
-advantages 39
-process parameters 43
-process steps 39
standard spraying tower 38
step changes 35
structure-property relationship 62
125
S supramolecular structures 14 15
surface energy 17
surface tension 17
surfactants 14 19
sustained release tablets 31
T theophylline 46 49
thermodynamic solubility 53 57
thermodynamics 1213
thermoplastic behavior 32, 36
thixotropic behavior 35
three-axes system 55 56
torque 33, 35
transdermal drug delivery systems 31
transmucosal drug delivery systems 31
Tricor

25
tube-like arrangements 15
twin-screw extruder 34
U unsaturations (poloxamers) 103
UV/VIS spectroscopy 57 59
V vapor sorption 30
variability of bioavailability 19
vitamin A palmitate 83 84, 91, 98 99
vitamin D 92, 99
vitamin E 74 77, 99
vitamin E -malabsorption 74
volatile organic compound (VOC) 19
X x-ray diffraction (XRD) 29
-theophylline 49

-carotene -bioavailability 24
-structure 11
12
126
Note
This document, or any answer or information provided herein by BASF, does not
constitute a legally binding obligation on the part of BASF. While the descriptions, de-
signs, data and information contained herein are presented in good faith and believed
to be accurate, it is provided for your guidance only. Because many factors may af-
fect processing or application/use, we recommend that you make tests to determine
the suitability of a product for your particular purpose prior to use. It does not relieve
our customers from the obligation to perform a full inspection of the products upon
delivery or any other obligation. No warranties of any kind either express or implied,
including warranties of merchantability or tness for a particular purpose are made
regarding products described or designs, data or information set forth, or that the
products, designs, data or information may be used without infringing the intellec-
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October 2011
127
Hot-Melt Extrusion with
BASF Pharma Polymers
Extrusion Compendium
K. Kolter, M. Karl, S. Nalawade, N. Rottmann
Pharma Ingredients & Services.
Welcome to more opportunities.
Hot-Melt Extrusion with BASF Pharma Polymers
Extrusion Compendium
K. Kolter, M. Karl, S. Nalawade, N. Rottmann
H
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This book is intended for pharmaceutical technologists who are
already, or are considering, working with hot-melt extrusion.
The relevant properties of the various BASF pharma polymers,
plasticizers and solubilizers intended for use in hot-melt extrusion
as well as combinations of these are described in detail.
Furthermore, information is provided on how to process actives
in hot-melt extrusion, how to characterize the resulting formula-
tions and how to develop stable drug delivery systems. Practical
recommendations for applications involving hot-melt extrusion
are also given.
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Extrusion Compendium by BASF
Read more about hot-melt extrusion in
BASFs Extrusion compendium. The
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Solubility Enhancement with BASF Pharma Polymers
Solubilizer Compendium
Thomas Reintjes (Editor)
This book is intended for pharmaceutical technologists in industry
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Relevant properties as well as typical applications are described in
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