title: The protective effect of lactose on lyophilization of CNK-20402.
abstract: The goal of this research was to assess the feasibility of using 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 used 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 used to assess the formulations' physicochemical properties and stability. Initial physical characterization from powder x-ray diffraction revealed that the mannitol- and glycine-containing formulations were crystalline with the patterns of the pure excipient, whereas the remaining formulations were amorphous in structure. Chemically, the formulations stored at 50 degrees C for 1 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 was 1.22%, 1.00%, and 0.55%, respectively, when stored at 40 degrees C/75% relative humidity 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% (wt/wt) could inhibit the recrystallization 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 a result of (1) the drug-lactose interaction, and (2) competition between lactose and drug for the residual water in the formulation.
authors.affiliation: Pharmaceutical Sciences, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. yung-chi.lee@pfizer.com
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Lee
authors.forename: Jared
authors.initials: J
authors.lastname: Nelson
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Sueda
authors.forename: Donna
authors.initials: D
authors.lastname: Seibert
authors.forename: Wen-Yaw
authors.initials: WY
authors.lastname: Hsieh
authors.forename: Bryan
authors.initials: B
authors.lastname: Braxton
mesh_terms: D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D015507:Drugs, Investigational / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D007785:Lactose / Q000737:chemistry*
chemical_list: D015507:Drugs, Investigational; D005079:Excipients; D007785:Lactose