1

Dissolution Enhancement
Techniques

Introduction

For complete absorption and good bioavailability of orally administered drug, the drug must be
dissolved in gastric fluids. Dissolution of drug is the rate-controlling step which determines the rate
and degree of absorption. Drugs with slow dissolution rates generally show erratic and incomplete
absorption leading to low bioavailability when administered orally. Since aqueous solubility and
slow dissolution rate of BCS class II and class IV drugs is a major challenge in the drug
development and delivery processes, improving aqueous solubility and slow dissolution of BCS
Class II and Class IV drugs have been investigated extensively. Various techniques have been used
in attempt to improve solubility and dissolution rates of poorly water soluble drugs which include
solid dispersion, micronization, lipid based formulations, melt granulation, direct compaction,
solvent evaporation, coprecipitation, adsorption, ordered mixing, liquisolid compacts, solvent
deposition inclusion complexation and steam aided granulation. In these techniques carrier plays an
important role in improving solubility and dissolution rate. Polymers, superdisintegrants, surfactants
are extensively studied in recent years for dissolution enhancement in drugs. This part of this review
discusses technological overview and effect of polymers, superdisintegrants and surfactants on
dissolution enhancement of drugs while Part II [Int J Health Res, Sept 2009; 2(3)] describes the role
and applications of cyclodextrins, carbohydrates, hydrotropes, polyglocolized glycerides,
dendrimers, acids and miscellaneous carriers in enhancing dissolution of drugs.

Nearly one-third of drugs in development are water insoluble and one-half fail in trials because of
underprivileged pharmaco- kinetics [1]. These poorly water soluble drugs are allied with slow drug
absorption leading to inadequate and variable bioavailability and
G.I. mucosal toxicity of drugs [2]. Poorly water soluble drugs belong to BCS class II and Class IV
[3] group of compounds. In the process of absorption of drug from oral route dissolution is the rate
limiting step for lipophilic drugs. Therefore it is necessary to enhance dissolution of these drugs to
ensure maximum therapeutic utility of these drugs. Before studying the various approaches to
enhance dissolution it is necessary to understand the basic process of dissolution. Dissolution is a
process by which a solid substance goes into solution. The extent to which the dissolution proceeds,
under a given set of conditions is referred to as the solubility of the substance in the solvent i.e. rate
of solution (dissolution) and amount that can be dissolved (solubility) are not same. The dissolution
rate of a drug is directly proportional to its solubility as per Noyes- Whitney equation and therefore
solubility of a drug substance is a major factor that determines its dissolution rate and hence its
absorption and bioavailability eventually [4].

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The various properties of drug that affect drug dissolution and its rate includes solubility, particle size,
polymorphism, salt form, complexation, wettability, etc [5] and can be targeted to enhance dissolution
of poorly water soluble drugs. Use of water soluble excipients is common and simplest way to enhance
dissolution rate of hydrophobic drugs. These excipients namely polymers, superdisintegrants,
carbohydrates, surfactants hydrotropes, acids etc work in different ways to enhance water solubility of
drugs. The role of techniques of preparation of formulation is as imperative as the choice of the carriers
to enhance dissolution of drugs due to difference in reduction of crystallinity of the product and surface
characteristics of the particles. Part I of this review highlights various dissolution
enhancement techniques for poorly water soluble drugs as well as role of few
water soluble carriers, viz. polymers, superdisintegrants and surfactants, in
dissolution enhancement. While part II [Int J Health Res, Sept 2009; 2(3)]
describes use of cyclodextrins, carbohydrates, hydrotropes, polyglocolized
glycerides, dendrimers, acids and miscellaneous carriers in enhancing dissolution
of drugs.

The term hydrotropic agent was first introduced by Neuberg (1916) to designate
anionic organic salts which, at high concentrations, considerably increase the
aqueous solubility of poorly soluble solutes[1].Hydrotropy is a solubilization
phenomenon whereby addition of large amount of second solute results in an
increase in the aqueous solubility of another solute. However, the term has
been used in the literature to designate non-micelle-forming substances, either
liquids or solids, organic or inorganic, capable of solubilizing insoluble
compounds. The chemical structure of the conventional Neuberg’s hydrotropic
salts (proto-type, sodium benzoate) consists generally of two essential parts, an
anionic group and a hydrophobic aromatic ring or ring system. The anionic
group is obviously involved in bringing about high aqueous solubility, which is
a prerequisite for a hydrotropic substance. The type of anion or metal ion
appeared to have a minor effect on the phenomenon[2]. On the other hand,
planarity of the hydrophobic part has been emphasized as an important factor
in the mechanism of hydrotropic solubilization. Solute consists of alkali metal
salts of various organic acids. Hydrotropic agents are ionic organic salts.
Additives or salts that increase solubility in given solvent are said to “salt in”
the solute and those salts that decrease solubility “salt out” the solute. Several
salts with large anions or cations that are themselves very soluble in water
result in “salting in” of non electrolytes called “hydrotropic salts” a
phenomenon known as “hydrotropism”. Hydrotropic solutions do not show
colloidal properties and involve a weak interaction between the hydrotropic
agent and solute[3].
 
Solubility enhancement of various poorly soluble compounds is a challenging
task for researchers and pharmaceutical scientists. Solubility is one of the
important parameter to achieve desired concentration of drug in systemic
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circulation for pharmacological response to be shown[2]. The study on

solubility yields information about the structure and intermolecular forces of
drugs. Drug efficacy can be severely limited by poor aqueous solubility and
some drugs also show side effects due to their poor solubility. There are many
techniques which are used to enhance the aqueous solubility. The ability to
increase aqueous solubility can thus be a valuable aid to increase efficiency
and/or reduce side effects for certain drugs. This is true for parenterally,
topically and orally administered solutions.
 
General parameters affecting solubility are particle size, shape and surface area
physicochemical properties of drugs, and physical forms of drugs, solvents, pH
of the medium, temperature and use of surfactants[3]. The pharmacopoeia lists
solubility in terms of dissolve 1g of solute. If exact solubilities are not known,
the pharmacopoeia provides general terms to describe a given range. These
descriptive terms are listed in (Table 1).
 
NEED OF SOLUBILITY
 
Therapeutic effectiveness of a drug depends upon the bioavailability and
ultimately upon the solubility of drug molecules. Solubility is one of the
important parameter to achieve desired concentration of drug in systemic
circulation for pharmacological response to be shown[5]. Due to advanced
research & development, there are varieties of new drugs & their derivatives
are available. But more than 40% of lipophilic drug candidates fail to reach
market due to poor bioavailability, even though these drugs might exhibit
potential pharmacodynamic activities. The lipophilic drug that reaches market
requires a high dose to attain proper pharmacological action. The basic aim of
the further formulation & development section is to make that drug available at
proper site of action within optimum dose[6].
 
MECHANISM OF SOLUBILITY
 
The term ‘solubility’ is defined as maximum amount of solute that can be
dissolved in a given amount of solvent. It can also be defined quantitatively as
well as qualitatively. Quantitatively it is defined as the concentration of the
solute

PROCESS OF SOLUBILISATION[5]
The process of solubilisation involves the breaking of inter-ionic or intermolecular bonds in the
solute, the separation of the molecules of the solvent to provide space in the solvent for the solute,
interaction between the solvent and the solute molecule or ion.

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MECHANISM OF HYDROTROPE ACTION[2]

A hydrotrope is a compound that solubilises hydrophobic compounds in aqueous solutions.
Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (like surfactants) but the
hydrophobic part is generally too small to cause spontaneous self-aggregation. Hydrotropes do not
have a critical concentration above which selfaggregation 'suddenly' starts to occur. Instead, some
hydrotropes aggregate in a step-wise self-aggregation process, gradually increasing aggregation size.
However, many hydrotropes do not seem to selfaggregate at all, unless a solubilisate has been added.
Maheshwari et al[10]; enhanced the aqueous solubility of paracetamol, a poorly water-soluble drug
by use of concentrated solution of urea (a hydrotropic agent). This hydrotropic phenomenon was
employed to prepare solid dispersion (SD) and syrup of paracetamol. SD was evaluated for
dissolution rate and a marked increase in dissolution rate was observed with SD. IR analysis revealed
that there was no complexation/interaction between paracetamol and urea. Paracetamol syrups
prepared with urea showed good chemical stabilities.

