Recent Approaches in Solubility Enhancement of Poorly Water Soluble Drug Simvastatin

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
S. J. Wadher et al. World Journal of Pharmacy and Pharmaceutical Sciences

Volume 3, Issue 4, 366-384. Review Article ISSN 2278 4357
RECENT APPROACHES IN SOLUBILITY ENHANCEMENT OF

POORLY WATER SOLUBLE DRUG SIMVASTATIN: A REVIEW
S. J. Wadher*, S.G. Gattani, Y. A. Jadhav, T. M. Kalyankar
School of Pharmacy, SRTM University, Nanded
Article Received on ABSTRACT

10 February 2014, Solubility of simvastatin (hypolipidemic drug) is one of the critical
Revised on 26 February 2014 aspects in formulation and development. At present 40% of new drugs
Accepted on 18 March 2014
is poorly water soluble and less permeable. Pharmacological action of
the simvastatin can be achieved by attaining required concentration of
*Correspondence for Author
Dr. shailesh wadher drug in systemic circulation. Simvastatin (SIM) is a crystalline
School of Pharmacy, SRTM compound and practically insoluble in water and hence poorly
University, Nanded, India. absorbed from the GI tract. There are various techniques for solubility
enhancement of poorly soluble drug. In order to increase the
bioavailability of poorly water soluble drugs, knowledge of solubility, absorption and
dissolution are most important parameters. Enhancement of solubility and dissolution of
simvastatin is achieved by formation of nanobiocomposites using microwave irradiation
Method, High-Pressure Homogenization, Solvent Evaporation, Solid dispersions and Spray
drying method.
Keywords: Solubility, Simvastatin, Techniques, Absorption.
INTRODUCTION
Simvastatin is hypolipidemic drug which having poor water solubility. Simvastatin is widely
used in the treatment of hypercholesterolemia and for the reduction in the risk of cardiac
heart disease mortality and cardiovascular events. Therapeutic effectiveness of a drug
depends upon the bioavailability and ultimately upon the solubility of drug molecules.
Solubility of Simvastatin (hypolipidemic drug) is one of the critical aspects in formulation
and development. At present 40% of new drugs is poorly water soluble and less permeable.
Pharmacological action of the Simvastatin can be achieved by attaining required
concentration of drug in systemic circulation.
www.wjpps.com Vol 3, Issue 4, 2014. 366

According to the Biopharmaceutical Classification Systems (BCS) the simvastatin drug

belongs to the class-II drug having low solubility and high permeability. The BCS was
proposed by the Amidon et al in 1995. The BCS is arranged in four subtypes which are
according to drugs bioavailability means parameter like solubility and intestinal
permeability[1].
Classification of BCS[1]
According to the BCS class drugs are classified in four subtypes such as
A. Class I drugs
In this class drugs belong to the high solubility and high permeability. There is no problem
related for bioavailability of this class drugs.
E.g. Verapamil, Diltizem, Metoprolol, Propranolol.
B. Class II drugs
In this class drugs belong to the low solubility and high permeability. There is problem
related for bioavailability of this class drugs. Due to this for solubility improvement there are
some techniques to improve solubility such as High-Pressure Homogenization, Solvent
Evaporation, Solid dispersions and Spray-Drying Method.
E.g. Simvastatin, Valsartan, Glipizide, Omeprazole.
C. Class III drugs

In this class drugs belong to the high solubility and low permeability. Due to the low
permeability of drug it is rate limiting step for drug absorption.
E.g. Acyclovir, Captopril, Cimetidine, Neomycin.
D. Class IV drugs
In this class drugs belong to the low solubility and low permeability. Due to the low
solubility and low permeability of drug it is challenging for the oral route of absorption.
E.g. Taxol, Hydrochlorothizide.

Table 1. Biopharmaceutical Classification Systems (BCS) of drugs

Class I Class II
High solubility Low solubility
High permeability High permeability
e.g. Verapamil, Propranolol. e.g. Simvastatin, Valsartan.
Class III Class IV
High solubility Low solubility
Low permeability Low permeability
e.g. Acyclovir, Captopril. e.g. Taxol, Hydrochlorothizide.
As discucced earlier, simvastatin belongs to BCS class II which having low solubility and
high permeability. Simvastatin is Hypolipidemic drug which is having poor water solubility,
dissolution. Therapeutic effectiveness of a drug depends upon the bioavailability and
ultimately upon the solubility of drug molecules. Solubility is the important parameter to
achieve desired concentration of drug in systemic circulation for pharmacological response to
be shown. Hence there is need of enhancement of solubility and dissolution of such types of
drug.
Fig. 1 Chemical Structure of Simvastatin (Sim)
Simvastatin is a lipid-lowering agent, which is obtained from a fermentation product

of Aspergillus terreus. Simvastatin is white crystalline powder and non-hygroscopic. The
IUPAC name of Simvastatin is (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6
oxotetrahydro-2H-pyran-2yl]ethyl] 3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl2,2-
dimethylbutanoate. Molecular formula for Simvastatin is C25H38O5 having molecular weight
[2,3]
418.6 and melting Point is 135-138c . The Simvastatin is practically insoluble in water
0.0013 to 0.0015 mg/ml at 23C but freely soluble in alcohol [4]. The Simvastatin drug is
marketed generically under the trade name zocor after the patent expires [5].
Methods for Solubility Enhancement

There are various method available for the improvement of the solubility of poorly soluble
drugs. Some of the technique to improve the solubility is as follows [6, 7, 8, 9]

