INTRODUCTION:

Orally administered drugs completely absorb only when they show fair solubility in gastric medium and such drugs show good bioavailability. Recently more than 40% new chemical entities developed in pharmaceutical industry are practically insoluble in water. ^[1] These poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before they get the opportunity to fully dissolve and be absorbed into the blood circulation ^[2] and are allied with slow drug absorption leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. As about 70% of the human body is made up of water, a drug must be water-soluble and thus possess an acceptable bioavailability level. ^[2] Therefore, the improvement of drug solubility thereby its oral bioavailability remains one of most challenging aspects of drug development process especially for oral drug delivery system. As the size of the solid particle influences the solubility because the particle becomes smaller, the surface area to volume ratio increases.

The larger surface area allows a greater interaction with the solvent, so, the micronization is most important in this point of view as our aim is to micronize the drug particles and to enhance the solubility and bioavailability. There are numerous approaches available and reported in review to enhance the solubility of poorly water soluble drug. The techniques are chosen on the basis of certain aspects such as properties of drug under consideration, nature of excipients to be selected, if any and nature of intended dosage form. ^[1]

Table 1: Solubility definitions ^[3]

Definition	Parts of solvent required for one part of solute
Very soluble	< 1
Freely soluble	1-10
Soluble	10-30
Sparingly soluble	30-100
Slightly soluble	100-1000
Very slightly soluble	1000-10,000
Insoluble	>10,000

Factors affecting solubility^[3]

The solubility depends on the following factors.

a. Particle Size

b. Temperature

c. Pressure

d. Nature of the solute and solvent

e. Molecular size

f. Polarity

g. Polymorphs

Techniques of solubility enhancement^[4]

These are the various approaches which are useful to improve the solubility of poorly soluble drugs. It is basically applied to class II drugs of the BCS classification system, i.e. drugs having a good permeability but a low bioavailability due to their poor solubility and low dissolution velocity.

A. Physical modifications

1. Particle size reduction

- Micronization

- Nanotechnology approaches

- Sonocrystallization

- Supercritical fluid process

2. Modification of the crystal habit

- Polymorphs

- Pseudo polymorphs

3. Drug dispersion in carriers

- Eutectic mixtures

- Solid dispersions

- Solid solutions

4. Complexation

- Use of complexing agents

5. Solubilization by surfactants

- Microemulsions

- Self microemulsifying drug delivery systems

B. Chemical modifications

C. Other methods

- Co-crystallisation

- Co-solvency

- Hydrotrophy

- Solvent deposition

- Selective adsorption on soluble carrier

- Use of soluble prodrugs

- Functional polymer technology

- Porous micro particle technology

Micronization by various approaches for solubility enhancement

A. Micronization by spray drying or air attrition methods ^{[1, 5, 6]}

Micronization is for the particle size reduction. Micronisation means transfer of the coarse drug powder to an ultrafine powder with a mean particle size being typically in the range of 2-5 μm, size distributions normally ranges from approximately 0.1 to 25 μm. But, the point to be highlighted here is that only a very little fraction of the population lies below 1μm size range. The solubility of drug is often intrinsically related to drug particle size as a particle becomes smaller, the surface area to volume ratio increases. Particle size and surface area of a solid drug are inversely related to each other. The larger surface area allows a greater interaction with the solvent which causes increase in solubility. Micronization of drugs is done by spray drying or by use of air attrition methods (jet mill or fluid energy mill), rotor stator colloid mills, etc. The process is known as micromilling. Examples of the drugs whose bioavailability have been increased by micronization include griseofulvin and several other steroidal and sulpha drugs. Not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug. The solid active pharmaceutical ingredient (API) dissolution rate is proportional to the surface area available for dissolution as described by the Nernst–Brunner/Noyes–Whitney equation:

dc = D A Kw/o (Cs – Cb)

dt V h

Where,

dc/dt = Rate of dissolution

D = Diffusion co- efficient of the drug

A = Surface area of the drug

Kw/o = Water/oil partition co-efficient of the drug considering the fact that dissolution body fluids are aqueous. Since the rapidity with which a drug dissolves depends on the Kw/o. It is called as intrinsic dissolution rate constant. It is a characteristic of the drug.

