Study of Poles apart Properties and Appliances of Colloidal Dispersion

 

O. M. Bagade*, S. N. Dhole, D. N. Bhargude, D. R. Bhosale, D. R. Kad and S. K. Kahane

Department of Pharmaceutics, Modern College of Pharmacy For Ladies, Moshi, Pune-412 105, MS India.

*Corresponding Author E-mail: ombagadescop@gmail.com

 

 

ABSTRACT:

Colloidal system is a dispersion wherein dispersed particles i.e. internal phase are distributed uniformly in a dispersion medium i.e. external phase or continuous phase. The size range consume the nanometer (10–9m) to micrometer (10–6m) rang.

 

Dispersed system consist of particulate matter (dispersed phase) and dispersion medium (continuous medium). Classifications of dispersion system according to particle size are molecular dispersion, colloidal and coarse dispersion. Colloidal dispersion is classified into three types lyophilic, lyophobic and association colloids. Surfactant are use to increase stability of colloid. Colloidal dispersion is safe and improves the therapeutic efficacy. Solubility of drug is improved by colloidal system containing surface active agents. This article represents more recent emphasis on the poles apart properties of colloidal dispersion and its solubility, stability, characteristics of dispersed phase as well as medium. It mainly spotlights the appliance and traits of colloidal dispersion to form craving dosage form to give desire biological activities.

 

In a stable dispersion the particle collisions do not lead to aggregation because inter-particle repulsion forces dominate. Poorly water soluble drugs are normally solubalised in aqueous solution by employing association colloids. Usually colloidal system is found due to the nature of the substances dissolved in the media and does not depend on aggregation, chemical nature and origin.

     

KEYWORDS: Colloidal dispersion, Properties, Absorption, Solubility, Stability.

 


 

INTRODUCTION:

Lyophilic sols (water loving) are formed spontaneously when the dry coherent material (e.g. gelatin, rubber, and soap) is brought in contact with the dispersion medium; hence they are thermodynamically more stable than in the initial state of dry colloid material plus dispersion medium. yophobic sols (water heating) (e.g. gold sol) cannot be formed by spontaneous dispersion in the medium. They are thermodynamically unstable with respect to separation into macroscopic phases but they may remain for long times in metastable state. 1

 

The particles (or in case of emulsions: droplets) dispersed in the liquid or solid matrix (the “dispersion medium") are assumed to be statistically distributed. Therefore, for dispersions usually percolation theory is assumed to appropriately describe their properties.

 

Figure 1: Particles in a different way

 

 


Classification of dispersed system

Molecular dispersion                                                       Colloidal dispersion                                           Coarse dispersion

Less than 1µm                                                                   1µm to 500 µm                                                    Greater than 500 µm

Particles undergo rapid diffusion                                      Very slow diffusion                                             Don’t diffuses

Particles invisible in                                                          Particles resolved by electron                              Particles observed under                 

electron microscope                                                           microscope                                                          ordinary microscope 

Pass through filter paper &                                                Pass through filter paper not                               Do not pass through filter

semipermeable membrane                                                 easily pass through                                              paper& semipermeable

                                                                                           Semipermeable membrane                                  membrane

 

 


Properties of colloids

A) Kinetic properties.

B)    Optical properties

C)    Electrical properties

 

A)   Kinetic properties:

Which relate to the motion of the particles within the dispersion medium as following:

a)     Brownian motion.

b)    Diffusion

c)     Sedimentation.

d)    Osmotic pressure

e)     The Donnan membrane effect

f)     Viscosity.

 

a)    Brownian motion:

 

Figure 2: Brownian motion

 

The presumably random  moving of particles suspended in a water (a liquid or a gas) with respect to pollen grain resulting from their collision with the quick atoms or molecules in the gas or liquid.

i.      Definition: colloidal particles are subjected to random collision with molecules of the dispersion medium (solvent) so each particle move in irregular and complicated zigzag pathway.

ii.     First observed by Robert Brown (1827) with pollen grains suspended in water.

iii.    Increasing the viscosity of dispersion medium (by glycerin) decrease then stop Brownian motion.1

 

b)    Diffusion:

i.      Definition: As a result of Brownian motion particles pass (diffuse) from a region of higher concentration to one with lower conc.

ii.     Rate of diffusion is expressed by, Fick’s first law: Particles diffuses spontaneously from a region of high concentration to a lower concentration region until diffusion equilibrium is attained. dm/dt = -DA dc/dx

 

Figure 3: Diffusion

 

Where dm is the mass of substance diffusing in time dt is across sectional area under the influence of a concentration gradient -dC/dx. The minus sign denotes that diffusion takes place in the direction of decreasing concentration. D is the diffusion coefficient.

