Indo American Journal of Pharmaceutical Research, 2014

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ISSN NO: 2231-6876

INDO AMERICAN
JOURNAL OF
PHARMACEUTICAL
RESEARCH

SOLID DISPERSION: A TECHNIQUE TO IMPROVE SOLUBILITY OF POORLY WATER

SOLUBLE DRUG
Mittal Ankit*, Yadav Manish, Choudhary Dinesh
Jaipur National University, Jaipur, Rajasthan 302017, India.
ARTICLE INFO
Article history
Received 07/06/2014
Available online
08/07/2014
Keywords
Solid Dispersion,
Solubility,
Bioavailability,
Biopharmaceutical
Classification System (BCS).

ABSTRACT
Solid dispersion is a strategy to improve solubility of poorly water soluble drug. Solid
dispersion is refers as dispersion of active ingredient in a carrier at solid state which is prepare
by melting method , solvent evaporation method, melt solvent method, kneading method,
spray drying method, freeze drying method, hot melt extrusion method, supercritical fluid
method, melt agglomeration process, co evaporation method, co-precipitation method etc. on
the basis of carriers solid dispersion is classified as first generation, second generation, third
generation solid dispersion. Solid dispersion can be evaluated for various characterizations
like drug carrier interaction, drug carrier miscibility, surface property, stability, amorphous
content, dissolution rate.

Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Mittal Ankit et al. Solid Dispersion: A Technique to Improve Solubility of Poorly Water Soluble
Drug. Indo American Journal of Pharm Research.2014:4(06).

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Corresponding author
Ankit Mittal
School of pharmaceutical Sciences
Jaipur National University,
Jaipur, Rajasthan 302017,
India.
ankitm815@gmail.com

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INTRODUCTION
The term solubility is defined as maximum amount of solute that can be dissolved in a given amount of solvent.
Quantitatively it is defined as the concentration of the solute in a saturated solution at a certain temperature. [1]
Table 1: Definitions of solubility [2]
Definition
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly soluble
Insoluble

Parts of solvent required for one part of solute

<1
1 10
10 30
30 100
100 1000
1000 - 10,000
> 10,000

There are several techniques to improve solubility of drug.

Figure 1:- Different approaches to improve solubility of poorly water soluble drugs [3]
Solid dispersion is defined as solid product consists of at least 2 components 1) hydrophilic carrier 2) hydrophobic drug.
Chiou and Riegelman defined solid dispersion as A dispersion of one or more active ingredient in an inert carrier or matrix at solid
state prepared by fusion, solvent or melting solvent method. The matrix can either be crystalline or amorphous.
Main purpose of making solid dispersion is to enhance solubility of drug. Drug candidate which comes under BCS class II have low
solubility and high permeability. General all classes of BCS is given below.
Table 2: BCS Classification [4]
Class
Class I
Class II
Class III
Class IV

Solubility
High
Low
High
Low

Permeability
High
High
Low
Low

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Classification of solid dispersion

Solid dispersion can be classified according to molecular arrangement.

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Figure 2:- Diagramatic repraesentation of Classification of solid dispersion based on molecular arrangement [5]
Classification of solid dispersion based on their molecular arrangement [6]
Table 3: Classification of solid dispersion based on their molecular arrangement.
Matrix

Drug

Observation

1.

Eutectics

2.

Amorphous precipitations
in crystalline matrix
Solid solution
Continuous
solid
solutions
Discontinuous
solid
solutions

The first type of solid dispersion

prepared
Rarely encountered

Substitutional solid
solutions

4.

Interstitial
solid solutions

5.

Glass suspension

6.

Glass suspension

7.

Glass solution

3.
I.
II.

III.

