Journal of Applied Pharmaceutical Science Vol. 2 (10), pp.

170-175, October, 2012

Available online at http://www.japsonline.com
DOI: 10.7324/JAPS.2012.21031
ISSN 2231-3354

Solid Dispersion: Methods and Polymers to increase the solubility of

poorly soluble drugs
Ladan Akbarpour Nikghalb1, Gurinder Singh2, Gaurav Singh2 and Kimia Fazaeli Kahkeshan1*
1
Gautam College of Pharmacy, Bangalore, Karnataka, India.
2
Department of Pharmaceutics, Al-Ameen College of Pharmacy Bangalore, Karnataka, India.

ARTICLE INFO ABSTRACT

Article history: The solubility behaviour of drugs remains one of the most exigent aspects in formulation development.
Received on: 27/09/2012 These days, the number of new chemical entities has dramatically increased having hiccups of poor
Revised on: 14/10/2012 solubility and poor permeability. Solid dispersion as a dosage form has been established a superior option
Accepted on: 24/10/2012 for the drugs having poor aqueous solubility. Solid dispersions in water-soluble carriers have engrossed
Available online: 30/10/2012
considerable interest as a means of improving the dissolution rate and bioavailability of hydrophobic
drugs. Although solid dispersions have tremendous potential for improving drug solubility and only a few
Key words:
marketed products using this approach. There are various methods available to improve the solubility of
Dissolution,
Solid Dispersion, the new drug in which solid dispersion emerged promising. A Solid dispersion generally composed of two
Solubility, components- the drug and the polymer matrix. Numerous methods are existing to prepare the solid
Cellulose Derivatives, dispersions such as melting method, solvent evaporation method, fusion method, kneading method,
Polyethylene glycol. melting method, spray drying method, co-grinding method, lyophilization technique, hot melt extrusion,
melt agglomeration, supercritical fluid (SCF) technology etc. A variety of hydrophilic carriers have been
investigated for enhancement of dissolution characteristics and bioavailability of poorly aqueous-soluble
drugs. In this review an endeavour is made to discuss about the comprehensive methods of preparation
and numerous carriers are used for solid dispersions.

INTRODUCTION available such as liquisolid, in which drug in solution state or

dissolved drug is adsorbed over insoluble carriers (Nokhodchi et
Solubility is a significant physicochemical factor
al., 2005; Spireas et al., 1992; Javadzadeh et al., 2005). To
affecting absorption of drug and its therapeutic effectiveness.
improve wettability and solubility of various lipophilic substances
Formulation development would lead to be failure if drug having
surfactants can also be used in formulations (Bakatselou et al.,
poor aqueous solubility. The low dissolution rate and low
1991). Micronization of drug is not ideal because micronized
solubility of drug substances in water in aqueous G.I.T fluid
product has the propensity of agglomeration, which leads to
frequently leads to inadequate bioavailability. The venture to
reduced effective surface area for dissolution. But solid dispersion
improve the solubility and dissolution of hydrophobic drugs
is the mainly promising method to formulators because of its
remain one of the trickiest tasks in drug development. Several
simplicity of preparation, ease of optimization, and reproducibility
methods have been introduced to triumph over this problem
(Chiou et al., 1971; Goldberg et al., 1966; Leuner et al., 2000).
(Ford, 1986; Dressman et al., 2000).
The term ‘solid dispersion’ has been employed to describe a family
For enhancement of solubility and dissolution rate of
of dosage forms whereby the drug is dispersed in a biologically
poorly soluble drugs, abundant commercially viable methods are
.

