Polymorphism of rac-5,6-Diisobutyryloxy-2-Methylamino- 1,2,3,4-Tetrahydro-Naphthalene Hydrochloride (CHF 1035). I. Thermal, Spectroscopic, and X-ray Diffraction Properties FERDINANDO GIORDANO, 1 ALESSANDRA ROSSI, 1 JOSE RAMON MOYANO, 1 ANDREA GAZZANIGA, 2 VINCENZO MASSAROTTI, 3 MARCELLA BINI, 3 DORETTA CAPSONI, 3 TIZIANA PEVERI, 4 ENRICO REDENTI, 4 LORENZA CARIMA, 4 MASSIMILIANO DAGLI ALBERI, 4 MARGHERITA ZANOL 4 1 Dipartimento Farmaceutico, University of Parma, Viale delle Scienze, I-43100 Parma, Italy 2 Istituto Chimico Farmaceutico, University of Milan, Viale Abruzzi 42, I-20132 Milan, Italy 3 Dipartimento di Chimica Fisica, University of Pavia, Viale Taramelli 16, I-27100 Pavia, Italy 4 Chiesi Farmaceutici, Chemical and Biopharmaceutical Department, Via Palermo 26/A, I-43100 Parma, Italy Received 30 June 2000; revised 1 February 2001; accepted 7 February 2001 ABSTRACT: The polymorphism of rac-5,6-diisobutyryloxy-2-methylamino-1,2,3,4-tet- rahydro-naphthalene hydrochloride (CHF 1035) was investigated. Three different crystal forms (Form I, Form II, and Form III) were obtained by recrystallization procedures from common organic solvents. The polymorphs were characterized by Raman and carbon-13 nuclear magnetic resonance ( 13 C NMR) spectroscopy, in solution and in solid state (cross polarization-magic angle spinning), powder X-ray diffracto- metry, and thermal methods (differential scanning calorimetry, hot stage microscopy, and thermogravimetry). Moreover, the diffraction patterns of Form I, collected at controlled temperatures, gave evidence of the presence of two reversible structural rearrangements at 60 and 75 8C. These structural variations were con®rmed by the results obtained by differential scanning calorimetry and hot stage microscopy techniques. The analysis of the Raman spectra allowed the identi®cation of peculiar absorption bands for each polymorph. Form III was the stable crystal form at room temperature as determined by the basis of slurry conversion method. ß 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1154±1163, 2001 Keywords: polymorphism; racemic compound; 2-aminotetralin derivative; thermal properties; spectroscopic properties INTRODUCTION Modern pharmaceutical research and develop- ment acknowledge the great importance of the relationship between crystal structures and phy- sical properties of drugs. Different crystalline forms of drugs, as well as amorphous forms, have different physical properties that may affect both stability and bioavailability. In this respect, the investigation for polymorphic phases is a manda- tory requirement during the very early stages of solid-state characterization on new drugs. Proper preformulation studies that anticipate poly- morphism in solid dosage forms are of great value to the rapid development of effective tablet and capsule formulations. When chirality is involved, single enantiomers and their mixtures (conglo- merates and/or racemic compounds) contribute to the overall complexity of the solid-state charac- terization. In particular, a thorough characteriza- tion of the solid-state properties of racemates is also highly recommended as a prerequisite for the design of industrial scale resolution processes 1 1154 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 8, AUGUST 2001 Correspondence to: F. Giordano (Telephone: 39-0521- 905079; Fax: 39-0521-905006; E-mail: ferdinando.giordano@unipr.it) Journal of Pharmaceutical Sciences, Vol. 90, 1154±1163 (2001) ß 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association