Crystal growth kinetics of salicylamide and two polymorphs of piracetam

The crystal growth process and associated kinetics of two active pharmaceutical ingredients (API) has been investigated using three crystal growth methods. The impact of organic solvent, supersaturation, temperature, polymorph form, and crystal seed quality on the crystal growth was studied. Isothermal seeded desuperaturation (ISD) growth method was used to investigate the growth rate of multiple salicylamide (SAM) crystals simultaneously. In-situ fourier transform infrared (FTIR) spectroscopy probe was employed for the determination of solution concentration and supersaturation decay data obtained was modelled using several growth rate equations and growth models, also tested different representations of the driving force. ISD provides kinetic data which was statistically representative of the crystal population due to the large number of crystals studied. Measuring the interfacial angle between faces combined with preferred orientation X-ray diffraction (XRD) was found to be the most accurate and reliable method leading to successful identification of each predicted SAM crystal face. Cuvette (CV) growth method was used to study the growth of single SAM crystals and the crystal growth rates were measured for both primary nucleated crystals and seed crystals manually inserted into the cuvette. As each facet had been face indexed it allowed for the growth of specific crystal facets, i.e. (200) of SAM, to be extracted directly from single crystals using a microscope. In an attempt to study multiple single crystals at once under controlled hydrodynamics, crystal seeds were grown using a new approach called the rotating disk (RD) growth method. Wherein seed crystals were attached to a disk that was rotated in a supersaturated solution by which the diffusion resistance was found to be eliminated. RD method was used to study the growth of two APIs including SAM and FII & FIII polymorphs of piracetam (PCM). It was deduced that ethyl acetate was adsorbed more strongly on the faces of SAM than the other solvents tested, the increased size of which, explained the irregular hexagonal plate habit obtained and relatively slow growth rates. Growth rate of the (011) facet of piracetam FII and FIII crystals was found to be reduced in isopropanol also due to its stronger interaction. Metastable PCM FII was found to have faster growth rates than the thermodynamically stable FIII. Within the range of experimental conditions, the growth rates of SAM and PCM were strongly affected by the temperature and also supersaturation. With a 10 °C increase resulting in a two to fourfold increase in the average growth rate depending on the solute – solvent system. Similarly, a two to fourfold increase in the average growth rate of both SAM and PCM was observed when the supersaturation was increased within the range of S-1 0.02 up to 0.10. Also SAM’s crystal seed quality was found to have a substantial impact on the growth rate, with rougher larger crystals leading to quicker growth due to the increased number of surface defects present which can act as attachment sites. Comparing the RD and CV growth rate data for SAM it indicated that the CV method led to growth rates which were controlled by the diffusion step. The growth order parameter determined in the ISD studies reveals a surface integration controlled growth process. Under similar conditions, both the RD and ISD methods produced comparable growth rates for SAM and also for PCM. Furthermore by examining the effect of the rotation speed on the crystal growth rates from RD method led to the finding that it was also surface integration controlled. The crystal growth rates of the (200) facet of SAM obtained via surface integration controlled growth resulted in 20 times faster growth rate than when grown under diffusion controlled growth.