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Miscible at all proportion, never

prepared
Partially miscible, 2 phases even
though drug is molecularly
dispersed
Molecular diameter of drug
(solute) differs less than 15%
from the matrix (solvent)
diameter. In that case the drug
and matrix are substitutional.
Can be continuous or discontinuous.
When
discontinuous: 2 phases even
though drug is molecularly
dispersed.
Drug
(solute)
molecular
diameter less than 59% of
matrix
(solvent)
diameter.
Usually limited miscibility,
discontinuous. Example: Drug
in helical interstitial spaces of
PEG.
Particle size of dispersed phase
dependent
on
cooling/
evaporation rate. Obtained after
crystallization of drug in
amorphous matrix
Particle size of dispersed phase
Dependent
on
cooling/
evaporation rate. Many solid
dispersions are of this type
Requires miscibility OR solid
solubility, complex formation
upon
fast
cooling
OR
evaporation during preparation,
many
(recent)
examples
especially with PVP

No. of
phases
2
2
1
2

1 or 2

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Solid dispersion type

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A: Amorphous
C: Crystalline
M: Matrix
Classification of solid dispersion according to carriers used
Solid dispersion can be classify on the basis of carriers used in first ,second, third generations.

Figure 3:Classification of solid dispersio based on carriers used[7]

First generation
Carriers which are crystalline in nature such as urea and sugar are used to prepare solid dispersion. These carriers were used
in preparation of first solid dispersion.
There are few disadvantages like formed solid dispersion is thermodynamically more stable, thus more energy is required to
release drug from solid dispersion.
Second generation
Carriers which are amorphous in nature are used to formulate solid dispersion.
Natural polymers: - ethyl cellulose (EC), Hydroxyl Propyl methyl cellulose (HPMC), Hydroxypropylcellulose (HPC), starch
derivatives such as cyclodextrins.
Synthetic polymers: - polyethylene glycol (PEG), povidone (PVP), polymethacrylates.

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Figure 4: Bioavailability Enhancement Scheme of Poorly Water- Soluble Drug by Solid Dispersion Compared with
Conventional formulation [8]

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Third generation
Carriers which increase aqueous solubility like surfactant are used to formulate solid dispersion. Examples of surfactants are
poloxamer 407, compritol 888 ATO, Gelucire 44/14, inulin, inutec SP 1 [10].

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Limitation of solid dispersion system

Scale up of manufacturing process,
Stability of drug and vehicles,
Method of preparation of solid dispersion ,
Reproducibility of Physico- chemical properties [3].
Pharmaceutical application of solid dispersion
To enhance absorption of drug,
To obtain homogenous distribution of small amount of drug in solid state,
To dispense liquid and gaseous compound,
To mask unpleasant taste and smell,
To reduce side effect,
To convert liquid compounds in to formulation,
To stabilize unstable drugs and protect against decomposition such as hydrolysis, oxidation, racemization, photo oxidation

[9]

Solvent selection for solid dispersion system

Solvents should be selected on the following criteria;
Dissolve both drug and carrier,
Toxic solvents should be avoided due to the risk residual level after preparation,
Water based systems is preferable,
Surfactant may be added to aid in dissolution but care should be taken because they can reduce glass transition temperature,
Ethanol can be used as alternative as it is less toxic.
Method of preparation
Solvent evaporation method
Drug and carrier dissolve in a common volatile solvent and then solvent is removed by evaporation. The removal of solvent
can be done by vacuum drying, slow evaporation of solvent at low temperature, heating of mixture, rotary evaporator, spray drying
and freeze drying. Solvent evaporation method can be use for thermo-labile drugs because in this method mixture of drug and carrier
heated at low temperature. Tachibani and Nakumara (1965) was first to develop solid solution by dissolving drug and carrier in
common solvent and then solvent is evaporated under vacuum [10].
Market Formulation Formulated By Solvent Evaporation Method
Table 4: Market formulation made by Solvent evaporation method
Technique Used
Solvent Evaporation Method

Name of Drugs
Glibenclamide[11], Atorvastatin[12]
Aceclofenac[13], Chlordiazepoxide[14]
Allopurinol[15], Indomethacin[16]

Spin coated films

It is a new process to prepare solid dispersion by the solvent evaporation method, which consists of dissolving drug and
carrier in a common solvent that is dropped on to a clean substrate highly spinned. Solvent is evaporated during spinning. This process
is indicated to moisture sensitive drug since it is performed under dry condition [17].

