Crystal structures of drugs: advances in determination, prediction and engineering

Vippagunta, S. R., Brittain, H. G. & Grant, D. J. W. Crystalline solids. Adv. Drug Deliv. Rev. 48, 3–26 (2001). Review of the structure and properties of crystalline pharmaceuticals.

Byrn, S. R., Pfeiffer, R. R. & Stowell, J. G. Solid State Chemistry of Drugs (SSCI, West Lafayette, 1999).

Hancock, B. C. & Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 86, 1–12 (1997).

Borka, L. & Haleblian, J. K. Crystal polymorphism of pharmaceuticals. Acta Pharm. Jugosl. 40, 71–94 (1990).

Haleblian, J. K. Characterization of habits and crystalline modification of solids and their pharmaceutical applications. J. Pharm. Sci. 64, 1269–1288 (1975).

Brittain, H. G. & Fiese, E. F. in Polymorphism in Pharmaceutical Solids (ed. Brittain, H. G.) 331–362 (Marcel Dekker, New York, 1999).

Phadnis, N. V. & Suryanarayanan, R. Polymorphism in anhydrous theophylline: implications on the dissolution rate of theophylline tablets. J. Pharm. Sci. 86, 1256–1263 (1997).

Otsuka, M. & Matsuda, Y. Effects of environmental temperature and compression energy on polymorphic transformation during tableting. Drug Dev. Ind. Pharm. 19, 2241–2269 (1993).

Otsuka, M., Hasegawa, H. & Matsuda, Y. Effect of polymorphic transformation during the extrusion-granulation process on the pharmaceutical properties of carbamazepine granules. Chem. Pharm. Bull. 45, 894–898 (1997).

Otsuka, M., Hasegawa, H. & Matsuda, Y. Effect of polymorphic forms of bulk powders on pharmaceutical properties of carbamazepine granules. Chem. Pharm. Bull. 47, 852–856 (1999).

Otsuka, M., Nakanishi, M. & Matsuda, Y. Effects of crystalline form on the tableting compression mechanism of phenobarbital polymorphs. Drug Dev. Ind. Pharm. 25, 205–215 (1999).

Otsuka, M., Ohtani, H., Otsuka, K. & Kaneniwa, N. Effect of humidity on solid-state isomerization of various kinds of lactose during grinding. J. Pharm. Pharmacol. 45, 2–5 (1993).

Wong, M. W. Y. & Mitchell, A. G. Physicochemical characterization of a phase change produced during the wet granulation of chlorpromazine hydrochloride and its effects on tableting. Int. J. Pharm. 88, 261–273 (1992).

Miyamae, A. et al. X-ray powder diffraction study on the grinding effect of the polymorphs of a novel and orally effective uricosuric agent: FR76505. Drug Dev. Ind. Pharm. 20, 2881–2897 (1994).

Chongprasert, S. et al. Effects of freeze-dry processing conditions on the crystallization of pentamidine isethionate. J. Pharm. Sci. 87, 1155–1160 (1998).

Morris, K. R., Griesser, U. J., Eckhardt, C. J. & Stowell, J. G. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv. Drug Deliv. Rev. 48, 91–114 (2001). Explains the importance of crystal structure in pharmaceutical processing.

Morris, K. R. et al. Advances in pharmaceutical materials and processing. Pharm. Sci. Technol. Today 1, 235–245 (1998).

Khankari, R. K. & Grant, D. J. W. Pharmaceutical hydrates. Thermochim. Acta 248, 61–79 (1995).

Grant, D. J. W. in Polymorphism in Pharmaceutical Solids (ed. Brittain, H. G.) 1–33 (Marcel Dekker, New York, 1999).

Ghosh, S., Ojala, W. H., Gleason, W. B. & Grant, D. J. W. Relationships between crystal structures, thermal properties and solvate stability of dialkylhydroxypyridones and their formic acid solvates. J. Pharm. Sci. 84, 1392–1399 (1995).

Ojala, W. H., Khankari, R. K., Grant, D. J. W. & Gleason, W. B. Crystal structures and physical chemical properties of nedocromil zinc heptahydrate and nedocromil magnesium pentahydrate. J. Chem. Crystallog. 26, 167–178 (1996).

Giordiano, F. et al. Physical properties of parabens and their mixtures: solubility in water, thermal behavior, and crystal structures. J. Pharm. Sci. 88, 1210–1216 (1999).

Zhu, H. J., Young, V. G. Jr & Grant, D. J. W. Crystal structure and thermal behavior of nedocromil nickel octahydrate. Int. J. Pharm. 232, 23–33 (2002).

