A Review on Solid Dispersion as a Technique for Enhancement of Bioavailability of Poorly Water Soluble Drugs

 

Sneha D. Bhore

Ambabai Talim Sanstha’s Diploma in Pharmacy College, Miraj-416 414, Dist.-Sangli  Maharashtra India

*Corresponding Author E-mail: bhores3112@rediffmail.com

 

ABSTRACT:

The enhancements of oral bioavailability of poorly water soluble drugs often show poor bioavailability because of low and erratic levels of absorption. Drugs that undergo dissolution rate limited gastrointestinal absorption generally show improved dissolution and bio availability as a result of reduction in particle size. Oral bioavailability of drugs depends on its solubility and/or dissolution rate, therefore major problems associated with these drugs was its very low solubility in biological fluids, which results into poor bioavailability after oral administration. Solid dispersions have achieved considerable interest as an efficient means of improving the dissolution rate and hence the bioavailability of a range of poorly water soluble drugs. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic inert carrier or matrix and a hydrophobic drug. Improving oral bioavailability of drugs which are given as solid dosage forms remains a challenge for the formulation scientists due to solubility problems. The dissolution rate for such drugs can be the rate-limiting process in the absorption. Solid dispersions of poorly water-soluble drugs with water soluble carriers have been reduced the incidence of these problems and enhanced dissolution. This article summarizes on solid dispersion technology, limitations of solid dispersion, classification of solid dispersion techniques, and advantages and disadvantages of solid dispersion techniques.

 

KEYWORDS: Solubility, Solid Dispersions, BCS Classification, Carrier, Bioavailability.

 

 


INTRODUCTION:

The enhancements of oral bioavailability of poorly water-soluble drugs often show poor bioavailability because of low and erratic levels of absorption. Drugs that undergo dissolution rate limited gastrointestinal absorption generally show improved dissolution and bio availability as a result of reduction in particle size1.Oral bioavailability of drugs depends on its solubility and/or dissolution rate, therefore major problems associated with these drugs was its very low solubility in biological fluids, which results into poor bioavailability after oral administration2-5.

 

However, micronizing of drugs often leads to aggregation and agglomeration of particles, which results in poor wettability. Solid dispersions of poorly water-soluble drugs with water-soluble carriers have been reduced the incidence of these problems and enhanced dissolution1.Therefore, pharmaceutical researchers’ focuses on two areas for improving the oral bioavailability of drugs include:

 

(i) Enhancing solubility and dissolution rate of poorly water-soluble drugs and (ii) enhancing permeability of poorly permeable drugs5,6. In the Biopharmaceutical Classification System (BCS) drugs with low aqueous solubility and high membrane permeability are categorized as Class II drugs. Therefore, solid dispersion technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs7.

 

The rate and extent of absorption of class II and class IV compounds is highly dependent on the bioavailability which ultimately depends on solubility. Thus, a greater understanding of dissolution and absorption behavior of drugs with low aqueous solubility is required to successfully formulate them into bio-available drug products8.


Table 1: Various methods to increase the solubility of drugs

Physical Modification

1. Particle size reduction

2. Modification of the crystal habit

3. Drug dispersion in carriers

4. Complexation

 

5. Solubilisation by surfactants

a. Micronization

b. Nanosuspension

• Homogenization

• Wet milling

c. Sonocrystallization

d. Supercritical fluid process

e. Spray drying

a. Polymorphs

b. Pseudo Polymorphs

a. Eutectic mixtures

•Hot plate method

•Solvent evaporation method

•Hot-melt extrusion

•Melting-solvent method

a. Eutectic mixtures

• Hot plate method

• Solvent evaporation method

• Hot-melt extrusion

•Melting-solvent method

1. Microemulsions

2.Self microemulsifying drug delivery systems

 

Chemical Modification

a. Soluble prodrugs

b. Salt formation

Other Techniques

a. Co-crystallisation

b. Cosolvency

c. Hydrotrophy

d. Solubilizing agents

e. Nanotechnology approaches

 


Biopharmaceutics Classification System:9

The Biopharmaceutics Classification System is the technique used to differentiate the drugs on the basis of their solubility and permeability is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. The fundamental basis for the BCS was established by Gordon Amidon, who was presented with a Distinguished Science Award at the August 2006 International Pharmaceutical Federation (FIP) congress in Salvador, Brazil.  This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factors are highly important because 85% of the most sold drugs in the United States and Europe are orally administered. According to the Biopharmaceutics Classification System, drug substances are classified as follows

 

Class I - High permeability, high solubility

Example: Metoprolol

Those compounds are well absorbed and their absorption rate is usually higher than excretion.

