Template induced polymorphic selectivity in pharmaceutical crystallisation
Creators: name: Parambil, Jose Varghese
Publisher: name: Imperial College London
Year: 2015

description: Polymorphism in pharmaceutical drug crystals causes differences in their bioavailability, stability and processability. Hence, identifying different crystal polymorphs of an active ingredient during the early stages of drug development and controlling crystal polymorphism during the manufacturing process are important aspects of pharmaceutical crystallisation. Nucleation and growth of different polymorphs in a crystallising solution are regulated by a delicate balance between thermodynamic and kinetic factors. Crystal nucleation predominantly occurs via heterogeneous nucleation pathway as it is energetically favourable than homogeneous nucleation. Template-induced nucleation approach aims to utilise the advantage of heterogeneous nucleation to induce nucleation of specific crystal polymorphs through interfacial interactions between a preformed solid surface and solute molecules at the nucleation stage. In template-induced crystallisation, templates with specific surface properties that can act as heterogeneous nucleation sites are introduced in contact with the crystallising solution. Specific interactions between the template surface and solute molecules are known to influence nucleation and growth of crystal polymorphs. However, the effects of template surface chemistry and other operating conditions such as temperature and supersaturation on template-induced crystallisation is not clearly understood. Hence, the aim of this study is to probe the combined effects of surface chemistry, crystallisation temperature, supersaturation, and solvent on template-induced crystallisation experimentally and consequent development of a molecular modelling approach to study template-induced nucleation. This could help in establishing template-induced nucleation as a method to achieve preferential nucleation of crystal polymorphs and to support template chemistry as a novel parameter for polymorph screenings. Carbamazepine (CBZ) was selected as the model drug compound and silanised glass vials were chosen as the template surfaces. CBZ crystallisation from ethanol solutions on templates with cyano functional surface groups led to selective nucleation of metastable form II crystals while the control surfaces resulted in concomitant nucleation of both form II and stable form III crystals. On mercapto and fluoro templates, CBZ crystallised preferentially as form III polymorph. These variations in the polymorphic outcome with template chemistry, temperature and supersaturation were mapped on to template-induced polymorphic domain (TiPoD) plots. The analysis of TiPoD plots showed that the template-induced nucleation mechanism was prominent within a narrow range of supersaturation across the temperature range studied. The influence of solvents on template-induced nucleation of CBZ polymorphs was also investigated by constructing TiPoD plots in five different solvents. These studies revealed that the templates were less effective in altering polymorphic outcome in highly polar solvent in comparison with the less polar solvents. Interfacial interactions between the template surface and CBZ crystal polymorphs were calculated through molecular modelling. The simulation results suggest that those templates exhibiting favourable interaction energies with the dominant crystal facets of a specific polymorph preferentially induce nucleation of that crystal form.