Brittain, H. G. The impact of polymorphism on drug development: a regulatory viewpoint. Am. Pharm. Rev. 3, 67–68, 70 (2000). Explains the regulatory issues related to the polymorphism of pharmaceuticals.

Bernstein, J. Polymorphism in Molecular Crystals (Oxford Univ. Press, New York, 2002). Comprehensively summarizes the current knowledge and understanding of the polymorphism of molecular crystals.

Morris, K. R. in Polymorphism in Pharmaceutical Solids (ed. Brittain, H. G.) 125–181 (Marcel Dekker, New York, 1999).

Andreetti, G. D. Crystallographic studies of inclusion compounds. Inclusion Compounds 3, 129–146 (1984).

Lipkowski, J. in Crystallography of Supramolecular Compounds NATO Science Series C Vol. 480 (eds Tsoucaris, G. et al.) 265–283 (Kluwer Academic, Boston, 1996).

Brittain, H. G. & Grant D. J. W. in Polymorphism in Pharmaceutical Solids (ed. Brittain, H. G.) 279–330 (Marcel Dekker, New York, 1999).

Bechtloff, B., Nordhoff, S. & Ulrich, J. Pseudopolymorphs in industrial use. Cryst. Res. Technol. 36, 1315–1328 (2001). Explains the importance of pseudopolymorphs (solvates and hydrates) in the pharmaceutical industry.

Berge, S. M., Bighley, L. D. & Monkhouse, D. C. Pharmaceutical salts. J. Pharm. Sci. 66, 1–19 (1977).

Neau, S. H. in Water-Insoluble Drug Formations (ed. Liu, R.) 405–425 (Interpharm, Buffalo Grove, 2000).

Puddipeddi, M., Serajuddin, A. T. M., Grant, D. J. W. & Stahl, P. H. in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (eds Stahl, P. H. & Wermuth, C. G.) 19–38 (Wiley, Weinheim, 2002).

Giron, D. & Grant, D. J. W. in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (eds Stahl, P. H. & Wermuth, C. G.) 41–81 (Wiley, Weinheim, 2002). Explains the importance of salt forms of pharmaceuticals in the stabilization and processing of pharmaceutical formulations.

Stahl, P. H. & Byrn, S. R. in Molecular Modeling Applications in Crystallization (ed. Myerson, A. S.) 313–345 (Cambridge Univ. Press, New York, 1999).

Shah, R. D. & Nafie, L. A. Spectroscopic methods for determining enantiomeric purity and absolute configuration in chiral pharmaceutical molecules. Curr. Opin. Drug Discov. Devel. 4, 764–775 (2001).

van Eikeren, P. Commercial manufacture of chiral pharmaceuticals. Chiral Separations 9–35 (1997).

Gu, C. H. & Grant, D. J. W. in Handbook of Experimental Pharmacology: Stereochemical Aspects of Drug Action and Disposition Vol. 153 (eds Eichelbaum M., Testa, B. & Somogyi, A.) 113–137 (Springer, Berlin, 2003). Explains the structural basis of the solid-state properties of chiral pharmaceuticals.

Li, Z. J. & Grant, D. J. W. Relationship between physical properties and crystal structures of chiral drugs. J. Pharm. Sci. 86, 1073–1078 (1997).

Abgada, C. O. & York, P. Dehydration of theophylline monohydrate powder: effects of particle size and sample weight. Int. J. Pharm. 106, 33–40 (1994).

Sun, C. & Grant, D. J. W. Improved tableting properties of p-hydroxybenzoic acid by water of crystallization — a molecular insight. Pharm. Res. (in the press).

Bandopadhyay, R. & Grant, D. J. W. Plasticity and slip system of plate-shaped crystals of L-lysine monohydrochloride dihydrate. Pharm. Res. 19, 491–496 (2002).

Sun, C. & Grant, D. J. W. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm. Res., 18, 274–280 (2001).

Cullity, B. D. Elements of X-ray Diffraction 3rd edn (Prentice Hall, New Jersey, 2001). Provides an excellent introduction to crystal structures and X-ray crystallography.

Buerger, M. J. Elementary Crystallography 253–273 (Wiley Interscience, New York, 1963).

Zorky, P. M. Symmetry, pseudosymmetry and hypersymmetry of organic crystals. J. Mol. Struct. 374, 9–28 (1996).

Cambridge Crystallographic Data Centre, Cambridge Structural Database, University Chemical Laboratory, Cambridge, UK (1999). This databank includes more than 250,000 crystal structures and is a site reference for crystal structure reports.