Physical Modications:
Particle size reduction
i. Micronization
ii. Nanosuspension
Modication of the crystal habit
i. Polymorphism
Drug dispersion in carriers
i. Eutectic mixtures,
ii. Solid dispersions,
iii. Solid solutions
iv. Cryogenic techniques.
Chemical Modications.
Change of pH.
Complexation
i. Kneading Method.
ii. Lyophilization/Freeze-DryingTechnique.
iii. Microwave Irradiation Method.
Salt formation
Miscellaneous Methods.
Supercritical uid process.
Solubilisation
i. Micellar Solubilization
ii. Co-solvency
iii. Hydrotrophy
Physical Modications
The solubility of drug is depends on the partical size of the drug. As the drug partical size is
small the greater the solubility which depends upon the surface area of the drug. The larger
the surface area of the drug partical which allow the greater the contact of solvents which
causes enhancement of the solubility.
1) Micronization
Micronization is the conventional technique for partical size reduction which

influence on the solubility of the drug. The micronization improves the solubility of drug by
increasing the surface area which is not affected equilibrium solubility. Some milling
techniques like Jet mill, rotor stator colloid mills are used for the micronization but the
disadvantages of this method is that it does not change the drugs saturation solubility, due to
this it is not suitable for the drugs having large dose number. There are some drug examples
where micronization process is applicable like griseofulvin, progesterone, fenofibrate and
spironolactone. The effect of micronization is improved their digestive absorption and
ultimately their bioavailability and clinical efficacy[6].
From the dissolution studies solubility of simvastatin drug is enhanced by using the dry ball
milling process[21].
2) Nanosuspension
Nanosuspension means very small sized (200 and 600 nm) drug partical in dispersion
medium stabilized by surface active agents[6]. It consist of the poorly water-soluble drug
without any matrix component suspended in dispersion. Nanosuspension is helpful for
solubility improvement of poorly soluble drug in aqueous and oily medium. Due to this
improved solubility, maximum plasma level is gained immediately by the increased flow of
the active compound. By Nanosuspension high drug dose can be achieved as a drug remains
in the pure solids form and due to this decreases the volume of administration of high
dose[10].
Preparation Methods of Nanosuspension

i. Precipitation Technique
ii. High Pressure Homogenization
iii. Media Milling.
i ) Precipitation Technique
In this technique the drug is firstly dissolved in a solvent and then this solution is mixed with
a miscible antisolvent in the presence of surfactants. Due to the rapid addition of a drug
solution to the antisolvent (mostly water) leads to the formation of sudden supersaturation
of the drug in mixed solution and generation of ultrafine crystalline or amorphous drug
solids. Precipitation process involves two phases such as nuclei formation and crystal
growth[6]. While preparing the stable suspension with the smaller particle size and required
low growth rate is necessary but higher nucleation growth is required. Both rates are depends

upon temperature, the optimum temperature for nucleation might lie below that for formation
of crystal growth, due to which temperature is optimized. There are some drug examples
where precipitation process is applicable like Simvastatin, Carbamazepine, Danazol,
Naproxen, Cyclosporine, Griseofulvin nanosuspensions are prepared by this method [10].
The solid nanopartical produced by the sonoprecipitation method using stabilizer such as
F68, PVK30, and HPMCE5 for solubility enhancement of simvastatin[22].In the preparation
of simvastatin nanosuspension PVK 30 is used as stabilizer by using nanoprecipitation
technique due to this there is solubility enhancement of nanosized simvastatin as compared to
the pure suspension of simvastatin[23].
ii ) High pressure homogenization

High pressure homogenization method is widely useful method for the preparation of the
nanosuspension belongs to the drug having poorly water solubility[6]. In this method under
the high pressure, suspension of a drug and surface active agents is forced through a
nanosized aperture valve of a high pressure homogenizer[10].
From the studies such as in vitro drug release and solubility it shows solubility enhancement
of simvastatin by using high pressure homogenization as compared to the unprocessed pure
drug[24].
iii ) Media Milling

In the media milling technique, nanosuspensions are produced using pearl or high shear
media mills. The media mill mostly consists of a recirculation chamber, milling chamber and
a milling shaft. The nanoparticles of drug are obtained by subjecting the drug to mill [6]. High
energy and shear forces generate as a result of collision of the milling media with the drug
provide the necessary energy input to disintegrate the microparticulate drug into nano range
sized particles. The medium for milling mostly consist of zirconium oxide or highly cross-
linked polystyrene resin, glass. In nanosuspensions, the particles are charged with polymeric
media. The mill can be operated in a batch or recirculation mode. Slurry consisting of drug,
water and stabilizer is fed into the milling chamber and processed into nanocrystalline
dispersion. There are some drug examples where Precipitation process is applicable like
cilostazol, danazol and naproxen. Nanosuspensions are prepared by this method [10].
Polymorphism
If any element or compound exists more than one crystalline form then that compound or

element shows polymorphism property. Due to this polymorphs of same drugs are chemical
properties but they shows different physical properties such as melting point, solubility,
stability, density, texture etc[6].
Drug dispersion in carriers

