(737d) Crystal Growth Kinetics of Salicylamide Investigated Under Different Crystallisation Processes and Also Environmental Conditions

Crystallisation is a very important technique, especially in the Pharmaceutical Industry, as it is used in purification and recovery of the crystalline active pharmaceutical ingredients (API) [1]. Despite this, crystallisation fundamentals are still insufficiently understood. Efforts have been made by researchers to understand the kinetics’ of salicylamide nucleation [2]. This research focuses on improving knowledge of crystal growth process and kinetics of salicylamide by investigating under rotating disk and also seeded desupersaturation agitated tank experiments. Observed the growth of individual crystals as well as populations of crystals. Crystal growth is also studied under different environmental conditions to detect any influence of the solvent, temperature and supersaturation.

The rotating disc experiments uses inverted optical microscope integrated with a camera, combined with a PC with image/ video capture and analysis software to capture micrographs of each crystal before and after growth. Multiple individual seed salicylamide crystals are fixed onto a rotating glass disc, and placed into a supersaturated solution for a growth period of 1 hour and rotated at 200rpm. Crystals are observed in-situ, so allows for the growth of specific faces to be measured and also view overall habit. The agitated tank experiments use a reactor vessel to perform seeded isothermal desupersaturation experiments. The concentration decay is recorded with a FTIR probe and first principles data treatment is applied to extract the concentration information from IR spectra; besides, FBRM is used for detection of nucleation during crystal growth. In the agitated tank experiments the average growth rate of a certain mass of seeds (better statistics) can be determined at hydrodynamic conditions closer to an industrial process.

The rotating disk crystal growth of salicylamide crystals at 15°C was measured as a function of relative supersaturation (S-1) in the range from 0.01 – 0.04, and in four different solvents (acetone AC, acetonitrile MeCN, ethyl acetate EA and methanol MeOH), rotating the disc at 200rpm. Different rotation speeds where tested in the range of 50 - 350rpm, and 200 rpm was found to be sufficient to essentially eliminate the film mass transfer resistance. The growth of a minimum of 25 crystals was determined for each system. The growth rates of the length and width of each individual crystal was measured using the maximum and minimum feret diameter respectively, also growth of the (200) face was measured. The studies revealed that salicylamide crystals grown from seed in different solvents, at different supersaturations and also within each solvent receive different shapes. There is a significant spread in the crystal growth rates obtained within each system, e.g. 0.05 μm/s up to 0.55 μm/s in one system; this is due to the crystal quality, where lower quality results in increased growth. The average growth rates increase with increasing supersaturation in each solvent. The average individual crystal growth rate behaviour, as a function of solvent and supersaturation, is similar for length and width. The average crystal growth rate of the (200) face of individual seed crystals decreases in the order MeOH>MeCN>AC>EA at supersaturation of 0.03. Salicylamide crystal surface was examined before and after the growth process using scanning electron microscopy; noticed growth steps and layers clearly present after growth indicating rough interfacial growth mechanism. The agitated tank experiments were also performed in all four solvents (AC, MeCN, EA and MeOH) and at 4 temperatures (10, 15, 20, 25°C). The empirical power law equation, spiral growth mechanism (BCF) equation and the birth & spread mechanism (B+S) equation were fitted to the data. In all four solvents, the growth rate increases with temperature as expected. The average crystal growth rate decreases in the order AC>MeOH>MeCN>EA at supersaturation of 0.03. The interfacial energy values for crystal growth depend on solvent, and where obtained by fitting the B+S model; the order is EA>AC>MeCN>MeOH. Due to the fact that low interfacial energy tends to lead to high crystal growth rate, which is in agreement with the result from the rotating disc experiments. The growth rate is faster in the agitated tank experiments as compared to rotating disc which possibly reflects an influence of mass transfer resistance in the latter.

In all growth processes, salicylamide was found to have the slowest growth kinetics in ethyl acetate. Molecular modelling was performed which high lightened the strong hydrogen bond propensity of ethyl acetate and due to its high molecular weight results in slow growth. These crystallisation studies with salicylamide in different solvents, supersaturations and temperatures have shown that crystal growth rates are affected significantly by the use of different environmental conditions.

Reference:

1. Lacmann, R., Crystallization, Third Edition. J. W. MULLIN, Butterworth-Heinemann, Oxford 1997, 527 Seiten, zahlr. Abb. und ISBN 0-7506-3759-5. Chemie Ingenieur Technik, 1998. 70(11): p. 1468-1468.
2. Nordstrom, F.L., M. Svard, and A.C. Rasmuson, Primary nucleation of salicylamide: the influence of process conditions and solvent on the metastable zone width. CrystEngComm, 2013. 15(36): p. 7285-7297.