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Melt solvent method

Melting solvent method is combination of melting method and solvent evaporation method. Drug is dissolved in solvent and
carrier is melted. Then drug solution is mixed in molted carrier then cooled for solidification. The solidified mass is crushed,
pulverized and passed through sieve. There is lower risk of thermo-labile drug degradation because this method requires low
temperature [4].

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Melting method
Melting / fusion method
In this method, the carrier is heated to a temperature just above its melting point and drug is
Incorporated in to the matrix. The melt is solidified in an ice bath under rigorous stirring, pulverized and then sieved. Rapid
congealing is desirable. The first solid dispersions created for pharmaceutical applications were prepared by the fusion method. The
dispersion consisted of sulfathiazole and urea as a matrix which were melted using a physical mixture at the eutectic composition,
followed by a cooling step. The eutectic composition is formed to obtain Simultaneous crystallization of drug and matrix during
cooling. Solid dispersion produces by this method is soft and tacky, having poor flow property and compressibility [18].

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Melt agglomeration process

This technique has been used to prepare solid dispersion where the binder acts as a carrier. Solid dispersions are prepared
either by heating binder, drug and excipients to a temperature above the melting point of the binder or by spraying a dispersion of drug
in molten binder on the heated excipients by using a high shear mixer. The effect of binder type, method of manufacturing and particle
size are critical parameters in preparation of solid dispersions by melt agglomeration [17].
Hot melt extrusion
Hot melt extrusion method is same as fusion method except that an extruder is used for intense mixing of component. Melt
extrusion offers the potential to shape the heated drug matrix mixture into implants, ophthalmic inserts or oral dosage form. Solubility
parameters are investigated to predict the solid state miscibility and to select the matrix suitable for melt extrusion. High shear force
resulting in high temperature in extruder to be a problem for heat sensitive materials. This technique is suitable for large scale
production. Product is easier to handle because at the outlet of the extruder the shape can be adapted to next processing step without
grinding [19].
Kneading method
A mixture of accurately weighed drug and carrier is wetted with solvent, kneaded thoroughly in glass mortar; the paste is
dried and sieved [4].
Co-evaporation method
Drug and copolymer are dissolved separately in same organic solvent and then these two solutions are mixed with further
evaporation of solvent under either vacuum or using flash evaporation to give evaporates. Co-evaporates have mainly been employed
for dermatological products, e.g., co-evaporates of hydrocortisone acetate-PVP and betamethasone dipropionate-PVP, both of which
showed improved cutaneous penetration [17].
Co- precipitation method
Co-precipitates are produced by adding a nonsolvent with agitation to a drug and polymer mixture in an organic solvent. The
co-precipitates are later filtered and dried [17].
Co-Grinding method
Drug and carrier were weighed accurately and mixed by the help of blender. After mixing, mixture was placed in ball mill for
grinding[17].
Spray drying
Spray drying method consist of suspending or dissolving drug and polymers in common solvent, then drying in heated air to
remove solvent. Solvent is evaporated rapidly due to large surface area of droplets and solid dispersion is formed quickly as
comparison to other methods. Manufacture of milk powder was one of the first applications of spray drying when method was
developed in 1920[17].
Drawbacks of spray drying methods are as follow;
High cost of formulation due to use of organic solvents and incorporation of unit operations to remove residual solvent after
preparation [20].

Role of carriers in formulation of solid dispersion

Carriers play an important role in pharmaceutical formulations especially in solid dispersion. Without carriers drug can not be
administered or desired pharmacological effect of drug can not be obtain.

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Supercritical fluid method

Supercritical fluid method is mostly applied with carbon dioxide, which is used as solvent for drug and carriers. When
supercritical CO2 is used as solvent, matrix and drug are dissolved and sprayed through nozzle in to an expansion vessel with low
pressure and particles are immediately formed. The adiabatic expansion of mixture results in rapid cooling. This technique does not
require use of organic solvents. This technique is referred to as solvent free. The application of this technique is very limited because
solubility of CO2 in most of pharmaceutical compound is very low (<0.01wt-%) and decrease with increasing polarity [19].