V = Volume of dissolution medium.

h = thickness of the stagnant layer.

(Cs – Cb) = Concentration gradient for diffusion of the drug.

B. Nanonisation/Nanotechnology ^{[4, 5, 6]}

Nanotechnology is defined as the science and engineering carried out in the nanoscale that is 10^-9 meters. Nanonization is one of the most promising approaches to improve the bioavailability of lipophilic drugs by an increase in surface area and saturation solubility via reduction of the particle size to less than 1 μm.

Figure 1.1: Surface enlargement and increase in number of crystals by particle size diminution ^[7]

Drug nanocrystals are nanoparticles being composed of 100 % drug without any matrix material. [Figure 1.2]

Figure 1.2: Nanocrystal technology ^[9]

Nanosuspensions ^[4] are sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants. The nanosuspension approach has been employed for drugs including tarazepide, atovaquone, amphotericin B, paclitaxel and bupravaquone. All the formulations are in the research stage.

Method of preparation ^[6]

Mainly two methods for preparation.

1. The conventional method of precipitation is called “Bottom up technology”. In bottom up technology, the drug is dissolved in a solvent, which is then added to non-solvent to precipitate the crystals. The basic advantage of precipitation technique is the use of simple and low cost equipments. The basic challenge of this technique is that during the precipitation procedure the growing of the drug crystals needs to be controlled by addition of surfactant to avoid formation of microparticles. The limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and this solvent needs to be miscible with nonsolvent. Moreover precipitation technique is not applicable to drugs, which are simultaneously poorly soluble in aqueous and nonaqueous media.

2. The “Top down technologies” are the disintegration methods and are preferred over the precipitation methods. These technologies include media milling (NanoCrystals® or Nanosystem), high pressure homogenization in water (DissoCubes), high pressure homogenization in nonaqueous media (Nanopure®) and combination of precipitation and high-pressure homogenization (NANOEDEGE^TM), etc.

1. Media milling/Pearl milling (NanoCrystals® or Nanosystem) ^[1]

The method is first developed and reported by Liversidge et al in 1992. The nanosuspensions are prepared by using high-shear media mills. The milling chamber charged with milling media, water, drug and stabilizer is rotated at a very high shear rate under controlled temperatures for several days (at least 2-7 days). The milling medium is composed of glass, zirconium oxide or highly cross-linked polystyrene resin. The high energy shear forces are generated as a result of the impaction of the milling media with the drug resulting into breaking of microparticulate drug to nanosized particles. The benefit is applicable to the drugs those are poorly soluble in both aqueous and organic media and very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/mL to 400 mg/mL drug quantity.

Disadvantages

1. Nanosuspensions contaminated with materials eroded from balls may be problematic when it is used for long therapy.

2. The media milling technique is time consuming.

3. Some fractions of particles are in the micrometer range.

4. Scale up is not easy due to mill size and weight.

2. High pressure homogenization

Depending on the dispersion media and the homogenization temperature, there are two technologies developed.

(a) DissoCubes® technology ^[6] and

(b) Nanopure® technology ^[6]

(c) Combination technologies (NANOEDGE technology - microprecipitation and high shear forces - NANOEDGE^TM) also developed.

Table 1.2: Overview of the technologies and patents/patent applications on which the various homogenization processes are based ^{[1, 9]}

Product (Nanocrystals)	Company	Patent/patent application examples
Hydrosol	Novartis	GB 22 69 536, GB 22 00 048
Nanomorph^TM	Soligs/Abbott	D 19637517
Nanocrystals^TM	e’lan nanosystems	US 5,145,684
DissoCubes®	Skyepharma	US 5,858,410
Nanopure®	Pharmasol	PCT/EP00/0635
NANOEDGE^TM	Baxer	US 6,884,436

3. Homogenization in water (DissoCubes® technology) ^[6]

Principle

In piston gap homogeniser particle size reduction is based on the cavitation principle. Pressure of 1500-150 bars is used and a narrow ring gap piston is used (3-15 micrometer gap size). Particles are also reduced due to high shear forces and the collision of the particles against each other. The dispersion contained in 3cm diameter cylinder; suddenly passes through a very narrow gap of 25µm. According to Bernoulli’s Law the flow volume of liquid in a closed system per cross section is constant. The reduction in diameter from 3cm to 25µm leads to increase in dynamic pressure and decrease of static pressure below the boiling point of water at room temperature.

