Crystal and electronic structure of two polymorphic modifications of famotidine. An experimental and theoretical study G.G. Ferenczy a,b, * , L. Pa ´rka ´nyi c , J.G. A ´ ngya ´n d , A. Ka ´lma ´n c , B. Hegedu ˝s a a Gedeon Richter Ltd., H-1475 Budapest, P.O. Box 27, Hungary b Department of Inorganic Chemistry, Technical University of Budapest, H-1111 Budapest, Szent Gelle ´rt te ´r 4, Hungary c Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences H-1525 Budapest, P.O. Box 17, Hungary d Laboratoire de Chimie The ´orique, Universite ´ Henri Poincare ´, Institut Nancie ´ien de Chimie Mole ´culaire, CNRS UMR 7565, B.P. 239, F-54506 Vandoeuvre-le `s-Nancy Cedex, France Abstract The antiulcer agent (i.e. a histamine H 2 receptor antagonist), famotidine is known to crystallize in two polymorphic modifications. A comparison of the two forms based on single crystal X-ray data and on quantum chemical calculations is presented. Form A is constructed from molecules with higher internal energy. The crystal field together with the intermolecular hydrogen bond network causes important deformation of the molecular charge densities with respect to that of the free molecules. This charge density deformation is more pronounced in form A as it is manifested by an increased dipole moment and by enhanced electrostatic and polarisation interaction energies. Thus the excess internal energy of form A with respect to form B is largely counterbalanced by the increased intermolecular interaction energy in the former modification.  2000 Elsevier Science B.V. All rights reserved. Keywords: Famotidine; Polymorphism; SCMP; Crystal structure calculation 1. Introduction Pharmaceutical research invokes several disci- plines in order to find effective drugs. Towards the end of the research process the problem of finding an appropriate drug formulation evolves. Similar to other fields of drug research consider- able effort has been devoted to reinforce rational elements in developing appropriate formulae for solid phase drugs. This includes the research of relations between crystal structures and constituent molecules. Secondary interactions arising in the crystalline phase affect properties like solubility and stability, which, in turn, may have profound influence on drug actions. Moreover, compounds may exist in several polymorphic forms that may exhibit considerably different drug characteristics. In addition to its practical relevance in drug formulations, the understanding of the relation between the structure of a crystal as a supermole- cule and its constituent molecules is an exciting scientific problem and the field of active research. The realization of a particular crystal structure is governed by kinetic and thermodynamic factors, neither of them is completely understood. Never- theless, considerable progress is achieved in devel- oping theoretical methods for studying and characterizing molecular crystals. In the present contribution the self-consistent Madelung potential approach [1] implemented with the semiempirical Journal of Molecular Structure (Theochem) 503 (2000) 73–79 0166-1280/00/$ - see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0166-1280(99)00364-4 www.elsevier.nl/locate/theochem * Corresponding author.