Effect of salt form on chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist in solid dosage forms.
The effect of salt form on the stability of an ester prodrug of a IIb/IIIa receptor antagonist was investigated. The pH of maximum stability for the ester prodrug is approximately 4. The mesylate salt is thought to provide lower microenvironment pH, closer to the pH of maximum stability, than the acetate salt. Stability of drug product manufactured using the mesylate salt (DMP 755) was studied and compared with that for the acetate salt (DMP 754). Formulations contained disodium citrate as a pH modifier to control formulation pH, since solid state stability for this compound is dependent on the microenvironment pH. The pH modifier was not able to achieve adequate microenvironment pH control for the DMP 754 drug product when added using a dry manufacturing process. While DMP 754 required the use of a pH modifier added in solution during wet granulation in order to improve drug product stability, DMP 755 was able to achieve similar results using the dry granulation process. Stability of DMP 755 drug product was independent of effectiveness of the pH modifier. This study showed that the choice of the salt form may provide an alternative for maximizing drug product stability.
Badawy
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Pharmaceutical R&D, DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80400, Wilmington, DE 19880-0400, USA. sherif.i.badawy@dupontpharma.com
D000596:Amino Acids / Q000008:administration & dosage / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*
D000596:Amino Acids; C116275:DMP 755; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; C104283:roxifiban acetate