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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.
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.
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.
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.
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].
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].
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].
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.
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
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.
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].
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.
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