Figure 1.3: Basic principle of high pressure homogenization using a piston gap homogenizer ^[7]

The size of the drug nanocrystals that can be achieved mainly depends on factors like temperature, number of homogenization cycles, and powder density of homogeniser and homogenization pressure.

Advantages

1. It does not cause the erosion of processed materials.

2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/mL to 400 mg/mL drug quantity.

3. It is applicable to the drugs that are poorly soluble in both aqueous and organic media and allows aseptic production of nanosuspensions for parentral administration.

Disadvantages

1. Pre-processing like micronization of drug is required.

2. High cost instruments are required that increase the cost of dosage form.

3. Chemical instability of fragile drugs under the harsh production conditions, Ostwald ripening in long-term storage, toxicity of surfactants, redispersibility of the dried powder, batch-to-batch variation in crystallinity level and finally the difficulty of quality control and the stability of the partially amorphous nanosuspensions.

4. Homogenization in non-aqueous media (Nanopure® technology) ^{[6, 8]}

Similar effective particle size reduction can also be obtained in nonaqueous or water reduced media. The production of nanocrystals in non-homogenization media is a very effective method to obtain direct formulation. The nanocrystals of the drug dispersed in liquid polyethylene glycol (PEG) or various oils can be directly filled as drug suspensions into hydroxyl propyl methyl cellulose (HPMC) capsules or gelatin. Cavitation is the major force in particle size reduction. Against this theory, this technology was developed. Even in non-aqueous media, the particle size diminution can be achieved. Tablets, pellets and capsules must be formed. The advantage of this technique is dispersion medium need not be removed and evaporation is faster and under milder conditions (when water and water miscible liquids are used). Useful for temperature sensitive drugs and for intravenous injections, isotonic nanosuspensions are obtained by homogenizing in water-glycerol mixtures. Water reduction causes decrease in the energy required for the various steps carried out such as fluidized bed drying, spray drying or layering of suspension onto the sugar spheres.

5. Combination technologies (Microprecipitation and high shear forces – NANOEDGE^TM) ^{[6, 8]}

The Baxter Company gave the concept of the NANOEDGE® technology. The NANOEDGE® technology is highly suitable for drugs which are suitable in non–aqueous media such as N-methyl–2– pyrrrolidinone. All the basic principles outlined for precipitation and for high pressure homogenization are also valid for this combination technology called as NANOEDGE®. At lab scale, it is easy to remove the solvents by various methods such as counter current flow but problem arises in case of large scale production. Hence, this combination technology removes mainly, all the drawbacks of the precipitation process. But it should also be mentioned that combination techniques are costlier than the conventional one step process, especially when producing sterile products.

6. Emulsification-solvent evaporation technique

The technique involves preparing a solution of drug followed by its emulsification in another liquid that is a non-solvent for a drug. Evaporation of the solvent leads to precipitation of the drug. Crystal growth and particle aggregation can be controlled by creating high speed stirrer.

7. Hydrosol method ^[1]

This is similar to emulsification-solvent evaporation technique. The only difference between the two methods is that the drug solvent is miscible with the drug anti-solvent. Higher shear force prevents crystal growth and Ostwald ripening and ensures that the precipitates remain smaller in size.

C. Sonocrystallization ^[10]

Recrystallization of poorly soluble materials using liquid solvents and antisolvents has also been employed successfully to reduce particle size. The novel approach for particle size reduction on the basis of crystallisation by using ultrasound is Sonocrystallisation. Sonocrystallisation utilizes ultrasound power characterised by a frequency range of 20–100 kHz for inducing crystallisation. It’s not only enhances the nucleation rate but also an effective means of size reduction and controlling size distribution of the active pharmaceutical ingredients. Most applications use ultrasound in the range of 20 kHz - 5 MHz.

