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

Abstract

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.

Simultaneous determination of formic acid and formaldehyde in pharmaceutical excipients using headspace GC/MS

“…Excipients that react chemically with the drug and result in an increase in the levels of degradation products are typically not used for further formulation development [1][2][3][4][5]. This decrease in the stability of the drug substance during the compatibility studies is often attributed to trace levels of impurities present in the excipients studied.…”

Modulation of Microenvironmental Acidity: A Strategy to Mitigate Salt Disproportionation in Drug Product Environment

“…While pH modulation provides an attractive formulation strategy to mitigate disproportionation, often the selection of the appropriate pH modifier, its concentration, and method of incorporation into the formulation largely remains an empirical approach. Traditionally, the slurry/suspension pH, measured with a pH meter, has been used to determine the effective concentration of pH modifier required to achieve the desired microenvironmental pH in the solid formulation. − On the basis of excipient slurry pH values, Merritt et al described a semiquantitative, empirical model to predict salt disproportionation. Model predictions were used to determine the effectiveness of pH modifier acids (citric acid and para-toluene sulfonic acid) to prevent disproportionation of a weakly basic drug.…”

Application of FTIR Spectroscopic Imaging to Study the Effects of Modifying the pH Microenvironment on the Dissolution of Ibuprofen from HPMC Matrices

“…There is a plethora of literature in this area. 6 There are many examples of adding pH modifiers to tablet matrices to adjust the solubility of weakly basic drugs. [7][8][9] Less work exists on the use of pH modifiers for modifying the release of weakly acidic drugs.…”