Induced Supersaturation by Hydroxypropylmethyl Cellulose Under Aqueous Acidic Conditions of a Series of Carboxylic Acid Drugs

Abstract

Supersaturation of four structurally related crystalline carboxylic acid drugs (naproxen, indomethacin, ibuprofen, and etodolac) was studied in aqueous acidic conditions at 37ºC in the absence and presence of pre-dissolved HPMC. A solvent-shift method was used in which drug-containing DMSO solution concentrates were prepared with each molecule and carefully added to aqueous acidic solutions while stirring. Tests were performed to measure drug dissolved concentration as a function of time and to characterize any resulting precipitate. Supersaturation was observed for all four model carboxylic acid drugs in the presence of HPMC-containing aqueous acidic solutions. When precipitation occurred the isolated solid drug was characterized and shown to increase in amorphous character or produce completely amorphous solid. The solution and solid-state data suggests that the mechanisms by which HPMC induces supersaturation include both increased equilibrium solubility and crystallization inhibition in the presence of HPMC in naproxen, indomethacin, and ibuprofen. In etodolac, there was no observed significant increase of equilibrium solubility, and only a loss of crysallinity upon precipitation in kinetic solubility studies. Additional studies with etodolac showed that the grade and viscosity of HPMC did not significantly affect the degree of supersaturation maintained. However, an increased initial degree of supersaturation of etodolac results in a decreased onset time of precipitation. Within the range studied the optimal degree of supersaturation of etodolac was 5 in which no precipitation occurred, at a degree of supersaturation of 7 precipitation occurred after 3 hours, whereas at a degree of supersaturation of 10 precipitation occurred immediately. The studies suggest that the solubilizing and supersaturating-promoting effects of HPMC may be useful in designing preclinical, clinical and commercial formulations and drug products to potentially improve the oral bioavailability of poorly water-soluble compounds.