Ronald John Roberts

Crystal chemistry and solvent effects in polymorphic systems: Sulfathiazole

Sulfathiazole, a compound that forms four known crystal structures, has been examined with a view to understanding its polymorphism. A graph set approach was used to classify the structural differences and similarities of the polymorphs, the results of which indicated packing motifs common to three of the four structures. By combining this analysis with experimental morphological data, it has been possible to examine the origins of the observed solvent dependence of polymorph appearance in this system. In particular, the possible link between the observed hydrogen-bond motifs of each form and the associated processes of nucleation and crystal growth from n-propanol, nitromethane, ethanol, water and ammonia solution, have been considered.

Disappearing polymorphs and the role of reaction by-products: the case of sulphathiazole

Abstract A combined modelling and experimental strategy has been applied to the problem of reaction by-product influence on the appearance of sulphathaizole polymorphs from aqueous solution. From pure aqueous solution after 24 h the most stable phase, form IV was isolated. This work shows for the first time that a reaction by-product, ethamidosulphathiazole, from the final hydrolysis stage at concentrations as low as 1 mol.% stabilises the metastable modification, form I. In the presence of 1.0–0.5 mol.% forms II and III are stabilised. Only at concentration below 0.5 mol.% does the transformation proceed to form IV as in the pure solution. The role of the impurity was accounted for from an analysis of the respective hydrogen bond networks and crystal morphologies of each phase.

Examples of successful crystal structure prediction: polymorphs of primidone and progesterone.

The field of crystal structure prediction and its potential value to the pharmaceutical industry is described. The process of structure prediction employed here is summarized and the results of its application to primidone and progesterone are reported. It is shown that the process successfully generates the known polymorphs of these molecules, starting from the molecular structure alone. Observations related to the application of the structure prediction process are reported.

Potential polymorphs of aspirin

Aspirin is only found experimentally in one crystal structure. In this article, the method of Karfunkel and Gdanitz is used to predict potential polymorphs of aspirin. The known structure, containing a nonplanar conformer is found, along with a number of other low energy structures, many of which are based on a planar conformer. Semiempirical and ab initio calculations show that the planar conformer is less stable than the experimentally known one. Force field calculations suggest that the planar conformer is more stable. The lattice energy of the experimentally known crystal structure is 1.4 kcal/mol lower than any of the potential crystal structures, even though there are a number of structures with lower total (lattice+intramolecular) energies. Conformational maps indicate that another stable conformation occurs within a few kilocalories per mole of the known structure. Polymorphs are predicted for this conformer, but it is found to pack poorly. It is proposed that routes to producing polymorphs of aspirin might be found if consideration is given to promoting the stability of the planar conformer with appropriate solvents or additives. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 262–273, 1999

The mechanical properties of two forms of primidone predicted from their crystal structures

Molecular modelling is used to predict the mechanical properties of aspirin and forms A and B of primidone. It is shown that the predictive method gives values which are in good agreement with the experimental ones. The method is therefore of great potential value to those interested in the compaction characteristics of pharmaceutically active compounds, as it obviates the need for measurements which can be difficult to make.

17 salts of ephedrine: crystal structures and packing analysis

The structures of two neutral and 17 salt forms of the base (1R, 2S)-(-)-ephedrine are reported. These structures are discussed in the light of the conformers of the ephedrine moiety, the existence of bilayers and the structure determining role of the counterions. Overall, most of the salt structures are essentially derived from the observed packing of the neutral base and are dominated by the amphiphilic nature of the ephedrine molecular structure. In a few cases the size and hydrophobicity of the counterion disrupts this behaviour.

Artificial intelligence in pharmaceutical product formulation: neural computing and emerging technologies

Abstract The pharmaceutical formulation process is highly specialized and requires specific domain knowledge and often years of experience. Neural computing, machine learning, knowledge-based systems and expert systems, derived from research into artificial intelligence, can assist in the efficient formulation of products and increase productivity, consistency and quality. The authors provide an introduction to the technology of neural computing and other emerging technologies.

Further errors in polymorph identification: furosemide and finasteride

Reassessment of the reported single-crystal X-ray diffraction characterization of polymorphs of furosemide and finasteride shows that, in each case, incomplete data collections have resulted in the mistaken identification of two forms that are, in fact, identical.

Generation of crystal structures of acetic acid and its halogenated analogs

The approach of Karfunkel and Gdanitz has been used to predict possible crystal structures of acetic acid and three of its monohalogenated analogs starting with the molecular structure alone. The results demonstrate that this approach is capable of finding many, if not all, of the possible packing arrangements of molecules of this size, but that it is not currently capable of correctly ranking these structures in terms of their enthalpy. This deficiency is probably due to inadequacies in the force field used to minimize the structures. The inadequacies relate to the description of acidic hydrogen bonds and halogen–halogen interactions. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1–20, 1998

Artificial intelligence in pharmaceutical product formulation: knowledge-based and expert systems

Abstract The pharmaceutical formulation process is a highly specialized task requiring specific domain knowledge and often years of experience. Knowledge-based systems, expert systems, neural computing and machine-learning derived from research into artificial intelligence can assist the efficient formulation of products and therefore increase productivity, consistency and quality. The authors provide an introduction to the technology of knowledge-based and expert systems.