SELECTION OF HYDROTROPES FOR POORLY WATER-

SOLUBLE DRUGS[11]
It is evident from the literature survey that more is the concentration of hydrotrope; more is the
aqueous solubility of poorly water-soluble drugs. Therefore, highly concentrated solutions of
hydrotropic agents were used in the present investigation. Distilled water was used in making
hydrotropic solutions. 2 M sodium benzoate (2 M SB), 2 M niacinamide (2 M NM), 2 M sodium
salicylate (2 M SS), 4 M sodium acetate (4 M SA), 10 M urea (10 M UR) and 1.25 M sodium citrate
(1.25 M SC) were employed as hydrotropic solutions.

In order to select suitable hydrotropes (for sufficient enhancement in solubility) for various poorly
watersoluble drugs, following method (an approximate solubility determination method) was used.
Twenty five ml of distilled water/hydrotropic solution was taken in a 50 ml glass bottle and gross
weight (including the cap) was noted. Then, few mg (by visual observation) of fine powder of drug
was transferred to the bottle. The bottle was shaken vigorously (by hand). When drug got dissolved,
more drugs (few mg by visual observation) were transferred to the bottle and again the bottle was
shaken vigorously. Same operation was repeated till some excess drug remained undissolved (after
constant vigorous shaking for 10 minutes).

Then, again gross weight was noted. From the difference in two readings (of weight), an approximate
solubility was determined and solubility enhancement ratios (solubility in hydrotropic
solution/solubility in distilled water) were calculated for all selected drugs for all six hydrotropic
solutions. When the determined solubility enhancement ratio was at least 5, such hydrotropic solution
was selected for that drug. R K Maheshwari, Mithun Singh Rajput, Sampada Sinha[23] were
developed titrimetric analysis method to solubilize the slightly water soluble topical antifungal drug,
benzoic acid by 1.0 M calcium disodium edetate solution. There was more than 15 fold enhancement

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in aqueous solubility of benzoic acid in 1.0 M calcium disodium edentate solution as compared to the
solubility in distilled water. Jayakumar C, Deepak Kumar K, Nesakumar D, Nagendra Gandhi N[15]
were performed titrimetric estimation has been developed using 2 M sodium salicylate as a
hydrotropic solubilizing agent for the quantitative determination of theophylline in bulk, a sparingly
water?soluble keratolytic drug. There was more than a 18?fold enhancement in aqueous solubility of
theophylline in 2 M sodium salicylate solution. The results of analysis obtained by the proposed
method are comparable with the results of a

As a most discussed but still not completely resolved issue, solubility or dissolution enhancement
techniques remain a most vibrant field for the researchers in formulation science. Solubility and
dissolution are the core concepts of any physical or chemical science including biopharmaceutical
and pharmacokinetic considerations in therapy of any medicine. But as the synthetic approach is
growing successfully to deliver many promising lead compounds for most of the pharmacological
categories, they are also taking the molecules towards bulkier structures.

As a result, more than 40% of new candidates entering drug development pipeline fail because of
non-optimal biopharmaceutical properties 1. These properties e.g. rate and extent of absorption, rate
of distribution, dose to achieve minimum effective concentration and to avoid side effects can exert a
significant influence on the drug’s absorption, distribution, metabolism, excretion, and toxicity. Over
the years, tools of drug discovery have caused a perceptible shift in biopharmaceutical properties.

Pharmaceutical companies have been primarily employing two strategies: rational drug design
(RDD) and high throughput screening (HTS) for drug discovery. In both, lead compounds are
identified according to screening in an environment in relation to biological system. RDD generally
lead to compounds with higher molecular weight which ultimately result in to poorer permeability.

On the other hand, HTS has led to compounds with increased lipophilicity and molecular weight; this
consequently gives poorer solubility characteristics. Drugs have this property of lipophilicity too
little or too much is a bad thing. When this property expressed as Log P gets above about 5, the drug
is getting too lipophilic 2.

The idea of permeability and solubility characteristics had been helpful to classify the drug under
four classes prescribed by Biopharmaceutics Classification System (BCS). The poor solubility and
low dissolution rate of poorly water soluble drugs in the aqueous gastro-intestinal fluids often cause
insufficient bioavailability. Especially for class II substances, the bioavailability may be enhanced by
increasing the solubility and dissolution rate of the drug in the gastro-intestinal fluids 3.

Therefore, uptake of poorly soluble drug cannot be completed within the time at absorption site due
to slow dissolution rate and perhaps leading to possibilities of gastric decomposition of drug due to
longer GI residence time. There are two parameters useful for identifying poorly soluble drugs. One
is its aqueous solubility should be less than 100ug/ml and another is dose: solubility ratio. Dose to

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solubility ratio can be defined as volume of gastrointestinal fluids necessary to dissolve the
administered dose.

Recently, a quantitative BCS has highlighted the importance of transit flow, in addition to solubility
and permeability, on the drug absorption process 4. The BCS defines three dimensionless numbers-
dose number (Do), dissolution number (Dn), and absorption number (An) to characterize drug
substances 5. These numbers are a combination of physicochemical properties of the drug and
physiological parameters. The Do attaches a physiological relevance to dose by considering the
volume of fluid required to dissolve the total dose. Drugs with Do < 1 are classified as highly soluble,
whereas those with Do > 1 are termed poorly soluble. In a recent attempt to categorize WHO
essential drugs based on BCS, 27.7% of drugs were reported to be poorly soluble 6. The BCS has not
only transformed the way scientists today approach drug delivery, but it has also revolutionized the
development of new drug molecules.

The solubility of a substance at a given temperature is defined as the concentration of the dissolved
solute, which is in equilibrium with the solid solute. Solubility of molecules depends on H-bond
donor and acceptor properties of the molecule and of water and crystal lattice of molecule. Effects of
these factors can be well explained by equation 1 7

Techniques for Dissolution Enhan- cement

There are several techniques reported in literature for formulation of hydrophobic
drugs with enhanced dissolution rate. These techniques are carefully selected on
the basis of properties of drug, excipients and dosage forms.

Solid Dispersion
Solid dispersion is defined as a dispersion of one or more active ingredients in an
inert carrier or matrix at solid state prepared by the melting (fusion), solvent, or
melting- solvent method [6]. In melting method carrier is melted and drug is added
with stirring and melted until homogenous melt is obtained which is then cooled to
room temperature while in solvent method drug and carrier is dissolved in minimum
amount of solvent and solvent is removed by evaporation under reduced pressure [7].
Solid dispersions are also prepared by dissolving drug and carrier in a common
solvent followed by evaporation of the solvent. Melting-solvent method involves use
of heating and solvent action to dissolve the drug and carrier in solvent followed by
evaporation of the solvent. Solid dispersion technique improves the solubility,
dissolution rate, and as a result the bioavailability of poorly water-soluble drugs [8].

The higher dissolution rates of solid dispersions can be ascribed to a number of factors which includes:

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1. The formation of higher energy metastable states of the components as a function of the carrier system
being used and the proportion of carriers present [9].
2. The reduction of particle size to nearly a molecular level [10]. As the soluble carrier dissolves, the
insoluble drug is exposed to dissolution medium as very fine particles leading to an increase in both
surface area and solubilization for fast dissolution and absorption [6].
3. Formation of amorphous forms of drug and carriers [11].
4. The presence of carrier may also prevent aggregation of fine drug particles, thereby providing a larger
surface area for dissolution. The wetting properties are also greatly increased due to
the surfactant property of the polymer, resulting in decreased interfacial tension between the
medium and the drug, hence higher dissolution rates. The presence of carrier polymers also
inhibits crystal growth of the drug which facilitates faster dissolution [9].
5. Cosolvent effect on the drug by the water soluble carriers [11].
6. Intermolecular hydrogen bonds between drug and carrier [12].
7. Local solubilization effect of carrier at the diffusion layer [7].
Various factors affecting dissolution of drug from solid dispersion includes the method of
preparation of the solid dispersion, amount and properties of the polymer carriers, drug polymer
contact and drug-polymer interactions [13].