Perlstein, J. in Crystal Engineering: from Molecules and Crystals to Materials NATO Science Series C Vol. 538 (eds Braga, D., Grepini, F. & Orpen, G. A.) 23–42 (Kluwer Academic, Boston, 1999).

Buckingham, A. D. in Crystal Engineering: the Design and Application of Functional Solids NATO Science Series C Vol. 539 (eds Seddon, K. R. & Zaworotko, M.) 49–68 (Kluwer Academic, Boston, 1999).

Pimental, G. C. & McClennan, A. L. The Hydrogen Bond (W. H. Freeman, San Francisco, 1960).

Scheiner, S. Hydrogen Bonding: A Theoretical Perspective (Oxford Univ. Press, Oxford, 1997).

Desiraju, G. R. Hydrogen bridges in crystal engineering: interactions without borders. Acc. Chem. Res. 35, 565–573 (2002).

Jeffrey, G. A. An Introduction to Hydrogen Bonding (Oxford Univ. Press, New York, 1997).

Desiraju, G. R. & Steiner, T. The Weak Hydrogen Bond in Structural Chemistry and Biology (IUCr Monographs on Crystallography 9) 15–47 (Oxford Univ. Press, New York, 1999).

Beyer, A., Karpfen, A. & Schuster, P. Energy surfaces of hydrogen complexes in the vapour phase. Topics Curr. Chem. 120, 1–40 (1984).

Perlstein, J. Molecular self-assemblies 4. Using Kitaigorodskii's Aufbau principle for quantitatively predicting the packing geometry of semiflexible organic molecules in translation monolayer aggregates. J. Am. Chem. Soc. 116, 11420–11432 (1994).

Smith, E. R. Electrostatic energy in ionic crystals. Proc. R. Soc. Lond. A 375, 475–505 (1981).

Haleblian, J. K. & McCrone, W. C. Pharmaceutical applications of polymorphism. J. Pharm. Sci. 58, 911–929 (1969).

Burger, A. & Ramberger, R. On the polymorphism of pharmaceuticals and other molecular crystals. I. Theory of thermodynamic rules. Mikrochim. Acta II, 259–271 (1979).

Burger, A. & Ramberger, R. On the polymorphism of pharmaceuticals and other molecular crystals. II. Applicability of thermodynamic rules. Mikrochim. Acta II, 273–316 (1979).

Henck, J. O. & Kuhnert-Brandstatter, M. Demonstration of the terms enantiotropy and monotropy in polymorphism research exemplified by flurbiprofen. J. Pharm. Sci. 88, 103–108 (1999).

Yu, L., Reutzel, S. M. & Stephenson, G. A. Physical characterization of polymorphic drugs: an integrated characterization strategy. Pharm. Sci. Technol. Today 1, 118–127 (1998).

Grunenberg, A., Henck, J. O. & Siesler, H. W. Theoretical derivation and practical application of energy/temperature diagrams as an instrument in preformulation studies of polymorphic drug substances. Int. J. Pharm. 129, 147–158 (1996).

Yu, L. Inferring thermodynamic stability relationship of polymorphs from melting data. J. Pharm. Sci. 84, 966–974 (1995).

Gu, C. H., Young, V. Jr & Grant, D. J. W. Polymorph screening: influence of solvents on the rate of solvent-mediated polymorphic transformation. J. Pharm. Sci. 90, 1878–1890 (2001).

Toscani, S. An up-to-date approach to drug polymorphism. Thermochim. Acta 321, 73–79 (1998).

Stahl, P. H. in Towards Better Safety of Drugs and Pharmaceutical Products (ed. Braimer, D. D.) 265–280 (Elsevier/North-Holland Biomedical, Amsterdam, 1980).

Giron, D. et al. Solid state characterizations of pharmaceutical hydrates. J. Thermal Anal. Cal. 68, 453–465 (2002).

Morris, K. & Rodriguez-Hornedo, N. in Encyclopaedia of Pharmaceutical Technology Vol. 7 (eds Swarbrick, J. & Boylan, J. C.) 393–440 (Marcel Dekker, New York, 1993).

Florey, K. in Analytical Profiles of Drug Substances Vol. 2 (ed. Florey, K.) 1–62 (Academic, New York, 1973).

Sugawara, Y., Kamiya, N., Iwasaki, H., Ito, T. & Satow, Y. Humidity controlled reversible structure transition of disodium adenosine 5'-triphosphate between dihydrate and trihydrate in a single crystal state. J. Am. Chem. Soc. 113, 5440–5445 (1991).

Sun, C., Zhou, D., Grant, D. J. W. & Young, V. G. Jr. Theophylline monohydrate. Acta Cryst. E 58, O368–O370 (2002).