1) Eutectic mixture
A normally eutectic mixture consists of two compounds which are completely miscible in the
liquid state but only to a very limited extent in the solid state. Whereas for liquid state
denotes by I and solid state denotes by II. When a mixture of I and II with an appropriate
composition is cooled, I and II crystallize out. When one component of mixture is cooled
then at that time second component start to crystlize before the first component,it is
simultaneously proceeds. Solid eutectic mixtures are mostly prepared by rapid cooling of a
co-melt of two compounds in order to obtain a physical mixture of very fine crystals of the
two components. Sekiguchi and co-workers have proposed that when the eutectic mixture is
exposed to in contact with the gastrointestinal uids, at that time the soluble carrier rapidly
dissolves and insoluble drug goes in extremely fine state means subdivision is occurs. Due to
this the surface area of resulting suspension is improved which ultimately enhance
dissolution rate due to which bioavailability is also improved [11].
For the solubility enhancement of simvastatin there is formation of the eutectic mixture with
acetylsalicylic acid [25].
B) Solid Dispersion
Solid dispersions technique a useful pharmaceutical technique for increasing the dissolution
rate, absorption rate, and therapeutic ecacy of drugs in dosage forms. Solid dispersion
means it is a group of solid products which contain at least two different component mostly
this are hydrophobic drug and hydrophilic matrix. There are some example of the generally
used hydrophilic carriers for solid dispersions include polyethylene glycols (PEGs),
polyvinylpyrrolidone (Povidone, PVP), Plasdone S630. Surfactants like sodium lauryl
sulphate (SLS), docusate sodium and Tween-80 also find a place in the formulation of solid
dispersion.
Techniques to prepare the solid dispersion (S.D.)

i. Hot-Melt Method (Fusion Method).
ii. Solvent Evaporation Method

iii. Hot-Melt Extrusion.
a) Hot-Melt Method (Fusion Method)

In this technique the physical mixture of a drug and a water-soluble carrier are heated
directly until the drug and carrier melt. The melted mixture is then cooled and solidied
rapidly in an ice bath with careful stirring. The final solid mass is then pressurized,
pulverized and lastly screen out which can be compressed into tablets by the additions of the
excipient. The melting point of a component is dependent upon its composition that is, the
selection of the carrier and the drugs melting point[12]. By the hot melt method simvastatin
solubility is improved using polymer polyethylene glycol (PEG) 6000 [26].
b) Solvent Evaporation Method

In this technique both the drug and the carrier dissolve in a common solvent and then
evaporate the solvent under vacuum to produce a solid solution. The benefit of this technique
is the it can prevent the thermal decomposition of the drug and carrier. In this method solvent
also removed by spray-drying or by freeze dying method for solvent evaporation purpose
between the temperature range 23-65C. There are some drugs on which solid dispersion by
using solvent evaporation technique is carried out such as simvastatin, meloxicam, naproxen,
and nimesulide[6].
By the solvent evaporation method simvastatin solubility is improved using polymer

polyethylene glycol (PEG) 6000[26], -cyclodextrin, hydroxylpropyl -cyclodextrins,
[27] [28]
hydroxylbutyl -cyclodextrins , PEG 12000, PEG 20000 , Sodium Glycolate, Starch,
[29]
Sodium Croscarmellose, Sodium Starch Glycolate , PVP, HPMC K3 LV(Rota
[30]
Evaporator) , HPMC K3 LV (Spray Dryer) , Aerosil 200 (Spray Dryer)[31] ,
Crospovidone[32], Fenugreek gum [33], Chitosan (Spray Dryer) [34].
c) Hot-Melt Extrusion
The drug and carrier are mixed by using typically by using a twin-screw extruder. In this
technique the drug and carrier are mixed simultaneously melted, uniformly mixed and then
extruded and shaped as required dosage forms like tablets, granules, pellets, sheets, sticks or
powder. In the hot melt extrusion method the drug and carrier are mixture placed to a higher
temperature for about 1 min due to this there is the chances for the heat sensitive drug and
carrier also. This method is carried out by co-rotating twin-screw extruder methods. In the
dispersion medium the drug concentration is nearly about 40 % (w/w)[6].

In the hot-melt Extrusion technique simvastatin solubility is improved by using polymer such
as HPMC E5 LV[35], Soluplus, KolliphorTM TPGS, KolliphorTM P 118, KolliphorTM P 407[36].
C) Solid Solutions
The solid solution means in which the solid solute dissolves in the solid solvents.The solid
solution is either amorphous or crystalline form. In the amorphous solid solution the drug is
dispersed in the carrier matrix and its having effective surface area due to this dissolution
rate is increased. While in the crystalline solid solution the drug is dispersed in the crystalline
polymeric carrier.
According to the limits of miscibility of the solid solute and solid solvents there is two
subtypes of the solid solution such continuous and discontinuous type. The continuous solid
solution means both component of solutions are completely miscible in each other. Whereas
discontinues solid solution means both component of solutions are incompletely miscible in
each other but miscible at extrems of the composition. By the solid solution method there is
no any work with simvastatin drug for solubility enhancement purpose[14].
D) Cryogenic techniques[6]
In this techniques solubility enhanced by the generating the nanostructures of amorphous
drug partical with high degree of porosity at a low temperature conditions. It can be defined
by the type of injection device, location of nozzle and the composition of cryogenic liquid.
After the completion of the process dry powder is obtained and it can be obtained by the
process like atmospheric freeze drying, lyophilisation, vacuum freeze drying and spray
freeze drying. By cryogenic techniques the there is no any work with simvastatin drug for
solubility enhancement purpose.
Chemical Modications
1) Change of PH
The ph of the system is the simplest and most effective parameter in the solubility of the
drug. For the solubility enhancement of drug the alteration of the PH of the medium because
is it affects on the ionization behaviour. The adjustment of PH for the dosage form is mainly
affects on the both oral and parenteral administration. In the administration of parenteral
dosage form like intravenous administration of poorly soluble drug there is chances of the
precipitation of the drug due to the blood having PH range 7.2-7.4.There are some equation

