DOI: 10.1002/cphc.200600308 Computationally-Assisted Approach to the Vibrational Spectra of Molecular Crystals: Study of Hydrogen-Bonding and Pseudo- Polymorphism** Mariela M. Nolasco, [a] Ana M. Amado, [b] and Paulo J. A. Ribeiro-Claro* [a] 1. Introduction Caffeine (1,3,7-trimethylpurine-2,6-dione; CA), theophylline (1,3-dimethylpurine-2,6-dione; TP), and theobromine (3,7-dime- thylpurine-2,6-dione; TB) are three methylated xanthine deriva- tives (see Figure 1) widely found in the human diet that repre- sent three different systems of important pharmaceutical inter- est. They naturally occur in food products such as tea, coffee, and cocoa beans (with TB and CA being the two most abun- dant xanthines in chocolate, for instance). On the other hand, these compounds are also used in a variety of medical applica- tions, being routinely prescribed. For instance, CA is used as a central nervous system, cardiac and respiratory stimulant, while TP and TB are widely used as smooth muscle relaxants. TP is also used as a bronchodilator, for the treatment of bron- chial asthma and neonatal apneia [1] and in the treatment of ep- ilepsy. [2] All three compounds are also known to cause diure- sis, [3] while CA administration seems to protect mice against a whole-body lethal dose of g-irradiation. [4] The polymorphic behavior of drugs is a major concern of the pharmaceutical industry since different packing arrange- ments of the same molecular species (polymorphism) can have markedly different biopharmaceutical properties. [5] It is well documented that CA and TP are sensitive to polymorphic and pseudo-polymorphic transformations that affect their dissolu- tion profiles and, consequently, their bioavailability. [6–11] In fact, they crystallize into different states (hydrate and anhy- drous) [12–15] and are good model compounds for the accurate characterization of both the polymorphic form and hydration states. In this way, the knowledge of the structural characteristics of these compounds from a molecular point of view is of utmost relevance for a rational understanding of the structure-activity A new computationally-assisted methodology (PiMM), which ac- counts for the effects of intermolecular interactions in the crystal, is applied to the complete assignment of the Raman and infrared vibrational spectra of room temperature forms of crystalline caf- feine, theobromine, and theophylline. The vibrational shifts due to crystal packing interactions are evaluated from ab initio calcu- lations for a set of suitable molecular pairs, using the B3LYP/6- 31G* approach.The proposed methodology provides an answer to the current demand for a reliable assignment of the vibration- al spectra of these methyl-xanthines, and clarifies several mis- leading assignments. The most relevant intermolecular interac- tions in each system and their effect on the vibrational spectra are considered and discussed. Based on these results, significant insights are obtained for the structure of caffeine in the anhy- drous form (stable at room temperature), for which no X-ray structure has been reported. A possible structure based on C (8)  H···N (9) and C (1,3) H···O intermolecular interactions is suggested. Figure 1. Schematic representation of the xanthine derivatives: theophylline (TP), theobromine (TB), and caffeine (CA). [a] Dr. M. M. Nolasco, Prof. P. J. A. Ribeiro-Claro CICECO, Departamento de Química Universidade de Aveiro, 3810-193 Aveiro (Portugal) Fax: (+ 351) 234 370 084 E-mail: pclaro@dq.ua.pt [b] Dr. A. M. Amado Química-Física Molecular, Departamento de Química FCTUC, Universidade de Coimbra 3004-535 Coimbra (Portugal) Fax: (+ 351) 239 826 541 [**] in Theophylline, Theobromine, and Caffeine. 2150 # 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemPhysChem 2006, 7, 2150 – 2161