 

c)     Sedimentation:

Stoke’s law; at small particle size (less than 0.5 um) Brownian motion is significant & tend to prevent sedimentation due to gravity &promote mixing instead. So, we use an ultracentrifuge which provides stronger force so promote sedimentation in a measurable manner.

 

d)    Osmotic pressure:

The method is based on Vant's Hoff's law;

 

P = RTC / M, from the equation;

 

The osmotic pressure (P) depends on molar conc. of the solute (C) & on absolute temp. (T).The osmotic pressure is inversely proportional to molecular weight (M). R= molar gas constant.

 

e)     The Donnan membrane effect:

Definition: Diffusion of small ions through a membrane will be affected by the presence of a charged macromolecule that can’t penetrate the membrane due to its size. Donnan membrane equilibrium principle is used to enhance the absorption of drug.

 

The principle of donnan membrane equilibrium is as follows: A solution of sodium chloride is placed on one side of the semipermeable membrane. On the other side, a solution of negatively charged colloid together with its counter ions is placed. The volumes of solution on the two sides of the membrane are considers to be equal.

 

Sodium and chloride ions move freely across the semipermeable membrane, but colloidal particles, R-, are not diffusible. Soon equilibrium is attained.

 

Apply the condition of electro neutrality, i.e., the positive and negative charges on either side of the membrane must be balanced. 1, 2, 4

 

f) Viscosity

Definition: The resistance to flow of a system under an applied pressure. Spherocolloidal dispersions are of relatively low viscosity. On the other hand linear colloidal dispersions are of high viscosity. If linear colloidal particles coil up into spheres the viscosity of the system falls due to changing the shape.

 

B) Optical properties:

a)       Light scattering (Tyndall effect).b) Ultra microscope. c)  Electron microscope.

 

a)    Light scattering (Tyndall effect):

True solutions do not scatter light and appear clear but colloidal dispersions contain opaque particles that do scatter light and thus appear turbid.

 

Tyndall effect: When a beam of light pass through a colloidal sol, scattered light cause the sol to appear Turbid  

 

Figure 4: Tyndall effect

 

b)    Ultra microscope:

Ultramicroscope has been used to observe the tyndall beam. Particles appear as spots of light against the dark background of the microscope. Used in the technique of micro electrophoresis.                                                                                                                                          

 

Figure 5: Ultramicroscope

 

c)     Electron microscope:

Give actual picture of the particles (up to 5A). Used to observe the size, shape and structure of Sols. High energy electron beams are used. (Have greater resolving power).one disadvantage is; only dried samples can be examined.

 

Figure 6: Electron microscopy

 

C) Electrical properties.

Zeta potential is a scientific term for electro kinetic potential in colloidal systems. From a theoretical viewpoint, zeta potential is electric potential in the interfacial double layer (DL) at the location of the slipping plane versus a point in the bulk fluid away from the interface. In other words, zeta potential is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle.

 

Figure 7: Zeta potential

 

Electrical double layers: The electrical double layer (EDL) is a structure which describes the variation of electric potential near a surface, and has a significant influence on the behavior of colloids and other surfaces in contact with solutions or solid-state fast ion conductors.21-24

 

Figure 8: Scheme on double layer on electrode

 

The primary difference between a DL on an electrode and one on an interface is the mechanisms of surface charge formation. With an electrode, it is possible to regulate the surface charge by applying an external electric potential. This application, however, is impossible in colloidal and porous DLs, because for colloidal particles, one does not have access to the interior of the particle to apply a potential difference.

 

Types of solutions

 

Figure 9: Types of solutions

 

Drug release kinetic:

a)    Burst mechanism:

In burst mechanism water diffuses into the core through biodegradable or non-biodegradable coating, creating sufficient pressure that ruptures the membrane. The burst effect is controlled by particles size of the dispersed molecules. 6, 4

 

b)    Pore diffusion:

In pore diffusion penetrating water to diffuses. This dispersed protein or drug dissolve creating a water filled pore network through which active principle diffuses out in a controlled manner. Colloidal diffusion express by Ficks law of diffusion: The rate of diffusion across a membrane (dc/dt) is proportional to the difference in concentration on each side of that membrane.

