title: Effect of different acids on solid-state stability of an ester prodrug of a IIb/IIIa glycoprotein receptor antagonist.
abstract: DMP 754 is an ester prodrug of a fibrinogen glycoprotein IIb/IIIa receptor antagonist. The purpose of this study was to determine whether the addition of acids to blends containing DMP 754 and anhydrous lactose could improve the stability at 40 degrees C/75% relative humidity. DMP 754 drug substance was stable at this accelerated condition. Blending of DMP 754 with anhydrous lactose accelerated the hydrolysis of both the ester and the amidine groups. The pH of a saturated solution of lactose is approximately 6, whereas the pH of maximum solution stability for the drug substance is approximately 4. Acids were incorporated into the blend so that the microenvironment would be more acidic and afford improved drug stability. Addition of acids decreased the rate of hydrolysis of the amidine group and this effect was more pronounced with stronger acids. However, the more acidic ingredients led to more rapid hydrolysis of the ester group.
authors.affiliation: Pharmaceutical R&D, DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Badawy
authors.forename: R C
authors.initials: RC
authors.lastname: Williams
authors.forename: D L
authors.initials: DL
authors.lastname: Gilbert
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007555:Isoxazoles / Q000737:chemistry*; D007785:Lactose; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000596:Amino Acids; D004952:Esters; D007555:Isoxazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; C104283:roxifiban acetate; D007785:Lactose