Study of the effect of solvent on the morphology of crystals using molecular simulation : Application to a-resorcinol and ~-n-octy~-~-g~uconam~de Sohrab Kboshkhoot and Jamshed Anwar* Computational Pharmaceutical Sciences, Department of Pharmacy, King 's College London, Manresa Road, London, UK SW3 6LX The interaction of water as a solvent on selected faces of crystals of N-n-octyl-D-gluconamide and a-resorcinol has been examined using the Monte Carlo molecular simulation technique. The interaction energies for N-n-octyl-~-gluconarnide are in good agree- ment with the experimentally observed contact angles, and indicate that a favourable interaction between the solvent and a crystal face is consistent with observed slow growth. For a-resorcinol, the interaction energies for the two faces studied are similar even though one of the faces is known to grow considerably faster in water than the other. Examination of the structural features revealed that at the (01 1) interface (the slow-growing face) the water is incorporated into pocket-like grooves. This suggests that the low growth rate of the (011) face is due to the strong and specific interactions of water at these pockets rather than a general nun-specific interaction. These simulations indicate that in predicting the effect of solvent on the morphology, one needs to consider not only the non-specific interaction of the soIvent with the face but also any possible specific interactions. The morphology of crystals is important in the phar- maceutical and chemical industries. It can influence the ease of syringing suspensions, the compressibility and tablet-making behaviour of crystals,' the ease of product separation (filtration of crystallising solutions), material h a n d h g (i.e. flow properties through machinery), and product stability2 and quality.' The ability to be able to control and engineer the morphology of crystals is therefore highly desirable. When crystals are obtained by crystallisation from solution, the choice of solvent is an important parameter that can influence the morphology of the crystals. It is generally accepted that the solvent exerts its effect by preferential adsorption onto the growing crystal surfaces and retards the deposition of the solute m01ecuIes.~-~ Crystal faces whose rate of growth is retarded become morphologically important whilst those that are growing relatively faster show a decrease in importance. An alternative and somewhat contradictory hypothesis is the surface roughness theory. In this case it is considered that a favourable interaction between a solvent and a crystal face results in the reduction of interfacial tension and the conver- sion of the face from a smooth to a roughened surface. This causes the affected face to grow faster and become less mor- phologically Polar crystals are ideal for studying the effects of solvent on crystal morphology. For these crystals the variation in the rate of growth of two opposite faces that lie along the same polar direction is considered to result primarily from their interaction with the solvent. The polar crystals N-n-octyl- D-ghconamide, CH3(CH,)8NHCO(CHOH),CH,0H and a- resorcinol, C6H4(OH)2 , are both well characterised, and have been the subject of studies designed to elucidate the effect of solvent on crystal morphology.'-'* For both of these crystals, the growth of certain faces is highly influenced by the solvent. The (010) face of N-n-octyl-D-gluconamide when exposed to polar solvents (s.9. methanol) grows about five times slower than the (010) face under the same conditions.'* Crystals of a-resorcinol grow unidirectionally along the polar c axis in aqueous solutions with growth occurring primarily along the t Present Address: Department of Pharmaceutics, School of Phar- macy, Tehran University of Medical Sciences, Tehran, Iran. {On] face." It has been proposed that the preferred direction of growth results from the relativeIy stronger adsorption of solvent at the opposite face. Whilst the growth kinetics of N-n-octyl-D-ghconamide in a polar solvent fully support this hypothesis in that the slowest growing face is indeed the more hydrophilic, the case for a-resorcinol is not so clear cut. The surface interactions of crystalline a-resorcinol with water have been studied using potential-energy calculations.' The study involved the calculation of the van der Waak surface area, the binding energy of a single water molecule at various sites, and the generation of a surface potential map for the two crystal faces. This data, however, did not yield the required interfacial energy between the solvent and crystal, but rather enabled one to assess the polarity of the face and then to make some assessment as to the average interaction of the face with water. In view of this, the conclusions were not definite. Potential-energy calculations using the atom-atom poten- tial method5.' have been successful in predicting crystal mor- phology. The results have been particularly impressive for crystals obtained from the vapour phaseI4 and for predicting the effect of tailor-made additives present in so1ution.l5 Pre- dictions of the effect of solvent have been only partially suc- cessful." In general these studies have employed static potential-energy calculations. Such calculations cannot deal adequately with a solvent. It is necessary to consider all pos- sibIe orientations and positions of the solvent moIecules and then average the interaction energy in an appropriate manner. More recently, molecular dynamics simulations of the crystal/ water interface have been carried out,16-18 but these simula- tions focussed only on the structural features and did not yield the interaction energies for the specific faces studied. In these investigations, two different crystaI faces were exposed to the solvent at the same time and the computer programs utilised probably lacked the facility to keep separate accounts for the interfacial energies. Clearly, a better understanding of the molecular inter- actions and the energetics characterising the solvent/crystal interface could provide important insights. To this end, we have carried out molecular simulations of the interface using the Metropolis Monte Carlo technique." The interaction of water as a solvent on seIected faces of crystals of N-n-octyl-D- gluconamide and a-resorcinol has been examined. The results J. Chem. SOC., Faraday Trans., 1995,92(6), 1023-1025 1023