In this work, the polymorphism of the active pharmaceutical ingredient carbamazepine (CBZ) was investigated by using molecular dynamics simulations with an enhanced sampling scheme. A single molecule of CBZ attaching to flat surfaces of different polymorphs was used as a model for secondary nucleation in water. A novel approach was developed to compute the free energy profile characterizing the adsorption of molecules with orientation aligned with the crystal structure of the surface. The distribution of states that showed alignment was used to rescale the adsorption free energy to include only the contribution that is consistent with crystal growth. The resulting free energy surfaces showed favorable thermodynamics for the most stable form, Form III and the second most stable form, Form I. The primary crystallization product, a dihydrate, was found to be less favorable, implying a nonclassical crystallization pathway. We suggest that a major contribution determining the energetics is the hydrophobicity of the surface. This thermodynamic ranking provides valuable information about the molecular pathways of polymorph growth and will further contribute to the understanding of the crystallization process of CBZ, which is imperative since polymorph formation can alter the physical properties of a drug significantly.

The solubility of molecular crystals is of interest in many areas of chemistry, of which pharmaceutical applications are of particular importance. Predicting solubility using atomistic first-principle methods, that compare the chemical potential of the solid and the solvated phase, has become more common, but remains challenging due to the difficulty in modeling both the crystal form, including its polymorphs, and the interactions with the solvent. Here we aim to compute the solubilities of three active pharmaceutical ingredients of increasing size and complexity: paracetamol, carbamazepine and indomethacin. The known anhydrous polymorphs of each compound are considered in the calculation of the free energy of the solid form and the solvation is explored both in water and in some organic solvents (ethanol, methanol and acetonitrile). The compounds are categorized as poorly soluble or well-soluble based on the comparison of the solid form free energy and the solvation free energy of a single molecule at infinite dilution. Poor solubility then prompts the use of a solubility estimation based on excess free energies, while for well-soluble molecules their chemical potential has to be calculated as a function of concentration. This is done using the recently developed S⁰ method. While promising results are obtained for paracetamol, carbamazepine and indomethacin predictions systematically underestimate the solubility. This can be ascribed to incomplete descriptions of intermolecular interactions by the force field, but the order of stability of the solid forms and systematic nature of the deviations point toward additional problems originating in the accuracy of the method used to calculate the solid free energies.

Solution-mediated polymorphic transitions of active pharmaceutical ingredients are of particular interest to the optimization of the drug manufacturing process since the exposure of raw crystal material to solvent is a common occurrence. This paper explores the transition of the metastable form II of carbamazepine to its stable form III in ethanol, 2-propanol, acetonitrile and nitromethane by means of molecular dynamics. Simulations of saturated solutions of carbamazepine at different supersaturation ratios revealed strong interactions between the alcohols and the solute, while carbamazepine molecules interacted more with each other in acetonitrile and nitromethane. A dimer aggregate that could serve as a precursor for the stable form III could be seen in all solvents. Slabs of the 001, 010 and 100 faces of form II in the solvents showed some dissolution at lower supersaturation, while very high concentrations stabilized the interfaces in most solvents. When placed in a severely undersaturated solvent, dissolution occurred preferentially at the 001 surface in all solvents except 2-propanol.Based on the combined results the transformation is confirmed to be dissolution-controlled in 2-propanol, while in ethanol, acetonitrile and nitromethane, the transformation is likely dominated by both the nucleation and crystal growth of the stable form III. On the basis of the solvent properties it is suggested that a potential stabilizing additive should show strong hydrogen bonding at the 001 surface, but interact with the 010 and 100 surfaces via non-polar parts.

The transformation of the stable form III of carbamazepine to its metastable form IV has been observed in mechanochemical processes under a range of different conditions, of which several highlight the role of amorphization in the process. This paper models the effect of shear stress on three different facets of form III, which are first roughened up and, subsequently, collided at two different nominal velocities. From this, three configurations at different pressures are extracted and sheared against each other at different shearing velocities. The loss of crystallinity can be seen both visually in the increased amorphous material generated in the middle of the slabs, and using a collective variable that depends on the relative orientations of the molecules to each other. The latter is also used to assess separately the effect of the shearing on the hydrogen bonded network and the non-polar interactions. The 010 surface showed the largest ’ripple effect’ in amorphization with both types of interactions affected equally. On the other hand the 100 surface suffered a loss of hydrogen bonding and the 001 surface decreased in aromatic, non-polar interactions. It is speculated that the preserved orientation of the aromatic parts of the molecule can facilitate the nucleation of the stable form III, which shows the same orientations in its aromatic system. However, it is more likely that the main effect of shear stress is increased amorphization on all facets.