such as pH-partition hypothesis and Handerson- Hesselbatch equation. The ionization of a

compound is dependent on the pH of media and pKa of drug[6].
Complexation[6]
In this technique there is the association between two or more molecules to form a non-
bonded entity with a well defined stoichimetry. Complexation is formed by the inseartion of
the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the
cavity of another molecule or group of molecule(known as host). The mostly used molecule
as a host is cyclodextrin (CD). The cyclodextrin are having this properties such as
nonreducing, crystalline, water soluble, and cyclic oligosaccharides consisting of glucose
monomers arranged in a circular shaped ring in three dimensional having hydrophobic
cavity and hydrophilic outer surface. There are three types of cyclodextrin such as -
cyclodextrin, -cyclodextrin, and -cyclodextrin. By the inclusion complexes technique
method simvastatin solubility is improved by using polymer such as - cyclodextrin, -
cyclodextrin, HP -cyclodextrin, -cyclodextrin.
There are some method to prepare the inclusion complexes of poorly water soluble drugs
with cyclodextrins such as
i. Kneading Method.
ii. Lyophilization/Freeze-Drying technique
iii. Microwave Irradiation Method
a) Kneading Method
In this method the cyclodextrin is added with small quantity of water or hydroalcoholic
solutions solution due to the cyclodextrin it converts into the paste. The drug is then added to
the above paste and kneaded for a particular required time. After that the kneaded mixture is
then dried and passed through a sieve if it required. In laboratory scale means smaal scale,
kneading can be achieved by using a mortar and pestle. In large scale, kneading can be
achieved by utilizing the extruders and other machines[6].
By the kneading method simvastatin solubility is improved by using polymer such as PEG
4000, PEG 6000[37], HP cyclodextrin[38,39,44], -cyclodextrin [40,43,45]
, POLAXAMER
188[41] , cyclodextrin [42].

b) Lyophilization/Freeze-DryingTechnique [6]
In this technique from the solution solvent system is removed by freezing and then it will be
drying of the solution which contain both drug and cyclodextrin at a reduced pressure .
Thermo labile substances can be successfully made into complex form by this method. This
technique is suitable for to form a porous, amorphous powder with high degree of interaction
between drug and cyclodextrin. The some limitations of this technique is the use of
specialized equipment and yield poor powdered product. This technique is as an alternative
to solvent evaporation and involves molecular mixing of drug and carrier in a common
solvent.
C) Microwave Irradiation Method

1A microwave is a form of electromagnetic energy, which found at the lower end of the
electromagnetic spectrum and is defined in a measurement of frequency as 300 to 300,000
Megahertz it corresponding to wavelengths of 1 cm to 1 m. Wavelengths between 1 cm and
25 cm are extensively used for RADAR transmissions and remaining wavelength range is
used for telecommunications[15].
The use of microwave energy is the most effective tool in pharmaceutical industry for the
purpose of the dosage form development[6]. By supplying microwave energy it induces
drying, drug polymeric interaction, polymeric cross linkages and also modify the structure of
drug crystal via effects of heating on the dosage form[18]. Heating mechanism involve-
dielectric polarization and conduction. In the pharmaceutical dosage forms the use of
microwave oven is a new approach to control the physicochemical properties and drug
delivery profiles without the need of excessive heat, lengthy process or toxic reactants[19].
The benefit of microwave heating compared with conventional heating includes selective and
faster heating which allows energy and time saving[20]. By Microwave Irradiation Method the
there is no any work with simvastatin drug for solubility enhancement purpose.
Salt formation
In general any drug belongs to acid or base have less solubility than its having salt forms.
Hence this technique mostly preferred for the solubility enhancement of poorly soluble drug.
Salt formation is the most common approach for enhancement of solubility, dissolution and
bioavailability of poorly water-soluble ionizable drugs in solid dosage forms. During salt
formation care must be taken like there is prevent the chances of the conversion of salts to

their respective free acid or base forms. By Salt formation the there is no any work with
simvastatin drug for solubility enhancement purpose[6].
Miscellaneous Methods
Supercritical uid process (SCF)
Supercritical fluids are fluids whose temperature and pressure are greater than its critical
temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both
liquid and gas. At near-critical temperatures, Supercritical uid process are high
compressible, allows mild changes in pressure to greatly alter the density and mass transport
characteristics of a fluid that largely determine its solvent power. Once the drug particles are
solubilized within SCF, they may be recrystallized at greatly reduced particle sizes. The
flexibility and accuracy offered by SCF processes allows micronisation of drug particles
within narrow ranges of particle size, mostly to sub-micron levels[7] .
There are some SCF process such as precipitation with compressed antisolvants process
(PCA), solution enhanced dispersion by SCF (SEDS), and supercritical antisolvants
processes (SAS), Rapid Expansion of Supercritical Solutions (RESS), Gas Anti Solvent
Recrystallization (GAS) and aerosol supercritical extraction system (ASES).
By the Supercritical uid process simvastatin solubility is improved by using polymer HP-
cyclodextrin[46].
Micellar Solubilization
The use of surface active agent to improve the dissolution performance of poorly soluble
drug. Surface active agent reduce surface tension and improve the dissolution of lipophilic
drugs in aqueous medium. Surface active agents are also used to stabilise drug suspensions.
When the concentration of surfactants greater than their critical micelle concentration (CMC,
which is in the range of 0.050.10% for most surfactants), micelle formation occurs which
entrap the drugs within the micelles. This is known as micelle formation and generally results
in enhanced solubility of poorly soluble drugs. There are some micelle formation technique
such as microemulsion, dried emulsion and microemulsion by solvent evaporation technique.
In the microemulsion technique simvastatin solubility is improved by using surface active
agent such as cremophore RH 40 and Transcutol p. In the dried emulsion technique
simvastatin solubility is improved by using surface active agent such cremophore EL and
tween 80. In the microemulsion by solvent evaporation technique simvastatin solubility is
improved by using surface active agent such PVP, tween 80 and soyabean lecithin [16].

