Article pubs.acs.org/crystal
Solution Mediated Polymorphic Transformation: Form II to Form III Piracetam in Ethanol Anthony Maher,* Denise M. Croker, Åke C. Rasmuson, and Benjamin K. Hodnett Solid State Pharmaceuticals Cluster, Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland ABSTRACT: The polymorphic transformation of the Piracetam (2oxo-1-pyrrolidine acetamide) metastable form II to the stable form III has been investigated in ethanol, by ex-situ X-ray diffraction analysis of the solid phase combined with in situ infrared analysis of solution concentrations. The main factors studied were temperature, mass of solids loading, and pretreatment of the loaded solids. At increasing temperature, the solubility ratio decreases and, hence, the transformation driving force decreases. In spite of this, the nucleation induction time of the stable form and the time for completion of the transformation decrease with increasing temperature. The transformation rate is governed by the nucleation and growth of the stable form, with nucleation likely to take place on the faces of the metastable form crystals and the rate increasing with surface area of the metastable form.
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INTRODUCTION While the crystallization of an active pharmaceutical ingredient (API) in the correct form is an important step in the manufacture of a drug product, the stability of that form in the final product and during its shelf life is just as critical. Polymorphism, defined as the ability of a material to crystallize and exist in different crystal structures, is a phenomenon often observed in the pharmaceutical industry.1,2 In the case of ritonavir, the API in Norvir (Abbott Laboratories, Chicago), a more stable polymorph (form II) identified after the product was on the market, had an adverse effect on the bioavailability of the drug.3 Differences in properties between polymorphs in a system have led to tight regulation of polymorphism in the pharmaceutical industry. Piracetam (Structure 1) is a nootropic drug used to treat diseases associated with cognitive dysfunction.4,5 Throughout the literature, there is some confusion over the nomenclature of the different polymorphs. The system employed in this work for naming polymorphs was outlined previously.6 The numerical value of the a-lattice parameter in angstroms, which appears in the corresponding Cambridge Crystallographic Data Centre (CCDC) file, is added to the polymorph label. In the case of FII piracetam, the file name is BISMEV, and the value of a is 6.403 Å, hence FII(6.403).7 In the case of FIII, the file name is BISMEV01 and a is 6.525 Å, hence FIII(6.525).7 As verified by solubility data, FIII(6.525) is the stable polymorph under ambient conditions, while FII(6.403) is metastable.6,8−10 Following Ostwald's rule of stages, FII(6.403) has been reported to transform to FIII(6.525) in numerous solvents.8,11−13 However, this transformation does not occur in the solid state.14 © 2012 American Chemical Society
Solution mediated polymorphic transformations are composed of three stages; dissolution of the metastable phase, nucleation of the stable phase, and growth of the stable phase. Under certain conditions, a polymorph can exist in a metastable region, provided the stable polymorph is not present.15 Nucleation of the stable form “activates” the transformation, making it a critical step. In an extensive review, Croker et al.16 observed that, in solution-mediated polymorphic transformations, nucleation of the stable polymorph tends to occur on, or at, the surface of the existing polymorph. The nucleation of the stable βL glutamic acid was proved to be surface mediated in the presence of the metastable αL form. Additives, which selectively adsorbed to the surface of the metastable form, prevented nucleation of the stable form.17 Further studies confirming the surface mediated nature of the transformation by Scholl et al.18 found that the transformation rate was faster when a smaller particle size of the αL glutamic acid was employed, indicating that the rate of nucleation of the βL form increases concurrently with the surface area of the metastable Received: September 5, 2012 Revised: October 22, 2012 Published: October 23, 2012 6151
dx.doi.org/10.1021/cg301290z | Cryst. Growth Des. 2012, 12, 6151−6157
Crystal Growth & Design
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appearance tests. It also complies with a heavy metals limit of
