INTRODUCTION:

Most of the therapeutic agent newly synthesized are weak electrolytes or non-electrolytes. These drugs possess low or unpredictable bioavailability which limits their pharmacological action. Different methods are employed to overcome the problem related to solubility and permeability. Some of the currently used method are solid dispersion method, complexation method, hydrotropic solubilization, fluctuating the pH and using cosolvents. In this research work the objective is to enhance the solubility of Glipizide an antidiabetic drug belonging to the sulfonylurea class used to treat type 2 diabetes and develop syrup formulation of Glipizide¹. According to biopharmaceutical classification Glipizide is categorized under BCS class II. It has low aqueous solubility and short half-life of 2 hours.

Mixed solvency is used to enhance the solubility of glipizide, both hydrotrophy and co-solvency method are applied. Hydrotrophy is a process of solubilization in which a large amount of second solute is added to increase the aqueous solubility of another solute. Solute which are alkali metal salts of different organic acids can be used as hydrotropic agents and these substances are called as “Ionic organic salts”. Achievements of science that involves in the increment of solubility in the given solvent are known as “salt in” the solute. Some of the water-soluble additives known as hydrotropes like sodium benzoate, sodium ascorbate, sodium citrate, niacinamide, urea^2-4.

Cosolvency method improves solubility of poorly water soluble drugs by increasing their miscibility in the given solvent by interfacial tension between the solvent and the hydrophobic solute. It have been used in parenteral preparation but focus has to be given on the safety of the cosolvent used and it should not cause precipitation. Some examples of cosolvents are Glycerine, Peg, Diethyl acetamide, Ethyl lactate, Ethanol and Propylene glycol. Using this mixed solvency method various appropriate dosage forms viz. solutions, syrups, injections, topical solutions etc)^5,6.

The objective of the present work is to use the mixed solvent system to formulate monophasic dosages form of glipizide. Inadequate aqueous solubility of the drug offers obstacles in formulation of syrup of glipizide. First the solubility of drug in various concentration of co-solvent is determined. The best suitable concentration of cosolvent is selected which offers maximum solubility to the drug. To this hydrotropes are added to further enhance the solubility of the drug and after fixing the amount of suitable hydrotropes the monophasic dosages form is formulated. Various preformulation and post formulation evaluations are conducted^7,8.

MATERIAL AND METHOD:

Glipizide and polyethylene glycol 400 and Propylene glycol was purchased from CDH -R.K Enterprises Meerut, U.P. India. were purchased by CDH- R.K Enterprises, Meeru U.P., India and remaining cosolvents Glycine and ethanol as well as hydrotropes sodium benzoateµ, sodium citrate and sodium salicylate were purchased from Ambay Biotech, Greater Noida U.P. India. All solvents and other chemical were of HPLC /analytical grade.

Experimental:

Estimation of glipizide:

Stoke solution was prepared by adding 10mg of drug in 100ml and further by dilution with distilled water 10µg/ml, 20µg/ml, 30µg/ml, 40µg/ml, 50µg/ml concentration was obtained and standard curve of glipizide was plotted after UV spectroscopic analysis at 278nm (UV- 1700, Shimadzu, Japan.)⁹.

Solubility determination:

Equilibrium solubility method was used to determine the solubility of glipizide in various solubilizers solution. Excess amount of glipizide was added to 10ml screw-capped glass vials containing 5ml of aqueous solution of individual co-solvent ratios at two different temperatures of 25⁰C and 37⁰C (Table 1) and the vails were subjected to thermostatic mechanical shaking for 6 hours. Finally, the solutions were let to equilibrate for the next 24 hours. The supernatants of each vial are filtered through Whatman filter paper of 0.45µm and the filtrate collected and analysed for drug content after suitable dilution by UV visible spectrophotometer at 278nm^10,11.

The effect of various pH from 1.2, 2.2, 4.0, 5.8, 8.0, 9.0 and 10.0 on solubility was also determined according to the above-mentioned method.

Enhancement ratio = Solubility of drug in the solubilizer solution\ Solubility of drug in water.

Determination for additive or synergistic effect on solubility in mixed solvent blends:

Depending on the value of solubility power the the appropriate cosolvent along with the ratio of co- solvent and water would be decided. To this fixed solubilizer solution different concentration of various hydrotropes as per table 3 were added and the solubility of glipizide was ascertained by equilibrium solution method^12,13.