 

Class II - High permeability, low solubility

Example: Glibenclamide, Bicalutamide, Ezetimibe

The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

 

Class III - Low permeability, high solubility

Example: Cimetidine

The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied.

 

Class IV - Low permeability, low solubility

Example: hydrochlorothiazide

Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

 

SOLID DISPERSION:

Chiou and Riegelman defined the term solid dispersion as “A dispersion involving the formation of eutectic mixtures of drugs with water soluble carriers by melting of their physical mixture” 3,10 The term solid dispersion refers to a group of solid products consisting of at least two different components, a hydrophilic matrix and a hydrophobic drug. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles10.

 

ADVANTAGES OF SOLID DISPERSIONS:11

There are various reasons for the improvement of solubility of poorly water-soluble drug using solid dispersion technology. The reasons for solid dispersion or advantages of solid dispersions are as follows:

 

1. Particles with reduced particle size:

Molecular dispersions, as solid dispersion, represent the last state on particle size reduction, and after inert carrier or matrix dissolution the drug is molecularly dispersed in the dissolution medium. A high surface area is formed which results an increased dissolution rate and further improved the bioavailability of the poorly water soluble drug.

 

2. Particles with improved wettability:

The solubility enhancement of the drug is related to the drug wettability improvement verified in solid dispersion.

 

3. Particles with higher porosity:

Particles in solid dispersions have been found to have a higher degree of porosity and the increase in porosity also depends on the properties of the carrier. When polymers having linear structure are utilized it produces larger and more porous particle as compared with SDs that prepared with reticular polymers. More porous nature of the particle results higher dissolution rate.

 

4. Drugs in amorphous state:

Poorly water-soluble crystalline drugs, when in the amorphous state tend to have higher degree of solubility. Drug in its amorphous state shows higher drug release because no energy is required to break up the crystal lattice during the dissolution process.

 

 


Table-2: Types of solid dispersion

Sr. No.

Solid dispersion type

Matrix *

Drug **

Remarks

No. of phases

I

Eutectics

C

C

The first type of solid dispersion prepared

2

II

Amorphous precipitations incrystalline matrix

C

A

Rarely encountered

2

III

Solid solutions

 

 

 

 

 

Continuous solidsolutions

C

M

Miscible at all composition, never prepared

1

 

Discontinuous solid solutions

C

M

Partially miscible, 2 phases even though drug is molecularly dispersed.

2

 

Substitutional solid solutions

C

M

Molecular diameter of drug (solute) differs less than 15% from the matrix (solvent)diameter. In that case the drugand matrix are substitutional.Can be continuous ordiscontinuous.When discontinuous: 2 phaseseven though drug is molecularly dispersed.

1or 2

 

Interstitial solid solutions

C

M

Drug (solute) moleculardiameter less than 59% ofmatrix (solvent) diameter.Usually limited miscibility,discontinuous. Example: Drug inhelical interstitial spaces of PEG.

2

IV

Glass suspension

A

C

Particle size of dispersed phase dependent on cooling/ evaporation rate. Obtained after crystallization of drug in amorphous matrix

2

V

Glass suspension

A

A

Particle size of dispersed phase dependent oncooling/evaporation rate. Manysolid dispersions are of this type.

2

VI

Glass solution

A

M

Requires miscibility OR solid solubility, complex formation or upon fast cooling ORevaporation during preparation, many examples especially with PVP.