Hydrotrophy
In the process of Hydrotrophy there is the addition of a large amount of second component,
the hydrotropic agent results in an increase in the aqueous solubility of rst component.
These agents are ionic organic salts, mostly consists of alkali metal salts of various organic
acids. Salt in means, Additives or salts means solute that increase solubility in given solvent
and Salt out means, Additives or salts means solute that decrease solubility in given solvent.
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. Hydrotrophy mostly used for the increase in solubility in water due to the
presence of large amount of additives[17].
Co-solvency
The solubility of a poorly water soluble drug can be enhanced by the addition of a water
miscible solvent in which the drug has good solubility known as Co-solvency and the solvent
which are used for that purpose known as co-solvent. The molecule which are non-polar
molecule and weak electrolytes frequently have poor water solubility. Due to this there is the
addition of water miscible solvent is used to increase the solubility. In the process of co-
solvency it decreases the interfacial tension between hydrophobic solute and aqueous solute.
There are some example of co solvents such as glycerine, propylene glycol, ethanol, and
polyethylene[17].
Lipid based drug delivery system technique

In this technique some factors affects on the absorption of drug such as including particle
size, degree of emulsication and rate of dispersion and precipitation of drug upon
dispersion. There are some lipid formulation techniques such as solid lipid nanoparticle, self
emulsifying drug delivery system. In self emulsifying drug delivery system simvastatin
solubility is improved by using polymer such as Captex 355, Capmul MCM, Lauroglycol 90
and Cremophore EL[49]. In solid lipid nanoparticle techniques simvastatin solubility is
improved by using polymer such as compitrol 888ATO, span 60, poloxamer 188[51]glyceryl
monostearate, poloxamer 407[52].
Drug-dendrimer complex formation

In this technique dendrimer increases the pharmacokinetics and biopharmaceuticals
properties of drug and helps in drug delivery of drugs effectively. There are three types of
dendrimers such as poly (amidomine) (PAMAN), diaminobutane (DAB) and

polypropyleneimine (PPI). Simvastatin solubility is improved by using dendrimer such as

Poly(amidoamine)[PAMAN] G4-PAMAMNH2, G4-PAMAMOH, G4-PAMAMPEG[56].
Table 2.Techniques for the solubility enhancement of the Simvastatin

Techniques Method Polymer References
Milling method Not involved Rades T et al [21]
Sonoprecipitation PVK30,HPMCE5 Jiang T et al [22]
Precipitation
PVK30 Pandya V et al [23]
Partical size Technique
reduction High Pressure Athul P et al [24]
Not involved
Homogenization
Eutectic mixture Not involved Gorniak A et.al [25]
Hot-Melt Method Polyethylene glycol(PEG) Jatwani S et al [26]
(Fusion Method). 6000
PEG 6000 Jatwani S et al [26]
-cyclodextrins,
hydroxylpropyl Hosny K et al [27]
cyclodextrins &
hydroxylbutyl-
cyclodextrins.
(PEG) 6000, (PEG) 12000,
Bolourchiana N et al [28]
(PEG) 20000
Sodium Glycolate, Starch,
Rao M et al [29]
Sodium Croscarmellose
HPMC K3 LV
Gattani S et al [30]
(Rota Evaporator)
HPMC K3 LV
Gattani S et al [30]
(Spray Dryer)
Drug dispersion Solvent
PVP, Aerosil 200
in carriers Evaporation Mahadik K et al [31]
(Spray Dryer)
Method
Crospovidone, Sodium
Srinu S et al [32]
Starch Glycolate
Fenugreek gum Sav A et al [33]
Chitosan Pattewar S et al [34]
(Spray Dryer)
HPMC E5 LV Javeer V et al [35]

Soluplus
KolliphorTM TPGS,
Hot-Melt Extrusion. Tawde V et al [36]
KolliphorTM P 118,
KolliphorTM P 407
PEG 4000,PEG 6000 Mandal D et al [37]
-CD , HP -CD Patil J et al [38]
HP -CD Vyas A et al [39]
-CD Punitha S et al [40]
Kneading Method. Poloxamer 188 Sandeep K et al [41]
Complexation CD Patil J et al [42]
-CD & -CD Wen X et al [43]

Inclusion complex HP -CD Ungaro F et al [44]