Cox, J. S. G., Woodgard, G. D. & McCrone, W. C. Solid state chemistry of cromolyn sodium (disodium cromoglycate). J. Pharm. Sci. 60, 1458–1465 (1971).

Stephenson, G. A. & Diseroad, B. A. Structural relationship and desolvation behaviour of cromolyn cefazolin and fenoprofen sodium hydrates. Int. J. Pharm. 198, 167–177 (2000).

Chen, L. R., Young, V. G., Lechuga-Ballesteros, D. & Grant, D. J. W. Solid state behavior of cromolyn sodium hydrates. J. Pharm. Sci. 88, 1191–1200 (1999).

Zhu, J., Padden, B. E., Munson, E. J. & Grant, D. J. W. Physicochemical characterization of nedocromil bivalent metal salt hydrates. 2. Nedocromil zinc. J. Pharm. Sci. 86, 418–428 (1997).

Khankari, R. K., Ojala, W. H., Gleason, W. B. & Grant, D. J. W. Crystal structure of nedocromil sodium heptahemihydrate and its comparison with that of nedocromil sodium trihydrate. J. Chem. Crystallogr. 25, 859–866 (1995).

Ahlqvist, M. U. A. & Taylor, L. S. Water dynamics in channel hydrates investigated using H/D exchange. Int. J. Pharm. 241, 253–261 (2002).

Li, Z. J. & Grant, D. J. W. Relationship between physical properties and crystal structures of chiral drugs. J. Pharm. Sci. 86, 1073–1078 (1997).

Reddy, I. K., Kommuru, T. R., Zaghloul, A. A. & Khan, M. A. Chirality and its implications in transdermal drug development. Crit. Rev. Ther. Drug Carrier Syst. 17, 285–325 (2000).

Collet, A. & Vigne-Maeder, F. Increase of the occurrence of spontaneous resolution due to the crystallization of racemates under high pressure. New J. Chem. 19, 877–880 (1995).

Jacques, J., Collet, A. & Wilen, S. H. Enantiomers, Racemates, and Resolutions 3–213 (John Wiley & Sons, New York, 1981).

Burger, A., Rollinger, J. M. & Brueggeller, P. Binary system of (R)- and (S)-nitrendipine-polymorphism and structure. J. Pharm. Sci. 86, 674–679 (1997).

Kuhnert-Brandstaetter, M. & Ulmer, R. Contribution to the thermal analysis of optical antipodes-mandelic acid. Mikrochim. Acta 5, 927–935 (1974).

Langhammer, L. Binary systems of enantiomeric nicotine derivatives. Arch. Pharm. 308, 933–939 (1975).

Zhang, G. G. Z., Paspal, S. Y. L., Suryanarayanan, R. & Grant, D. J. W. Racemic species of sodium ibuprofen: characterization and polymorphic relationships. J. Pharm. Sci. 92, 1356–1366 (2003).

Jacques, J. & Gabard, J. Optical antipode mixtures. III. Solubility diagrams for several types of racemates. Bull. Soc. Chim. Fr. 1, 342–350 (1972).

Flack, H. D. Chiral and achiral crystal structure. Helv. Chim. Acta 86, 907–921 (2003).

Bel'skii, V. K. & Zorkii, P. M. Distribution of organic homomolecular crystals by chiral types and structural classes. Acta Cryst. A33, 1004–1006 (1977).

Stout, G. H. & Jensen, L. H. X-Ray Structure Determination: A Practical Guide 2nd edn (John Wiley & Sons, New York, 1989).

Fagan, P. G., Hammond, R. B., Roberts, K. J., Docherty, R. & Edmondson, M. in Crystal Growth of Organic Materials Third International Workshop on Crystal Growth of Organic Materials Conference (eds Myerson, A., Green, D.A. & Meenan, P.) 22–27 (Oxford Univ. Press, New York, 1996).

Jones, P. G. Crystal growing. Chem. Br. 17, 222–225 (1981). Describes the common methods for growing single crystals.

Threlfall, T. L. Analysis of organic polymorphs, a review. Analyst 120, 2435–2460 (1995).

Guillory, J. K. in Polymorphism in Pharmaceutical Solids (ed. Brittain, H. G.) 183–226 (Marcel Dekker, New York, 1999).

Mullin, J. W. Crystallization 4th edn (Butterworth–Heinemann, Boston, 2001).

Mitchell, C. A., Yu, L. & Ward, M. D. Selective nucleation and discovery of organic polymorphs through epitaxy with single crystal substrate. J. Am. Chem. Soc. 123, 10830–10839 (2001).