Evaluation of Physicochemical properties of the mixed solvent solution:

Different physicochemical properties like pH, viscosity, surface tension and specific gravity. The pH of preparation was determined by using pH meter (LI614, Elico Ph analyzer). Viscosity was dictated by Ostwald viscometer. Surface tension was calculated using by stalagmometer. Specific gravity of the drug by pycnometer.^14,15.

Compatibility drug-excipient studies by FTIR analysis:

The interaction between the drug and solubilizers were studied. All the components were physically mixed with the drug in a ratio of 1:1. The KBr was first dried in microwave oven and then KBr and drug excipient pellets were prepared and analyzed by FTIR spectrometer¹⁶.

Formulation of oral syrup of Glipizide:

Glipizide syrup was formulated based on solubility analysis result obtained from the final blends of mixed solvent. All the solubilizers were added in necessary quantities to 50ml of warm water taken in 100ml volumetric flask. To this 1g of drug and 40g of sucrose was added and shaken vigorously then the volume was made up to 100ml. The flask was set aside to bring it to the room temperature and then transferred to an airtight container. The glipizide content in the oral syrup formulation is 20mg per 5ml.

Evaluation of oral syrup formulation of Glipizide:

a. Drug content analysis: 1ml of the syrup was taken and after appropriate dilution the sample was spectrophotometrically analysed and the drug content was estimated using the regression equation y = 0.0072x + 0.0154.

b. Evaluation of physical properties of glipizide oral syrup formulation

The physical parameters analysed were absorbance, viscosity, specific gravity and pH. The pH was measured using Brookfield viscometer.

RESULTS:

Glipizide is an N-sulfonylurea, a member of pyrazines, it has an aromatic amide along with monocarboxylic acid amide. The solubility analysis data reveals that with increase in pH (Fig 2) the solubility of glipizide increases, this may be attributed to the acidic nature of the drug molecule.

The aqueous solubility of glipizide was 35mg/L at 25°C and 40.67mg/L at 37⁰C. This indicates an increase in solubility of glipizide with increase in temperature suggesting an endothermic process. The solubility and solubility enhancement ratio of glipizide in different co-solvent in decreasing order were PEG> PG>glycerin> ethanol. The enhancement of solubility don’t have a linear relationship with co-solvents. The PEG was selected as the suitable co-solvent as max solubility compare to others. From the literature review on safety and toxicity amount of PEG has to be considered while fixing its concentration for formulating a dosages form. Here 40% v/v of PEG is used. Then to the above solution of water and cosolvent various concentration of different hydrotropes are added. From the solubility data it was found that the Glipizides solubility in hydrotropes ranked in decreasing order sodium salicylate> sodium benzoate> sodium citrate. The highest of glipizide can be described based on the reason given by Poochikian and Gradock’s (1974) in the presence of one hydrotrope over other. In case of sodium salicylate and sodium benzoate they have the parent benzene nucleus and mobile Electron cloud which forms non-bonded and Vander Waal’s interaction with water-cosolvent system as well as with glipizide. 40% w/v of sodium salicylate is considered for the formulation of glipizide syrup.

Fig.1. Standard Curve of Glipizide.

Fig.1. Solubility of Glipizide at different pH.

Fig. 3. Solubility of Glipizide in (A) PEG, (B)PG, (C)Glycerine, (D)Ethanol.

Table .1. Solubility enhancement ratio of Glipizide in cosolvent at different temperature

Cosolvent/ water ratio	10:90		20:80		40:60		60:40		80:20		100:0
Temperature	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C
PEG/Water	17.90857	18.71429	19.24857	19.48	22.22571	25.94029	23.40857	34.08286	27.59114	34.08286	32.191430	37.14286
PG/Water	16.68657	17.66	17.41257	17.738	17.54743	25.29743	18.67457	25.29743	20.71429	26.21429	25.857140	32.61086
Glycerin/ Water	13.69429	16.91657	14.46429	17.1625	16.05543	21.25371	17.23	24.738	18.88486	29.15057	21.71429	31.38857
Ethanol/ Water	11.452	15.82514	11.62286	16.76	15.03171	20.37686	15.48	21.742	17.36886	25.64571	20	28.15057

Fig.4. Concentration of hydrotropes in (A) Sodium Citrate, (B) Sodium Benzoate and (C) Sodium Salicylate.

