Ian Rosbottom

The solid state, surface and morphological properties of p-aminobenzoic acid in terms of the strength and directionality of its intermolecular synthons

Empirical force-field calculations utilising the atom–atom method were used to examine the strength, directionality and chemical state of the intermolecular interactions (synthons) present in the polymorphic forms (α and β) of p-aminobenzoic acid (pABA). This is set within the context of predicting the morphology of both forms in terms of the unsatisfied synthons at each growth surface. The α lattice energy was calculated to be −24.54 kcal mol−1 with the dominant intermolecular interactions found to consist of OH⋯O carboxylic acid H-bonding dimers and head to head π–π stacking interactions. The β lattice energy was calculated to be −22.73 kcal mol−1 and the dominant interactions found to consist of a 4-membered H-bonding ring made up of two identical NH⋯O and OH⋯N interactions, plus strong head to tail π–π stacking interactions. The NH2 group was calculated to contribute more to the β lattice energy than to the α, as it acts as a H-bonding donor and acceptor in the β structure, whilst acting solely as a donor in α. Conversely, the COOH group was found to contribute more strongly to the α lattice energy due to the formation of the OH⋯O H-bonds and also NH⋯O H-bonds, while the COOH group in the β structure forms only weaker O⋯HN and OH⋯N interactions. Morphological prediction of the β form gave greater resemblance to the experimental morphology compared to α. Surface chemistry analysis revealed that the strength, character and directionality of the synthons present varies in terms of their anisotropy between these two polymorphs. The strength and character of the unsaturated synthons exposed at the major surfaces of the α crystal were found to significantly vary, which results in a needle-like morphology. In contrast, the strength and character of the synthons exposed at the major surfaces of the β morphology were found to be much more similar, which results in the more equant morphology. Overall, this paper presents a synthonic, analytical approach which holistically links the molecular properties with the bulk and surface synthons, and through this rationalises their contributions to the growth and morphology of this organic crystalline system.

Solvent and additive interactions as determinants in the nucleation pathway: general discussion

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole1 and found that it was relatively straightforward. Following your paper, we have reclassified the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures.

Crystallographic Structure, Intermolecular Packing Energetics, Crystal Morphology and Surface Chemistry of Salmeterol Xinafoate (Form I).

Single crystals of salmeterol xinafoate (form I), prepared from slow cooled supersaturated propan-2-ol solutions, crystallize in a triclinic P1¯ symmetry with 2 closely related independent salt pairs within the asymmetric unit, with an approximately double-unit cell volume compared with the previously published crystal structure. Synthonic analysis of the bulk intermolecular packing confirms the similarity in packing energetics between the 2 salt pairs. The strongest synthons, as expected, are dominated by coulombic interactions. Morphologic prediction reveals a plate-like morphology, dominated by the {001}, {010}, and {100} surfaces, consistent with experimentally grown crystals. Although surface chemistry of the slow-growing {001} face comprises large sterically hindering phenyl groups, although weaker coulombic interactions still prevail from the alcohol group present on the phenyl and hydroxymethyl groups. The surface chemistry of the faster growing {010} and {100} faces are dominated by the significantly stronger cation/anion interactions occurring between the carboxylate and protonated secondary ammonium ion groups. The importance of understanding the cohesive and adhesive nature of the crystal surfaces of an active pharmaceutical ingredient, with respect to their interaction with other active pharmaceutical ingredient crystals and how that may affect formulation design, is highlighted.

Crystal Growth and Morphology of Molecular Crystals

Organic molecular crystals are often the main active ingredient in pharmaceutical drug products. The crystal morphology of these materials plays a significant role in their ease of separation from the mother solution phase, physical behaviour during downstream unit processes and their dissolution profiles and delivery of the active ingredient to the patient. Molecular modelling can be used to predict crystal morphologies, in terms of the strengths of their internal intermolecular interactions and their external crystallisation environment, hence providing a guide to the experimental conditions required to produce a pre-defined crystal morphology.

The crystal morphology and growth kinetic mechanisms of para-aminobenzoic acid

The Crystal Morphology and Growth Kinetic Mechanisms of Para-AminoBenzoic Acid I. Rosbottom1, C.Y Ma1, R.A. O’Connell1, R. Docherty2, K.J. Roberts1 1. Centre for Digital Design of Drug Products, School of Chemical and Process Engineering, University of Leeds, LS2 9JT, UK 2. Pfizer Global Research & Development, Pharmaceutical R & D (i.p.c 612), Sandwich, Kent CT13 9NJ Needle-like crystal morphologies can cause problems during downstream unit processes assoicated with pharmaceutical and fine chemical product manufacture, due to their fragility under compaction, difficulties in filtering and tendency to block pipes. Tailoring a crystal morphology from solution requires an understanding of the molecular scale surface chemistry and the crystal growth kinetic mechanisms, forming the basis of the design of a solution environment. α-para amino benzoic acid (pABA) crystallises as a needle-like morphology from most organic solvents, such as ethanol, water and acetonitrile1. Here the bulk solid-state intermolecular interactions (intrinsic synthons) are discussed in terms of the α-pABA stability, and the surface terminated intermolecular interactions of the major (101), (10-1) and (01-1) surfaces2, in terms of their interaction with the surrounding solution and crystal morphology. The experimentally elucidated crystal growth kinetic mechanisms of the side (10-1) and capping (01-1) surfaces, in ethanol, are linked to the extrinsic synthons and crystal morphology observed3. The surface entropic α-factors are calculated to estimate the interfacial roughening of the individual faces in ethanol, and how this can affect the crystal growth kinetics. A model for the temporal evolution of a equilibrium crystal morphology of α-pABA at different supersaturation is presented, in terms of guiding the residence time for industrial batch crystallisation. Finally, the effect of addition of nitromethane to the ethanol solutions on the crystal morphology of α-pABA is presented. This demonstrates that through a careful choice of solvent, based on a molecular and kinetic understanding of the crystal surface can successfully modify a crystal morphology from solution.