Solution stability of factor Xa inhibitors as a function of pH.
The stability of two factor Xa inhibitors (MLN1021 and CT54004) as a function of pH was investigated in order to better characterize the compounds and to locate the optimum pH for a stable formulation that might be used in a first-in-person (FIP) clinical study. The compounds prepared in buffer solutions over a pH range of 1-10 were stored at 60 degrees C, and assayed for pH and purity at different time points. The pH-rate profiles indicated that both compound was quite stable in the middle pH range, and least stable at pH<3 and >8. The optimum pH for stability of the compounds was around 6, which is consistent with the theoretical predictions by a mathematical model. The mechanism of the reaction is not a specific-acid/base-catalyzed reaction. Based on the experience of this study, an ideal experimental design is proposed, which will be useful for future study on similar drug candidate.
Yang
Pei
P
Drug Development, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. peiyangusa@yahoo.com
Macdonald
Fraser
F
D002021:Buffers; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D065427:Factor Xa Inhibitors; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008433:Mathematics; D019999:Pharmaceutical Solutions; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013997:Time Factors
D002021:Buffers; D065427:Factor Xa Inhibitors; D019999:Pharmaceutical Solutions; D015842:Serine Proteinase Inhibitors