Inclusion Complexation
This is most widely used method to enhance water solubility and increase stability of hydrophobic drugs
by using cyclodextrins.

Solid inclusion complexes can be prepared by using following methods:

a) Kneading Technique
In this technique, cyclodextrin (CD) is impregnated with water and converted to
paste. Drug is then added and kneaded for specified time. The kneaded mixture is
then dried and passed through sieve if required [14].

b) Coprecipitation
Required amount of drug is added to the solution of β-CD. The system is kept
under magnetic agitation with controlled process parameters and protected from
the light. The formed precipitate is separated by vacuum filtration and dried at
room temperature in order to avoid the loss of the structure water from the
inclusion complex [15].

c) Neutralization

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Drug is added in alkaline solution like sodium hydroxide, ammonium hydroxide. A

solution of - Cyclodextrin is then added to dissolve the joined drug. The clear
solution obtained after few seconds under agitation is neutralized using HCl
solution until reaching the equivalence point. At this moment, the appearance of a
white precipitate could be appreciated, corresponding to the formation of the
inclusion compound. The precipitate is then filtered and dried [16].

d) Co-grinding
Drug and cyclodextrin are mixed and the physical mixture is introduced in a suitable mill
like oscillatory mill and grinded for suitable time [15].

• Spray-Drying Method
Drug is dissolved in suitable solvent and the required stoichiometric amount of
carrier material like β cyclodextrin is dissolved in water. Solutions are then mixed
by sonication or other suitable method to

produce a clear solution, which is then spray- dried using spray dryer [15].

• Microwave Irradiation Method

Drug and cyclodextrins mixture is reacted in microwave oven to form inclusion. It is a novel
method for industrial scale preparation due to its major advantage of shorter reaction time and
higher yield of product [17].

Steam-Aided Granulation
Steam instead of water can be used in wet granulation because it provides a higher diffusion rate
into the powder and a more favorable thermal balance during the drying step. After condensation
of the steam, water forms a hot thin film, requiring only a small amount of extra energy for its
elimination and evaporates more easily. The use of steam instead of liquid water in a wet
granulation method can considerably decrease the amount of water used and as a result the whole
operational time [18].

Cogrinding / Comicronization
Cogrinding of a poorly water-soluble drug with water-soluble polymers like hydroxypropyl
methylcellulose (HPMC), poly vinyl alcohol (PVA) etc in the presence of small amount of water
is extremely effective to improve its apparent solubility with maintenance of drug crystallinity to
some extent [19]. Small particles produced by milling or micronization have increased surface
area and expected to have enhanced dissolution rate. However, energy added to reduce particle
size results in increased van der Waal’s interactions and electrostatic attraction between particles

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leading to reduce effective surface area due to agglomeration thus decreasing dissolution rate.
Comicronization of drugs by using excipients like microcrystalline cellulose can be used as an
alternative to reduce or eliminate cohesive and electrostatic forces. This approach increases
apparent surface area available for drug dissolution by creating an ordered mixture, thereby
causing

a reduction in particle-particle agglomeration or by reducing van der Waal’s

interactions. Increase in true surface area of the ordered powdered mixture is
expected due to the inherent surface roughness and porosity of the microcrystalline
cellulose-drug mixture [20].

Lipid-based formulations
Lipid-based delivery systems like emulsions, microemulsions, liposomes,
microspheres, solid-lipid nanoparticles, etc have ability to avoid resistant chemical
and physical barriers to oral absorption and are most successful in enhancing the
bioavailability of molecules that are poorly water-soluble but highly permeable
drug molecules (BCS class II). Some proposed mechanisms of action of lipid-
based systems to enhance oral bioavailability of compounds include [21]:

a) Particle size reduction to molecular size yielding a solid-state solution within the carrier.
b) Enhanced wetting of hydrophobic solids resulting in enhanced dissolution.
c) Increased rate of dissolution into aqueous environment from oil droplets of high surface
area.
d) Promotion of absorption via intrinsic lipid pathways.
e) Enhanced thermodynamic activity via supersaturation of the aqueous
environment of the gastrointestinal tract.

Melt granulation
powdered drugs are efficiently agglomerated by the use of a meltable binder
which can be a molten liquid, a solid or a solid that melts during the process usually
in high shear mixers, where the product temperature is raised higher than the melting
point of the binder either by a heating jacket or, when the impeller speed is high
enough, by the heat of friction generated by the impeller blades [22]. In this
technique no water or organic solvents are
needed and there is no drying step therefore the process is environmentally safe, less time
consuming and uses less energy than conventional wet granulation [23]. Polyethylene glycol is
widely used as a molten binder due to its complimentary solution properties, low melting point,
rapid solidification rate, low toxicity and little cost [22]. The increase in dissolution rate can be
ascribed to the hydrophilic character of the system due to the presence of water-soluble carriers and
the fact that the drug forms monotectic mixtures with PEG [23].

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Direct Compaction
In this process polymer like hydroxypropyl methylcellulose and drug is dry-blended, compressed
into slugs and then milled into a granular powder. The process results in enhanced dissolution rate
of poorly water- soluble drugs without the use of solvent or heat addition to overcome the
disadvantages of solid dispersion by these methods. This process is also cost effective and quicker.
The compaction processes are believed to be particularly effective at enhancing the rate of drug
dissolution because the drug particles are maintained in direct contact with the polymer particles
during drug dissolution, in contrast with a physical mixture where the drug and polymer particles
may rapidly disperse and be separated in the dissolution medium [24].

Solvent Evaporation by Ultra-Rapid Freezing (URF)

This process involves freezing a drug contained in a polymer solution onto the surface of a
cryogenic substrate with a thermal conductivity (k) between 10 and 20 W/(m K), collecting the
frozen particles and removing the solvent. Because of rapid conductive heat transfer, resulting in
high supersaturation and nucleation rates, the URF technology has the potential to create powders
with superior physicochemical properties, similar to those produced by other rapid freezing
technologies. As in other freezing technologies, the rapid freezing of

the drug/polymer composition is decisive in preventing phase separation

during freezing, allowing for the active to be molecularly dispersed with the
polymer. Recrystallization of the drug is avoided by the inclusion of high
glasstransition temperature (Tg) polymers such as PVP or hypromellose (HPMC).
This technique is widely applicable to enhance in- vivo absorption for the BCS class
II compounds [25].

Coevaporate System / Coprecipitation

Weak basic drugs like prochlorperazine maleate contain good solubility in acidic
pH but in alkaline pH solubility is significantly reduced and when a conventional
formulation containing weak base is given orally precipitation of poorly soluble
free base occurs within formulation in intestinal fluid. Precipitated drug is no
longer capable of release from formulation leading to decrease in bioavailability of
drug. This problem can be solved by use of coevaporate system which incorporates
a carrier with solubilizing effect in alkaline intestinal fluid which may operate in
the microenvironment, immediately surrounding the drug particle and polymers for
controlling the dissolution rate to formulate dosage forms ensuring maximum
bioavailability with controlled release of weak base [26].

Ordered/Interactive Mixing
Ordered mixing is described as method to prepare ordered units in the mix such
that the ordered unit will be the smallest possible sample of the mix and will be of

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near identical composition to all the other ordered units in the mix. Ordered mixing
yields nearly the perfect mix and may be obtained in a number of ways like
mechanical means, adhesion, coating and other methods [27]. Prerequisite for fast
dissolution from an ordered mixture includes that the carrier particle should
dissolve rapidly, delivering a fine particulate suspension of drug particles [28].
Higher concentration of drug shows reduced dissolution rates particularly at
loadings above monolayer coverage

because high concentration of drug forms agglomerates rather than discrete particles with resulting
decreased surface area and thicker diffusional layers causing reduction in dissolution rates [29]. In
an ordered powder mix fine drug particles are distributed fairly evenly on coarse carrier particles.
The drug powder is therefore deagglomerated in the dry state. This may be used to increase the
dissolution rate of drug powders because a larger contact surface area is exposed to the dissolution
medium [28].