Hilden, J. L. et al. Capillary precipitation of a highly polymorphic organic compound. Cryst. Growth Des. 3, 921–926 (2003).

Zaccaro, J., Matic, J., Myerson, A. S. & Garetz, B. A. Nonphotochemical, laser-induced nucleation of supersaturated aqueous glycine produces unexpected γ-polymorph. Cryst. Growth Des. 1, 5–8 (2001). References 96–98 describe newer methods of generating polymorphs: epitaxy, capillary crystallization and laser-induced nucleation.

Beckmann, W., Otto, W. & Budde, U. Crystallization of the stable polymorph of hydroxytriendione: seeding process and effects of purity. Org. Process Res. Dev. 5, 387–392 (2001).

Wang, B., Lu, Z. P., Shi, E. W. & Zhong, W. Z. Twinning morphologies and mechanisms of β-BaB2O4 (BBO) crystal grown by TSSG method. Cryst. Res. Technol. 33, 929–935 (1998).

Wadhawan, V. K. A tensor classification of twinning in crystals. Acta Cryst. A 53, 546–555 (1997).

von Laue, M. Eine quantitative prüfung der theorie für die interferenz-erscheinungen bei röntgenstrahlen. Sitz. Math. Phys. Klasse Bayer. Akad. Wiss. 363–373 (1912).

Bragg, W. L. Diffraction of short electromagnetic waves by a crystal. Proc. Cambridge Philos. Soc. 17, 43–57 (1913).

Giacovazzo, C. Fundamentals of Crystallography (Oxford Univ. Press, New York, 2002).

Hanh, T. International Table of Crystallography Vol. A 5th edn (Kluwer Academic, Dordrecht, 2002).

Sayre, D. in Computational Crystallography (ed. Sayre, D.) 65–140 (Claredon, Oxford, 1982).

Giacovazzo, C. in International Tables for Crystallography 2nd edn Vol. B (ed. Shmueli, U.) 210–234 (Kluwer Academic, Dordrecht, 2002).

Giacovazzo, C. Direct Phasing in Crystallography: Fundamentals and Applications (Oxford Univ. Press, Oxford, 1998). Explains the most common technique for solving crystal structures from single crystal X-ray diffraction patterns.

Kirkpatrick, S., Gelatt, C. D. & Vecchi, M. P. Optimization by simulated annealing. Science 220, 671–680 (1983). This seminal paper explains the value and the process of simulated annealing.

Catlow, C. R. A., Thomas, J. M., Freeman, C. M., Wright, P. A. & Bell, R. G. Simulating and predicting crystal structures. Proc. R. Soc. Lond. A 442, 85–96 (1993).

Bond, A. D. & Jones, W. Structure prediction as a tool for solution of the crystal structures of metallo-organic complexes using powder X-ray diffraction data. Acta Cryst. B 58, 233–243 (2002).

Gavezzotti, A. & Filippini, G. Polymorphic forms of organic crystals at room conditions: thermodynamic and structural implications. J. Am. Chem. Soc. 117, 12299–12305 (1995).

Lommerse, J. P. M. et al. A test of crystal structure prediction of small organic molecules. Acta Cryst. B 56, 697–714 (2000).

Giovannini, J., Perrin, M. A., Louer, D. & Leveiller, F. Ab initio crystal structure determination of three pharmaceutical compounds from X-ray powder diffraction data. Mater. Sci. Forum 2, 582–587 (2001).

Bond, A. D., Feeder, N., Teat, S. J. & Jones, W. The solid-state structure of 3-hydroxy-4-methyl-2(3H)-thiazolethione: prediction and measurement. Tetrahedron 56, 6617–6624 (2000).

Motherwell, W. D. S. et al. Crystal structure prediction of small molecules: a second blind test. Acta Cryst. B 58, 647–661 (2002). Describes the results from the most recent Cambridge Crystallographic Data Centre (CCDC) workshop for testing the feasibility of the various programs in predicting the crystal structure of three compounds from their individual molecular structures only.

Freeman, C. M. & Catlow, C. R. A. Structure predictions in inorganic solids. J. Chem. Soc. Chem. Comm. 2, 89–91 (1992).

Gdanitz, R. J. in Theoretical Aspects and Computer Modeling of the Molecular Solid State (ed. Gavezzotti, A.) 185–201 (Wiley, Chichester, 1997). Explains the ab initio method of crystal structure prediction.

Karfunkel, H. R. & Gdanitz, R. J. Ab initio prediction of possible crystal structures for general organic molecules. J. Comp. Chem. 13, 1171–1183 (1992).

