This study demonstrates the effect of active pharmaceutical ingredient (API) particle habit on the sticking propensity of ibuprofen. Four diverse crystal habits with similar physico chemical properties are reported and the sticking propensity was found to increase with shape regularity. The surface energy of the extreme habits were shown to be different where particles that were more regular in shape exhibited surface energies of 9mJ/m2 higher than those that were needle-like in habit. Computational and experimental data reveals that the increase in surface energy of the regular shaped particles can be attributed to the increase in the specific (polar) component, which is due to greater presence of faces which contain the carboxylic acid functionality at the surface. The increase in the specific energy component is shown to correlate with the sticking propensity of ibuprofen. It is proposed that investigation of the chemical causality of sticking, for this API and others, using the techniques demonstrated in this paper will be of increasing importance.

The lattice energy and crystal morphologies of the α and β forms of p-aminobenzoic acid are correlated to experimentally grown crystals by calculating their strength, directionality and chemical state of their bulk (intrinsic) and surface (extrinsic) synthons.

The crystal morphology of adipic acid (AA) and its mediation by the action of the homologous additives, caproic acid, glutaric acid, and succinic acid, has been investigated via computational molecular modeling-based simulation techniques (Clydesdale, G.; Docherty, R.; Roberts, K. J. HABIT95, Quantum Chemistry Program Exchange (QCPE), Bloomington, IN 17405, Program Number 670, 1996). With the aid of intermolecular and interatomic energetic analyses, the experimental effect of these impurities has been rationalized. The predicted morphologies are in good agreement with sublimation-grown experimental data. This is not so for solution growth data, reflecting the possible adsorption of water molecules onto exposed carboxylic acid groups via hydrogen bonding on the {100} faces, thus allowing this form to become dominant. Modeling the adsorption of the additives reveals preferential adsorption onto the {30(2) over bar} faces, consistent with good additive/host templating at the growth interface, as demonstrated experimentally. Intermolecular bonding interactions examined those that disappeared in the presence of the additives. It was shown that impurity incorporation disrupted the hydrogen-bonding network within the system, due to an increase in interaction distances and in atom-atom repulsions. Despite its industrial significance, this is the first detailed study of the intermolecular interactions involved in impurity incorporation within adipic acid crystallization, and so any conclusions concerning the effect of impurities within the crystallizing mixture will be most useful.

Using computational chemistry techniques, the structures of flavanthrone (1) and indanthrone (2) have been re-examined. The similarity in the packing motifs of indanthrone and flavanthrone has been studied and the important intermolecular interactions have been determined. The role of weak hydrogen bonds of the type C–HO in the formation of the three dimensional structures have been clarified.

Crystal packing calculations have been carried out on a number of commercially important organic pigments in an attempt to determine the important interactions and structural features holding pigment molecules together in selected arrangements in the solid state. The high performance pigments were found to be those with the most efficient packing and with the highest lattice energies. The most important intermolecular interactions identified were π–π stacking forces, traditional hydrogen bonds and weak hydrogen bonds.

When determining crystal structures of organic molecular materials from high-resolution powder diffraction data, the key step is the generation of reliable trial structures fur final refinement. The subject of the study reported here is the pharmaceutical material anhydrous theophylline (3,7-dihydro-1,3-dimethyl- 1H-purine-2,6-dione), which contains both oxygen and nitrogen as possible hydrogen bond acceptor atoms. A systematic search of direct space was employed to assess every possible packing arrangement of the asymmetric unit within the experimentally determined unit cell. Trial structures were ranked in terms of calculated lattice energy and weighted residuals from a comparison of calculated and experimental X-ray diffraction profiles. The systematic search found two packing arrangements with different intermolecular hydrogen-bonding motifs within the same unit cell. In one, denoted NH. . . N, the amino hydrogen is hydrogen bonded to the aldimine nitrogen, and in the other, denoted (NHO)-O-. . ., to the carbonyl oxygen neighboring the imidazole ring. These trial structures were "virtually indistinguishable" in terms of calculated lattice energy or X-ray profile fit. Solid-state NMR spectra of a commercial sample not only confirmed immediately that there was only one molecule in the crystallographic asymmetric unit but also produced distinctive C-13 and N-15 chemical shifts. The experimentally determined N-15 chemical shifts showed considerably better agreement with values from ab initio calculations for the trial crystal structure with N--H N hydrogen bonding. In these calculations, representative chains of three hydrogen-bonded molecules were employed as models for the (NHN)-N-. . . and (NHO)-O-. . . trial crystal structures. In addition, a more sophisticated analysis of the lattice energy hypersurfaccs. using a distributed multipole based intermolecular potential, indicated that the N-(HN)-N-. . . trial structure is the more stable. It was noted that the NH N packing motif identified by our studies is observed in a single-crystal determination for theophylline reported independently while our investigations were ongoing. Our study shows how the potential for polymorphism in a "given unit cell'' may be assessed successfully by combining several complementary experimental and theoretical approaches.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

An overview of recent work directed to the crystallographic structure solution of organic solids using a combination of X-ray powder diffraction and a grid-based direct space search for trial structures is presented. A number of study cases illustrate the application and potential of this approach. Additionally, the inherent limitations of powder diffraction as an isolated tool for structure determination are discussed together with an outline of ways to address these limitations in the future.

The crystal chemistry and torsional profiles of three polymorphic diarylamines have been compared and contrasted. Although they have similar potential energy surfaces (PESs) for the main rotatable bond, the torsional distribution of the observed polymorphs differs greatly. In particular there are reported crystal structures for some but not all of the molecules at various positions on the PES, some of which are either maxima or non-stationary points on the gas phase surface. We have explained the distribution of the observed torsion values and postulated new packing motifs based on those found in the other molecules. According to lattice energy calculations, some of these 'new polymorphs' are predicted to be more stable than those reported in the literature.