Adsorption of Drugs onto High Surface Area Carriers

In this technique drug is absorbed onto carriers having large surface area (like crosslinked
polyvinylpyrrolidone, Kollidone) from solutions of the drug in appropriate solvents like methanol,
polyethylene glycol, and 2-pyrrolidone. The dissolution rate of drug increases due to increase in
surface area and drug particles have good wettability due to the surrounding solubilising materials
[30].

Liquisolid Compacts
Liquid Compacts are compressible powdered forms of liquid medications. The term “liquisolid
medication” implies oily liquid drugs and solutions or suspensions of water- insoluble drugs
carried in suitable non- volatile solvent systems. Using this technique, a liquid medication may be
converted into a dry, non-adherent, free flowing and compressible powder by a simple blending
with selected powder excipients such as the carrier and coating material. Surfactants like tweens
are used to improve aqueous solubility of poorly soluble drugs [31].

Solvent Deposition / Evaporation

In this technique drug is dissolved in a solvent like methylene chloride to produce a clear solution.
The carrier is then dispersed in the solution by stirring and the solvent is removed by evaporation
under temperature and pressure. The resultant mass is then

dried, pulverized, and passed through a sieve. The Increase in the

dissolution rate is ascribed to the reduced particle size of the drug deposited on the
carrier and enhanced wettability of the particles brought about by the carrier [32] .

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Carriers for Dissolution Enhance- ment

Carriers, which are soluble and dissolve in water at a fast rate, are widely used in
pharmaceutical formulations to enhance dissolution of drugs. The carriers which
have been reported in literature are presented in Table 1 and are described in detail
under different categories.

Polymers
Polymers like polyethylene glycols (PEGs), hydroxypropyl methylcellulose (HPMC),
hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) etc when used in optimum
concentration lead to increase in dissolution rate due to reduction in particle size,
solubilization effect of the carrier, increase wettability and dispersibility, formation of
hydrogen bonds between drug and carrier (Table 2). When polymers are used in higher
proportion these can decrease dissolution rate due to leaching out of the carrier during
dissolution which might form a concentrated layer of solution around the drug particles and
the migration of the released drug particles to the bulk of the dissolution medium slows down
[12].

Solid dispersions (SDs) of glyburide were prepared using PEG 4000, PEG 6000
and a mixture of PEG 4000 and PEG 6000 (1:1 ratio) by fusion and solvent
method and selected solid dispersions were lyophilized. The dispersion containing
glyburide/PEG 6000, 1:8, showed 14-fold increase in dissolution and dispersion
containing glyburide/PEG 4000, 1:10, showed an 8-fold and dispersion containing
6 parts of PEG mixture show 12-fold increase as compared with pure drug.
Lyophylization of solid dispersions further supplement dissolution

Table 1: Classification of carriers enhancing dissolution of drugs

S/N Category Example of carriers

1. Polymers Polyvinylpyrrolidone, Polyvinylpolypyrrolidone,

Polyvinyl alcohol, Polyethylene glycols,
Hydroxypropyl methylcellulose, Hydroxypropyl
cellulose, Poly (2- hydroxyethylmethacrylate), Methacrylic
copolymers (Eudragit®
S100 sodium salts and Eudragit® L100 sodium salts)

2. Superdisintegrants Sodium starch glycolate, Croscarmellose sodium,

Cross-linked polyvinylpyrrolidone, Cross-linked alginic acid,
Gellan gum, Xanthan gum, Calcium silicate
3. Cyclodextrins β-Cyclodextrins, Hydroxypropyl-β-cyclodextrins
4. Carbohydrates Lactose, Soluble starch, Sorbitol, Mannitol,
β-(1-4)-2-amino-2-deoxy-D-glucose (Chitosan),
Maltose, Galactose, Xylitol, Galactomannan, British gum,
Amylodextrin
5. Surfactants Poloxamers (Lutrol® F 127, Lutrol® F 68), Polyglycolized glyceride (Labrasol), Polyoxyethylene sorbitan monoesters
(Tweens), Sorbitan esters (Spans), Polyoxyethylene stearates, Poly (beta-benzyl-L-aspartate) -b- poly (ethylene oxide), Poly

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(caprolactone) -b- poly (ethylene oxide)

6. Hydrotropes Urea, Nicotinamide, Sodium benzoate, Sodium salicylate, Sodium
acetate, Sodium-o-hydroxy benzoate, Sodium-p-hydroxy benzoate,
Sodium citrate
7. Polyglycolized glycerides Gelucire 44/14, Gelucire 50/13, Gelucire 62/05
8. Acids Citric acid, Succinic acid, Phosphoric acid
9. Dendrimers Starburst® polyamidoamine (PAMAM)
10. Miscellaneous Microcrystalline cellulose, Dicalcium phosphate, Silica gel,
Sodium chloride, Skimmed milk

due to increase in surface area and hence surface free energy [9].

Solid dispersions of norfloxacin with PEG 6000 in weight ratios of 10:90, 20:80, 30:70 and 50:50 were
prepared by fusion method. Solubility studies revealed no significant increase in solubility of norfloxacin
on addition of PEG. Dissolution studies showed maximum dissolution rate of drug with PEG 6000 in
30:70 and 20:80 weight ratios establishing the effect and importance of optimum weight fraction of
polymer [33].

Solid dispersions of piroxicam were prepared using polyvinylpyrrolidone K-30 in 1:0.5, 1:1, 1:2,
1:3, 1:5 and 1:6 ratio of drug to polymer by solvent method. The dissolution of drug in solid
dispersion was dependent on drug to

S/N. Polymer Technique

PVP ratio. The drug:PVP in 1:4 ratio, solid dispersion gave highest dissolution rate of
about a 38-fold higher than that of pure drug [12].

Carbamazepine/PEG 4000 and PEG 6000 solid dispersions were prepared by the
fusion method involving heating a physical mixture of carbamazepine and either PEG
4000 or PEG 6000 in 1:2, 1:4, 1:6 and 1:8
drug/carrier ratios, to the liquid state. Dissolution studies suggested that the dissolution of
carbamazepine from the solid dispersion was neither related to the molecular weight nor the weight
fraction of PEG. The enhancement in dissolution of solid dispersion may be ascribed to complex
formation between carbamazepine and PEG 6000 during melting and a polymorphic change during
the preparation of solid dispersion with carbamazepine

Table 2: Polymers and techniques employed for enhancing dissolution of poorly water soluble drugs

Drug Mechanism of Dissolution Enhancement Refere

1. Glyburide PEG 4000, PEG 6000 and Solid dispersion by fusion and Increase in surface area and hence surface free (9) there
mixtures solvent method energy resulting in an increase in the dissolution

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2. Norfloxacin PEG 6000 Solid dispersion by fusion method Solubilizing effect of PEG on the drug (33)
3. Piroxicam PVP K-30 Solid dispersion by solvent method Increase in drug wettability and the presence of (12)
intermolecular hydrogen bonds between
piroxicam and PVP
4. Carbamazepine PEG 4000 and PEG 6000 Solid dispersion by fusion method Complex formation between carbamazepine (34)
and PEGs during melting and a polymorphic
change during the preparation of solid
dispersion, with carbamazepine crystalling in
a metastable form of higher dissolution rate

5. Piroxicam PEG 4000 Solid dispersion by fusion and Increased wettability of drug, a local (7)
solvent method solubilization effect of carrier at the diffusion
layer, formation of amorphous phase of
piroxicam and particle size reduction resulted
from interaction of drug and PEG 4000

6. Flurbiprofen Polyvinyl pyrrolidone (PVP), Solid dispersion by solvent method Particle size reduction, improved (35)
Hydroxypropyl methylcellulose wettability of drug particle by the
(HPMC), Hydroxypropyl cellulose carriers, solubilizing effect of
(HPC), Poly ethylene glycol (PEG) carrier and possible conversion of
6000 crystalline drug into amorphous
form
7. Glibenclamide PEG 6000 Solid dispersion by fusion method Solubilizing effect of PEG on the drug (36)
8. Roxithromycin PEG 6000, HPMC K4M and Solid dispersion by coprecipitate Reduction of particle size of the drug and (10)
HPC method surface tension lowering effect of carriers
resulting in wetting of hydrophobic
roxithromycin surface
9. Gliclazide PEG 4000 and PEG 6000 Solid dispersion by solvent method Reduction of particle size resulting in (8)
enhancement of surface area and increase in
drug wettability

proportional to the increment in concentration of polymers from 0.5 to 3 % polymer solution. Angle of repose
and carr’s index studies indicated fine nature and good flow properties of the all formulations
[10].

