| The broad objective of the research was to better understand the influence of drug polymorphism on the physical chemistry of freeze-drying. The freezing and freeze-drying characteristics of glycine and sucrose-glycine solutions were studied. beta-glycine forms a eutectic mixture during slow cooling, with an onset melting temperature of -3.60°C and a composition of 11.80%. Rapidly-frozen glycine solutions exhibit two apparent glass transitions, two separate exotherms and five endotherms in the melting region. The two glass transitions are interpreted as a true glass transition of the freeze concentrate and a transition related to the beginning of ice melting. The lower-temperature exotherm arises from glycine crystallization. The nature of the higher-temperature exotherm is not understood. Eutectic melting of beta- and gamma-glycine and dissolution of alpha-glycine explain the complex melting characteristics. For sucrose-glycine-water (S/G), the crystallization of glycine in high S/G formulations is inhibited during slow cooling. Rapidly-frozen S/G solutions show two glass transitions, one or two or no exotherm(s), depending on the S/G ratios, and three endotherms in the melting region. The two glass transitions are interpreted as in the glycine system. The exotherm(s) arises from the crystallization of non-eutectic and eutectic beta-glycine, depending on crystallization temperature. Eutectic melting of beta-glycine and dissolution of either beta- or alpha-glycine explain the complex melting behavior. Non-eutectic beta-glycine undergoes phase conversion to either alpha- or gamma- or both, depending on the S/G ratios. Finally, the presence of different polymorphs of pentamidine isethionate (PI) in freeze-dried powders depends on the thermal history of freezing, concentrations and drying conditions. Rapid freezing results in the formation of form A regardless of concentration. At 1--4% w/v, form A is observed irrespective of the freezing method. At 10% w/v, forms A or B or a mixture of both forms are observed, depending upon whether the nucleation and growth of trihydrate occurs. The high-temperature form C cannot be produced under lyophilization conditions. The results underscore the significance of recognizing that the freezing and freeze-drying behavior of the formulations are sensitive to concentrations and freeze-drying conditions. Subtle changes in concentrations and processing conditions can dramatically impact the final product quality and process efficiency. |