-CD Csempesz F et al [45]
Supercritical uid HP- -CD Jun S et al [46]
process -- Varshosaz V et al [47]
Cremophore RH 40,
Microemulsion Srinivas C et al [48]
Transcutol p
Self emulsifying Captex 355, Capmul MCM,
drug delivery Lauroglycol 90, Patil P et al [49]
system Cremophore EL.
Dried Emulsion Tween 80, Cremophor EL Dixit R et al [50]
Compritol 888 ATO ,
Gambhire M et al [51]
Span 60 , Poloxamer 188
Solid Lipid
Compitrol 888ATO
Nanoparticle
Glyceryl monostearate, Tiwari R et al [52]
Poloxamer 407
PVP, Tween-80,
Miscellaneous Microemulsion- Ramani V et al [53]
Soybean lecithin
Methods solvent evaporation
-- Magdassi S et al [54]
Self- Meng Z et al [55]
microemulsifying
--
method
Poly(amidoamine)[PAMA
Drug-dendrimer N] G4-PAMAMNH2,
Kulhari H et al [56]
complex formation. G4-PAMAMOH ,
G4-PAMAMPEG
CONCLUSION
For the simvastatin drug Pharmacological action is achieved by attaining required
concentration of drug in systemic circulation. To obtain that required concentration there is
need of solubility enhancement. It has been observed that there are so many techniques like
Milling, Sonoprecipitation, High Pressure Homogenization, Eutectic mixture, Kneading,
Solvent Evaporation Method etc are available for the solubility improvement purpose. But
mostly specified means effective for the easy of preparation and efficacy purpose solvent
evaporation method and kneading method are used.
REFERENCES
1. Dash V, Kesari A. Role of Biopharmaceutical Classification System in Drug
Development Program. J Current Pharma Res 2011;5,(1);28-31.
2. USP Monograph: Simvastatin; Usp29,
http://www.pharmacopeia.cn/v29240/usp29nf24s0_m75450.html.

3. EP Monograph: Simvastatin,
http://lib.njutcm.edu.cn/yaodian/ep/EP5.0/16_monographs/monographs_q-
z/Simvastatin.pdf
4. Serajuddin A , Randive S. Relative Lipophilicites, Solubilities and Structure-
Pharmacological Considerations of 3-Hydroxy-3-Methyl Glutaryl-Coenzyme A (Hmg-
Coa) Reductase Inhibitors Pravastatin, Lovastatin, Mevastatin and Simvastatin. J Pharm
Sci 1991;80(9);830-834.
5. Drug bank open data drug and drug target database: Simvastatin,
http://www.drugbank.ca/drugs/DB00641.
6. Savjani T, Gajjar K. Drug Solubility: Importance and Enhancement Techniques. ISRN
Pharma 2012;1-10.
7. Thakur A. Various Techniques Enhancing Bioavailabilty of Poorly Water Soluble Drugs.
J Drug Delivery and Therapeutics; 2013;3(2);215-221.
8. Anil K. Review on Solubility Enhancement Techniques for Hydrophobic Drugs. Inter J
Comprehensive Pharm 2011,3(3);1-7.
9. Yellela S. Krishnaiah, Pharmaceutical Technologies for Enhancing Oral Bioavailability
of Poorly Soluble Drugs. J Bioequivalence and Bioavailability 2010;2;( 2);28-36.
10. Kumar G. Nanosuspensions: The Solution to Deliver Hydrophobic Drugs. International J
Drug Del 2011;3;546-557.
11. Dan L. Xueping F, Siling W, Increasing Solubility and Dissolution Rate of Drugs Via
Eutectic Mixtures: ItraconazolePoloxamer188 System. Asian J Pharm Sci ,2006;1(3-
4);213-221.
12. Pragati B. Solid Dispersion Technique: A Tool for Enhancing Bioavailability of Poorly
Soluble Drugs. J Chem and Pharma Sci 2011;4(4) ;170-179.
13. Kumar P. Singh C. A Study on Solubility Enhancement Methods for Poorly Water
Soluble Drugs. Am J Pharmacol Sci 2013;1(4);67-73.
14. Kapoor B. Solid Dispersion: An Evolutionary Approach for Solubility Enhancement of
Poorly Water Soluble Drugs. Inter J Recent Adv In Pharm Res 2012; 2(2): 1-16.
15. Solanki H. Microwave Technology - A Potential Tool in Pharmaceutical Science. Inter J
Pharm Tech Res 2010; 2(3);1754-1761.
16. Vemula V, Solubility Enhancement Techniques, Inter J Pharm Sci Review and Res,
2010;5;1;41-51.