 

Figure 10: Pore diffusion

 

Types of colloids:

1)    Lyophilic colloids:

i.      The dispersed phase does not precipitate easily the sols are quite stable as the solute particle

ii.     Surrounded by two stability factors:

a-     negative or positive charge

b-    Layer of solvent

iii.    If the dispersion medium is separated from the dispersed phase, the sol can be reconstituted by simply remixing with the dispersion medium.

iv.    Hence, these sols are called reversible sols.2,3

 

2)    Lyophobic colloids:

i.      Colloidal particles have very little or no attraction for the dispersion medium (solvent hating).

ii.     Colloidal particles: Inorganic particles (e.g. gold, silver, sulfur etc..)

      Dispersion medium: water.

a.     These colloids are easily precipitated on the addition of small amounts of electrolytes, by heating or by shaking.

b.     Less stable as the particles surrounded only with a layer of positive or negative charge.

c.     Once precipitated, it is not easy to reconstitute the sol by simple mixing with the dispersion medium. Hence, these sols are called irreversible sols.

iii.    Not obtained simply i.e. need special method for preparation.8,10

 

3)    Association colloids:

i.      Certain molecules or ions termed amphiphile (surface active agent SAA) are characterized by two distinct regions of opposing solution affinities within the same molecules or ions. At low concentration: amphiphiles exist separately (sub colloidal size)

ii.     At high concentration: form aggregates or micelles (50 or more monomers) (colloidal size)5,8

 

Amphiphiles may be:

Anionic (e.g., Na. lauryl sulfate), Cationic (e.g., cetyltriethylammonium bromide), Nonionic (e.g., polyoxyethylene lauryl ether).

 

Surface active agents:

A     surface active agent (surfactant) is a substance which lowers the surface tension of the medium in which it is dissolved, and/or the interfacial tension with other phases, and, accordingly, is positively adsorbed at the liquid/vapour and/or at other interfaces.

 

The term surfactant is also applied correctly to sparingly soluble substances, which lower the surface tension of a liquid by spreading spontaneously over its surface. As the concentration is increased, aggregation occurs over a narrow concentration range. These aggregates are called micelles of size 50A0. The concentration of monomer at which micelle formed is termed Critical Miceller Concentration (CMC).When a surface active agent is added free energy of a system is reduced, surface tension also decreases up to the CMC. This may leads to increasing interfacial adsorption.

 


 

Examples of colloidal system from daily life

Dispersed  phase                               Dispersion medium              Name                                              Examples                                                                                                                                                                                                                                                                               

Liquid                                                Gas                                          Liquid aerosol                                 Fog, liquid sprays

Solid                                                  Gas                                          Solid aerosol                                   Smoke, dust

Gas                                                    Liquid                                      Foam                                               Foam on soap solutions                      

                                                                                                                                                                   fire-extinguisher foam,     

Liquid                                                Liquid                                     Emulsion                                         Milk, mayonnaise

Solid                                                  Liquid                                     Sol, colloidal suspension                 Au sol(gold), AgI  sol              

                                                                                                          paste (high solid concentration)      (silver iodide); toothpaste             

Gas                                                     Solid                                      Solid foam                                        Expanded polystyrene

Liquid                                                Solid                                       Solid emulsion                                 Opal, pearl

Solid                                                  Solid                                       Solid suspension                               Pigmented plastics


Figure 11: Amphiphiles

 

Methods of preparations:

Preparation of Lyophilic colloids:

i.      The lyophilic colloids have strong affinity between particles of dispersed phase and dispersion medium.

ii.     Simply mixing the dispersed phase and dispersion medium under ordinary conditions readily forms these colloidal solutions.

iii.    For example, the substance like gelatin, gum, starch, egg, albumin etc. pass readily into water to give colloidal solution.

iv.    They are reversible in nature become these can be precipitated and directly converted into colloidal state

 

There are two principal ways of preparation of lyophilic colloids:

A.    Dispersion methods

a.     Milling and grinding process

b.     Peptization method

c.     Electric arc method

 

B.    Condensation method

a.     Addition of nonsolvent

b.     Chemical method

 

A.    Dispersion method:

The general principle involves mechanical dispersion, i.e., converting coarse particles into colloidal particles.