D. Supercritical fluid process (SCF) ^[4]

A SCF exists as a single phase above its critical temperature (Tc) and pressure (Pc). SCFs have properties useful to product processing because they are intermediate between those of pure liquid and gas (i.e. liquid-like density, gas-like compressibility and viscosity and higher diffusivity than liquids). Moreover, the density, transport properties (such as viscosity and diffusivity), and other physical properties (such as dielectric constant and polarity) vary considerably with small changes in operating temperature, pressure, or both around the critical points. Hence, it is possible to fine tune a unique combination of properties necessary for a desired application. These unique processing capabilities of SCFs, long recognized and applied in the food industry, have recently been adapted to pharmaceutical applications.

1. Rapid expansion from supercritical solutions (RESS) ^[4]

Principle

A supercritical solvent saturated with a solute of interest is allowed to expand at a very rapid rate, causing the precipitation of the solute. The rapid expansion/decompression is achieved by allowing into pass through a nozzle at supersonic speeds. This rapid expansion of supercritical solutions leads to super saturation of the solute in it and subsequent precipitation of solute particles with narrow particle size distributions. This process is also known as supercritical fluid nucleation (SFN). The characteristic of the particles produced using SCF technology are influenced by the properties of the solute (drug, polymer and other excipients), type of SCF used and process parameters (such as flow rate of solute and solvent phase, temperature and pressure of the SCF, pre-expansion temperature, nozzle geometry and the use of co-axial nozzles).

2. Gas antisolvent process (GAS) ^[11]

GAS technique proposed to overcome the limitations encountered with the RESS process. Particularly useful for those substrates which are not soluble in supercritical fluids. The GAS process is a batch technique, which entails the gradual introduction of a compressed gas into a liquid solution of the solute of the interest in a primary organic solvent. This method is based on the ability of the liquids to solubilise large amount of gases. This solubilisation generally induces large volumetric expansions of the liquid phase (several fold) and a decrease of its density. This is accompanied by a decrease of the liquid solvent strength, which causes the solid to precipitate as ultra fine particles.

3. Precipitation with compressed fluid antisolvents (PCA) or supercritical antisolvent (SAS) or aerosol solvent extraction systems(ASES) ^[10]

Principle

During the process, the precipitation results from two phenomena, one is the fast diffusion of the antisolvent into the liquid phase and the evaporation of the organic solvent into the continuous phase, generally in a supercritical state. Both transfers rapidly yield supersaturation, which causes the substrate to precipitate in the form of nano or micro particles.

4. Solution enhanced dispersion by supercritical fluid (SEDS) ^{[4, 10]}

The SEDS process was developed and patented by the University of Bradford to overcome some of the limitations of the RESS and GAS methods. The use of a coaxial nozzle provides a means whereby the drug in the organic solvent solution mixes with the compressed fluid CO₂ (antisolvent) in the mixing chamber of the nozzle prior to dispersion and flows into a particle-formation vessel via a restricted orifice. Such nozzle achieves solution break up through the impaction of the solution by a higher velocity fluid. The high velocity fluid creates high frictional surface forces, causing the solution to disintegrate into droplets. A key step in the formation of nanoparticles is to enhance the mass transfer rate between the droplets and the antisolvent before the droplets coalescence to form bigger droplets. The main advantage of SEDS over the other SCF‐based techniques is the direct control over the mean size and size‐distribution of the product by controlling the pressure, temperature and flow rates.

5. Particles from gas saturated solutions (PGSS) ^[10]

The compound(s) is melted/dissolved in a compressed gas until the saturation is reached. Then, rapidly expanded towards a low‐pressure vessel which causes precipitation of solid fine particles of insoluble drug. This can be achieved because of the lower melting temperature of materials in high pressure CO₂ atmosphere. This PGSS technique has been tried for nifedipine, felodipine, finofibrate and others.

E. Cryogenic technologies ^[10]

Cryogenic techniques have been developed to enhance the dissolution rate of drugs by creating nanostructured amorphous drug particles with high degree of porosity at very low temperature conditions. Cryogenic inventions can be defined by the type of injection device (capillary, rotary, pneumatic, ultrasonic nozzle), location of nozzle (above or under the liquid level) and the composition of cryogenic liquid (hydrofluoroalkanes, N₂, Ar, O₂, organic solvents). After cryogenic processing, dry powder can be obtained by various drying processes like spray freeze drying, atmospheric freeze drying, vacuum freeze drying and lyophilisation.

