Kinetic driving effects of phase transformations in mechanically activated powders

Yan Zhang, Purdue University

Abstract

Solid state transformations including polymorphic transition, amorphization and hydration/dehydration are commonly observed in pharmaceutical manufacturing processes such as milling, dry granulation (roller compaction), wet granulation, tablet compression, spray drying, etc. The understanding, monitoring and control process induced transformations is critical given their effects on drug quality, safety and efficacy. Mechanical activation is one of the major factors leading to the solid state transitions. This study focuses on the understanding of mechanical activated polymorphic transformation and amorphization induced during milling, as well as on the physical stability of milled powders. The first chapter provides a review of the basic concepts of solid state in the context of solid state transformations. Two types of solid states, crystalline and amorphous state, are covered in detail, regarding the classification, mechanism of transformations and their relevance in their pharmaceutical field. The concepts of surface energy and nanoindentation are also covered. Chapter 2 studies the amorpization induced by cryomilling of the crystalline form I of sulfamerazine (SMZ-I). The study covers the effects of heating rate (in non-isothermal crystallization) and annealing temperature (isothermal crystallization) on the stability of milled powders. It was found that amorphous material produced by different milling durations exhibited distinct crystallization kinetics and crystallization products in terms of polymorphic forms. In addition, other crystallization conditions also presented significant effect on crystallization kinetics as well as the product of crystallization. Chapter 3 presents a mechanism of ball milling induced polymorphic transformation of SMZ. The evidence for the "amorphous solid mediated" mechanism critically examined. The study also reveals that the particular crystal form produced is strongly dominated by the kinetics of crystal growth and not by thermodynamics. Chapter 4 explores the effect of the presence of a polymer subjected to co-milling with the drug powder on the induced solid state transformations of sulfamerazine. Mixtures of SMZ-I and polyvinyl pyrrolidone (PVP) (50/50%wt) were processed by ball milling as well as cryomilling. A gradual amorphization was observed from both milling processes. The presence of PVP in the milled material inhibited the formation of the crystal form II of sulfamerazine (SMZ-II). The inhibition effect was not limited to milling process, but was also present on the crystallization subsequent to milling, taking place during storage. It was found that inhibiting effect of PVP lies on nucleation and not growth of SMZ-II. The polymer precludes the creation of SMZ-II nuclei from the amorphous form. However, if SMZ-II is present (as by seeding), the form will grow in the presence of PVP. Chapter 5 studies the effects of high shear wet milling and dry milling on the surface energy of milled powders using inverse gas chromatography (IGC). It was found that the bulk properties of both model compounds (succinic acid and sucrose) were virtually unaffected by the milling method. However, the milled powders showed significantly higher surface energies than the unmilled. Wet milling caused a higher surface energy than dry milling for both compounds. It was found that the surface energy difference between the dry milled and wet milled powders was not attributable to specific solvent adsorption and was shown to be caused by the effect of the solvent on particle attrition. In addition the solvent medium had a strong effect on the surface energy of wet milled sucrose powder. Generally, the higher solvent polarity, the higher surface energy.

Degree

Ph.D.

Advisors

Pinal, Purdue University.

Subject Area

Pharmacy sciences

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