Smith, E. D. L. et al. The determination of the crystal structure of anhydrous theophylline by X-ray powder diffraction with a systematic search algorithm, lattice energy calculations, and 13C and 15N solid-state NMR: a question of polymorphism in a given unit cell. J. Phys. Chem. B 105, 5818–5826 (2001).

Ko, G. H. & Fink, W. H. A combined quantum chemistry and classical molecular interaction energy method for the determination of crystal geometries and energies. J. Chem. Phys. 116, 747–754 (2002).

Gavezzotti, A. Organic crystals: engineering and design. Curr. Opin. Solid State Mater. Sci. 1, 501–505 (1996).

Buttar, D., Charlton, M. H., Docherty, R. & Starbuck, J. Theoretical investigations of conformational aspects of polymorphism. Part 1: o-acetamidobenzamide. J. Chem. Soc. Perkin Trans. I 2, 763–772 (1998).

Childs, S. L. Nonbonded Interactions in Molecular Crystal Structures (Emory Univ., Atlanta, 2001).

Filippini, G., Gavezzotti, A. & Novoa, J. J. Modelling the crystal structure of the 2-hydronitronylnitroxide radical (HNN): observed and computer-generated polymorphs. Acta Cryst. B 55, 543–553 (1999).

Gavezzotti, A. Methods and current trends in the simulation and prediction of organic crystal structures. Nova Acta Leopold. 79, 33–46 (1999).

Gao, D. W. & Donald, E. Molecular packing groups and ab initio crystal-structure prediction. Acta Cryst. A 55, 621–627 (1999).

Williams, D. E. I. in Crystal Engineering: From Molecules and Crystals to Materials NATO Science Series C Vol. 538 (eds Braga, D., Grepini, F. & Orpen, G. A.) 295–310 (Kluwer Academic, Boston, 1999).

Mooij, W. T. M., van Eijck, B. P. & Kroon, J. Ab initio crystal structure predictions for flexible hydrogen-bonded molecules. J. Am. Chem. Soc. 122, 3500–3505 (2000).

Allen, F. H., Kennard, O. & Taylor, R. Systematic analysis of structural data as a research technique in organic chemistry. Acc. Chem. Res. 16, 146–153 (1983).

Sarma, J. A. R. P. & Desiraju, G. R. The supramolecular synthon approach to crystal structure prediction. Cryst. Growth Des. 2, 93–100 (2002).

Mooij, W. T. M., van Eijck, B. P. & Kroon, J. Transferable ab initio intermolecular potentials. 2. Validation and application to crystal structure prediction. J. Phys. Chem. A 103, 9883–9890 (1999).

Leusen, F. J. J. Ab initio prediction of polymorphs. J. Cryst. Growth 166, 900–903 (1996).

Dong, Z. et al. Crystal structure of neotame anhydrate polymorph G. Pharm. Res. 19, 1549–1553 (2002).

Chin, D. N. Improving the efficiency of predicting hydrogen-bonded organic molecules. Trans. Am. Cryst. Assoc. 33, 33–43 (1999).

Gdanitz, R. J. Prediction of molecular crystal structures by Monte Carlo simulated annealing without reference to diffraction data. Chem. Phys. Lett. 190, 391–396 (1992). Explains the application of the Monte Carlo method in predicting crystal structures.

Hammond, R. B., Roberts, K. J., Docherty, R. & Edmondson, R. B. in Crystal Growth of Organic Materials International Workshop 4th edn (ed. Ulrich, J.) 53–60 (Shaker, Aachen, 1997).

Hammond, R. B. et al. Determining the crystal structures of organic solids using x-ray powder diffraction together with molecular and solid state modeling techniques. Molecular Crystals and Liquid Crystals Science and Technology A 356, 389–405 (2001).

Harris, K. D. M. & Tremayne, M. Crystals structure determination from powder diffraction data. Chem. Mater. 8, 2554–2570 (1996). Explains the prediction of the crystal structure of compounds from their powder diffraction data only.

Aakeroy, C. B., Beatty, A. M., Tremayne, M., Rowe, D. M. & Seaton, C. C. A combination of X-ray single crystal diffraction and Monte Carlo structure solution from X-ray powder diffraction data in a structural investigation of 5-bromonicotinic acid and solvates thereof. Cryst. Growth Des. 1, 377–382 (2001).

Will, G. POWLS: a powder least-squares program. J. Appl. Cryst. 12, 483–485 (1979).

Pawley, G. S. Unit-cell refinement from powder diffraction scans. J. Appl. Cryst. 14, 357–361 (1981).

Langford, J. I. & Louer, D. High-resolution powder diffraction studies of copper (II) oxide. J. Appl. Cryst. 24, 149–155 (1991).