1. Spray freezing into liquid (SFL) ^[10]

The SFL technology was developed and patented by the University of Texas at Austin in 2003 and commercialized by the Dow Chemical Company. This technique involves atomizing an aqueous, organic, aqueous-organic co-solvent solution, aqueous-organic emulsion or suspension containing a drug and pharmaceutical excipients directly into a compressed gas (i.e. CO₂, helium, propane, ethane) or the cryogenic liquids (i.e. nitrogen, argon or hydrofluoroethers). The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders.

2. Spray freezing onto cryogenic fluids ^[10]

Briggs and Maxwell invented the process of spray freezing onto cryogenic fluid. In this technique, the drug and the carrier (mannitol, maltose, lactose, inositol or dextran) were dissolved in water and atomized above the surface of a boiling agitated fluorocarbon refrigerant. Sonication probe can be placed in the stirred refrigerant to enhance the dispersion of the aqueous solution.

3. Spray freezing into vapour over liquid (SFV/L) ^[10]

Freezing of drugs solution in cryogenic fluid vapours and subsequent removal of frozen solvent produces fine drug particles with high wettability. During SFV/L, the atomized droplets typically start to freeze in the vapour phase before they contact the cryogenic liquid. As the solvent freezes, the drug becomes supersaturated in the unfrozen regions of the atomized droplet, so fine drug particles may nucleate and grow.

4. Ultra rapid freezing (URF) ^[10]

Ultra‐rapid freezing is a novel cryogenic technology that creates nanostructured drug particles with greatly enhanced surface area and desired surface morphology by using solid cryogenic substances. Application of drugs solution to the solid surface of cryogenic substrate leading to instantaneous freezing and subsequent lyophilisation for removal of solvent forms micronized drug powder with improved solubility. Ultra rapid freezing hinders the phase separation and the crystallization of the pharmaceutical ingredients leading to intimately mixed, amorphous drug‐carrier solid dispersions and solid solutions. This technique has been investigated for solubility enhancement of repaglinide.

Table 1.3: Evaluation and characterization of the nanosized/micronized product ^[13]

Sr. No.	Parameters	Methods
1.	Particle size and size distribution	Photon correlation spectroscopy, Transmission electron microscopy, Scanning electron microscopy, Laser diffractometry, Coulter counter
2.	Charge determination	Laser droppler anetometry, Zeta potentiometer
3.	Surface hydrophobicity	Water contact angle measurements, Rose bengal(dye) binding, Hydrophobic interaction chromatography, x - ray photoelectron spectroscopy
4.	Chemical analysis of the surface	Static secondary ion mass spectrometry, Sorptometer
5.	Carrier - drug interaction	Differential scanning calorimetry
6.	In-vitro release profile	In-vitro release characteristic under physiologic and sink conditions
7.	Crystallinity	x-ray diffraction, Differential scanning calorimetry, Differential thermal analysis
8.	Drug stability	Bioassay of drug extracted from nanoparticles
9.	Molecular weight	Gel permeation chromatography
10.	Density	Helium compression pycnometry
11.	In-vivo study	By possible animal model
12.	Saturation solubility and dissolution velocity	Depends on temperature and the properties of the dissolution medium. Explained by Kelvin equation and Ostwald - Freundlich equation

Table 1.4: Commercial products in the market ^[7]

Brand Name	Description	Advantages	Company	US FDA approval/ marketed
Rapamune	Nanocrystallized Rapamycin (immune-suppressant) in a tablet	Enhanced dissolution rate and bioavailability	Wythe-Ayerst laboratories	2000
Emend®	Nanocrystal aprepitant (antiemetic) in a capsule	Enhanced dissolution rate and bioavailability	Merck and Co.	2003
Rexin-G®	A retroviral vector carrying cytotoxic gene	Effective in pancreatic cancer treatment	Epeins Biotechnology Corporation	2003
Abraxane	Paclitaxel (anticancer drug) bound albumin particles	Enhanced dose tolerance and hence, elimination of the effect of the solvent associated toxicity	American Bioscience Inc., and American Pharmaceutical Partners Inc	2005
Imudrops	Unique micro emulsion technology providing cyclosporine particle size of less than 1 micron	Better, faster absorption and penetration. Negligible local irritation, burning and stinging reaction	Cipla Pharmaceutical Ltd.	2010
Tricor®	Fenofibrate nanocrystals	Enhanced dissolution rate and bioavailability	Abbot Laboratories	Marketed
Megace ES®	Megestrol also has direct cytotoxic effects on breast cancer cells in tissue culture and suppresses luteinizing hormone release from the pituitary.	Enhanced dissolution rate and bioavailability	Par Pharmaceutical Companies, Inc.	Marketed
Triglide	Fenofibrate as active material useful in Hypercholesterolemia	Enhanced dissolution rate and bioavailability	Sciele Pharma Inc.	Marketed
Paxceed®	Paclitaxel	Anti -inflammatory	Angiotech	Phase III

