Organic Process Research & Development 2005, 9, 911−922
Process Design and Scale-Up Elements for Solvent Mediated Polymorphic Controlled Tecastemizole Crystallization Kostas Saranteas,* Roger Bakale, Yaping Hong,† Hoa Luong,‡ Reza Foroughi, and Stephen Wald Chemistry and Pharmaceutical Sciences, Sepracor Inc., 84 Waterford DriVe, Marlborough, Massachusetts 01752, U.S.A.
Abstract: Tecastemizole, an active metabolite of the histamine H1-receptor antagonist Astemizole (Hismanal), crystallizes out in two polymorphic forms (form A and form B). Thermodynamic stability screening results show that form A is more stable and form B is kinetically favorable (metastable) in the temperature range of process interest. A process design switch from a seed controlled growth approach to a solvent mediated interconversion based approach was adopted for reasons of simplicity and robustness during early Phase II development. The effects of dissolution, mass transfer, and surface-controlled growth on the observed interconversion rate were studied under well-defined seeding conditions. The experimental results show a significant effect of operating temperature on the interconversion rate and also show that the rate-limiting step is the growth of form A. Growth controlled kinetic parameters were estimated and are reported here. A nonlinear cooling profile was developed to take advantage of the temperature rate effect on form interconversion. Scale-up of the modified procedure was performed at both pilot and full-scale manufacturing, and the results confirmed the laboratory findings.
Introduction The polymorphic behavior of drugs can be of crucial importance in the pharmaceutical industry. Polymorphs are by definition substances of the same molecule but with different physical properties. Some of the polymorph physical property differences include storage stability, crystal shape, compressibility, density (important in formulation), and intrinsic dissolution rates (an important factor determining bioavailability). From thermodynamic considerations at a given temperature and pressure, only one polymorph will be stable, the one with the lowest free energy at that temperature and pressure. From the industrial crystallization point of view, however, thermodynamic stability is not sufficient to ensure that the stable polymorph will always be produced. During the primary nucleation in an unseeded environment it is the unstable polymorph or pseudo polymorph in the form of hydrate or solvate that may crystallize out first. This is in essence Oswald’s rule of stages,1 which basically states that an unstable system does not transform directly to the most stable state but rather it transforms to a * To whom correspondence should be addressed. Telephone: 508-357-7655. E-mail:
[email protected]. † Currently with VioQuest Pharmaceuticals, Monmouth Junction, NJ 08852. ‡ Currently with Millennium Pharmaceuticals, Cambridge MA 02139. (1) Threlfall, T. Structural and Thermodynamic Explanations of Ostwald’s Rule. Org. Process Res. DeV. 2003, 7, 1017-1027. 10.1021/op050101n CCC: $30.25 © 2005 American Chemical Society Published on Web 09/13/2005
Figure 1. Chemical structure of Astemizole (1) and Tecastemizole (2).
transient stage whose formation from the original is accompanied by the smallest loss of free energy. A classical example of such a system is sodium sulfate, which precipitates as the heptahydrate crystal at room temperature before the thermodynamically stable decahydrate form appears.2 An eventual phase transition to the most stable phase is inevitable, but the transformation time can be extremely fast or extremely slow depending on the process conditions present. Most transformations occur in suspension and are solvent mediated. Solid-state transformations are less often observed probably due to the low molecular mobility.3 Some polymorph transformations can be reversible in nature when the relative solubility of the polymorphs reverses with changing temperature (enantiotropic). Other transformations can be irreversible (monotropic). In an industrial process, if the stable form is the desirable product, a solvent phase induced transformation should include analysis of all the factors that may affect such a transformation. These factors may include temperature, solvent composition, hydrodynamics, and seeding among others. Several solution-mediated transformations have been reported in the literature: Cardew and Davey4 on copper phthalocyanine; Kitamura et al. on L-glutamic acid;5 Brecevic, Scrtic, and Garcide on calcium (2) Tavare, N. S. Industrial Crystallization: Process Simulation Analysis and Design; Plenum Press: New York, 1995. (3) Beckmann, W. Seeding Strategies for the Crystallization of the Desired Polymorph. Possibilities and Limitations. 1st International Symposium on Aspects of Polymorphism and Crystallization, Hinckley, Leicestershire, U.K., 1999. (4) Cardew, P. T.; Davey R. J. The Kinetics of Solvent-mediated Phase Transformation. Proc. R. Soc. London 1985, A398, 415-428. Vol. 9, No. 6, 2005 / Organic Process Research & Development
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Figure 2. Intrinsic dissolution comparison for the two Tecastemizole polymorphs.
