Y Guo1, S R Byrn, G Zografi. 1. School of Pharmacy, University of Wisconsin-Madison, 53706, USA.
Abstract
PURPOSE: To prepare amorphous quinapril hydrochloride (QHCl) by lyophilization and to compare its physical characteristics and chemical stability as a function of the initial pH of the pre-lyophilized solution. METHODS: Amorphous QHCl samples were prepared by lyophilization from aqueous solutions. Solid-state characteristics were evaluated by DSC, PXRD, and optical microscopy. Chemical degradation was monitored by an HPLC assay. RESULTS: Amorphous QHCl samples obtained from lyophilization exhibited variable glass transition temperatures, depending on the pH and/or concentration of the starting aqueous solutions. Neutralized quinapril (Q) in the amorphous form, which has a Tg of 51 degrees C, lower than that of its HCl salt (91 degrees C), was significantly more reactive than QHCl at the same temperature. The Tg of lyophilized samples prepared at various initial pH values correlated well with values predicted for mixtures of QHCl and Q. Their different reaction rates were related to their glass transition temperature, consistent with the results from earlier studies obtained with amorphous samples made by precipitation from an organic solution and grinding of the crystal solvate. CONCLUSIONS: Lyophilization of different QHCl solutions produces mixtures of amorphous QHCl and its neutralized form Q, with Tg values intermediate to the values of QHCl and Q. As the fraction of Q increases the overall rate of chemical degradation increases relative to QHCl alone, primarily due to the increase in molecular mobility induced by the plasticizing effects of Q.
PURPOSE: To prepare amorphous quinapril hydrochloride (QHCl) by lyophilization and to compare its physical characteristics and chemical stability as a function of the initial pH of the pre-lyophilized solution. METHODS: Amorphous QHCl samples were prepared by lyophilization from aqueous solutions. Solid-state characteristics were evaluated by DSC, PXRD, and optical microscopy. Chemical degradation was monitored by an HPLC assay. RESULTS: Amorphous QHCl samples obtained from lyophilization exhibited variable glass transition temperatures, depending on the pH and/or concentration of the starting aqueous solutions. Neutralized quinapril (Q) in the amorphous form, which has a Tg of 51 degrees C, lower than that of its HCl salt (91 degrees C), was significantly more reactive than QHCl at the same temperature. The Tg of lyophilized samples prepared at various initial pH values correlated well with values predicted for mixtures of QHCl and Q. Their different reaction rates were related to their glass transition temperature, consistent with the results from earlier studies obtained with amorphous samples made by precipitation from an organic solution and grinding of the crystal solvate. CONCLUSIONS: Lyophilization of different QHCl solutions produces mixtures of amorphous QHCl and its neutralized form Q, with Tg values intermediate to the values of QHCl and Q. As the fraction of Q increases the overall rate of chemical degradation increases relative to QHCl alone, primarily due to the increase in molecular mobility induced by the plasticizing effects of Q.
Authors: S Klutchko; C J Blankley; R W Fleming; J M Hinkley; A E Werner; I Nordin; A Holmes; M L Hoefle; D M Cohen; A D Essenburg Journal: J Med Chem Date: 1986-10 Impact factor: 7.446