Solid dispersions of gliclazide were prepared using PEG 4000 and PEG 6000 in 1:1, 1:3, and
1:5 ratio of drug to polymer by solvent method using chloroform as solvent. Drug: carrier ratio
of 1:5 was found to be optimum for improving dissolution rate of gliclazide for both polymer
systems and PEG 6000 solid dispersions showed faster dissolution than PEG 4000 solid
dispersions [8]. Solid dispersions of albendazole were prepared using PEG 6000 in 1:1, 1:3 and
1:5 ratio of drug to polymer by fusion, solvent and kneading method. Solid dispersions
improved dissolution compared to physical mixtures owing to increased surface area for mass
transfer, thermodynamically enhanced dissolution of a higher energy amorphous form from the
carrier, improved wetting and solubilization of the drug [37].

Solid dispersions of rofecoxib with PVP, PEG 4000 and PEG 6000 in 50%, 75% and 90% w/w
were prepared by hot-melt method. The solubility efficiency of polymers was in the order of
PVP >> PEG 4000 > PEG 6000 due to high amorphizing properties of PVP than the PEGs.
Significant dissolution improvement was observed at the highest carrier amoumt i. e. 90% and
was ascribed to the formation of interstitial solid solutions [2].

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15

Solid molecular dispersion of diclofenac sodium, naproxen and piroxicam using Poly
(2hydroxyethylmethacrylate) (PHEMA) hydrogel as carrier were prepared by solvent method
using 90:10 ethanol:water for diclofenac sodium, 100% ethanol for naproxen, and 100% acetone for
piroxicam. The results showed threshold drug loading level of about 30% in these solid dispersions,
above which amorphous

to crystalline transition may occur. The presence of hydrogen bonding between drug and polymer
improves the compatibility between

drug and polymer. Stability studies under varying conditions of humidity (22-92 RH %) showed
transition from clear sample to an opaque one on increasing humidity due to increased mobility in
the glassy PHEMA matrix and solid dispersion remains in amorphous form longer at low relative
humidity [38].

Coground mixtures of nifedipine, griseofulvin, and indomethacin were prepared by dispersing

drug in the fused PEG 6000 and then adding HPMC, MC, and PVA polymers to the mixture. After
cooling to room temperature, the solidified mass was ground using a ball mill. Then solvent like
water, methanol, ethanol, dichloromethane was added to observe the effect of solvents and further
ground and dried to remove solvent. The resultant mass was lightly pulverized to pass through a
200 µm screen. Hydroxyl groups in the water-soluble polymer participate in the solubility
enhancement and some interactions between drug and the polymer occurs during the cogrinding
process through the functional groups in a small amount of water added (highly polar
environment). Solubility also increased in the presence of organic solvents suggesting that the
pulverizing effect for drugs like nifedipine also promote the drug- polymer interactions [19].

Lipid based formulations of piroxicam were prepared using 1,2-dimyristoyl-sn-glycero-3-

phosphatidylcholine (DMPC) phospholipids alone in 1:1and 2:1 ratio of drug:DMPC and a
mixture of DMPC and PEG 4600 in 2:1:1 ratio. Dissolution studies showed highest increase in
drug release from combination of lipid with PEG as compared to lipid alone due to solubilizing
effect of PEG on the drug thus enhancing the dissolution rate. Storage stability studies at 4°, 25°
and 60°C revealed stability of at least 6 months but beyond this decrease in dissolution rates for
formulations containing PEG 4600 due to formation of a crystalline mass upon storage for
extended period. Stabilizers like polyvinyl alcohols can be added to increase storage stability of all
these preparations [21].

Fast release rate formulation of carbamazepine was prepared by melt granulation technique
using PEG 4000 as a melt binder without using solvents or water. Solid-state analysis indicated
only a limited reduction of the crystallinity of the drug and no changes in its polymeric form.
Granulates showed a significant improvement of in vitro drug dissolution behavior but the
intragranular addition of crospovidone (PVP- CL) was found to be necessary to produce tablets
with a satisfactory disintegration time and a remarkable increase of the drug dissolution rate
[22].

Granules of griseofulvin (2.5, 5.0%) were prepared by melt granulation technique using PEG
3350 and Gelucire 44/14 both in 20% concentration as a melt binder and transferred into hard

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gelatin capsules. Dissolution rate of all prepared granules was higher as compared to pure drug
and its physical mixtures. Granules having PEG as binder showed large dissolution
enhancement relative to both physical mixtures and drug alone while granules containing
Gelucire 44/14 as binder showed a significant dissolution enhancement as compared to drug but
slightly enhancement compared to physical mixtures. The increase in dissolution rate was
ascribed to the highly polar environment provided by water-soluble carriers, part of the drug
dissolved in the binder and formation of monotectic mixture of drug and PEG [23].

Compacts of naproxen, nifedipine, and carbamazepine at a 1:1 polymer:drug weight ratio were
prepared using HPMC USP Type 2208 (K3LV), HPMC USP Type 2910 (E3LV and E5LV) and
methyl cellulose polymers by slugging and roller compaction method. The roller compaction
and slugging methods produced comparable rate and extent of drug dissolution. This method
require no solvent or heat for formulation and is cost effective, quicker, readily scalable at
industrial scale [24].

Micronized danazol powders were prepared by ultra rapid freezing using polyvinylpyrro- lidone
K-15 at a 1:2 ratio and 0.55% total solid in either tert-butanol heated to 313 K or acetonitrile
solvent at room temperature with enhanced dissolution of danazol. Use of different solvents
markly alters surface morphology of powder. Danazol powder produced by acetonitrile were
spherical and uniform in size as a result of the more rapid and uniform cooling of the droplets
S/N Drug Superdisintegrant Technique Mechanism of Dissolution Enhancement Refer
relative to tert-butanol. This process is viable and robust for producing high surface area nano-
structured powders for enhancing dissolution [25].

Coevaporates of prochlorperazine maleate (PCPM) were prepared by solvent evaporation method

using hydroxypropyl methylcellulose phthalate as a carrier for solubilization of drug in alkaline
medium and ethyl cellulose, hydroxypropyl cellulose for controlling the dissolution rates of weak
basic drug PCPM. This method ensures maximum bioavailability with controlled release of drug
from preparation [26].

