Chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist 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 was 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 dry and wet granulation processes contained disodium citrate as the pH modifier. Although aqueous wet granulation of a hydrolyzable drug is usually avoided, tablets and capsules manufactured by wet granulation were more stable in this case than those manufactured by the dry granulation process. This was attributed to the more uniform distribution of the pH modifier. Although the compression process resulted in enhanced degradation of the binary blend of DMP 754 and anhydrous lactose, tablets manufactured by the wet granulation process were more stable than capsules manufactured by the same process. Decreasing excipient-to-drug ratio enhanced the stability of tablets manufactured by the wet granulation process.
Badawy
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SI
Pharmaceutical R&D, DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80400, Wilmington, Delaware 19880-0400, USA. sherif.i.badawy@dupontpharma.com
Williams
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RC
Gilbert
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DL
D000596:Amino Acids / Q000737:chemistry*; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D002951:Citrates; D004339:Drug Compounding; D004355:Drug Stability; D004577:Electron Probe Microanalysis; D005079:Excipients; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D007555:Isoxazoles / Q000737:chemistry*; D007785:Lactose; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000737:chemistry*; D000077559:Sodium Citrate; D013056:Spectrophotometry, Ultraviolet; D013607:Tablets
D000596:Amino Acids; D002214:Capsules; D002951:Citrates; D005079:Excipients; D007555:Isoxazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D013607:Tablets; C104283:roxifiban acetate; D000077559:Sodium Citrate; D007785:Lactose