Chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptorantagonist in solid dosage forms

DMP 754 is an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist that undergoes ester and amidine hydrolysis in the presence of excipients. A means for the stabilization of DMP 754 was needed for the formulation of a stable drug product. Incorporation of a pH modifier in the formulation wa s used to control the microenvironment pH to coincide with that of maximum stability for DMP 754. Stability of tablets and capsules manufactured by (a ) trituration process, (b) dry granulation process, and (c) wet granulation process was evaluated in HDPE bottles. Formulations manufactured by the dr y and wet granulation processes contained disodium citrate as the pH modifi er. Although aqueous wet granulation of a hydrolyzable drug is usually avoi ded, tablets and capsules manufactured by wet granulation were more stable in this case than those manufactured by the dry granulation process. This w as attributed to the more uniform distribution of the pH modifier. Although the compression process resulted in enhanced degradation of the binary ble nd of DMP 754 and anhydrous lactose, tablets manufactured by the wet granul ation process were more stable than capsules manufactured by the same proce ss. Decreasing excipient-to-drug ratio enhanced the stability of tablets ma nufactured by the wet granulation process.