Fast-dissolving mucoadhesive microparticles for sublingual administration could be a suitable

alternative to fast-dissolving tablets because the sublingual absorption can be improved as a
consequence of prolonging residence time on the mucosa and reducing the amount of swallowed
drug. Low- swellable mucoadhesive methacrylic copolymers, namely viz. Eudragit ® L sodium salt
and Eudragit® S sodium salt, were used as effective carriers for the preparation of the
microparticles in ratio ranging from 15/85 to 85/15% (m/m) by spray drying. Their intrinsic
dissolution rates are faster than those of most commonly used mucoadhesive polymers. Piroxicam
was present in amorphous form in all the prepared microparticles which was anticipated due to H-
bond between the NH group of piroxicam and a CO group of the copolymers. The best delivery
system made of piroxicam and Eudragit ® L sodium salt in the ratio 70/30% (m/m) was able to
increase the apparent

Table 3: Superdisintegrants and techniques employed for enhancing dissolution of poorly water soluble drugs

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1. Naproxen Cross-linked Drug loading on the surface of a Higher surface area of the carrier and capillary (51) polyvinylpyrrolidone
carrier action of carrier

2. Methlprednisolone, Sodium starch glycolate Wet granulation Swelling action of carrier (44)
Phenylbutazone

3. Nifedipine Croscarmellose sodium and Physical mixtures Swelling action of croscarmellose sodium and (44)
Crospovidone capillary action of crospovidone

4. Oxazepam Cross-linked sodium (Ac-Di- Ordered mixing Swelling action of carrier (44)
Sol)

5. Furosemide Crospovidone Formation of coprecipitates by Capillary action of carrier (45) solvent method
6. Flurbiprofen Sodium starch glycolate Dispersible tablets by wet Swelling action of carrier (46) (Primogel) granulation
7. Tenoxicam Primogel, Ac-Di-Sol, and Coprecipitation/Solvent Swelling action of sodium starch glycolate, (47)
Kollidon CL evaporation method croscarmellose sodium and capillary action of
crospovidone
8. Amorphous Ibuprofen Cross-linked Solvent deposition Faster dissolution from amorphous ibuprofen, (48)
polyvinylpyrrolidone drug deposition on carrier surfaces and
polymer swelling
9. Aspirin Sodium starch glycolate, Direct compression Swelling action of sodium starch glycolate, (49)
Croscarmellose sodium, croscarmellose sodium and
Crospovidone capillary action of crospovidone

10. Hydrochlorthiazide Sodium starch glycolate, Direct compression Swelling action of carriers (49)
Croscarmellose sodium

11. Carbamazepine, Cross-linked By adsorption of drugs onto Capillary action of carrier (30)
Nifedipine polyvinylpyrrolidone (Kollidon high surface area carriers
CL-M)
12. Chloroquine phosphate Sodium starch glycolate, Wet Swelling action of sodium starch glycolate, (52)
granulation croscarmellose sodium and capillary
Croscarmellose sodium and action of crospovidone
Crospovidone

was independent of whether or not the water solvent contains an additional surfactant [43] and the
dissolution rate increased so markedly that about 90% of the composition has passed into solution
after two minutes.

Improvement of dissolution rate of nifedipine by solid deposition on high percentages of sodium starch
glycolate and croscarmellose sodium respectively, was explained by deagglomeration of the micronized
drug by the superdisintegrant particles and solid deposition upon the surface of strongly swelling
superdisintegrants which act as a carrier. As an effect of swelling of the superdisintegrants, the ‘wetted’
surface of the carrier increases, this promotes wettability and dispersibility of the particulate system [44].

Coprecipitates of furosemide-crospovidone were prepared by solvent method using methanol with

enhanced dissolution rate due to association between the functional group of furosemide and
crospovidone at the molecular level. The association was probably between imino and sulfonylamide
group of furosemide and carboxyl group of crospovidone [45].

Dispersible tablets of flurbiprofen were formulated using pregelatinised starch, microcrystalline cellulose
and sodium starch glycolate disintegrants alone and in different combinations containing different
concentrations of disintegrants by wet granulation method by employing starch paste as binder. Among

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all, tablets formulated by employing sodium starch glycolate disintegrated rapidly and gave faster
dissolution of flurbiprofen [46].

Coprecipitates of tenoxicam with sodium starch glycolate (Primogel), Ac-Di-Sol, and crosslinked PVP
(Kollidon CL) were prepared by solvent evaporation method with enhanced dissolution of tenoxicam.
Kollidon CL was found to be most effective disintegrant of the three evaluated, especially at 1:9 ratios
[47].

Drug/carrier systems of amorphous ibuprofen and cross-linked polyvinylpyrroli- done were prepared
as physical mixes, and drug was loaded onto the polymer by hot mix and solvent deposition method.
Increased dissolution rate of ibuprofen were achieved in the descending order of solvent deposition,
hot mixes, physical mixes. The increased dissolution rate could be ascribed to a combination of faster
dissolution from amorphous ibuprofen, drug deposition on carrier surfaces and polymer swelling [48].

Tablets of aspirin were prepared by direct compression technique using sodium starch glycolate,
croscarmellose sodium, crospovidone as superdisintegrants. It was found that the disintegration time
was comparable for tablets formulated with 1% croscarmellose sodium, 2% crospovidone, or 5%
sodium starch glycolate. However the dissolution of aspirin from these tablets varied in the following
descending order despite the closeness of their disintegration times: croscarmellose sodium, sodium
starch glycolate, crospovidone [49]. Similarly hydrochlorthiazide tablets were prepared by direct
compression method using sodium starch glycolate, croscarmellose sodium as superdisintegrants with
enhanced dissolution [50].

Carbamazepine and nifedipine were dissolved in methanol, polyethylene glycol, 2-pyrrolidone and
adsorbed onto the surface of cross-linked polyvinylpyrrolidone (Kallidone). The solvent binding
capacities decreased in the order of methanol, PEG 4000, 2-pyrrolidone. Improved dissolution rate of
drugs was observed due to high surface area of the carrier [30]. Similarly increase in dissolution rate of
naproxen by loading on surface of cross-linked polyvinylpyrrolidone was observed [51].

Tablets of chloroquine phosphate using sodium starch glycolate, croscarmellose sodium, and
crospovidone as disintegrants in 2% w/w concentration were prepared by wet granulation technique
using intragranular and extragranular methods. Disintegration
and dissolution studies revealed intragra- nular method of application of disintegrants more suitable which
help the tablet to burst into smaller particles as well as it may help to dissolve the drug faster.
Croscarmellose sodium incorporated intragranular method gave better results than extragranular method
as well as better than sodium starch glycolate and crospovidone incorporated extragranular and
intragranular methods for the chloroquine phosphate [52].
All above formulations prepared using superdisintegrant indicates that use of superdisintegrants is an easy
alternate to enhance dissolution of poorly water soluble drugs without the addition of any other excipient
and changing the methodology of preparation of specific drug. The only disadvantage associated with the
use of superdisintegrants is its cost but overall cost of formulation is less as compared to opting specific
measure to enhance dissolution.

Surfactants

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Various surfactants like Polyglycolized glyceride (Labrasol), Tweens, Spans, Polyoxyethylene stearates
and synthetic block copolymers like Poly (propylene oxide)-poly (ethylene oxide) – poly (propy- lene
oxide), an example of poloxamers based micelles, Poly (beta-benzyl-L- aspartate) -b- poly (ethylene
oxide), Poly (caprolactone) -b- poly (ethylene oxide) etc are used as carrier for dissolution enhancement
(Table 4). Improvement of drug solubility by using the amphiphilic surfactants is due to lowering surface
tension between drug and solvent, improvement of wetting characteristics and micellar solubilization of
the drugs. Micelles are supramolecular self assemblies of macromolecules where unimers are held by non-
covalent interactions. The core of the micelles solubilizes drugs whereas the corona/shell allows for their
suspension in aqueous media [1].

Solid dispersions of albendazole using poloxamer 407 as surfactant at 1:1, 1:3, 1:5 weight ratio were
prepared and results revealed a requirement of 0.75% as minimum concentration of poloxamer for
solubility enhancement due to surface active property and critical micellar concentration. The
albendazole-poloxamer melt (1:5 ratio) showed 16.1 fold dissolution rate and 9.4 fold in dissolution
efficiency as compared to that of pure drug due to solubilization effect in the diffusion layer [37].

Solid dispersions of rofecoxib were prepared by hot-melt method using poloxamers (Lutrol ®
F127 and Lutrol® F68) in 50%, 75% and 90% w/w proportion. Enhancement in solubility of system was
observed due to micellar solubilization and/or reduction of activity coefficient of the drug through
reduction of hydrophobic interaction(s) and higher dissolution was observed at high (90%) carrier
concentration [2].

