Solubility enhancement of cox-2 inhibitors using various solvent systems

Abstract

INTRODUCTIONThis study examined the solubility enhancement of 4 cox-2 inhibitors, celecoxib, rofecoxib, meloxicam, and nimesulide, using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerol, and polyethylene glycol 400 (PEG 400) were used as solvents and water-ethanol, glycerol-ethanol, and polyethylene glycol-ethanol were used as mixed-solvent systems. A pH-solubility profile of drugs was obtained in the pH range 7.0 to 10.9 using 0.05M glycine-sodium hydroxide buffer solutions. Lower alcohols, higher glycols, and PEG 400 were found to be good solvents for these drugs. The aqueous solubility of celecoxib, rofecoxib, and nimesulide could be enhanced significantly by using ethanol as the second solvent. Among the mixedsolvent systems, PEG 400-ethanol system had highest solubilization potential. In the case of meloxicam and nimesulide, solubility increased significantly with increase in pH value. Physico-chemical properties of the solvent such as polarity, intermolecular interactions, and the ability of the solvent to form a hydrogen bond with the drug molecules were found to be the major factors involved in the dissolution of drugs by pure solvents. The greater the difference in the polarity of the 2 solvents in a given mixed solvent, the greater was the solubilization power. However, in a given mixedsolvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations has also been discussed in this study.Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed medications in the world. As a therapeutic class, NSAIDs exhibit analgesic, antiinflammatory, antipyretic, and platelet inhibitory properties. 1,2 However, these drugs have serious side effects such as gastrointestinal (GI) toxicities, gastric mucosal ulcerations and hemorrhage due to inhibition of prostaglandin production.3,4 The mechanism of action of NSAIDs has been attributed to their ability to inhibit the cyclooxygenase enzyme (cox). Out of the 2 isoforms of cyclooxygenase, cox-1 is responsible for mediating the production of prostaglandin while cox-2 is primarily associated with inflammation, pain, and fever. 5,6 The traditional NSAIDs are nonselective cox inhibitors. Cox-2 selective NSAIDs are, therefore, ideal anti-inflammatory drugs with minimum drug-related side effects, since they spare cox-1 activity.The very poor aqueous solubility and wettability of cox-2 inhibitors, however, give rise to difficulties in the design of pharmaceutical formulations and lead to variable oral bioavailability. The use of cosolvents has been employed by a number of workers [7][8][9] to enhance the solubility of poorly soluble drugs. Some attempts have been made to increase the solubility of nimesulide and meloxicam 10-13 by using techniques other than the use of cosolvents. Enhancement of solubility of celecoxib and rofecoxib has not received much attention so far. In the present study, an attempt has b...

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