The purpose of the present study was to examine and compare the cosolvency using three different cosolvents, namely PEG 400, PG, and glycerin on the aqueous solubility enhancement of a poorly aqueous soluble drug, etoricoxib, since solubilization of nonpolar drugs constitutes one of the important tasks in the formulation design of liquid dosage forms. The aqueous solubility of etoricoxib was
Solubility is defined in quantitative terms as the concentration of the solute in a saturated solution at a certain temperature. In qualitative terms, solubility may be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion [
Cosolvency, pH adjustment, surfactant addition, and complexation are the most commonly encountered pharmaceutical approaches for solubilising drug candidates with low aqueous solubility [
Etoricoxib, 5-chloro- 6′-methyl- 3[4-(methyl sulfonyl) phenyl] - 2, 3′–bypyridine, is a highly selective second generation cyclooxygenage-2 (COX-II) inhibitor administered orally as an analgesic and nonsteroidal anti-inflammatory drug [
Chemical structure of etoricoxib.
Etoricoxib was gift samples by Zydus Health Care Ltd. India. PEG 400, PG, and glycerin were purchased from Qualigen Fine Chemicals, India. All other chemicals were of analytical reagent grade, and freshly prepared distilled water was used throughout the study.
Estimation of etoricoxib was made in distilled water at
Distilled water and cosolvents (PEG 400, PG, and glycerin) will be mixed volumetrically to form mixtures containing 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100% various cosolvents in screw cap amber color bottles. Excess drug will be added directly into the pure and cosolvant mixed solvents. These bottles will be shaken using a shaker at 50 rpm and room temperature (25 ± 1°C) for 24 h in order to obtain equilibrium. After 24 h of equilibrium, aliquots will be withdrawn, filtered (0.22
The solubility of etoricoxib in water, PEG 400, PG, and glycerin at room temperature is given in Table
Solubility profile of etoricoxib in water, PEG 400, PG, and glycerin at room temperature.
Solvent | Dielectric constant | Solubility of etoricoxib (mg/mL) (Mean ± S.D., |
---|---|---|
Water | 78.36 | |
PEG 400 | 12.40 | |
PG | 32.00 | |
Glycerin | 42.50 |
Cosolvent addition is a highly effective technique for enhancement of solubility of poorly soluble drugs [
Solubility profile of etoricoxib in water-PEG 400 mixture at room temperature.
Water (% v/v) | Polyethylene glycol 400 (% v/v) | Dielectric constant | Solubility of etoricoxib ( |
---|---|---|---|
0 | 100 | 12.50 | |
10 | 90 | 19.00 | |
20 | 80 | 25.59 | |
30 | 70 | 32.19 | |
40 | 60 | 38.78 | |
50 | 50 | 45.38 | |
60 | 40 | 51.98 | |
70 | 30 | 58.57 | |
80 | 20 | 65.17 | |
90 | 10 | 71.76 | |
100 | 0 | 78.36 |
Solubility profile of etoricoxib in water-PG mixture at room temperature.
Water (% v/v) | PG (% v/v) | Dielectric constant | Solubility of etoricoxib ( |
---|---|---|---|
0 | 100 | 32.00 | |
10 | 90 | 36.64 | |
20 | 80 | 41.27 | |
30 | 70 | 45.91 | |
40 | 60 | 50.54 | |
50 | 50 | 55.18 | |
60 | 40 | 59.82 | |
70 | 30 | 64.45 | |
80 | 20 | 69.09 | |
90 | 10 | 73.72 | |
100 | 0 | 78.36 |
Solubility profile of etoricoxib in water-glycerin mixture at room temperature.
Water (% v/v) | PG (% v/v) | Dielectric constant | Solubility of etoricoxib ( |
---|---|---|---|
0 | 100 | 42.50 | |
10 | 90 | 46.09 | |
20 | 80 | 49.67 | |
30 | 70 | 53.26 | |
40 | 60 | 56.84 | |
50 | 50 | 60.43 | |
60 | 40 | 64.02 | |
70 | 30 | 67.60 | |
80 | 20 | 71.19 | |
90 | 10 | 74.77 | |
100 | 0 | 78.36 |
Dielectric constants of the solvent mixtures were calculated from the relation
where
The solubilization of hydrophobic solutes in water-cosolvent mixtures can be described by the log-linear model [
The above expression predicts a straight line for log Sm as a function of cosolvent concentration, corresponding to an exponential increase in solubility by the addition of an organic cosolvent. The log-linear model accounts for the effect of solute-solvent interactions in the mixture as the (volume fraction) weighted average of the solute-solvent interactions present when the solute is dissolved in each of the individual solvents [
The log-linear model is frequently expressed in the alternative form
where
Using the solubility of etoricoxib in water-cosolvent mixture data, we have drawn log-linear solubilization plot (
Solubilization powers of PEG 400, PG, and glycerin calculated from the log-linear solubilization plot by regression analysis.
Solvent | Solubilization power | |
---|---|---|
PEG 400 | 1.4358 | 0.9466 |
PG | 1.3080 | 0.9622 |
Glycerin | 1.0154 | 0.9582 |
Comparative solubility profile of etoricoxib in various water-cosolvent mixtures by log-linear solubilization plot. Cosolvents used were PEG 400, PG, and glycerin.
The cosolvents usually reduce chemical potential of solution by decreasing hydrogen bond density of water, thus create a less-polar environment in the balk, resulting in more drug molecules going into solution. As expected, PEG 400 being less-polar exhibited better solubilization power (1.4358) in comparison with PG (1.3080) and glycerin (1.0154). These results indicate that the drug molecules preferably solubilize in nonpolar environment rather than polar environment.
The structure of PEG 400 is H-(O-CH2-CH2)
The present study evaluated and compared aqueous solubility enhancement of etoricoxib using three different cosolvents, namely, PEG 400, PG, and glycerin. PEG 400 has been an acceptable cosolvent in terms of side-effect profile and most efficient solubilizing cosolvent. The study may also generate an array of data for solubilisation of etoricoxib using various pharmaceutically accepted cosolvents like PEG 400, PG, and glycerine, which will be useful in formulation design and development of liquid dosage forms containing etoricoxib.
The authors are grateful to the Principal and Management of Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, India for proving research facilities.