1

 


Disadvantages of solid dispersions11:

The major disadvantages of SDs are related to their instability. Several systems have shown changes in crystallinity and a decrease in dissolution rate on ageing. By absorbing moisture, phase separation, crystal growth or a change from metastable crystalline form to stable form can take place which leads to the reduction of drug solubility. Moisture and temperature have more of deteriorating effect on solid dispersions than on physical mixtures. Sometimes it is difficult to handle because of tackiness.

 

Limitations of solid dispersions11:

Although a great research interest in solid dispersion in the past some decades, the commercial utilization is very limited. Problems of solid dispersion involve (i) the physical and chemical stability of drugs and vehicles, (ii) method of preparation, (iii) reproducibility of its physicochemical properties, (iv) formulation of solid dispersion into dosage forms, and (v) scale-up of manufacturing processes.

 

Preparation of Solid Dispersions:

Common Methods Used for Preparation of SolidDispersion:12,15 Various methods used for preparation of solid dispersion system. These methods are given below.

1. Melting method/ Fusion method

2. Solvent methods

3. Melting solvent method (melt evaporation)

4. Melt extrusion methods

5. Lyophilization techniques

6. Melt agglomerations Process

7. The use of surfactant

8. Electro spinning

9. Super Critical Fluid (SCF) technologies

 

1. Melting method/ Fusion method13:

The melting or fusion method is the preparation of physical mixture of a drug and a water-soluble carrier and heating it directly until it melts. The melted mixture is then solidified rapidly in an ice-bath under vigorous stirring. The final solid mass is crushed, pulverized and sieved. Appropriately this has undergone many modifications in pouring the homogenous melt in the form of a thin layer onto a ferrite plate or a stainless steel plate and cooled by flowing air or water on the opposite side of the plate. In addition, a super-saturation of a solute or drug in a system can often be obtained by quenching the melt rapidly from a high temperature. Under such conditions, the solute molecule is arrested in the solvent matrix by the instantaneous solidification process. The quenching technique gives a much finer dispersion of crystallites when used for simple eutectic mixtures. However many substances, either drugs or carriers, may decompose during the fusion process which employs high temperature. It may also cause evaporation of volatile drug or volatile carrier during the fusion process at high temperature. Some of the means to overcome these problems could be heating the physical mixture in a sealed container or melting it under vacuum or in presence of inert gas like nitrogen to prevent oxidative degradation of drug or carrier. The main advantages of this method are its simplicity and economy. The disadvantages are: i) that the method is only applied when the drug and matrix are compatible and when they mix well at the heating temperature. When the drug and matrix are incompatible two liquid phases or suspension can be observed in the heated mixture which results in an inhomogeneous solid dispersion and this problem can be prevented by using surfactants. ii) Another problem may arise during cooling when the drug-matrix miscibility changes. In this case phase separation can occur. Indeed, it was observed that when the mixture was slowly cooled, crystalline drugoccurred, whereas fast cooling yielded amorphous solid dispersions. iii) Many substances, either drugs or carriers, may decompose during the fusion process at high temperatures.

 

2. Solvent Method14

This method involves two steps-

1. The preparation of a solution containing both matrix material and drug. 2. The removal of solvent(s) resulting information of a solid dispersion. Using the solvent method, the pharmaceutical engineer faces two challenges:

 

1. The first challenge is to mix both drug and matrix in one solution, which is difficult when they differ significantly in polarity. To minimize the drug particle size in the solid dispersion, the drug and matrix have to be dispersed in the solvent as fine as possible preferably drug and matrix material are in the dissolved state in one solution.

 

2. The second challenge in the solvent method is to prevent phase separation, e.g. crystallization of either drug or matrix, during removal of the solvent(s). Drying at high temperatures speeds up the process and reduces the time available for phase separation. On the other hand, at high temperatures the molecular mobility of drug and matrix remains high, favoring phase separation (e.g., crystallization).

 

Table3:  Organic Solvents

Sr.

No.

Solvents

Melting

Point (°C)

Boiling

Point (°C)

Vapour

Pressure at 25°C (kPa)

1.

Water

0

100

3.16

2.

Methanol

-93.9

65

16.9

3.

Ethanol

-117

78.5

5.79

4.

