Effect of Hydrotropes and Physical Properties on Solubility of Glibenclamide

P. Sabitha Reddy*, C. Swetha and K. Ravindra Reddy

Department of Pharmaceutics, P. Rami Reddy Memorial College of Pharmacy, Kadapa-516003, Andhra Pradesh, India

ABSTRACT:

The aim of present study was to increase the solubility of glibenclamide in water by hydrotropic solubilization. Sodium acetate, sodium citrate, sodium salicylate and sodium benzoate were used as the hydrotropic agents. In order to elucidate the probable mechanism of solubilization, the solution properties such as surface tension, viscosity, specific gravity were studied. Sodium salicylate was found to be the most suitable hydrotropic agent to increase the solubility of glibenclamide. The solubility of Glibenclamide by various hydrotropes was in decreasing order of Sodium acetate>sodium salicylate>sodium citrate>sodium benzoate. Initial increase in solubility of Glibenclamide was due to the weak ionic interactions between the hydrotropes and glibenclamide molecules, multifold increase in solubility at higher concentration of hydrotrope was due to molecular aggregation.

KEYWORDS: Glibenclamide, solubility enhancement, hydrotropic agents.

INTRODUCTION:

Aqueous solubility of a therapeutically active substance is a key property as it governs dissolution, absorption and thus the efficacy in vivo. Solublisation may be defined as the preparation of a thermodynamically stable solution of a substance that is normally insoluble or very slightly soluble in a given solvent by the introduction of one or more amphiphilic compound. Recently more than 40% NCEs (new chemical entities) developed in Pharmaceutical Industry are practically insoluble in water. In the case of poorly water-soluble drugs, dissolution is the rate-limiting step in the process of drug absorption. Potential bioavailability problems are prevalent with extremely hydrophobic drugs (aqueous solubility less than 0.1 mg/ml at 37°C), due to erratic or incomplete absorption from GIT¹.

In the context of drug delivery, solubility issues are one of the major factors that are concern for the development of the pharmacologically effective dosage form. The precise value of the solubility parameter of a drug is of significance, in terms of bioavailability. Lower solubility of a therapeutically active substance is often associated with the bioavailability problems, lack of in-vivo and in-vitro correlation, lack of patient compliance, and inter subject variations. These variations assume a practical significance for drugs with a low safety margin, for example, digoxin. In order to acquire the desired bioavailability and subsequent therapeutic response, the drug must be soluble in aqueous solutions, which leads to its absorption at an optimum rate and extent and also facilitates the systemic delivery of the drug to the body. Solubility is an extrinsic physiochemical property of bioactive molecules, which can be used to explain the drug action² structure activity relationship,³ drug transport kinetics,⁴and in- situ drug release profile. The therapeutic efficacy of any drug is often diminished by its incapability to gain access to the site of action and it is often in close proximity with poor solubility of the drug in the body’s aqueous compartment.

Glibenclamide {1-[[4-[2-[(5-Chloro-2-methoxybenzoyl) amino]ethyl]phenyl]sulphonyl] 3-cyclohexylurea} is an oral hypoglycemic of the sulphonyl urea group that is frequently prescribed for treatment of non-insulin dependent diabetes mellitus.⁵ Glibenclamide is a low dose, poorly soluble drug with possible content uniformity problems and dissolution rate-limited bioavailability.^6-7 Various techniques have been proposed to overcome the solubility problems of therapeutic moieties are use of buffering agents, soluble salts, use of surface active agents(miscellar solubilization), hydrates and solvates, polymorphism, complexation, hydrotropic solubilization and conventional grinding and trituration.⁸ Among these techniques, hydrotropic solubilization is considered as the safest method of solubilization.^9-10aqueousolubility of insoluble drug can be achieved by addition of hydrotropic agents.

MATERIAL AND METHODS:

Glibenclamide was obtained as a gift sample by Unichem laboratories, Mumbai, India. Sodium acetate, sodium benzoate, sodium salicylate, sodium citrate were purchased from Qualigens Chemicals, Mumbai, India. Ethanol was procured from Qualigens chemicals. All other chemicals and solvents were of analytical grade and freshly prepared distilled water was used throughout study.