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Freeze drying
The drug and carrier is dissolved in common solvent and immersed in liquid nitrogen until it is completely frozen. Then the
frozen solution is lyophilized. Advantage of freeze drying is that the drug is subjected to minimal thermal stress during the formation
of solid dispersion [20].
Advantages of freeze drying are chances of phase separation is minimized, provide solid dispersion in micronized form,
technique can be use for thermo labile drugs and provide solid dispersion of amorphous structure.
There are few drawbacks like tablets are fragile, process is expensive, and Technique is not suitable for all types of product [21].

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Suitable properties of a carrier for solid dispersion

Should have high water solubility which improves wettability
Should have high glass transition point which improves stability
Should soluble in common solvent with drug
Should have low melting point
Should have low vapor pressure
Should be non- toxic and physiologically inert
Should have high molecular weight
Should be Chemical compatible with the drug [3].
There are certain types of carriers use in solid dispersion

Table 5: List of carriers used in solid dispersions [4]

S.No.
1
2
3

Carriers
Sugars
Acids
Polymeric material

4
5

Insoluble or enteric
polymers
Surfactants

Miscellaneous

Examples
lactose, sorbitol, maltose, mannitol, sucrose
succinic acid, Citric acid
methyl cellulose(MC), polyethylene glycol, hydroxyl propyl
cellulose(HPMC), , hydroxyl ethyl(HE), Povidone, cellulose, pectin
Eudragit RS, hydroxyl propyl methyl cellulose phthalate

methyl

Poloxamer 188, Polyoxyethylene stearate, Twens, Renex, , Texofor AIP,

deoxycholioc acid, , spans
Hydroxylalkylxanthins, Urea, urethans

Sugar
Although sugars and related compounds are highly water soluble but few sugars have toxicity issues, they are less suitable
than other carriers for the manufacture of solid dispersions. Lactose is useful as a carrier for the production of solid dispersions of
drugs prepared by melting and rapid cooling showed marked increase in dissolution rate. Chitosan has also been used as a carrier in
solid dispersions. Mannitol can be employed in some cases to prepare dispersions by the hot melt method [4].
Table 6: Examples of solid dispersion formulation use Mannitol.
Carrier Used
Mannitol

Sorbitol

Name of Drugs
Aceclofenac[22] Glibenclamide[11]
Roxithromycin[23] Atorvastatin[12]
Aceclofenac[24] Allopurinol[14]
Aceclofenac[25] Chlordiazepoxide[15]
Glibenclamide[11] Indomethacin[16]
Chlordiazepoxide[26]

Acids

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Polymeric materials
Polyethylene glycol
Polyethylene glycol (PEG) are polymers of ethylene oxide which have range of from 200 to 3, 00,000. PEG grades of 200
600 are in liquid form; grades 1000 and above grades are solids at room temperature. All grades of PEG have melting point lies under
65c. Hygroscopicity of PEG is decrease with increasing molecular weight.Viscosity of PEG increase with increasing molecular
weight. Accepted daily intake of PEG is at up to 10 mg/kg body weight according to WHO [27].

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Organic acids such as citric acid, succinic acid and their derivatives with varying functional groups can be used as carriers for
solid dispersion formulations. They improve solubility of API, thus ultimately increase the release rate and consequently
bioavailability of API will be increase.
Citric acid monohydrate occurs as colorless or translucent crystals, or as a white crystalline, efflorescent powder. It is
odorless and has a strong acidic taste Citric acid is used, to adjust the pH of solutions. Citric acid monohydrate is used in formulation
of effervescent granules and anhydrous citric acid is used in the formulation of effervescent tablets [27].

