Solubility of Pioglitazone Hydrochloride in Binary and Ternary Mixtures of Water, Propylene Glycol, and Polyethylene Glycols 200, 400, and 600 at 298.2 K

Glitazones (GZs) or thiazolidinediones are oral hypoglycemic agents used in the treatment of type II diabetes. They are acting as insulin sensitizers by regulating the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. The first report of their glucose-lowering effects was published in 1980s, and troglitazone was launched as an oral hypoglycemic agent in 1997, and two others, i.e., pioglitazone (PGZ) and rosiglitazone, were approved by the FDA in 1999 (1,2). Troglitazone was withdrawn because of its hepato-toxicity; the incidence of liver toxicity of PGZ and rosiglitazone are minor; however, investigations for finding more active glitazones with less side effects are still ongoing (2). PGZ is the most popular drug, and its prescription is increased by the rate of 14% during 2005–2007 (3). In addition to its antidiabetic activity, it demonstrates other activities including reduction of reactive oxygen species from adipose tissue (4) and improving cognition and regional cerebral blood flow in patients with mild Alzheimer (5). PGZ hydrochloride (PGZ-HCl) is used in pharmaceutical formulations to achieve a more soluble form of the drug; however, the aqueous solubility of PGZ-HCl is still low, and a number of investigations were reported dealing with solubilization of PGZ or PGZ-HCl (6–10). Common cosolvents in pharmacy are ethanol, propylene glycol (PG), glycerin, polyethylene glycol 400 (PEG 400), and N-methyl-2-pyrrolidone (NMP; 11). Polyethylene glycols (PEGs) are linear or branched polyethers with the approximate molecular weight of 200–36,000. PEG 200 to PEG 800 are in liquid form, whereas PEG 1000 and higher molar masses are solids. Liquid PEGs are commonly used as cosolvents for solubilization of drugs in preclinical and clinical studies (12). Because of strong H-bonding between PEGs and water, they are freely soluble in water and in many organic solvents. PEGs have variety of applications in the pharmaceutical, chemical, cosmetic, and food industries (13). Their low toxicity and high water solubility enable their use for purification of biological materials. Among them, PEG 400 is the most commonly used cosolvent in the pharmaceutical industries for preparation of cosmetics, ointments, suppositories, ophthalmic solutions, and sustained-released oral pharmaceutical formulations (14). Propylene glycol is a stable and low toxic pharmaceutical cosolvent which is used in many commercially available oral and parenteral formulations of poorly soluble drugs (15,16). The well-known parenteral formulations containing PG are diazepam, fenoldopam mesylate, melphalan HCl, oxytetracycline, paricalcitol, pentobarbital Na, phenytoin Na, chlordiazepoxide HCl, lorazepam, and phenobarbital. PG is also used in many oral formulations of drugs including amprenavir, clofazimine, cyclosporine A, digoxin, lopinavir, ritonavir, sirolimus, loratadin, and itraconazole (15). Our intent was to measure the solubilities of PGZ-HCl in a series of aqueous and non-aqueous solvent systems containing ethanol, PG, NMP, and PEGs at 298.2 K which extends the available database of drugs solubilities in mixed solvents (17), fitting the data to the Jouyban-Acree model that relates the solubilities in solvent mixtures to the fractions of the solvent components and constants computed by a regression analysis (18). In previous reports, the solubility of PGZ-HCl in aqueous solutions of ethanol, PG, and NMP (8), in binary mixtures of PEG 600 with water and ethanol, ternary mixtures of PEG 600-ethanol-water (9), and also in binary mixtures of PEG 400 with ethanol, PG, NMP, and water (10) were discussed. In this work, the solubility of PGZ-HCl in binary and ternary mixtures of water, PG, and PEGs 200, 400, and 600 at 298.2 K are reported. The generated data are predicted using numerical methods, and the accuracies of different methods are discussed.