Phase solubility studies (UV method for analysis):

Glibenclamide is freely soluble in ethanol. Hence it was used as solvent to develop the calibration curve. A stock solution of (1mg/ml) was prepared by using 100mg of the drug and transferred to 100ml volumetric flask containing 75ml ethanol. The volume made upto 100ml with ethanol to make a primary stock solution of 1000μg/ml.

1ml of primary stock solution was taken in 100ml volumetric flask containing ethanol to give secondary stock solution (10µg/ml).From the secondary stock solution different concentrations of glibenclamide Viz, 2, 4, 6, 8, 10µg/ml were prepared by making up the volume with ethanol and absorbance of each concentration was measured at 230nm using spectrophotometer.¹¹

Properties of hydrotropic solution:

In order to interpret the probable mechanism of solubilization, UV spectral studies of Glibenclamide were performed in different hydrotropic solutions. Various solution properties such as viscosity, surface tension, specific gravity were studied inorder to reason out the increase in solubility of Glibenclamide with increase in hydrotropic concentration.

Comparative solubility analysis with different hydrotropic agents:

Solubility studies were performed according to Higuchi and Connors.¹² It was determined with various hydrotropic solutions. Various hydrotropic solutions used in this study are sodium aceteate, sodium benzoate, sodium salicylate, and sodium citrate. Excess of drug was added to 20ml volumetric flasks containing 10ml aqueous solutions of different agents of concentration 1M. Flasks were sonicated for 4hrs and kept at 25⁰ c for 24hrs and passed through 0.45µm filter. The clear solutions were then analysed at 230nm using spectrophotometer.

Solubility analysis with variation in concentration of optimum hydrotropic solution:

Excess of drug was added to 20ml volumetric flasks containing 10ml of aqueous solutions of different concentrations (1.5M, 2.0M, 2.5M, and 3.0M). Flasks were sonicated for 4hrs and kept at 25⁰c for 24hrs and passed through 0.45µm filter. The clear solutions were analyzed at 230nm using spectrophotometer. Then solubility was determined.

RESULTS AND DISCUSSION:

Solubility study:

Hydrotropes are amphiphilic in nature i.e. composed of hydrophilic as well as lipophilic portions. These molecules are genrally used as solubility enhancers (solublisers). This method is commonly known as micellar solublization since they forms micelles, which are association segregate of surfactants. Hydrotropic agents have been used to enhance aqueous solubility of hydrophobic drugs. In many instances, the aqueous solubility was increased by orders of magnitude simply by mixing with hydrotropic agents in water. Hydrotropy is a collective molecular phenomenon describing an increase in the aqueous solubility of a sparingly water-soluble drug by addition of a relatively large amount of a second solute. Hydrotropic agents self-associate into loose non- covalent assemblies of non-polar microdomains to solubilize hydrophobic solutes. However, the detailed mechanisms of hydrotropy have not been fully understood.

Solubility of Glibenclamide was increased with increase in concentration of hydrotropes and it can be noted that sodium acetate exerts more solubilization effect than other hydrotropes. Sodium acetate increases the solubility of glibenclamide. The solubility enhancement power of different hydrotropes could be ranked in decreasing order of Sodium acetate>sodium salicylate>sodium citrate> sodium benzoate. It was observed that the increase in solubility was not a linear function of hydrotrope concentration. On increasing the hydrotrope concentration, initially the drug solubility was increased slowly, but after a particular concentration, i.e. critical solute concentration (CSC) of the hydrotrope, there was many fold increase in solubility of glibenclamide.