inert matrix, usually with a view to enhancing oral bioavailability

* Corresponding Author (Noyes et al., 1997; Nernst, 1994).
Kimia Fazaeli Kahkeshan The mechanism by which the solubility and dissolution
Department of Pharmaceutics,Gautam College of Pharmacy, rate of the drug is augmented includes: the particle size of the drug
Bangalore, Karnataka, India.
E-mail: Kimia.Kahkeshan@yahoo.com
is abridged to submicron size or to the molecular size in the case
.
 Nikghalb et al. / Journal of Applied Pharmaceutical Science 2 (10); 2012: 170-175 171

where solid solution is achieved. The particle size reduction Various formulation parameters that play a crucial role
usually enhances the rate of dissolution; the changed from for successful formulation are aqueous solubility, stability at
crystalline to amorphous form, the high energetic state which is ambient temperature and humidity, photo stability, compatibility
very soluble; finally the wettability of the drug particle is enhanced with solvents and excipients etc. Of these, solubility is the most
by the dissolution carrier. Regardless of these promising important property for developing formulations. As per recent
advantages, the application of solid dispersion in pharmaceutical report, 46% of the total NDAs filed between 1995 to 2002 were
industry has certain boundaries (Ford, 1986; Dressman et al., BCS class IV, while only 9% were BCS class I drugs, revealing
2000). that a majority of approved new drugs were water insoluble
With the recent dawn of high throughput screening of (Kumar et al., 2009).
potential therapeutic agents, the number of poorly soluble drug Various hydrophilic carriers such as polyethylene glycol
candidates has increased sharply and the formulation of poorly [PEG], polyvinylpyrrolidone [PVP], hydroxypropyl cellulose,
soluble compounds for oral delivery currently presents one of the hydroxypropylmethyl cellulose, gums, sugar, mannitol, urea,
most frequent and utmost challenges to formulation scientists in hydroxypropylmethyl cellulose phthalate, gelucires, eudragits
the pharmaceutical industry (Noyes et al., 1997; Nernst, 1994). (Singh et al., 2011) and chitosan have been investigated for
Only small amounts of solid dispersion products are commercially improvement of dissolution characteristics and bioavailability of
exist. This is due to their poor physical characteristic for dosage poorly aqueous soluble drugs (Prajapati et al., 2007). Hydrophilic
form formulation. The solid dispersions prepared by employing swellable polymers viz., sodium carboxymethyl cellulose, sodium
water soluble carrier are soft and tacky mass which is hard to starch glycolate and pregelatinized starch are also used (Modi et
handle, particularly in the capsule-filling and tablet making al., 2006).
development e.g, pulverization, sieving and mixing.
Consideration of the modified Noyes-Whitney equation METHODS FOR PREPARING SOLID SOLUTIONS
gives some hints as to how the dissolution rate of even very poorly Kneading Technique
soluble compounds might be improved to diminish the limitations In this method, carrier is permeated with water and
to oral availability: transformed to paste. Drug is then added and kneaded for
particular time. The kneaded mixture is then dried and passed
through sieve if necessary.

Solvent evaporation method

where dC/dt is the rate of dissolution, A is the surface area
In this method, both drug and carrier are dissolved in
available for dissolution, D is the diffusion coefficient of the
organic solvent. After entire dissolution, the solvent is evaporated.
compound, Cs is the solubility of the compound in the dissolution
The solid mass is ground, sieved and dried. Ex. Solid dispersion of
medium, C is the concentration of drug in the medium at time t
furosemide with eudragits was prepared by solvent evaporation
and h is the thickness of the diffusion boundary layer adjacent to
method (Rasenack et al., 2003).
the surface of the dissolving compound.
More particularly, Chiou and Riegelman, 1971 defined Co-precipitation method
these systems as ‘the dispersion of one or more active ingredients Required amount of drug is added to the solution of
in an inert carrier matrix at solid-state prepared by the melting carrier. The system is kept under magnetic agitation and protected
(fusion), solvent or melting- solvent method’, while Corrigan from the light. The formed precipitate is separated by vacuum
(1985) suggested the definition as being a ‘product formed by filtration and dried at room temperature in order to avoid the loss
converting a fluid drug-carrier combination to the solid state’ of the structure water from the inclusion complex (Moyano et al.,
(Corrigan, 1985). In practice, these dosage forms have been 1997).
conventionally considered as being indistinguishable with systems
whereby the in vitro release of the drug is enhanced compared to Melting method
conventional dosage forms, with allied implications for in vivo Drug and carrier are mixed using mortar and pestle. To
release. accomplish a homogenous dispersion the mixture is heated at or
The main possibilities for improving dissolution above the melting point of all the components. It is then cooled to
according to this analysis are to increase the surface area available acquire a congealed mass. It is crushed and sieved. Ex.
for dissolution by decreasing the particle size of the solid albendazole and urea solid dispersion was prepared by this method
dispersion. However, the most attractive option for increasing the (Kalaiselvan et al., 2006).
release rate is improvement of the solubility through formulation
approaches like Polymorphs, Nanosuspensions, Co-grinding method
Pseudopolymorphs (including solvates), Use of cyclodextrines, Physical mixture of drug and carrier is mixed for some
Eutectic mixtures, Solid dispersions (non-molecular), Soluble time employing a blender at a particular speed. The mixture is then
prodrugs and salts (Leuner et al., 2000). charged into the chamber of a vibration ball mill steel balls are
172 Nikghalb et al. / Journal of Applied Pharmaceutical Science 2 (10); 2012: 170-175