 

a)    Milling and grinding process:

i.      The mill consists of two steel discs having a very small clearance between them. These discs are rotated at high speed in opposite direction.

 

Figure 12: Colloidal mill

 

ii.     When a suspension is allowed to pass through these discs the coarse particles are broken down into smaller particles.

iii.    This process is repeated until desired size of dispersion is obtained. 2,10,11

 

b)    Peptization method:

 

Figure 13: Peptization method

 

 

i.      It is defined as the breaking up of aggregates or secondary particles into particles of colloidal size.

ii.     Peptizing agent may be liquids, electrolytes or nonelectrolytes. In this method, flocculating agents, electrolytes are removed, or deflocculating agents, surfactants etc, are added.

 

c)       Electric arc method:

i.      This method is suitable for preparing dispersion of metals such as silver, gold etc. In this method, an intense electric arc is produced between two metal electrodes under the surface of cold water.

 

Figure 14: Bredig’s arc method

 

ii.     Due to intense heat generated by the arc part of the metal of the electrode is released as vapors, which condenses to form colloidal particles. These particles can be immediately stabilized by including potassium hydroxide in cold water.

 

B.    Condensation method:

In this method particles of sub colloidal ranges are made to aggregates or condensed into particles of colloidal range.

 

a)    Addition of nonsolvent:

Sulfur is soluble in alcohol. A concentrated alcoholic solution of sulfur is poured into an excess amount of water. The sulfur which is present in a molecular state in alcohol gets precipitated out as finely divided particles. These particles grow rapidly and form a colloidal dispersion. Acetone is also used in this method.

 

b)    Chemical method:

Chemical reaction may be carried out to prepared lyophobic sols. These methods are restricted to inorganic substances. A chemical method involves oxidation, reduction, and hydrolysis.

 

Colloidal stability:

A stable colloidal system is one in which the particles resist flocculation or aggregation and exhibits a long shelf-life. If all the particles have a mutual repulsion then the dispersion will remain stable. Stability of dispersion is explained on the basis of DLVO theory.

 

 

DLVO Theory-Derjaguin-Landau-Verwey-Oberbeek Theory:

The DLVO theory is important for understanding the stability and phase behavior of colloidal dispersions. There are two types’ interaction-attractions and repulsions. When attractions predominate, the particles adhere after collision and aggregate. When the repulsion predominates the particles rebound after collisions and remain individually dispersed. Repulsion is electro-osmotic force and attraction is van der walls force.

 

The interactions between particles are described as follows:

a.     Van der Waals attraction forces:  These forces depend mainly on the chemical nature and size of the particles. These forces are London type and cannot be altered readily. The potential energy of attraction is represented by VA. 1,12,13

 

b.    Electrostatic repulsive forces: The electrostatic repulsive forces depend mainly on the density surface charge and thickness of the double layer. These indicate the magnitude of zeta potential. The potential energy representing repulsion is denoted by VR.

 

c.     Net energy of interaction: An algebraic addition of the above two curves gives the net energy of interaction.

 

Figure 15: Potential energy vs. interparticle distance for particles in suspension.

 

The following conclusions may be drawn from the energy curves:

i.      Primary minimum (sign of precipitation):  When particles are much closed to each other, atomic orbital overlapped and penetrate each other. This is indicated by a rapid rise in potential energy. The net result is a stronger attraction which leads to precipitation.

ii.     Net energy peak (sign of better stability): At intermediate distances, appreciable repulsive forces operate (positive zeta potential energy).This potential barrier keeps the particles in Brownian movement and impart stability to the dispersion. At this peak the maximum potential is designated by Vm.

iii.    Secondary minimum (sign of aggregation): This is observed when the particles are separated by long distances about 1000 to 2000Å. The presence of a secondary minimum is taken advantageously in the controlled flocculation of a coarse dispersion.