Langford, J. I., Cernik, R. J. & Louer, D. The breadth and shape of instrumental line profiles in high-resolution powder diffraction. J. Appl. Cryst. 24, 912–918 (1991).

Will, G., Parrish, W. & Huang, T. C. Crystal-structure refinement by profile fitting and least-squares analysis of powder diffractometer data. J. Appl. Cryst. 16, 611–622 (1983).

Langford, J. I., Louer, D., Sonneveld, E. J. & Visser, J. W. Applications of total pattern fitting to a study of crystallite size and strain in zinc oxide powder. Powder Diffract. 1, 211–221 (1986).

David, W. I. F., Shankland, K. & Shankland, N. Routine determination of molecular crystal structures from powder diffraction data. Chem. Commun. (Camb.) 8, 931–932 (1998).

Shankland, K., David, W. I. F. & Csoka, T. Crystal structure determination from powder diffraction data by the application of a genetic algorithm. Zeit. fuer Kristall. 212, 550–552 (1997).

Harris, K. D. M., Johnston, R. L. & Kariuki, B. M. The genetic algorithm: foundations and applications in structure solution from powder diffraction data. Acta Cryst. A 54, 632–645 (1998). Explains the use of the genetic algorithm for predicting the crystal structure of compounds from their powder diffraction pattern.

Hammond, R. B., Roberts, K. J., Docherty, R. & Edmondson, M. Computationally assisted structure determination for molecular materials from X-ray powder diffraction data. J. Phys. Chem. B 101, 6532–6536 (1997).

Harris, K. D. M., Tremayne, M., Lightfoot, P. & Bruce, P. G. Crystal structure determination from powder diffraction data by Monte Carlo methods. J. Am. Chem. Soc. 116, 3543–3547 (1994).

Harris, K. D. M., Johnston, R. L., Kariuki, B. M. & Tremayne, M. A genetic algorithm for crystal structure solution from powder diffraction data. J. Chem. Res. Synop. 7, 390–391 (1998).

Harris, K. D. M. et al. Recent advances in opportunities for solving molecular crystal structures directly from powder diffraction data: new insights in crystal engineering contexts. Cryst. Eng. Comm. 4, 356–367 (2002).

Turner, G. W., Tedesco, E., Harris, K. D. M., Jonhston, R. L. & Kariuki, B. M. Implementation of Lamarckian concepts in a genetic algorithm for structure solution from powder diffraction data. Chem. Phys. Lett. 321, 183 (2000).

Habershon, S., Turner, G. W., Harris, K. D. M., Johnston, R. L. & Johnston, J. M. Gaining insights into the evolutionary behavior in genetic algorithm calculations, with applications in structure solution from powder diffraction data. Chem. Phys. Lett. 353, 185–194 (2002).

Lanning, O. J. et al. Definition of a 'guiding function' in global optimization: a hybrid approach combining energy and R-factor in structure solution from powder diffraction data. Chem. Phys. Lett. 317, 296–303 (2000).

Gilmore, C. Maximum entropy and Bayesian statistics in crystallography: a review of practical applications. Acta Cryst. A 52, 561–589 (1996). Explains the use of the maximum entropy algorithm for the prediction of the crystal structures of compounds and reviews its application.

Gilmore, C. J., Shankland, K. & Bricogne, G. Applications of the maximum entropy method to powder diffraction and electron crystallography. Proc. R. Soc. Lond. A 442, 97–111 (1993).

Presented at the fifteenth annual meeting of the National Science Teachers Association, 1966 in New York City, and reprinted from The Physics Teacher Vol. 7, issue 6, 1968, pp. 313–320 by permission of the editor and the author.

Braga, D., Desiraju, G. R., Miller, J. S., Guy Orpen, A. & Price, S. Innovation in crystal engineering. Cryst. Eng. Comm. 4, 500–509 (2002).

Pepinsky, R. Crystal engineering-new concept in crystallography. Phys. Rev. II 100, 971 (1955).

Schmidt, G. M. J. Photodimerization in solid state. Pure Appl. Chem. 647, 647–678 (1971).

Panunto, T. W., Lipkowska, Z. U., Johnson, R. & Etter, M. C. Hydrogen-bond formation in nitroanilines: the first step in designing acentric materials. J. Am. Chem. Soc. 109, 7786–7797 (1987).

Braga, D. & Fabrizia, G. in Crystal Engineering: From Molecules and Crystals to Materials (eds Braga, D., Grepioni, F. & Guy Orpen, A.) 421–441 (Kluwer Academic, Boston, 1999). Comprehensive work summarizing the recent achievements and future trends in crystal engineering.