The materials phenazine and perylene have been previously reported to exhibit polymorphic behavior. Experimental evidence suggests that both molecules can exist in at least two polymorphic forms. In the case of phenazine. only one polymorph has a fully described crystal structure. In the case of perylene, two polymorphs have a reported structure, from single-crystal studies; however, one structure solution is of poor quality. This paper reports the results of a molecular modeling study and postulates crystal structures for the two polymorphs which lack a reliable experimental determination. Systematic searches of potential packing arrangements were conducted in the reported cells for both the solved and unsolved polymorphs of phenazine and perylene. A recently validated search method (Hammond, R. B.; Roberts, K. J.; Docherty, R.; Edmondson, M. J. Phys. Chem. B 1997, 101, 6532) was employed to rank packing arrangements by considering nonbonded atom-atom distances in combination with calculated lattice energies. The molecular packing arrangements were compared and contrasted using the packing energy breakdown routines within the program HABIT95 (Clydesdale, G.; Roberts, K. J.; Docherty, R. Quantum Chemistry Program Exchange 1996, 16, 1).

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.

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

Computational chemistry is playing an increasingly important role in the study of molecular materials in general and Charge Generation Materials in particular. In this paper the basic theory behind lattice energy calculations is described along with the application of such procedures to crystal structure refinement in the case of oxotitanium phthalocyanines. The application of various computational tools to aid in structure solution from high resolution X-ray powder diffraction data is demonstrated for the X-form of metal free phthalocyanine. The potential for ab-initio prediction of crystal structures and potential polymorphs prior to synthesis and development is highlighted.

o-Acetamidobenzamide crystallises in two polymorphs designated alpha and beta. In the alpha-polymorph an intramolecular hydrogen bond is present, which is not found in the conformation adopted in the beta-polymorph. The geometries of the molecules found in the crystal structures have been studied in detail using molecular mechanics, semi empirical and ab initio quantum chemistry techniques. Conformational energy differences have been evaluated, and gas phase potential energy surfaces generated to explore the conformational freedom of o-acetamidobenzamide.It has been found that both observed solid state conformations occur close to, but not actually at, minima on the calculated gas phase potential energy surfaces. Conformational energy differences of 8-10 kcal mol(-1) have been found between the conformers found in the crystals, depending on the method used for the calculation. Based on lattice energy calculations for both polymorphs it would appear that the less stable conformation is not compensated for by an equivalent stabilisation of the crystal lattice. The total (intra-and inter-molecular) energy difference between polymorphs is greater than that conventionally accepted.The difficulties of using theoretical tools in conformational studies and the implications of our findings for ab initio crystal structure prediction are discussed.

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.

The in vitro and in vivo pharmacology of SDZ NKT 343 (2‐nitrophenyl‐carbamoyl‐(S)‐prolyl‐(S)‐3‐(2‐naphthyl)alanyl‐N‐benzyl‐N‐methylamide), a novel tachykinin NK1 receptor antagonist was investigated. SDZ NKT 343 inhibited [3H]‐substance P binding to the human NK1 receptor in transfected Cos‐7 cell membranes (IC50=0.62±0.11 nM). In comparison, in the same assay Ki values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13±0.04 nM, 0.96±0.20 nM, 0.15±0.06 nM and 1.77±0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50=451±139 nM). SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]‐substance P, suggesting a non‐competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone‐induced contraction of the guinea‐pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible. SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfected Cos‐7 cells (Ki of 0.52±0.04 μM and 3.4±1.2 μM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage‐activated Ca2+ and Na+currents in guinea‐pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)‐SDZ NKT 343 was about 1000 times less active at human NK1 receptors expressed in Cos‐7 cell membranes. Contractions of the guinea‐pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration‐dependent manner, with an IC50=1.60±0.94 nM, while the enantiomer (R,R)‐SDZ NKT 343 was 100 times less active (IC50=162±26 nM). In comparison, in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90±07 nM, 0.14±0.02 nM, 11.4±2.9 nM and 2.4±0.83 nM, respectively. In anaesthetized guinea‐pigs i.v. administered SDZ NKT 343 antagonized [Sar9]SP sulphone‐evoked bronchoconstriction (70% reduction at 0.4 mg kg−1, i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected. In conclusion, SDZ NKT 343 is a highly selective NK1 receptor antagonist with high potency at the human and guinea‐pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK1 receptor hyperfunction is involved.

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. (C) 1998 John Wiley & Sons, Inc.

3,5-Dinitro-4-methylbenzoic acid functions as a host accommodating guest molecules in cavities created due to the coupling of six neighbouring molecules through hydrogen bonding. 2,6-Dimethylnaphthalene is encapsulated within the cavity unlike naphthalene. It is thought that the latter is not able to effectively fill the cavity.

X-H...pi (phenyl) is the interaction of a hydrogen atom with the Pi-system of an aromatic ring in either an intermolecular or an intramolecular fashion. Although the existence of these types of interaction has gained recent attention in the literature, the geometry is poorly understood. This paper attempts to investigate the preferred geometry and interaction strength for O-H, N-H, N-H+, S-H, sp(2) C-H and sp(1) C-H interactions with phenyl rings. This has been done through searches of the Cambridge Structural Database, combined with semi-empirical and ab initio molecular orbital calculations. It is found that the classical image of T-shaped geometry is rarely adopted and that the preferred geometry involves direct interaction of X-H with the carbon atoms of the phenyl ring. The binding energy associated with the interaction decreases with the electronegativity of the donor atom X.