 

Instability of lyophobic colloids:

Coagulation or precipitation of the sol is defined as a state in which flocculation and settling of the dispersed particles is observed. Coagulation or flocculation indicates the instability of the dispersion.12,13

 

Reasons for coagulation of lyophobic particles:

A.    Removal of electrolytes

B.    Addition of excess electrolytes

C.    Electrolytes of opposite charge

D.    Addition of oppositely charged colloids.

 

A.      Removal of electrolytes:

i.        The repulsion between the approaching particles is reduced to such an extent those colliding with certain velocity can join together as shown below.

ii.       Thus coagulation occurs. The dispersed solids tend to settle at the bottom of the dispersion .This behavior correspond to the primary minimum in the DLVO theory.

 

Figure 16: Removal of electrolytes

 

iii.      In general colloidal particles are not diffusible while electrolytes are diffusible in dialysis. Therefore when colloids are purified by dialysis care should be taken to prevent complete removal of electrolytes.

 

B.      Addition of excess electrolytes:

i.        For the stabilization of sol, a minute charge on particles is desirable. When excess of electrolytes are added particles coagulate beyond a particular concentration.

 

Figure 17: Addition of excess of electrolytes

 

ii.     This is due to the accumulation of oppositely charged particles. This behavior corresponds to the secondary minimum in the DLVO theory.

 

C.    Electrolytes of opposite charge:

i.      Particles require charge to maintain electrostatic repulsion. Addition of substances with opposite charge induced the dispersed particles to coagulate. These behaviors correspond to the secondary minimum in the DLVO theory of energy curves. The charge and valence of the electrolyte and their effect on coagulation is described by Schulze-Hardy rule.

 

Figure 18: Electrolytes of opposite charge

 

ii.     Schulze-Hardy rule: states that the precipitating powers of an ion on a dispersed phase of apposite charge increase with the increase in the valence or charge of the ion.

iii.    The higher the valancy of the effective ion, the greater the precipitating power.

 

D.    Addition of oppositely charged colloids:

 

Figure 19: Addition of oppositely charged colloids

 

i.      When a hydrophilic or a hydrophobic colloid with an opposite charge is mixed with a hydrophobic colloid coagulation of colloidal particles will be observed.

ii.     The reason may be the reduction of zeta potential below a critical value. This behavior corresponds to the secondary minimum in the DLVO theory of energy curves.

 

Instability of lyophilic colloids

The stability of a lyophilic colloid in water is determined both by the electrical charge and by hydration. However particles may also undergo aggregation, coagulation or precipitation.

 

Reasons for coagulation of lyophilic particles:

A.    Addition of excess electrolytes

B.    Addition of oppositely charged colloids

C.    Addition of nonsolvent

 

A.    Addition of excess electrolytes:

When electrolytes are added in moderate quantities the zeta potential diminishes and coagulation does not result. But at higher quantities electrolyte do bring about coagulation. In general lyophilic colloidal are stable because of the solvent a sheath around the particles. In hydrophilic colloids hydration of particles is observed. When electrolytes are added at high concentration ions get hydrated and water is no more available for hydration of particles.

 

Figure 20: Addition of excess electrolytes

 

This results in flocculation or salting out of colloidal particles. The coagulating power of anions or cation on hydrophilic colloids is arranged by Hofmeister of lyotropic series.

 

Hofmeister rank order: states that the precipitating power of an ion is directly related to the ability of that ion to separate water molecules from the colloidal particles.

 

B.    Addition of oppositely charged colloids:

Mixing of Lyophilic colloid with oppositely charged colloids result in flocculation. It is believed that the shell of tightly bound water molecules surrounding the particles prevents them from coalescing, but the electrostatic attraction of their opposite charge holds a number of particles together.

 

Figure 21: Addition of oppositely charged colloids

 

The dispersion contains colloid-rich aggregates which settle at the bottom imparting greater viscosity. The upper layer is poor in colloid.

 

C.    Addition of nonsolvent:

Less polar solvent such as alcohol and acetone have greater affinity to water. When these are added to hydrophilic colloids dehydration of particles will be observed.

 

Figure 22: Addition of nonsolvent

 

The stability of particles depends on the charge they possess. Addition of even a small amount of electrolyte lead to flocculation. Thus a lyophilic colloid is converted to a lyophobic colloid.

