Polymorphic Transformations of Pharmaceutical Materials Induced by Mechanical Milling: A Review

Area of Science:

• Pharmaceutical Science
• Materials Science
• Solid-State Chemistry

Background:

• Polymorphic transformations are critical in pharmaceutical development, affecting drug efficacy and stability.
• Mechanical milling is a known method to induce solid-state transformations in pharmaceutical compounds.
• Understanding the mechanisms of milling-induced polymorphic changes is essential for controlling drug properties.

Purpose of the Study:

• To review and synthesize literature on polymorphic transformations induced by milling in pharmaceutical materials.
• To elucidate the underlying mechanism of milling-induced polymorphic transformations.
• To identify factors influencing the kinetics and occurrence of these transformations.

Main Methods:

• Comprehensive literature review of studies involving milling of pharmaceutical materials.
• Compilation and analysis of data from 18 different pharmaceutical compounds.
• Examination of parameters including crystalline forms, transition temperatures, and amorphization behavior.

Main Results:

• A two-step transformation mechanism was proposed: initial amorphization followed by recrystallization of the amorphous phase.
• Transformation kinetics are influenced by the accidental formation of the final crystalline form during milling.
• The observation of transient amorphous forms correlates with the material's glass transition temperature relative to milling temperature.

Conclusions:

• The proposed two-step mechanism (amorphization-recrystallization) appears independent of the enantiotropic or monotropic nature of the polymorphic forms.
• Glass transition temperature and milling temperature are key factors in controlling transient amorphization.
• This mechanistic understanding aids in predicting and controlling solid-state transformations during pharmaceutical processing.