Table .2. Solubility enhancement ratio of Glipizide in solution containing 40 % PEG as cosolvent and hydrotrope mixture at different concentration % w/v at different temperature:

Concentration of hydrotropes	5		10		15		20
Temperature	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C
Sodium Citrate	19.10314	19.67457	19.57143	22.73143	24.37686	27.00571	24.90457	28.69429
Sodium Benzoate	19.93143	20.60714	20.03571	24.70486	24.976	28.07143	25.87429	28.64571
Sodium Salicylate	20.76771	26.7	23.04286	31.58857	37.90571	40.19143	72.78857	79.55714

Table .2. continued

Concentration of hydrotropes	25		30		35		40
Temperature	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C	25⁰C	37⁰C
Sodium Citrate	28.37286	32.09714	28.924	34.38286	36.40057	39.14286	36.727430	44.57143
Sodium Benzoate	28.88086	34.53143	43.11143	45.84857	71.55714	79.04	97.39143	105.5886
Sodium Salicylate	94.44	103.1114	151.0486	155.9114	196.3943	211.5457	234.60860	244.7886

Table.3. Evaluation parameters of different formulations using Sodium Salicylate.

Sodium Salicylate	pH	Viscosity (centipoises)	Specific gravity (g/cm³⁾	Surface tension(dyne/cm)
F1	6.2	0.82	1.06	71.13
F2	6.4	0.87	1.08	67.56
F3	6.6	0.95	1.06	66.34
F4	6.8	1.06	1.09	65.78
F5	6.7	1.35	1.10	64.57
F6	6.5	1.46	1.18	62.54
F7	6.7	1.57	1.27	60.43
F8	7.0	2.10	1.48	60.55

Table.4. Evaluation parameters of formulation.

Formulation of Glipizide	Specific (gravity g/cm³⁾	pH	Viscosity (centipoises)	Absorbance
A1	1.170	7.7	3.9404	0.1711

A. Drug –excipient Compatibility study. B. FTIR of Glipizide.

Fig.5. Compatibility Study (A)Drug–Excipient and (B)FTIR of Glipizide.

The physicochemical properties like specific gravity, pH, viscosity and surface tension of different concentration solution of sodium salicylate were determined. The specific gravity was found that it slightly decreased with increase in concentration of hydrotropes it may indicate that the partial molar volume increases with aggregation due to expansion of hydrocarbon part of the molecule. The positive deviation in the viscosity indicates that aggregate formulation is associated with an increase in viscosity of hytrotrope concentration due to self-association of phenolic compounds. The surface tension very little decreases with increase in the hydrotrope concentration.

The syrup of glipizide was formulated taking 40% w/v of sodium salicylate, 40% v/v of Polyethylene glycol (PEG) and sucrose 40g and drug 1g to prepare 100ml of glipizide syrup. The properties of syrups given in table no.4.

Compatibility studies were carried to find out the interaction between the drug in formulation with the other excipient. From the FTIR studies (at wavelength 4000 cm-1 to 400 cm-1) comparing the formulation of syrup with pure drug disclosed that there were no major shifts, no loss of functional peaks.

It was found from the FTIR studies of glipizide that 3353.58 cm^-1 (N-H stretching),3325.80cm^-1 to 3251.27 cm^-1 (O-H), 2943.97cm^-1(aromatic C-H), 1444.63 cm^-1 (O-H bending), 1528.44(C-H), 1650.59(C=N), 1689.68 cm^-1 (COOH) peaks were found. But in formulation the peak were found to shift to higher wavenumbers for OH group stretching represented by 3435.50 cm^-1 and the CO group stretches toward the lower wave number. The intermolecular hydrogen bonding and the Vander Waals interaction which may occur between the pure drug and mixed solvent system may influence and cause the shifting of the peaks.

CONCLUSION:

Mixed solvent system technique can be utilized to formulate poorly water-soluble drugs belonging to BCS class II and IV drugs. The solubility of glipizide was found to increase in mixed solvent system compared to that in purified water. This method opens a new path for tackling the solubility problem associated with glipizide. Using this method syrup of glipizide was formulated and evaluated. Success of these formulation would increase the bioavailability and improve patient compliance of geriatric patients suffering from diabetes mellitus. The solubility of glipizide has improved drastically by mixed solvents.

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Received on 11.02.2020 Modified on 24.04.2020

Research J. Pharm. and Tech. 2021; 14(1):427-431.

DOI: 10.5958/0974-360X.2021.00077.9