17. Hameed M. A Recent Trends in Enhancement of Solubility and Dissolution Rate of

Poorly Soluble Hydrophobic Drugs By Using Physical and Chemical Modifications, J
Drug Dis and Therap , 2013;1(5);13-24.
18. Kushare S, Gattani S. Microwave-Generated Bionanocomposites For Solubility and
Dissolution Enhancement of Poorly Water-Soluble Drug Glipizidein-Vitro and In-Vivo
Studies. J Pharm and Pharmacol 2013;65;79-93.
19. Azam A, Ahmed F. One Step Synthesis and Characterization of Gold Nanoparticles and
their Antibacterial Activities Against E. Coli (ATCC 25922 Strain). Inter J Theoretical
and App Sci 2009;1(2);1-4.
20. Patel K, Kapoor S. Synthesis of Pt, Pd, Pt/Ag and Pd/Ag Nanoparticles By Microwave-
Polyol Method. J Chem Sci 2005;117( 4);311316.
21. Rades T, Zimper U. The Influence of Milling on the Dissolution Performance of
Simvastatin. Pharma 2010; 2;419-431.
22. Wang S, Xie Y. Enhanced Dissolution Rate and Oral Bioavailability of Simvastatin
Nanocrystal Prepared By Sonoprecipitation. Drug Dev Ind Pharm 2012;38(10);1230-39.
23. Pandya V, Patel J. Effect of Different Stabilizer on the Formulation of Simvastatin
Nanosuspension Prepared By Nanoprecipitation Technique. Res J Pharm, Bio and Chem
Sci 2010;1(4);910-917.
24. Athul P. Preparation and Characterization of Simvastatin Nanosuspension by
Homogenization Method. Inter J Pharm Tech Research 2013:5(1);193-197.
25. Gorniak A, Pluta J. Thermal Spectroscopic and Dissolution Studies of the Simvastatin-
acetylsalicylic acid mixtures. J Therm Anal Calorim 2013;111;212-2132.
26. Jatwani S, Singh G. Solubility and Dissolution Enhancement of Simvastatin using
synergistic effect of hydrophilic carriers, Der Pharmacia Lettre, 2011;3,(6);280-293.
27. Hosny K, Elhady S. Preparation and Evaluation of Orodispersible Tablets Containing
Hydroxylbutyl--Cyclodextrin-Simvastatin Solid Dispersion. Tropical J Pharma Res
2013;12 (4);469-476.
28. Bolourchian N. The Effect of PEG Molecular Weights on Dissolution Behavior of
Simvastatin in Solid Dispersions. Iranian J Pharm Res 2013;12;11-20.
29. Rao M, MandageY, Thanki K, Bhise S, Dissolution improvement of Simvastatin by
Surface Solid Dispersion Technology. Dis Tech2010;27-34.
30. Pandya P, Gattani S. Co-solvent Evaporation Method for Enhancement of Solubility and
Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitroIn vivo
Evaluation. Am Asso of Pharm Scientists Pharm Sci Tech 2008; 9(4);1247-1252.

31. Ambike A, Paradkar A. Spray-Dried Amorphous Solid Dispersions of Simvastatin, a

Low Tg Drug: In Vitro and in Vivo Evaluations. Pharma Res 2005;22,(6);990-998.
32. Ravi S. Design and Development of Fast Dissolving Tablets of Simvastatin Using Novel
Co-Processed Superdisintegrants. J Drug Delivery Res 2013;2,(1);27-52.
33. Sav A. Modified Fenugreek Gum For Solubility and Dissolution Rate Enhancement of
Simvastatin, World J Pharm and Pharma Sci 2013;2(5);4019-4029.
34. Pattewar S, Patil D, Bakade B. Natural Polymer Vis A Vis Synthetic Polymer For
Solubility Enhancement of Simvastatin. J Drug Deli and Therap 2012;2(3);110-117.
35. Javeer V, Patole R. Enhanced solubility and dissolution of Simvastatin by HPMC-based
solid dispersions prepared by hot melt extrusion and spray-drying method. J Pharm Inves
2013;DOI 10.1007/s40005-013-0092-1.
36. Tawde V, Chivate A. Solubility Enhancement of Simvastatin with Use of Novel
Polymeric Solubilizer Soluplus, 39th CRS Annual Meeting 2012, Canada.
37. Mandal D, Ojha P. Effect of Carriers on Solid Dispersions of Simvastatin (Sim):
PhysicoChemical Characterizations and Dissolution Studies. Der Pharmacia Lettre
2010; 2(4);47-56.
38. Patil J. Influence of Method of Preparation on Solubility, physicochemical properties and
in-vitro release profile of Simvastatin- cyclodextrin inclusion complexes: A comparative
study. International Journal of Chem Tech Research 2010;2(1);562-571.
39. Vyas A, Saraf S. Encapsulation of Cyclodextrin Complexed Simvastatin in Chitosan
nanocarriers: A novel technique for oral delivery. J Incl Phenom Macrocycl Chem
2010;66;251259.
40. Punitha S. Evaluation of Solubility of Simvastatin Using -Cyclodextrin by Solid
Dispersion Technique. Inter J Biomed Res 2010;1(2):4454.
41. Sandeep K. Effect of Non Ionic Surfactant on the Solubility and Enhancement of
Simvastatin. Inter Res J pharm 2011;2(3):100-102.
42. Patil J. Utilization of Superdisintegrants in the Design, Evaluation and Optimization of
Orodispersible Tablets containing Simvastatin-Cyclodextrin Inclusion Complexes.
RGUHS J Pharma Sci 2011;1(3);209-215.
43. Xianhong W , Ziyang L. Mass spectrometry and Molecular Modeling Studies on the
Inclusion Complexes Between , -Cyclodextrins and Simvastatin. Chemical Physics
Letters.2005;405;114117.