1-propanol

-85.8

97.4

2.27

5.

2-propanol

-127

82.4

5.85

6.

Chloroform

-63

62

26.1

7.

Dimethyl sulphoxide (DMSO)

19

189

0.08

8.

Acetic acid

17

118

1.64

9.

1,4-dioxane

12

102

4.92

10.

2-methyl-2-propanol (TBA)

25

82

5.49

 

 

3. Melting solvent method (melt evaporation) 15

It involves preparation of solid dispersions by dissolving the drug in a suitable liquid solvent and then incorporating the solution directly into the melt of polyethylene glycol, which is then evaporated until a clear, solvent free film is left. The film is further dried to constant weight. The 5 –10% (w/w) of liquid compounds can be incorporated into polyethylene glycol 6000 without significant loss of its solid property. It is possible that the selected solvent or dissolved drug may not be miscible with the melt of the polyethylene glycol. Also the liquid solvent used may affect the polymorphic form of the drug, which precipitates as the solid dispersion. This technique possesses unique advantages of both the fusion and solvent evaporation methods. From a practical stand point, it is only limited to drugs with a low therapeutic dose e.g. below50 mg.

 

4. Melt extrusion method:11, 16

Hot-stage extrusion (HME) consists of the extrusion, at high rotational speed, of the drug and carrier, previously mixed, at melting temperature for a small period of time. Solid dispersion by this method is composed of active ingredient and carrier, and prepare by hot-stage extrusion using a co-rotating twin-screw extruder. The drug/carrier mix is simultaneously melted, homogenized and then extruded and shaped as tablets, granules, pellets, sheets, sticks or powder. The intermediates can then be further processed into conventional tablets. An important advantage of the hot melt extrusion method is that the drug/carrier mix is only subjected to an elevated temperature for about 1min, which enables drugs that are somewhat thermolabile to be processed. The concentration of drug in the dispersions is always 40% (w/w). Samples are milled for 1 min with a cutting mill and sieved to exclude particles >355μ. A reduction in processing temperature can be achieved by the association of hot-stage extrusion with the use of carbon dioxide as a plasticizer which broadens the application of hot-stage extrusion to thermally labile compounds. HME also offers several advantages over traditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, and low temperature, short residence time which prevents the drug-carrier mixture from thermal degradation, more possibility of the formation of solid dispersions and improved bioavailability. This method has several disadvantages these are: (i) high shear forces may produce high local temperature in the extruder therefore it may create a problem for heat sensitive materials, (ii) just like traditional fusion method, miscibility of drug and carrier matrix can be a problem. Some examples of pharmaceutically approved polymeric materials which are used in hot-melt extrusion include vinyl polymers [polyvinylpyrrolidone (PVP), PVP-vinyl acetate (PVP-VA)], polyethylene oxide (PEO), Eudragit® (acrylates), Polyethylene glycol (PEG) and cellulose derivatives.

 

5. Lyophilization techniques: Freeze-drying17:

This process consists of dissolving the drug and carrier in a common solvent, which is immersed in liquid nitrogen until it is fully frozen. Then, the frozen solution is further lyophilized. Although it is concluded in literature that this is a promising and suitable technique to incorporate drug substances in stabilizing matrices, the technique is poorly exploited for the preparation of solid dispersions. An important advantage of freeze drying is that the drug is subjected to minimal thermal stress during the formation of the solid dispersion. However, the most important advantage of freeze drying is that the risk of phase separation is minimized as soon as the solution is vitrified.

 

6. Melt agglomerations Process17:

Melt agglomeration allows the preparation of solid dispersions in conventional high shear mixers. It is made by adding the molten carrier containing the drug to the heated excepients. It is prepare by heating a mixture of the drug, carrier and excipients to a temperature within or above the melting range of the carrier. It is also possible to produce stable solid dispersions by melt agglomeration in a rotary process.

