Crystallization in pharmaceutical materials: I. Cross-nucleation between polymorphs. II. Solubility of crystalline drugs in polymers.

摘要

This thesis work studied two problems in the crystallization of pharmaceutical substances: (i) cross-nucleation between polymorphs and (ii) solubility of crystalline drugs in polymers. Cross-nucleation between polymorphs is the nucleation of a new polymorph on an existing and growing polymorph. It is important to the control of polymorphism and to the basic understanding of crystal nucleation. This phenomenon has been studied in D-mannitol (sometimes containing polyvinylpyrrolidone to slow down crystallization) in spontaneous and seeded crystallization. The polymorphic outcome of a seeded crystallization depends on the seed polymorph, temperature, relative growth rates of polymorphs, and the crystallographic orientation of the seeds. The cross-nucleation process observed in spontaneous crystallization follows Poisson statistics. The dependence of the cross-nucleation rate on liquid thickness shows that the process occurs at the growth front of the initial polymorph, unaffected by container surfaces.;The solubility of crystalline drugs in polymers defines the maximal drug loading without the risk of crystallization and indicates the driving force for an amorphous drug to crystallize from its solid dispersion in a polymer matrix. This property is difficult to measure because the high viscosity of polymers makes achieving solubility equilibrium difficult. Two methods based on Differential Scanning Calorimetry (DSC) have been developed for measuring this property. The scanning method detects the dissolution endpoint of an intimate mixture of drug/polymer during slow heating. The scanning method holds a drug/polymer mixture for effectively as long as possible near the dissolution endpoint to ensure phase equilibrium and rescans the mixture to detect any undissolved crystals. The annealing method increases the likelihood of achieving phase equilibria and extends the temperature range of measurement closer to Tg. The methods were used to obtain, for the first time, the solubilities of crystalline D-mannitol, indomethacin, and nifedipine in polymers near the glass transition temperature. The solubilities have been compared in polymers of different structures, molecular weights, and hydrophilicity. The methods have the potential of providing useful data for designing physically stable formulations of amorphous drugs.