Several liquisolid compacts were prepared by dispersing piroxicam in tween 80 as liquid to prepare
liquid medication of the different drug concentrations with different ratios of drug:tween 80 ranging
from 1:1 to 1:9 using binary mixture of microcrystalline cellulose (carrier powder)-silica (coating
material) and finally compressing. Results revealed enhanced dissolution rate because drug is already in
solution in tween 80 and same time drug is carried by powder particles of the liquisolid vehicle. Thus,
its release is accelerated due to increased wettability and surface availability to the dissolution medium
[31].

When an active agent given orally, it must first dissolves in gastric and/or intestinal fluids before it can
permeate the membranes of the GI tract to reach systemic circulation. Therefore, a drug with poor aqueous
solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane
permeability will typically exhibit permeation rate limited absorption. Hence, two areas focus on improving
the oral bioavailability of active agents include:
1. Enhancing solubility and dissolution rate of poorly water-soluble drugs
2. Enhancing permeability of poorly permeable drugs 1.

The solubility is defined as a maximum quantity of solute that can dissolve in a certain quantity of solvent or
quantity of solution at a specified temperature 2. Almost More than 90% drugs are orally administered. Drug
absorption, bioavailability, pharmacokinetic profile of orally administered drug substances is highly
dependent on solubility of that compound in aqueous medium. More than 90% of drugs are approved since
1995 have poor solubility. It is estimated that 40% of active new chemical entities (NCEs) identified in
combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble 3.
Solvent is defined asthe component which forms major constituent of a solution and is capable to dissolve

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another substance to form a uniformly disperse mixture at the molecular level.Soluteis defined as asubstance
that present in small quantity and dissolves in solvent 2.

Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of
drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in
systemic circulation for pharmacological response to be shown. Oral drug delivery is the simplest and
easiest way of administering drugs due to its convenience, good patient compliance, greater stability,
accurate dosage and easy production. Drug solubility is the maximum concentration of the drug dissolved in
the solvent under specific condition of temperature, pH and pressure. It is important to improve the
solubility and/or dissolution rate for poorly soluble drugs because these drugs possess low absorption and
bioavailability. As solubility is an important determinant in drug liberation hence it plays a key role in its
bioavailability. Any drug to be absorbed must be present in the form of an aqueous solution at the site of
absorption4.
Table 1: Solubility description table5
Parts of solvent
Definition required for one
part of solute

Very Soluble <1

Freely soluble 1 – 10
Soluble 10 – 30
Sparingly
30 – 100
soluble
Slightly 100 – 1000
Very slightly
1000 – 10,000
soluble
Insoluble > 10,000
4,6
BCS CLASSIFICATION
Class I: High permeability and solubility.
Formulation independent: The bioavailability of class I compounds is determined only by delivery of the
drug solution to the intestine.
Examples: Loxoprofen , Benzapril, Sumatriptan etc.

Class II: High permeability but low solubility

Formulation dependent: The bioavailability of class II compounds is limited by drug
solubility/dissolution.
Examples: Aceclofenac , Valsartan, Nimesulide, Loratadine etc.

Class III: Low permeability but high solubility

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Dependent on barrier properties: The bioavailability of class III compounds is limited by intestinal
permeability.
Examples: Atropine, Gabapentine, Topiramate etc.

Class IV: Low permeability and low solubility

Formulation and barrier properties dependent: The bioavailability of class IV compounds is limited both
by solubility/dissolution and intestinal permeability. Examples: Hydrochlorthiazide, Meloxicam,
Furosemide etc.

TECHNIQUES FOR SOLUBILITY ENHANCEMENT

There are various techniques available to improve the solubility of poorly soluble drugs.
Some of the approaches to improve the solubility are
Micronization4,8
Particle size reduction leads to increase in the effective surface area resulting in enhancement of solubility
and dissolution velocity of the drug. Micronization technique is used to improve dissolution rates of drugs
into the biological environment, in order to improve the oral bioavailability. Particle size reduction
methods include recrystallization of the solute particles from solutions using liquid antisolvents, along
with labor intensive techniques like crushing, milling, grinding, freeze drying and spray-drying. The rapid
expansion of supercritical solutions (RESS) is an alternative technique for the micronization of particles
using supercritical carbon dioxide to quickly and naturally reduce the particle sizes of various drugs.
Micronization has some limitations; micronization of sparingly or poorly soluble drugs is by no means a
guarantee of better dissolution and absorption. A hydrophobic powder with small particle size leads to
aggregation, making it difficult to disperse. The particles float on the dissolution medium because of
entrapped air. It is difficult to remove or wet these particles. All these effects, in fact, reduce the rate of
dissolution.

Nanonization2,4,8
Various nanonization strategies have emerged to increase the dissolution rates and bioavailability of
numerous drugs that are poorly soluble in water. Nanonization broadly refers to the study and use of
materials and structures at the nanoscale level of approximately 100 nm or less. Nanonization can result
in improved drug solubility and pharmacokinetics, and it might also decrease systemic side-effects. For
many new chemical entities with very low solubility, oral bioavailability enhancement by micronization
is not sufficient because micronized product has the tendency to agglomerate, which leads to decrease
effective surface area for dissolution, the next step is nanonization. There are different techniques used
for nanonization of drug including Wet milling, Homogenization, Emulsification-solvent evaporation
technique, Pear milling, Spray drying etc. There are many examples of nanonization of drugs. A.
Nanocrystals:
The term drug nanocrystals imply a crystalline state of the discrete particles, but depending on the
production method they can also be partially or completely amorphous. Drug nanocrystals can be
produced by bottom up technologies (precipitation methods) or alternatively by top down technologies
(size reduction methods). The at present most industrially feasible methods are the top down technologies,
all products on the market are made by size reduction.

B. Nanosuspension:
Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilised by
surfactants. Nanosuspension technology solved the problem of drugs which are poorly aqueous soluble

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and less bioavailability. Stability and bioavailability of the drugs can be improved by the Nanosuspension
technology. Nanosuspensions are prepared by using wet mill, highpressure homogenizer, emulsion?
solvent evaporation, melt emulsification method and super critical fluid techniques. Nanosuspensions can
be delivered by oral, parenteral, pulmonary and ocular routes.

C. Nanoemulsion:
Nanoemulsions are a nonequilibrium, heterogeneous system consisting of two immiscible liquids in which
one liquid is dispersed as droplets in another liquid. Emulsions with nanoscopic droplet sizes (typically in
the range of 20–200 nm) are often referred to as submicron emulsions. Nanoemulsions are composed of
oil droplets dispersed in an aqueous medium and stabilized by surfactant molecules. The methods used for
the production of nanoemulsions include HPH, microfluidization, ultrasonication and spontaneous
emulsification. Commercial products that are nanoemulsions include Estrasorb and Flexogan.

Conclusion
Numerous technological advancements have been introduced for dissolution enhancement of poorly
water soluble drugs. Most of these
Table 4: Surfactants and techniques employed for enhancing dissolution of poorly water soluble drugs

S/N Drug Surfactant Technique Mechanism of Dissolution Reference

enhancement
1. Albendazole Poloxamer Solid dispersion by Surface active property of the (37)
e222p17 407 hot melt method carrier, decreased crystallinity
of the product
2. Rofecoxib Poloxamers Solid dispersion by Micellar solubilization and/or (2)
(Lutrol® hot melt method reduction of activity coefficient

F127 and of the drug through reduction

Lutrol® F68) of hydrophobic interaction(s)

3. Piroxicam Labrasol Semi-solid dispersion Increase wetting and micellar (11)

solubilization of the drug
4. Piroxicam Tween 80 Liquisolid compact Increased wettability and (31)
surface availability of the
drug to the dissolution
medium

techniques utilize inert carriers which improve the drug’s physicochemical properties like solubility,
particle size, crystal habit etc. Some of the carriers are especially capable of forming highly water soluble
amorphous forms when the drugs are dispersed in them or by size reduction (co- micronization).
Complexation of drug with suitable carrier also alters the solubility and dissolution characteristics due to
extremely high aqueous solubility of the carrier. The solubility and dissolution rate improvements are also
expected due to co-solvency effect and solubilisation effect of carriers in aqueous vehicles. In a nutshell it
could be said that carrier induced physical modifications are an important tool to a formulation scientist in
designing immediate and fast release drug delivery systems. The article continues as Part II [Int J Health

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Res, Sept 2009; 2(3)] which describes applications of cyclodextrins, carbohydrates, hydrotropes,
polyglocolized glycerides, dendrimers, acids and other carriers in enhancing dissolution of drugs .