oxalate;6 T. Ogino et al. on calcium carbonate;7 Wachter et al. on progesterone;8 and many others. More recent review publications include the role of solvent on transformation9 and also the multidisciplinary nature of the subject matter beyond organic molecules.10 Tecastemizole Drug Substance and Process Background Tecastemizole (Sepracor filed a New Drug Application for the use of tecastemizole in the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria diseases in 2001) or norastemizole or Soltara is an active metabolite of the histamine H1-receptor antagonist Astemizole (Hismanal)11 (Figure 1). The commercial process developed, including the crystallization step reported here, was transferred to a contract manufacturer site and successfully generated, at 8000-L crystallizer scale, metric ton quantities of drug substance. Although several syntheses of Tecastemizole are described in the literature,12-14 polymorphism of the solid product was (5) Kitamura, M. Polymorphism in the Crystallization of L-Glutamic Acid. J. Cryst. Growth 1989, 96, 541-546. (6) Brecevic, L.; Skrtic, D.; Garcide, J. Transformation of Calcium Oxalate Hydrates. J. Cryst. Growth 1989, 96, 541-546. (7) Ogino, T.; Suzuki, T.; Sawada, K. The Rate and Mechanism of Polymorphic Transformation of Calcium Carbonate in Water; J. Cryst. Growth 1990, 100, 159-167. (8) Wang, F.; Wachter, J. A.; Antosz, F. J.; Berglund K. A. An Investigation of Solvent-Mediated Polymorphic Transformation of Progesterone Using in Situ Raman Spectroscopy. Org. Process Res. DeV. 2000, 4, 391-395. (9) Chong-Hui Gu et al. Influence of Solvents on the Rate of Solvent-Mediated Polymorphic Transformation. J. Pharm. Sci. 2001, 90 (11). (10) Herbstein, F. H. Diversity Amidst Similarity: A Multidisciplinary Approach to Phase Relationships, Solvates, and Polymorphs. J. Cryst. Growth Des. 2004, 4 (6), 1419-1429. (11) Handley, D. A.; Magnetti, A.; Higgens, A. J. Therapeutic Advantages of Third-generation Antihistamines. Exp. Opin. InVest. Drugs 1998, 7, 10451054. (12) Janssens et al. Bicyclic Heterocyclyl Containing N-(Bicyclic Heterocyclyl)4-Piperidinamines. U.S. Patent No. 4,695,569 issued on September 22, 1987. (13) Hong, Y.; Bakale, R.; Senanayake, C. Method for Synthesizing 2-Substituted Imidazoles. U.S. Patent No. 5,817,823 issued on October 6, 1998. 912
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never before disclosed. Tecastemizole was found to exist in two polymorphic forms at Sepracor’s laboratories: a thermodynamically preferred, stable crystal form (designated as form A) and a kinetically formed, less stable crystalline modification (designated as form B). Both forms A and B were thoroughly characterized using DSC, TGA, optical microscopy, scanning electron microscopy, hot stage microscopy, single-crystal X-ray analysis, X-ray powder diffraction (XRPD), FT-IR and Raman spectroscopy, solid-state NMR, intrinsic dissolution, and true density. Raman/FT-IR spectroscopy and thermal analysis techniques traditionally associated with polymorphic mixture characterization studies proved ineffective in quantitative differentiation of the two forms. A comparison of intrinsic dissolution profiles for the two forms is illustrated in Figure 2, and a comparison of crystal habit by microscopy is illustrated in Figure 3. A more detailed comparison of physical and chemical properties of the two crystal forms is summarized in Table 1.15 In an attempt to characterize tecastemizole produced by other synthetic methods previously described in the literature, it was determined that in all cases the product was composed of greater than 80% of the kinetically favored form B.15 To more thoroughly study the formation and interconversion of the two polymorphic forms, SSCI Inc. was contracted to develop a suitable method to quantify the form B content of Tecastemizole.16 Both Raman spectroscopy and DSC were found to be unsuitable for this purpose. A synchrotron X-ray source was used to obtain reference spectra for each form, and the resulting method required the (14) Maynard, G. et al. Substituted n-Methyl-n-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)-2-(aryl)butyl Benzamides Useful for the Treatment of Allergic Diseases. U.S. Patent No. 5,922,737 issued on July 13, 1999. (15) Bakale, R.; Senanayake, C.; Hong, Y.; Saranteas, K.; Redmon, M.; Wald, S. U.S. Patent No. 6,627,646 issued on September 30, 2003. (16) Solid State Chemical/Pharmaceutical Information (SSCI), Inc., West Lafayette, IN, personal communications.
Figure 3. Tecastemizole polymorph crystal habit comparison by microscopy. Table 1. Tecastemizole polymorph physicochemical properties comparison parameter single-crystal X-ray data crystal system lattice parameters a b c β volume (Å3) space group Z value true density (calcd) (g/cm3) melting point (°C) USP hot stage microscopy aqueous solubility (ambient) (mg/mL) intrinsic dissolution rate (mean) (mg/mL-min)
form A
form B
orthorhombic
monoclinic
10.260(3) Å 33.335(3) Å 10.101(3) Å 3454(1) P212121 8 1.247
14.587(8) Å 14.111(5) Å 18.101(7) Å 111.85 (3)° 3458(3) Cc 8 1.246
217-220 218-226
217-219 218-224
0.17
0.20
0.0034
0.0026
utilization of Rietveld data analysis to quantitatively measure the relative amounts of the two crystal forms with a limit of detection of