added. The powder mixture is pulverized. Then the sample is problems associated with solvent evaporation (Bashiri et al.,
collected and kept at room temperature in a screw capped glass 2003).
vial until use. Ex. chlordiazepoxide and mannitol solid dispersion
was prepared by this method (Nokhodchi et al., 2007). Melt Extrusion Method
Solid dispersion by this method is composed of active
Gel entrapment technique ingredient and carrier, and prepare by hot-stage extrusion using a
Hydroxyl propyl methyl cellulose is dissolved in organic co-rotating twin-screw extruder. The concentration of drug in the
solvent to form a clear and transparent gel. Then drug for example dispersions is always 40% (w/w). Melt extrusion technique is used
is dissolved in gel by sonication for few minutes. Organic solvent in the preparation of diverse dosage forms in the pharmaceutical
is evaporated under vacuum. Solid dispersions are reduced in size industry e.g. sustained-release pellets (Karanth et al., 2006).
by mortar and sieved (Bhise et al., 2008).
Melt Agglomeration Process
Spray-Drying Method This technique has been used to prepare Solid Dispersion
Drug is dissolved in suitable solvent and the required where the binder acts as a carrier. SD(s) are prepared either by
amount of carrier is dissolved in water. Solutions are then mixed heating the binder, drug and excipient to a temperature above the
by sonication or other suitable method to produce a clear solution, melting point of the binder or by spraying a dispersion of drug in
which is then spray dried using spray dryer (Bakatselou et al., molten binder on the heated excipient by using a high shear mixer
1991). (Tsinontides et al., 2004). A rotary processor has been shown to be
alternative equipment for melt agglomeration because of easier
Lyophilization Technique control of the temperature and because higher binder content can
Freeze-drying involves transfer of heat and mass to and be incorporated in the agglomerates (Vilhelmsen et al., 2005).
from the product under preparation. This technique was proposed
as an alternative method to solvent evaporation. Lyophilization has CARRIERS
been thought of a molecular mixing technique where the drug and
carrier are co dissolved in a common solvent, frozen and sublimed Polyethylene glycol (PEG)
to obtain a lyophilized molecular dispersion (Betageri et al., 1995). Polyethylene glycols (PEG) are polymers of ethylene
oxide, with a molecular weight (MW) usually falling in the range
Electrospinning Method 200-300000. For the manufacture of solid dispersions and
The electrospinning technology used in the polymer solutions, PEGs with molecular weights of 1500-20 000 are
industry combines solid solution/dispersion technology with usually employed. As the MW rises, so does the viscosity of the
nanotechnology. In this procedure, a liquid stream of a PEG. At MW of up to 600, PEGs are fluid, in the range 800 -1500
drug/polymer solution is subjected to a potential between 5 and 30 they have a consistency that is best described as vaseline-like,
kV. When electrical forces prevail over the surface tension of the from 2000 to 6000 they are waxy and those with MW of 20 000
drug/polymer solution at the air interface, fibers of submicron and above form hard, brittle crystals at room temperature. Their
diameters are produced. As the solvent evaporates, the formed solubility in water is generally good, but reduces with MW. A
fibers can be collected on a screen to give a nonwoven fabric, or meticulous advantage of PEGs for the solid dispersions is that they
they can be collected on a spinning mandrel (Deitzel et al., 2001). have good solubility in numerous organic solvents. The melting
This technique has tremendous potential for the preparation of point of the PEGs of interest lies under 65 0C in every case (e.g.
nanofibres and controlling the release of biomedicine, as it is the m.p. of PEG 1000 is 30-400C, the m.p. of PEG 4000 is 50-
simplest and the cheapest this technique can be utilized for the 588C and the m.p.of PEG 20 000 is 60-630C) (Price JC et al.,
preparation of solid dispersions in future (Zhang et al., 2007). 1994). Additional attractive features of the PEGs include their
ability to solubilise some compounds (Betageri et al., 1995) and
Dropping method solution also to improve compound wettability. Even the dissolution rate of
The dropping method, developed by Ulrich et al. (1997) a relatively soluble drug like aspirin can be improved by
to facilitate the crystallization of different chemicals, is a new formulating it as a solid dispersion in PEG 6000 (Asker et al.,
procedure for producing round particles from melted solid 1975).
dispersions. This technique may overcome some of the difficulties
inherent in the other methods. For laboratory-scale preparation, a Problems with PEGs
solid dispersion of a melted drug-carrier mixture is pipette and In general, there are few toxicity concerns associated
then dropped onto a plate, where it solidifies into round particles. with the PEGs and they are approved for many purposes as
The use of carriers that solidify at room temperature may aid the excipients. The low molecular weights PEGs do, however, tend to
dropping process. The dropping method not only simplifies the show slightly greater toxicity than those of higher molecular
manufacturing process, but also gives a higher dissolution rate. It weight (Price et al., 1994). In addition, a vast number of drugs are
does not use organic solvents and, therefore, has none of the attuned with the PEGs. A hardly any cases have been observed in
 Nikghalb et al. / Journal of Applied Pharmaceutical Science 2 (10); 2012: 170-175 173