 

7. The use of surfactant18:

The utility of the surfactant systems in solubilization is well known. Adsorption of surfactant on solid surface can modify their hydrophobisity, surface charge, and other key properties that govern interfacial processes such as flocculation/dispersion, floatation, wetting, solubilization, detergency, and enhanced oil recovery and corrosion inhibition. Surfactants have also been reported to cause solvation/plasticization, manifesting in reduction of melting the active pharmaceutical ingredients, glass transition temperature and the combined glass transition temperature of solid dispersions. Because of these unique properties, surfactants have attracted the attention of investigators for preparation of solid dispersions.

 

8. Electrospinning19:

Electrospinning is a process in which solid fibers are produced from a polymeric fluid stream solution or melt delivered through millimeter scale nozzles. This process involves the application of a strong electrostatic field over a conductive capillary attaching to a reservoir containing a polymer solution or melt and a conductive collection screen. Upon increasing the electrostatic field strength up to but not exceeding a critical value, charge species accumulated on the surface of a pendant drop destabilize the hemispherical shape into a conical shape . Beyond the critical value, a charged polymer jet is ejected from the apex of the cone .The ejected charged jet is then carried to the collection screen via the electrostatic force. The Coulombic repulsion force is responsible for the thinning of the charged jet during its trajectory to the collection screen. The thinning down of the charged jet is limited by the viscosity increase, as the charged jet is dried.

 

9. Super Critical Fluid (SCF) technologies16,20:

The supercritical fluid antisolvent techniques, carbon dioxide are used as an anti solvent for the solute but as a solvent with respect to the organic solvent. Different acronyms were used by various authors to denote micronization processes: aero solvent extraction system, precipitation with a compressed fluid anti solvent, gas anti-solvent, and solution enhanced dispersion by supercritical fluids, and supercritical antisolvent. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing concurrently. Use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains strapped inside the polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature. Moreover, supercritical fluids are used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component).

 

Characterization of the solid dispersion system15, 21

Several different molecular structures of the drug in the matrix can be encountered in solid dispersions. Several techniques have been available to investigate the molecular arrangement in solid dispersions. However, most effort has been put into differentiate between amorphous and crystalline material. Many techniques are available which detect the amount of crystalline material in the dispersion.

 

1.Drug -carrier miscibility:

Hot stage microscopy

Differential scanning calorimetry

Powder X-ray diffraction

NMR 1H Spin lattice relaxation time

 

2. Drug carrier interactions:

FT-IR spectroscopy

Raman spectroscopy

Solid state NMR

 

3. Physical Structure:

Scanning electron microscopy

Surface area analysis

Surface properties

Dynamic vapor sorption

Inverse gas chromatography

Atomic force microscopy

Raman microscopy

 

4.Amorphous content:

Polarized light optical microscopy

Hot stage microscopy

Humidity stage microscopy

DSC (MTDSC)

ITC

Powder X-ray diffraction

 

5. Stability:

Humidity studies

Isothermal Calorimetry

DSC (Tg, Temperature recrystallization)

Dynamic vapor sorption

Saturated solubility studies

 

6.Dissolution enhancement:

Dissolution

Intrinsic dissolution

Dynamic solubility

Dissolution in bio-relevant media.

 

Practical limitations in technique22:

1. Problem concerned with dosage form development:

Poor Flow and Compressibility: It is usually found that, the solid dispersion show complexity in sieving and pulverization. Solid dispersion also shows poor compressibility and stability. To beat this problem the in- situ drug granulation method is used. In this method, the excipient (CaHPO4 and sodium starch glycolate) was pre-heated and then rotated in water jacketed blender at 70ºC. The drug carrier mixture that is melted at100ºC was then added to moving powder, after mixing the granules were passed through a 20-mesh sieve and allowed to harden at 25°C for 12 hrs, and then the granules are mixed with higher concentration of magnesium state (1%) and compressed into tablets. Also it is found that, in developing a tablet formulation for the solid dispersion, they were not Amenable to wet granulation because water could disrupt its physical structure. Sticking of Granules of Solid Dispersion to Die and Punches:-In general it is seen that, during compression the solid dispersion stick to dies and punches, to overcome the problem, the small pieces of grease proof paper were placed between metal surface and granules. Due to this direct contact between metal surface and granules is avoided. One of the new methods is, filling of drug-PEG melts in a hard gelatine capsule but care should be taken, while filling the temperature of drug-PEG melt should not exceed 70°C.