Desiraju, G. R. Supramolecular synthons in crystal engineering — a new organic synthesis. Angew. Chem. Int. Edn Eng. 34, 2311–2327 (1995)

Walsh, B. R. D. et al. Crystal engineering of the composition of pharmaceutical phases. Chem. Commun. 2, 186–187 (2003).

Bis, J. A., Shattock, T. R. & Zaworotko, M. J. Design of binary crystals that contain pharmaceutical molecules, Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, United States, March 23–27 (2003).

McMahon, J. A. & Zaworotko, M. J. Crystal engineering of novel pharmaceutical phases, Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, United States, March 23–27 (2003).

Fleischman, S., Morales, L. A. & Zaworotko, M. J. Crystal engineering of binary crystals that contain pharmaceutical molecules, Abstracts of Papers, 223rd ACS National Meeting, Orlando, FL, United States, April 7–11 (2002).

Remenar, J. F. et al. Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids. J. Am. Chem. Soc. 125, 8456–8457 (2003).

Payne, R. S., Roberts, R. J. & Rowe, R. C. The mechanical properties of two forms of primidone predicted from their crystal structures. Int. J. Pharm. 145, 165–173 (1996).

Roberts, R. J., Payne, R. S. & Rowe, R. C. Mechanical property predictions for polymorphs of sulphathiazole and carbamazepine. Eur. J. Pharm. Sci. 9, 277–283 (2000).

Roberts, R. J., Rowe, R. C. & Kendall, K. Brittle–ductile transitions in die compaction of sodium chloride. Chem. Eng. Sci. 44, 1647–1651 (1989).

Roberts, R. J. & Rowe, R. C. Determination of the critical stress intensity factor (KIC) of microcrystalline cellulose using radially edge-cracked tablets. Int. J. Pharm. 52, 213–219 (1989).

Bassam, F., York, P., Rowe, R. C. & Roberts, R. J. Young's modulus of powders used as pharmaceutical excipients. Int. J. Pharm. 64, 55–60 (1990).

Roberts, R. J., Rowe, R. C. & York, P. The relationship between Young's modulus of elasticity of organic solids and their molecular structure. Powder Technol. 65, 139–146 (1991).

Nangia, A. Database research in crystal engineering. Cryst. Eng. Comm. 4, 93–101 (2002).

Gavezzotti, A. Ten years of experience in polymorph prediction: what next? Cryst. Eng. Comm. 4, 343–347 (2002).

Rohl, A. L. Computer prediction of crystal morphology. Curr. Opin. Solid State Mater. Sci. 7, 21–26 (2003).

Rajeswaran, M. et al. Three-dimensional structure determination of N-(p-tolyl)-dodecylsulfonamide from powder diffraction data and validation of structure using solid-state NMR spectroscopy. J. Am. Chem. Soc. 124, 14450–14459 (2002).

Tishmack, P. A., Bugay, D. E. & Byrn, S. R Solid-state nuclear magnetic resonance spectroscopy — pharmaceutical applications. J. Pharm. Sci. 92, 441–474 (2003).

Reutzel-Edens, S. M. & Bush, J. K. Solid-state NMR spectroscopy of small molecules: from NMR crystallography to the characterization of solid oral dosage forms. Am. Pharm. Rev. 5, 112–115 (2002).

Bugay, D. E. Characterization of the solid-state:spectroscopic techniques. Adv. Drug Del. Rev. 48, 43–65 (2001).

Taylor, L. S. & Langklide, F. W. Evaluation of solid-state forms present in tablets by Raman spectroscopy. J. Pharm. Sci., 89, 1342–1353 (2000).

Kempf, D. J. et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl Acad. Sci. USA 92, 2484–2488 (1995).

Chemburkar, S. R. et al. Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development. Org. Process Res. Dev. 4, 413–417 (2000).

Young, A. The Rietveld Method International Union of Crystallography (Oxford Univ. Press, New York, 1993). Explains the Rietveld refinement method in detail.

McCusker, L. B., von Dreele, R. B., Cox, D. E., Louer, D. & Scardi, P. Rietveld refinement guidelines. J. Appl. Cryst. 32, 36–50 (1999).

Stephenson, G. A. & Young, R. Potential applications of Rietveld analysis in the pharmaceutical industry. Am. Pharm. Rev. 4, 46–51 (2001).

Kisi, E. H. Rietveld analysis of powder diffraction patterns. Mater. Forum 18, 135–153 (1994).

Rietveld, H. M. Profile refinement method for nuclear and magnetic structures. J. Appl. Cryst. 2, 65–71 (1969).