which the PEG confirmed to have stability problems during many of the others it is resistant to dissolution under gastric
manufacture by the hot melt method. (acidic) conditions. It dissolves readily at pH values above 5-6,
with lowest dissolution pH being dependent on the grade of the
Polyvinylpyrrolidone (PVP) CMEC. CMECs also dissolve readily in acetone, isopropanol 70%,
Polymerization of vinylpyrrolidone leads to ethanol 60% and 1:1 mixtures of dichloromethane and ethanol.
polyvinylpyrrolidone (PVP) of molecular weights ranging from Amorphous solid dispersions of nifedipine and spironolactone
2500 to 3000 000. These can be classified according to the K show enormous increases in the dissolution rate of the drug at pH
value, which is calculated using Fikentscher's equation (Walking values of 6.8 (Okimoto et al., 1997).
et al., 1994). The temperature of a given PVP is dependent not
only on its MW but also on the moisture content. In general, the 4. Hydroxypropylmethylcellulose phthalate (HPMCP)
glass transition temperature (Tg) is high; for example, PVP K25 HPMCPs are cellulose esters which are often used as
has a Tg of 1558C (Buèhler et al., 1993). For this reason PVPs enteric coatings. Depending on the grade, they dissolve first at pH
have only restricted application for the preparation of solid 5 (HP 50) or pH 5.5 (HP 55). They are having a type-dependent
dispersions by the hot melt method. Due to their excellent solubility in organic solvents. Their MWs ranges from 20,000 to 2
solubility in an ample variety of organic solvents, they are mostly 000,000 (Itai et al., 1985). The dissolution rate of griseofulvin at
suitable for the preparation of solid dispersions by the solvent pH 6.8 could be greatly enhanced by incorporating it in a
method. Improved wetting and thereby an improved dissolution coevaporate of HPMCP (Hilton et al., 1986). Using a spray-drying
rate from a solid dispersion in PVP has been demonstrated for technique to form a solid dispersion in HP 55, the dissolution rate
fufenamic acid (Itai et al., 1985). The aqueous solubility of the of the anti-fungal drug MFB-1041 could be increased by a factor
PVPs becomes poorer with increasing chain length and a further of 12.5 as compared to the best possible dissolution achievable by
disadvantage of the high MW PVPs is their much higher viscosity micronizing the drug (Harwood et al., 1994).
at a given concentration (Walking et al., 1994). Similarly, the
slower dissolution was observed of indomethacin from PVP K90 Polyacrylates and polymethacrylates
compared to PVP K12 was attributed to the higher viscosity Polyacrylates and polymethacrylates are glassy
generated by PVP K90 in the diffusion boundary layer adjacent to substances that are produced by the polymerization of acrylic and
the dissolving surface of the dispersion (Hilton et al., 1986). methacrylic acid, and derivatives of these polymers such as esters
amides and nitriles. In pharmaceuticals they are mainly used as
Cellulose Derivatives coatings to change the release of the drug from the dosage form.
1. Hydroxypropylmethylcellulose (HMPC) Commonly they are referred to by the trade name Eudragit drug