44. Francesca U, Concetta G. Use of Cyclodextrins as Solubilizing Agents for Simvastatin:

Effect of hydroxypropyl--cyclodextrin on lactone/hydroxyacid aqueous equilibrium.
Inter J Pharm 2011;404(12);4956.
45. Ferenc C. Induced Surface Activity of Supramolecular Cyclodextrin-Statin Complexes:
Relevance in drug delivery. J Colloids and Surfaces A: Phy and Eng Aspects
2010;354(13);308313.
46. Jun S, Kim V. Preparation and Characterization of Simvastatin/Hydroxypropyl-b
Cyclodextrin Inclusion Complex Using supercritical antisolvent (SAS) process. Euro J
Pharm and Biopharma 2007;66;413421.
47. Jaleh V. Enhanced Dissolution Rate of Simvastatin Using Spherical Crystallization
Technique. Pharma Devel and Techn 2011;16(5);529-535.
48. Srinivas C, Sagar S. Enhancing the Bioavailability of Simvastatin Using Microemulsion
Drug Delivery System. Asian J Pharm Clinic Res 2012;5(4);134-39.
49. Patil P, Patil V. Formulation of a Self-Emulsifying System for Oral Delivery of
Simvastatin: In vitro and In vivo Evaluation. Acta Pharma 2007;57;111122.
50. Dixit R, Nagarsenkar M. Dry Adsorbed Emulsion of Simvastatin: Optimization and in
vivo advantages, Pharma Deve and tech 2007;12(5)495- 504.
51. Gambhire M, Bhalekar M. Bioavailability assessment of simvastatin loaded solid lipid
nanoparticles after oral administration. Asian J Pharm Science 2011;6(6);251-58.
52. Tiwari R, Pathak K. Nanostructured lipid carrier versus solid lipid Nanoparticles of
simvastatin: Comparative analysis of characteristics, pharmacokinetics and tissue uptake.
Inter J Pharma 2011;415;232 243.
53. Ramani V, Chauhan S. Formulation and Evaluation of Nanoparticles of Hmg -Coa
Reductase Inhibitor. An Inter J Pharm Sci 2011;2,(4);42-58.
54. Katy G, Shlomo M. Formation of Simvastatin Nanopartical From Microemulsion,
Nanomedicine. Nanotechnology, Biology Medicine 2009;5(3);274-281.
55. Meng, Zhen. Application of Mixture Experimental Design to Simvastatin Apparent
Solubility Prediction in the Microemulsion Formed By Self Microemulsifying. Pharma
Dev and Tech 2007;33(9);927-931.
56. Kulharia H, Deep P. Performance evaluation of PAMAM dendrimer based Simvastatin
Formulations. Inter J Pharm 2011;405;203209.

Recent Approaches in Solubility Enhancement of Poorly Water Soluble Drug Simvastatin

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Recent Approaches in Solubility Enhancement of Poorly Water Soluble Drug Simvastatin

Uploaded by

Copyright:

Available Formats

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

S. J. Wadher et al. World Journal of Pharmacy and Pharmaceutical Sciences

RECENT APPROACHES IN SOLUBILITY ENHANCEMENT OF

S. J. Wadher*, S.G. Gattani, Y. A. Jadhav, T. M. Kalyankar

School of Pharmacy, SRTM University, Nanded

Article Received on ABSTRACT

Keywords: Solubility, Simvastatin, Techniques, Absorption.

www.wjpps.com Vol 3, Issue 4, 2014. 366

According to the Biopharmaceutical Classification Systems (BCS) the simvastatin drug

C. Class III drugs

www.wjpps.com Vol 3, Issue 4, 2014. 367

Table 1. Biopharmaceutical Classification Systems (BCS) of drugs

Fig. 1 Chemical Structure of Simvastatin (Sim)

Simvastatin is a lipid-lowering agent, which is obtained from a fermentation product

Methods for Solubility Enhancement

www.wjpps.com Vol 3, Issue 4, 2014. 368

www.wjpps.com Vol 3, Issue 4, 2014. 369

Preparation Methods of Nanosuspension

www.wjpps.com Vol 3, Issue 4, 2014. 370

ii ) High pressure homogenization

iii ) Media Milling

www.wjpps.com Vol 3, Issue 4, 2014. 371

Drug dispersion in carriers

Techniques to prepare the solid dispersion (S.D.)

www.wjpps.com Vol 3, Issue 4, 2014. 372

iii. Hot-Melt Extrusion.

a) Hot-Melt Method (Fusion Method)

b) Solvent Evaporation Method

By the solvent evaporation method simvastatin solubility is improved using polymer

www.wjpps.com Vol 3, Issue 4, 2014. 373

www.wjpps.com Vol 3, Issue 4, 2014. 374

such as pH-partition hypothesis and Handerson- Hesselbatch equation. The ionization of a

www.wjpps.com Vol 3, Issue 4, 2014. 375

C) Microwave Irradiation Method

www.wjpps.com Vol 3, Issue 4, 2014. 376

www.wjpps.com Vol 3, Issue 4, 2014. 377

Lipid based drug delivery system technique

Drug-dendrimer complex formation

www.wjpps.com Vol 3, Issue 4, 2014. 378

polypropyleneimine (PPI). Simvastatin solubility is improved by using dendrimer such as

Table 2.Techniques for the solubility enhancement of the Simvastatin

HPMC E5 LV Javeer V et al [35]

www.wjpps.com Vol 3, Issue 4, 2014. 379

Inclusion complex HP -CD Ungaro F et al [44]

www.wjpps.com Vol 3, Issue 4, 2014. 380

www.wjpps.com Vol 3, Issue 4, 2014. 381

17. Hameed M. A Recent Trends in Enhancement of Solubility and Dissolution Rate of

www.wjpps.com Vol 3, Issue 4, 2014. 382

31. Ambike A, Paradkar A. Spray-Dried Amorphous Solid Dispersions of Simvastatin, a

www.wjpps.com Vol 3, Issue 4, 2014. 383

44. Francesca U, Concetta G. Use of Cyclodextrins as Solubilizing Agents for Simvastatin:

www.wjpps.com Vol 3, Issue 4, 2014. 384

You might also like