References

1. Ahuja N, Katare OP, Singh B. Studies on dissolution enhancement and mathematical modeling of drug
release of a poorly water-soluble drug using water-soluble carriers. Eur J Pharm Biopharm 2007;65:26-38.
2. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug
classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res
1995;12:413-420.
3. Chawdhary KPR, Vijayasrinivas S. Biopharmaceutical classification system. Indian Pharmacist 2004;7-
10.
4. Jaiswal SB, Brahmankar DM. Biopharmaceutics and pharmacokinetics. A Treatise; 1999; 25:165.
5. Vadnere MK. Coprecipitates and melts. In: Swarbrick J, Boylan, JC, editors. Encyclopaedia of
pharmaceutical technology 2nd ed. New York, USA: Marcel Dekker, Inc.; 2002. 641-647 p.
6. Pan RN, Chen JH, Chen RRL. Enhancement of dissolution and bioavailability of piroxicam in solid
dispersion systems. Drug Dev Ind Pharm 2000;26:989-994.
7. Reddy SJ, Gudsoorkar VR. Solid dispersions of gliclazide. Indian Pharmacist Aug. 2005; IV:82-84.
8. Betageri GV, Makarla KR. Enhancement of dissolution of glyburide by solid dispersion and
lyophilization techniques. Int J Pharm 1995;126:155-160.
9. Patro S, Choudhary AA. Effect of some hydrophilic polymers on dissolution rate of roxithromycin. Indian
J Pharm Sci 2005;67:334-341.
10. Karatas A, Nilufer Y, Baykara T. Improved solubility and dissolution rate of piroxicam using gelucire
44/14 and labrasol. IL Farmaco 2005;60:777-782.
11. Tantishaiyakul V, Kaewnopparat N, Ingkatawornwong S. Properties of solid dispersions of piroxicam in
polyvinylpyrrolidone K-30. Int J Pharm 1996;143:59-66.
12. Rouchotas C, Cassidy OE, Rowley G. Comparison of surface modification and solid dispersion
techniques for drug dissolution. Int J Pharm 2000;195:1-6.
13. Parikh RK, Mansuri NS, Gohel MC, Sonlwala MM. Dissolution enhancement of nimesulide using
complexation and salt formation techniques. Indian drugs 2005;42:149-153.
14. Moyano JR, Blanco MJA, Gines JM, Giordano F. Solid-state characterization and dissolution
characteristics of gliclazide-beta-cyclodextrin inclusion complexes. Int J Pharm 1997;148:211- 217.
15. Doijad RC, Kanakal MM, Manvi FV. Studies on piroxicam beta-cyclodextrin inclusion complexes. Indian
Pharmacist Jan 2007;VI:94-98.
16. Deshmukh SS, Potnis VV, Shelar DB, Mahaparale PR. Studies on inclusion complexes of ziprasidone
hydrochloride with beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin. Indian Drugs 2007;44:677-
682.
17. Cavallari C, Abertini B, Rodriguez MLG, Rodriguez
L. Improved dissolution behaviour of steam- granulated piroxicam. Eur J Pharm Biopharm 2002;54:65-
73.

Dr. shri R.M.S institute of science and technology

College of pharmacy
24

18. Sugimoto M, Okagaki T, Narisawa S, Koida Y, Nakajima K. Improvement of dissolution characteristics

and bioavailability of poorly water- soluble drug by novel cogrinding method using water-soluble
polymer. Int J Pharm 1998;160:11- 19.
19. Spence JK, Bhattachar SN, Wesley JA, Martin PJ, Babu SR. Increased dissolution rate and bioavailability
through comicronization with microcrystalline cellulose. Drug Dev Ind Pharm 2005;10:451-460.
20. Prabhu S, Ortega M, Ma C. Novel lipid based formulations enhancing the in vitro dissolution and
permeability characteristics of a poorly water- soluble model drug, piroxicam. Int J Pharm 2005;301:209-
216.
21. Perissutti B, Rubessa F, Mariarosa M, Voinovich D. Formulation design of carbamazepine fastrelease
tablets prepared by melt granulation technique. Int J Pharm 2003;256:53-63.
22. Yang D, Kulkarni R, Behme RJ, Kotiyan PN. Effect of the melt granulation technique on the dissolution
characteristics of griseofulvin. Int J Pharm 2007;329:72-80.
23. Mitchell SA, Reynolds TD, Dasbach TP. A compaction process to enhance dissolution of poorly water-
soluble drugs using hydrxypropyl methylcellulose. Int J Pharm 2003;250:3-11.
24. Overhoff KA, Engstrom JD, Chen B. Novel ultra- rapid freezing particle engineering process for
enhancement of dissolution rates of poorly water- soluble drugs. Eur J Pharm Biopharm 2007;65:57- 67.
25. Nagarsenker MS, Garad SD. Physical characterization and optimisation of dissolution parameters of
prochlorperazine maleate coevaporates. Int J Pharm 1998;160:251-255.
26. Lantz, RJ, Schwartz JB. Tablets. In: Lieberman HA, Lachman L, editors. Pharmaceutical dosage forms.
2nd ed. New York, USA: Marcel Dekker, Inc.; 2005. 15-20 p, 69 p.
27. Nystrom C, Westerberg M. The use of ordered mixtures for improving the dissolution rate of low
solubility compounds. J Pharm Pharmacol 1986;38:161-165.
28. Alway B, Sangchantra R, Stewart PJ. Modelling the dissolution of diazepam in lactose interactive
mixtures. Int J Pharm 1996;130:213-224.
29. Friedrich H, Fussnegger B, Kolter K, Bodmeier R. Dissolution rate improvement of poorly water- soluble
drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers. Eur
J Pharm Biopharm 2006;62:171-177.
30. Javadzadeh Y, Shadbad MRS, Jalali MB, Nokhodchi A. Enhancement of dissolution rate of piroxicam
using liquisolid compacts. IL Farmaco 2005;60:361-365.
31. Jalali MB, Maleki N, Garjani A, Khandar AA. Enhancement of dissolution rate and anti- inflammatory
effects of piroxicam using solvent deposition technique. Drug Dev Ind Pharm 2002;28:681-686.
32. Guyot M, Fawaz F, Bildet J, Bonini F, Lagueny AM. Physicochemical characterization and dissolution of
norfloxacin / cyclodextrin inclusion compounds and PEG solid dispersions. Int J Pharm 1995;123:53-63.
33. El-Zein H, Riad L, El-Bary AA. Enhancement of carbamazepine dissolution: in vitro and in vivo
evaluation. Int J Pharm 1998;168:209-220.
34. Ganesan V, Sivakumar SM, Kannadasan M. Enhancement of dissolution rate of flurbiprofen. Indian
Pharmacist 2004;III:61-64.
35. Tashtoush BM, Al-Qashi ZS, Najib NM. Invitro and invivo evaluation of glibenclamide in solid
dispersion systems. Drug Dev Ind Pharm 2004;30:601-607.
36. Kalaiselvan R, Mohanta GP, Manna PK, Manavalan R. Studies on mechanism of enhanced dissolution of
albendazole solid dispersions with crystalline carriers. Indian J Pharm Sci 2006;599- 607.
37. Zahedi P, Lee PI. Solid molecular dispersions of poorly water-soluble drugs in poly(2hydroxyethyl
methacrylate) hydrogels. Eur J Pharm Biopharm 2007;65:320-328.

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38. Cilurzo F, Selmin F, Minghetti P. Fast-dissolving mucoadhesive microparticulate delivery system

containing piroxicam. Eur J Pharm Sci 2005;24:355-361.

Dr. shri R.M.S institute of science and technology

College of pharmacy