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Table 7: Examples of formulations which contains PEG

PEG 4000

PEG 6000

PEG 8000

Atorvastatin[24] Indomethacin[28]
Nifedipine[29] Etoricoxib[30]
Indomethacin[31] Allopurinol[15]
Simvastatin[32]
Glibenclamide[11] Piroxicam[33]
Ofloxacin[34] Clonazepam[35]
Glimepiride[36]
Gliclazide[37]

Polyvinyl pyrrolidone (PVP)

They are also known as povidone. Polymerization of vinyl pyrrolidone leads to (PVP) of molecular weight ranging from
2500 to 300000. These can classified according to k values.
PVP occurs as a fine, white to creamy-white colored, odorless powder and hygroscopic in nature. PVPs which have K-values equal to
or lower than 30 are manufactured by spray-drying and occur as spherical in shape. PVP K-90 and higher K-value PVP are
manufactured by drum drying and occur as plates .
Table 8: Examples of formulation which contain polyvinyl pyrrolidone.
PVP (PVP-K30)

Polyvinypyrrolidine (PVP-K25)
Polyvinypyrrolidine (PVP-K90)

Atorvastatin[12], Piroxicam[38]
Candesartan cilexetil[39]
Mefenamic acid[40]
Glimepiride[36]
Allopurinol[15]

Cellulose derivatives
Celluloses are polysaccharide which occurs naturally. They are of high molecular weight unbranched chains, in which the
saccharide units are fused by -1, 4-glycoside bonds. By the help of suitable alkylation, cellulose can be derivatized to form
Hydroxypropyl (HPC), methyl- (MC), Hydroxypropyl methylcellulose (HPMC) and other. Cellulose can be derivatised to form
cellulose acetate phthalate (CAP) and Hydroxypropyl Methylcellulose Phthalate (HPMCP) [27].
Pectin
Pectin is a complex polysaccharide made up of mainly esterified D-galacturonic acid residues in a-(14) chain. The acid
groups are esterified by methoxy groups in the natural product. Pectin gelation characteristics can be divided into two types: highmethoxy and low-methoxy gelation. High methoxy pectin gelation usually occurs at pH lower than 3.5. Low-methoxy pectin can be
gelled with calcium ions [27].
Emulsifier
Emulsifying agent improve release rate of drugs. There are two mechanisms by which they can do their action such as like by
improvement of wetting characteristics and solubilizing of drug. They are not used alone. They are suitable carriers at low dose.
Poloxamers are chemically triblock copolymers which are nonionic in nature as well as it has amphiphilic structure. There are an
example of recently used surfactant like Gelucire 44/14 and other grades of Gelucire. An example of natural surfactants is Bile
salts [27].

Insoluble or enteric materials

Polyacrylates and polymethacrylates are glassy substances that are produced by polymerization of acrylic and methacrylic
acid. They are used as film-coating agents to modify the release of drug. Eudragit RS, RL, NE, NE 40D, and 30D, NM30D are used to
form water-insoluble film coats for sustained-release products. Eudragit S, L and FS types are used as enteric coating agents because
they show resistant in gastric fluid. The neutral Eudragit NE/NM grades do not have any functional ionic group [41].

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Polyoxyethylene stearate
They are a series of polyethoxylated derivatives of stearic acid as well as nonionic in nature. . Ethylene oxide units determine
hydrophilicity or lipophilicity. If the no. of ethylene oxide units no. are greater then hyrophilic property will be more [27].

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Surfactant
Surfactants improve aqueous solubility by decreasing surface tension.