The UV absorption spectra of glibenclamide in various hydrotrope solutions showed a slight shift in λmax (230± 1 nm), which can be due to minor electronic changes in the structure of drug molecules. There was no basis to assume the formation of a complex between drug and hydrotrope molecules, complexation is evidenced by formation of new chromospheres (by appearance of a new peak or merging of two peaks to generate a common peak). The solubility of Glibenclamide at 25°C in the presence of Sodium acetate, Sodium benzoate, Sodium salicylate, Sodium citrate, is given in table-1 and with different concentrations of sodium acetate is given in table 2

Table1: Solubility study with different hydrotropes

Hydrotropic agent	Concentration of hydrotropic agent (M)	Solubility of drug (mg/ml)
Sodium acetate	1	10.589
Sodium citrate	1	0.699
Sodium benzoate	1	0.692
Sodium salicylate	1	9.62

Table2: solubility study with increase in concentration of sodium acetate

S.NO.	Concentration of sodium acetate(M)	Solubility of drug (mg/ml)
1.	1.5	0.784
2.	2.0	0.787
3.	2.5	0.794
4.	3.0	0.805

Properties of hydrotropic solution:

The positive deviation in the viscosity plots (Fig.1) support the aggregate formation and associated with an increase in viscosity of hydrotrope concentration, which is in agreement with the self-association of compounds.

Fig.1: Effect of Concentration on viscosity

The surface tension plots (Fig.2) showed a moderate decrease in surface tension on increasing the hydrotrope concentration, although hydrotropes are not surface active agents.¹³ It was revealed from different studies that at lower hydrotrope concentration, weak ionic interactions and while at higher hydrotrope concentration, the molecular aggregation seems to be the possible mechanism of hydrotropic solubilization.^13-16

Fig.2: Effect of Concentration on Surface tension

Table3: Effect of concentration on viscosity

S.NO.	Concentration of sodium acetate(M)	Viscosity (cp)
1.	1.5	1.12
2.	2.0	1.47
3.	2.5	1.73
4.	3	1.9

Table4: Effect of concentration on surface tension

S.NO.	Concentration of sodium acetate(M)	Surface tension. (dyne/cm)
1.	1.5	71.4
2.	2	76.80
3.	2.5	86.01
4.	3.0	75.67

Table5: Effect of concentration on specific gravity

S.NO.	Concentration of sodium acetate(M)	Specific gravity
1.	1.5	1.052
2.	2.0	1.058
3.	2.5	1.104
4.	3.0	0.995

The plots of specific gravity versus hydrotrope concentration (Fig.3) showed a negative deviation that indicates an increase in partial molar volume upon aggregation, and this increase in volume may be due to expansion of the hydrocarbon portion of the molecule or its partial removal from the high compressive force of water.¹⁷

Fig.3: Effect of Concentration on Specific gravity

The higher solubility of glibenclamide in presence of one hydrotrope over the other can be explained on the basis of Poochikian and Gradock’s explanations.¹⁸ The hydrotropes selected for the present study (Sodium acetate, Sodium benzoate, Sodium salicylate and urea) possess a hydrophobic centre which can interact due to large surface area and mobile electron cloud. These sites are available for nonbonded vanderWall’s interaction with water and glibenclamide.

The molecules of water join together to form clusters. For solubilization, the ionized hydrotropes break this association and use the ion dipoles of water for deliverance. The increasing hydrotrope concentration results in unassociated form of water to make a cluster of hydrotrope by hydrogen bonding and non-bonding interactions at various centers of drug molecule. Thus, charge delocalizing, along with an increase in π -cloud area on hydrotropic molecule, would account partially for difference in apparent drug solubility in presence of various hydrotropes.

CONCLUSION:

Review of literature indicates that hydrotropes can be used to increase the solubility and consequently the bioavailability of poorly water soluble drugs.

Thus in the present investigation an attempt was made to increase the solubility of Glibenclamide by various hydrotropic agents like sodium acetate, sodium benzoate, sodium salicylate and sodium citrate. Sodium acetate was found to be effective in increasing the solubility of glibenclamide. From the solution properties, it can be concluded that at the lower hydrotrope concentration, weak ionic interactions, and at higher hydrotope concentration, the formation of molecular aggregates are the possible mechanisms of hydrotropic solubilization.

ACKNOWLEDGMENT:

The authors wish to thank Unichem Laboratories, Hyderabad for supplying gift samples of pure drug required for our research work. The authors are thankful to PRRM College of pharmacy, Kadapa for their valuable support in carrying out this work.

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Received on 15.09.2011

Accepted on 30.09.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 3(6): Nov.- Dec., 2011, 294-297