The Protective Effect Of Lactose On Lyophilization Of CNK-20402

The Protective Effect Of Lactose On Lyophilization Of CNK-20402
Accepted September 16, 2004, Author's Final Version
Yung-Chi Lee*, Jared Nelson, Katsuhiko Sueda, Donna Seibert, Wen-Yaw Hsieh, Bryan Braxton, Pharmaceutical Sciences, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105
AAPS PharmSciTech
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ABSTRACT The goal of this research was to assess the feasibility of utilizing lyophilization to stabilize an exploratory compound, CNK-20402 with a minimal amount of impurity (CNK-20193) formation. A mixed-level full factorial experimental design was utilized to screen excipients of glycine, mannitol, lactose monohydrate, and povidone K-12. Cryostage microscopy, powder X-ray diffraction, Karl Fischer titration, HPLC, and water vapor sorption were utilized to assess formulationsÌ physicochemical properties and stability. Initial physical characterization from powder X-ray revealed that the mannitol- and glycine-containing formulations were crystalline with the patterns of the pure excipient, while the remaining formulations were amorphous in structure. Chemically, the formulations stored at 50 ?C for one month had 2.36, 1.05, 0.81, 0.79, and 0.49% CNK-20193 for glycine, mannitol, drug alone, povidone K-12, and lactose formulations, respectively. The formulations containing drug-mannitol, drug alone, and drug-lactose were selected for accelerated stability study based on statistical analysis. Recovery of CNK-20193 in these formulations were 1.22, 1.00, and 0.55%, respectively when stored at 40?C/75% RH storage conditions for 3 months. Water vapor sorption analysis revealed weight gains of over 7, 21, and 24% for the mannitol, lactose, and drug alone formulations, respectively. Testing formulations with different concentrations of lactose by water vapor sorption indicated that CNK-20402 concentrations as low as 10 % (w/w) could inhibit the re-crystallization of lactose. The lactose-containing formulation exhibited the best stability among the formulations tested. The protective mechanism of lactose on the CNK-20402, based on water vapor sorption studies, is believed to be due
to two reasons: (1) the drug-lactose interaction and, (2) competition between lactose and drug for the residual water in the formulation.
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