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Poloxamer
Poloxamers are nonionic polyoxyethylenepolyoxypropylene copolymers used primarily in pharmaceutical formulations as
emulsifying or solubilizing agents. The polyoxyethylene part is hydrophilic while the polyoxypropylene segment is hydrophobic in
nature. They are generally occur as white, waxy, free-flowing prilled granules. They are practically odorless and tasteless. At room
temperature, poloxamer 124 occurs as a colorless liquid. All poloxamer grades have melting point below 58c.
There are many of the trade names used for poloxamers, e.g. Pluronic F-68, first digit arbitrarily represents the molecular
weight of the polyoxypropylene portion and the second digit represents the weight percent of the oxyethylene portion [27].
Tweens
Tweens are also known as polysorbates. Tweens are ethoxylated spans. Tweens are a series of partial fatty acid esters of
Sorbitol as well as nonionic surfactants and hygroscopic and hydrophilic in nature and have solublility in water and dilute solution
of electrolytes. In aquous solution, solubility of tweens increases with increase in degree of ethoxylation and solubility decrease with
increase in ester groups[4]. Accepted daily intake for polysorbate 20, 40, 60, 65 and 80 is at up to 25 mg/kg body weight according to
WHO [27].
Spans
Spans are nonionic surfactant as well as have solubility in oil, organic solvent and insolublility in water and produced by
dehydration of Sorbitol. Accepted daily intake for spans is at up to 25 mg/kg body weight calculated as total sorbitan esters according
to WHO [27]
Urea
It is end product of human protein metabolism, give light diuretic effect and is non-toxic. It has aqueous solubility greater
than 1 in 1 and has good solubility in many common organic solvents. First solid dispersion which was formulated with sulphathiazole
and urea. In bioavailability study it is observed that sulphathiazole was better absorbed in rabbit [42].
Urethanes
It is also known as polyurethane. It comes under class of synthetic elastomers, which is used specially for long terms implant.
It is a polymer made of isocynates and polyols united by carbamate links [42].
Table 9: various characterization method to assess solid dispersion [5]
Characterization
Drug-carrier
interactions

Drug-carrier
miscibility

Amorphous content

Dissolution rate

Surface properties

Stability

Methods
Raman spectroscopy
Fourier transform infrared spectroscopy (FTIR)
Solid state NMR studies
Differential scanning calorimeter (DSC)
Nuclear magnetic resonance (NMR)Hot stage
microscopy (HSM)
X-ray Diffraction (XRD)
Powder XRD
DSC (MTDSC)
Polarized light optical microscopy
Humidity stage microscopy
Hot stage microscopy
Intrinsic dissolution
Dissolution studies
Dynamic solubility studies
Raman microscopy
Dynamic vapour sorption
Atomic force microscopy
DSC (Tg, temperature
recrystallisation)
Humidity studies
Saturated solubility studies
Isothermal calorimeter
Dynamic vapour sorption

To find out the amorphous

transition.

To find out amount and rate of

drug release
To study the morphology and
degree of crystallinity.
To find out the recrystallization
degree

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Marketed products of solid dispersion

Significance
To find out and type of
interaction between drug and
carrier
To find any kind of complex
formation between drug and
carrier.

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S. No
1

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Table 9: Preparation of solid dispersion of poorly soluble drugs by solvent evaporation method [43]
S.No.
1

Product
Gris PEG

Company
Pedina pharm inc.

Year approved
1975

2
3

Cesamet
Sporanox

Eli Lilly
J&J

1985
1996

4
5

Rezulin
Kaletra

Pfizer
Abbott

Torcetrapib

Pfizer

1997
2005
(sNDA)
Ph III

Technology
Melt process
Exact process unknown
Process unknown
Spray dry onto
Substrate
Extrusion
Extrusion
Spray drying

Table 10: Preparation of solid dispersion by melting method/fusion method.

Drug
Carvidilol
Atorvastatin
Ibuprofen
Naproxen
Terbinafine hydrochloride
Nimodipine

Carrier
PEG 6000
PEG 4000, mannitol
PEG 6000
PEG 6000, PEG 4000, Urea
PEG 6000, Mannitol
Hypromellose Phthalate (HPMCP)
Microcrystalline Cellulose (MCC)

Reference
44
24
45
46
47
48

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CONCLUSION
It has been realized that solid dispersion is an important technique in improving solubility of poorly water soluble drugs. In
recent years lot of knowledge of solid dispersion have accumulated, but their commercial application is limited. Various methods have
been tried to overcome the limitations. Various alternatives methods have used to resolve problem lies during formulation like spray
method and direct capsule filling method. Although there are few hurdles like scale up and manufacturing cost, but there is still a hope
that solid dispersion technique will helpful in dissolution of various water insoluble drugs to improve bioavailability.

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