 

2. Problem concerned with scale up and manufacturing:

Risk of Condensation of Moisture over Solid Dispersion during Cooling:-During evaporation there is risk of condensation of moisture over solid dispersion. To overcome this, a continuous cooling operation is done like cooling on the surface moving belt or rotating belt. Reproducibility of Physicochemical Properties:-The manufacturing conditions for solid dispersion might greatly influence the physicochemical properties of solid dispersions formed a range of investigators observed that heating rate, maximum temperature used, holding time at a high temperature, cooling method and rate, method of pulverization, and particle size may greatly influence the properties of solid dispersions prepared by the melt method. The powder X-ray diffraction patterns of the solid.

 

3. Problem concerned with Stability:

Commonly, the solid dispersion prepared by the hot melt method, a certain fraction of drug may remain molecularly dispersed in carrier. if the extent of such drug is high it may give rise to phase separation i.e. the crystalline and amorphous phase are get separated .for that reason some polymer like PVP,HPMC, HPMCAC are used now days . The polymer acts as a stabilizer in the preparation of solid dispersion by retarding crystallization of drug at low humidity. The preventing mechanism of crystallization is reducing the nucleation rate. This polymer affects nucleation kinetics by increasing their kinetic barrier to nucleation. The rate of performing as efficient barrier is directly proportional to the concentration of the polymer and is independent on the physicochemical properties of such polymer.

APPLICATIONS OF SOLID DISPERSIONS: 9, 22

Solid dispersion systems can provide numerous additional benefits; some of them are as follows:

1. In improving immunosuppressive therapy in lung transplant patients, dry powder formulation consisting of a solid dispersion (e.g. Cyclosporine A) for inhalation is prepared. It can avoid many problems like use of local anaesthesia and irritating solvents.

 

2. Solid dispersion formulations were demonstrated to accelerate the onset of action for drugs such as Non Steroidal Anti-Inflammatory Drugs (NSAIDS) where immediacy of action is crucial in relieving acute pain and inflammation.

 

3. Solid dispersion systems were shown to provide bio available oral dosage forms for anti-cancer drugs, which could be substituted for standard injections to improve patient comfort and compliance.

 

4. Solid dispersion systems were also found to reduce food effect on drug absorption, thus increasing the convenience of drug therapy as the need for some drugs to be taken with food was eliminated.

 

5. Solid dispersion- based dosage form allowed for greater drug loading per dose and improved stability over a soft gelatin capsule formulation which thereby improved the convenience of drug therapy by reducing the dosing regime and eliminating the need for refrigerated storage.

 

6. Improved absorption efficiency demonstrated for solid dispersion systems allows for a reduction in the content of active agent per dose, thus decreasing the cost associated with these drug therapies.

 

7. It also act as a functional carriers that offer the added benefit of targeting the release of highly soluble forms of poorly water soluble drugs to an optimum site for absorption. These benefits demonstrate the current contributions and future potential of solid dispersion systems toward improving drug therapies for a variety of important medical conditions whose treatment involves poorly water soluble drugs.

 

CONCLUSION:

The enhancement of oral bioavailability of poorly water soluble drugs remains one of the most challenging aspects of drug development. Dissolution of drug is the rate determining step for oral absorption of drugs, which can subsequently affect the in vivo absorption of drug. Proper selection of formulation method and carriers greatly append in solubility enhancement of poorly water soluble drugs. Improved understanding of physical stability of solid dispersions is the main driver for increasing future relevance of solid dispersions. Solid Dispersion technology is one of the possible modes that increase the solubility of poorly soluble drugs. Successful development of solid dispersion system for preclinical, clinical and commercial use has been feasible in recent years due to the availability of surface active carriers and self emulsifying carriers.

 

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Received on 27.10.2014       Modified on 12.11.2014

Accepted on 17.11.2014      © RJPT All right reserved

Research J. Pharm. and Tech. 7(12): Dec. 2014; Page 1485-1491