Table 1.5: Literature review

Researcher	Aim	Journals
Bhise S. B et al	Enhancement of dissolution rate of rifabutin by preparation of microcrystals using solvent change method ^[14]	Int. J. of Pharm. Tech. and Res.
M. Kenthil Kumar et al	Particle size reduction is a promising approach to improve the bioavailability of lipophilic drugs ^[6]	Int. J. of recent Adv. in Pharm. Res.
Muller R. H. et al	Bupravaquone mucoadhesive nanosuspension ^[15]	Int. J. of Pharm.
P. M Dandagi et al	Enhancement of solubility and dissolution property of griseofulvin by nanocrystallization ^[16]	Int. J. of drug Dev. and Res.
Aman Soni et al	Simvastatin-loaded PLGA nanoparticles for improved oral bioavailability and sustained release^[17]	Asian J. of Pharm.
Kohno S. et al	Amphotericin B encapsulated in polyethylene glycol immunoliposomes ^[18]	Adv. in drug delivery
Patel et al	Improvement in the dissolution of the anti-ulcer drug(famotidine) using media milling technique ^[19]	Thai J. of Pharm. Sci.
J Babu et al	Dissolution enhancement of poorly water soluble drugs(Itraconazole) nanoparticles ^[20]	Int. J. of Pharm.
K. Amighi et al	Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine ^[21]	Int. J. of Pharm. Sci.
Patil et al	Simvastatin nanoparticle for solubility enhancement ^[22]	Int. J. of Pharm. Res. and Dev.

F. Microemulsion ^[12]

Micro emulsions are thermodynamically clear, stable, isotropic systems which are formed spontaneously at certain concentrations of oil, water and surfactant. Formation of micro emulsion is limited only by diffusion of the molecules. Change in the free energy of dispersion shows a minimum equilibrium droplet size in the range of 10-100 nm for micro emulsion system.

It is having low viscosity, small droplet size, simple preparation technique, long shelf life, low toxicity to patient, high solubility of drug, clarity, high stability and ease of preparation, controlled drug release rate, slow degradation, target specificity when administered.

CONCLUSION:

The growing numbers of poorly water soluble drugs demand development of technologies for enhancing drug solubility. Various conventional techniques like cyclodextrin inclusion complexation, salt formation, co-solvency, hydrotrophy, solid dispersion, comminution and spray drying were being used but each were found with inherent problems of their efficacy or stability of final product. Novel technologies such as particle engineering by nanomilling, use of supercritical fluid and crystal engineering, etc. have been developed to improve drugs solubility. By using one of the above techniques mentioned in the review, can be useful for formulation of lipophilic drugs for better solubility and bioavailability.

REFERENCES:

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18. Kohno S., Otsubo T., Tanaka E., Maruyama K. and Hara K. Amphotericin B encapsulated in polyethylene glycol immunoliposomes for infectious diseases. Advance Drug Delivery. 1997; 24:325-329.

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22. Mukesh Patil, Kedar R Bavaskar, Ghanashyam A Girnar, Dr. Ashish S Jain and Dr. Avinash R Tekade. Praparation and optimization of simvastatin nanoparticle for solubility enhancement and in-vivo study. International Journal of Pharmaceutical Research and Development. Feb 2011; 2(12): 219-226.

Received on 23.05.2012 Modified on 19.06.2012

Research J. Pharm. and Tech. 5(8): August 2012; Page 999-1005