HPMCs are mixed ethers of cellulose, in which 16.5-30% (Harwood et al., 1994). Among the Eudragits, Eudragit E is often
of the hydroxyl groups are methylated and 4-32% are derivatized used to improve the release rate since it is soluble in buffer
with hydroxypropyl groups. For example, Type 2910 has an solutions at pH values up to 5 and swells at higher pHs, while
average methoxy content of 29% and an hydroxypropyl content of Eudragit L can be used when it is desirable to avoid release in the
10%. The molecular weight of the HPMCs ranges from about 10 stomach. When benipidine was formulated as a coevaporate with
000 to 1 500 000 and they are soluble in water and mixtures of Eudragit E, the rate of dissolution was much higher than from the
ethanol with dichloromethane and methanol with dichloromethane pure drug powder (Hasegawa et al., 1985; Asker et al., 1975). On
(Hilton et al., 1986). Other drugs which exhibit faster release from the other hand, Eudragit L has been successfully used to increase
solid dispersion in HPMC include the poorly soluble weak acids the dissolution of griseofulvin and spironolactone at a pH value of
nilvadipine (Hilton et al., 1986; Harwood et al., 1994) and 6.8. (Okimoto et al., 1997).
benidipine (Kohri et al., 1999).
Urea
2. Hydroxypropylcellulose (HPC) Urea is the end product of human protein metabolism,
Hydroxypropylcellulose (HPC) exhibits good solubility has a light diuretic effect and is regarded as non-toxic. Its
in a range of solvents, including water (up till 400C), ethanol, solubility in water is greater than 1 and it also reveals good
methanol and chloroform. The average MW of the HPCs ranges solubility in several common organic solvents. In one of the first
from 37 000 (Type SSL) to 1 150 000 (Type H) (Okimoto et al., bioavailability studies of solid dispersions, it was shown that
1997; Suzuki et al., 1996). Yuasa et al. carried out extensive sulphathiazole was better absorbed in rabbits when given as a
studies of the influence of the chain length and proportion of HPC eutectic with urea (Okimoto et al., 1997).
in the solid dispersion on the release behaviour of flurbiprofen. In the case of ursodeoxycholic acid the release rate from
The release rate enhanced as the ratio of HPC was amplified and urea dispersions prepared by the hot melt method was faster than
when lower MW HPCs were used as the carrier. from other carriers studied, including PEG 6000 (Hilton et al.,
1986). A two-fold increase in the dissolution rate of phenytoin has
3. Carboxymethylethylcellulose (CMEC) also been achieved with urea; however, in this case PEG 6000 was
CMEC also belongs to the cellulose ethers, but unlike far more efficient (Kohri et al., 1999).
174 Nikghalb et al. / Journal of Applied Pharmaceutical Science 2 (10); 2012: 170-175

Sugar, polyols and their polymers choice of the carrier it is also feasible to delay or slow down the
Although sugars and related compounds are highly water release pattern of a drug by formulating it into solid dispersion.
soluble and have few, if any, toxicity issues, they are less suitable
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