 

Purification of colloids

By following methods purification of colloids are occurs:

a) Dialysis.  b) Electro dialysis.  c) Ultra filtration.

a)  Dialysis:

 

Figure 23: Dialysis

 

i.      The removal of impurities of low-molecular-weight substances from colloidal systems. Use semi permeable membrane e.g. collodion (nitrocellulose, cellophane).

ii.     Pores prevent passage of colloidal particles & permit passage of small molecules & ions (impurities) such as urea, glucose, and sodium chloride, to pass through.

iii.    The colloidal dispersion is placed in the glass tube and is suspended in a vessel through which fresh water is continuously passed. Ions and other molecules diffuse out and in this way purification of colloids achieved.

 

b) Electro dialysis:

 

Figure 24: Electro dialysis

 

i.      An electric potential may be used to increase the rate of movement of ionic impurities through a dialyzing membrane and so provide rapid purification.

ii.     Electrodialysis is carried out in a three compartment vessel with electrodes in the outer compartments containing water and the sol in the center compartment.

iii.    Application of electrical potential causes cations to migrate to the negative electrode compartment and anions to move to the positive electrode compartment, in both of which running water. 1, 8, 14

 

c) Ultra filtration:

i.      Apply pressure (or suction) Solvent & small particles forced across a membrane while colloidal particles are retained.

ii.     The membrane must be supported on a sintered glass plate to prevent rupture due to high pressure.

 

Figure 25: Ultra filtration

 

iii.    Pore size of the membrane can be increased by soaking in a solvent that cause swelling e.g. cellophane swell in zinc chloride solution, collodion (nitrocellulose) swell in alcohol.

PHARMACEUTICAL APPLICATIONS OF COLLOIDS

i.      Medicine- Colloidal silver iodide, silver chloride & silver protein are effective germicides & not cause   irritation as ionic silver salts. Colloidal copper used in cancer. Colloidal gold used as diagnostic agent. Colloidal mercury used in syphilis.

ii.     Association colloids (SAA) are used to increase solubility & stability of certain compounds in aqueous & oily pharmaceutical preparations.

iii.    Efficiency of certain substances is increased when used in colloidal form due to large surface area. E.g. Efficiency of kaolin in adsorbing toxins from GIT, efficiency of aluminum hydroxide as antacid. 1-14

iv.    Artificial kidney machine-The human kidney purify the blood by dialysis through natural membrane. The toxic waste product such as urea and uric acid pass through the membrane, while colloidal sized particles of blood proteins are retained. Kidney failure leads to death due to accumulation of poisonous waste products in blood.

 

Figure 26: Artificial kidney machine

 

Now a day, the patient’s blood can be cleansed by shunting it into an artificial kidney machine. Here the impure blood is made to pass through a series of cellophane tubes surrounded by washing solutions. The toxic waste chemicals (urea, uric acid) diffuse across the tube walls into the washing solution. The purified blood is returned to the patient. The use of artificial kidney machine saves the life of thousands of persons each year.

v.     Formation of delta- The river contains colloidal particles of sand and clay which carry negative charge. The sea water on the other hand, contains positive ions such as Na+, Mg2+, and Ca2+. As the river water meets sea water, these ions discharge the sand or clay particles which are precipitated as delta.

vi.    Clarification of municipal water- The municipal water obtained from natural sources often contains colloidal particle. The process of coagulation is used to remove these. The sol particles carry a negative charge. When aluminum sulphate is added to water, a gelatinous precipitate of hydrated aluminum hydroxide is   formed.14

 

The positively charges floc attracts to it negative sol particles which are coagulated. The floc along with the suspended matter comes down, leaving the water clear.

 

CONCLUSION

Although Colloidal dispersion have been important in the pharmaceutical sciences for decades, with the advent of nanotechnology drug delivery systems and technology. Colloidal dispersion improves the biopharmaceutical aspects like controlled or sustained release and better drug targeting and so that Colloids are extensively used for modifying the properties of pharmaceutical agents. However, colloidal forms of many drugs exhibited substantially different properties when compared with traditional forms of these drugs. Drug substances may also be prepared as colloidal size particles to improve bioavailability or therapeutic activity such as- colloidal sulfur. Colloidal dispersion is safe and improves the therapeutic efficacy.                                           

 

Colloidal materials are used for a variety of pharmaceutical applications including therapeutic and diagnostic agents, drug delivery system, and pharmaceutical excipients.

 

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Received on 30.08.2013       Modified on 30.09.2013

Accepted on 24.10.2013      © RJPT All right reserved

Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1402-1412