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J. Phys. Chem. B 2006, 110, 26148-26159
Crystalline Polymorphism and Molecular Structure of Sodium Pravastatin A. P. Martı´n-Isla´ n,† M. C. Cruzado,‡ R. Asensio,‡ and C. Ignacio Sainz-Dı´az*,† Laboratorio de Estudios Cristalogra´ ficos, Instituto Andaluz de Ciencias de la Tierra, CSIC-UniVersidad de Granada, AV FuentenueVa s/n, 18002-Granada, Spain, and Ercros-Fyse s.a., Paseo del Deleite s/n, Aranjuez-Madrid, Spain ReceiVed: April 20, 2006; In Final Form: October 11, 2006
In this work different crystallization processes of sodium pravastatin are explored and a new polymorph is obtained. The analytical results of powder X-ray diffraction (PXRD) and thermal analysis for this new polymorph indicate that it is different from the polymorphs previously reported. This new crystal form shows different physical-chemical properties than the previous forms, such as crystallographic structure, thermal behavior, and melting point, 181.5 °C. Besides, all crystallization processes previously reported use an aprotic solvent as antisolvent. However, we propose a new crystallization process for sodium pravastatin that uses only protic solvents, overcoming industrial scaling and environmental problems. Variable-temperature PXRD experiments show a transformation between different crystal forms in the range of 80-120 °C. Solid-state 13 C NMR, reported in this work for the first time, and Fourier transform infrared (FT-IR) studies of some polymorphs show some differences in intermolecular interactions, especially with carboxylate and hydroxyl groups. Quantum mechanical calculations of the pravastatin molecule are also presented for the first time, obtaining a molecular structure similar to the experimental structure existing within the crystal lattice of the tert-octylamonium salt of pravastatin.
Introduction The sodium salt of pravastatin, (+)-(3R,5R)-3,5-dihydroxy7-{(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2-methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl}heptanoic acid (Figure 1), is an important member of the statins, a class of pharmaceutical compounds. Statins are highly effective in the therapeutic treatment for lowering serum cholesterol levels in patients with atherosclerosis and hypercholesteremia.1 Elevated cholesterol levels are a primary risk factor for coronary artery disease, especially in developed countries. Drug and dietary therapies can reduce serum cholesterol levels and decrease the risk of stroke and overall mortality. In addition to lowering cholesterol, statins appear to have useful additional effects, such as stimulation of bone formation and new blood vessel growth.2 Recently, the action of pravastatin on the cholesterol metabolism of cells has been found to be very useful for the antitumoral applications of this drug.3 Statins are becoming one of the most important and lucrative drug families in the worldwide pharmaceutical market. For example, one drug of this family, atorvastatin (Lipitor), is the world’s largest-selling drug with about $12 billion/year in sales. Besides, sodium pravastatin was in the top-selling drugs with sales of $1.3 billion in 2005.4 Therefore, the exploration of new crystallization methods and new crystal forms is very important for the statins’ market. This investigation is especially important for the generic drug market; recently pravastatin and simvastatin have been approved as generic drugs by the U.S. Food and Drug Administration.4,5 Polymorphism is the phenomenon in which a solid can present different crystal forms or polymorphs with different chemical and physical properties. The molecular packing during the generation of these forms is controlled by intermolecular † ‡
CSIC-Universidad de Granada. Ercros-Fyse.
Figure 1. Molecular structure of sodium pravastatin.
interactions, yielding different arrangements and conformations of molecules in the crystal lattice. The energy differences between these polymorphs are often very low and sometimes the existing polymorph at room temperature is not the most stable one. Fine control of the crystallization process is very important in order to produce a certain polymorph. Recently, the role and impact of polymorphs in pharmaceutical solids have increased significantly, creating several patent conflicts worldwide.6 In many cases the lack of a systematic study of polymorphism provokes many diffuse characterizations and conflicts in the regulatory decisions.6,7 One of our aims is to explore carefully the relative solubility and crystallization process of sodium pravastatin in order to find an additional polymorph. Pravastatin is a biological compound isolated as a metabolite of compactin.8,9 A single crystal suitable for X-ray analysis was obtained from the tert-octylamine salt of pravastatin.10 However, the pharmaceutical form is the sodium salt, and no crystal structure of the sodium salt has been reported. The polymorphism in drugs and the search for new crystalline forms has become very interesting for the pharmaceutical companies, in order to control the stability, to explore different behavior and activity of drugs, and to obtain new patent rights on the drugs. In this case, different crystalline forms of the sodium salt of
10.1021/jp0624449 CCC: $33.50 © 2006 American Chemical Society Published on Web 11/30/2006
Crystalline Polymorphism of Sodium Pravastatin
J. Phys. Chem. B, Vol. 110, No. 51, 2006 26149
TABLE 1: Solubility of Sodium Pravastatin in Different Solvents solvent
saturated concn (mg/mL)
water ethanol/water (96/4 v/v) poly(ethylene glycol) 200 2-propanol ethyl acetate acetonitrile
499 310 136 7
