Optimization of experimental conditions for the monitoring of nucleation and growth of racemic Diprophylline from the supercooled melt

Publication date: 15 August 2017
Source:Journal of Crystal Growth, Volume 472
Author(s): Aurélien Lemercier, Quentin Viel, Clément Brandel, Yohann Cartigny, Eric Dargent, Samuel Petit, Gérard Coquerel
Since more and more pharmaceutical substances are developed as amorphous forms, it is nowadays of major relevance to get insights into the nucleation and growth mechanisms from supercooled melts (SCM). A step-by-step approach of recrystallization from a SCM is presented here, designed to elucidate the impact of various experimental parameters. Using the bronchodilator agent Diprophylline (DPL) as a model compound, it is shown that optimal conditions for informative observations of the crystallization behaviour from supercooled racemic DPL require to place samples between two cover slides with a maximum sample thickness of 20µm, and to monitor recrystallization during an annealing step of 30min at 70°C, i.e. about 33°C above the temperature of glass transition. In these optimized conditions, it could be established that DPL crystallization proceeds in two steps: spontaneous nucleation and growth of large and well-faceted particles of a new crystal form (primary crystals: PC) and subsequent crystallization of a previously known form (RII) that develops from specific surfaces of PC. The formation of PC particles therefore constitutes the key-step of the crystallization events and is shown to be favoured by at least 2.33wt% of the major chemical impurity, Theophylline.