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.

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

“…Enhanced hydrolysis of DMP 754 in the presence of lactose was attributed, at least partly, to lactose catalysis, since lactose was shown to provide concentration-dependent catalysis of ester and amidine degradation in solution. 3 While catalysis of esters by sugars and polyhydric alcohols in aqueous solutions was reported, 4 this effect was not previously shown for the amidine group.…”

Microenvironmental pH Control and Mixed Polymer Approaches to Optimise Drug Delivery with Hydrophilic Matrix Tablets

“…In fact, the slurry pH will be dependent on the concentration of solid in the slurry, and this could be significantly different from the actual hydrogen ion activity in the solid dosage form. However, microenvironmental pH measured using the slurry method has demonstrated some success in correlating with the stability of immediate release formulations [11,12] and identifying the level of pH-modifying agent needed to provide the required microenvironmental pH which minimises the risk of salt disproportionation [13].…”

Tabletler Ve Tablet Basimina Etki Eden Kuvvetlerin Belirlenmesinde Kullanilabilecek Bazi Yeni Esitlikler

“…Rotari tablet preslerinin enstrümantasyonu, üst zımba ve alt zımbaya sensör yerleştirilmesi ve algılanan sinyallerin ölçülmesi esasıyla yapılmaktadır (30).…”