DOI: 10.1021/cg900105u
Published as part of a special issue of selected papers presented at the 8th International Workshop on the Crystal Growth of Organic Materials (CGOM8), Maastricht, Netherlands, September 15-17, 2008.
2009, Vol. 9 4324–4334
Polymorph-Directing Seeding of Entacapone Crystallization in Aqueous/ Acetone Solution Using a Self-Assembled Molecular Layer on Au (100) Ana Kwokal,*,†,‡ Thai T. H. Nguyen,‡ and Kevin J. Roberts‡ †
PLIVA Croatia, Teva Pharmaceutical Industries Ltd., Research and Development, Prilaz baruna Filipovi ca 29, Zagreb, Croatia, and ‡Institutes of Particle Science and Engineering and of Process Research and Development, University of Leeds, LS2 9JT, Leeds, U.K. Received January 30, 2009; Revised Manuscript Received July 17, 2009
ABSTRACT: Crystallization of the active pharmaceutical ingredient Entacapone, which exhibits strong polymorphic behavior in aqueous/acetone solutions, is examined with and without the presence of a self-assembled molecular layer of Entacapone (SALE) on an Au (100) surface. SALE characterization by electrochemical and spectroscopic tools confirms the existence of a well-ordered layer structure. These surfaces are found to act as nucleation catalysts providing polymorph-specific templates which enable secondary nucleation through provision of oriented adsorption and molecular recognition at the SALE/solution interface. In particular, crystallization of the stable prismatic polymorphic form A is observed from aqueous/acetone solutions in the presence of an SALE compared to needle-shaped crystals of the metastable form D which usually form. The quiescent crystallization of Entacapone from the same aqueous/acetone solutions in the presence of an Au (100) surface produces an assembly of single crystals form A epitaxially grown at the surface with concomitantly form D being produced in the bulk solution confirming the surface-sensitive nature of the crystallization process. The research reveals the possibility of switching nucleation from uncontrolled nucleation sites toward a more directed crystallization process, and hence more stable polymorphic form, through the selective choice of adsorbed species. The future potential of this concept and methodology for larger scale size processes is discussed.
1. Introduction Batch crystallization is an essential step in pharmaceuticals production, for intermediate isolation, removal of impurities, or final product isolation and purification. However, crystallization processes can be difficult to control thus producing significant challenge in terms of optimizing the overall process. A key step in a crystallization process is to be able to effectively control the nucleation stage and its associated free energy of activation.1 In real systems, nucleation is likely to occur heterogeneously at the energetically most favorable sites such as reactor walls, impeller surfaces, solid impurities, or dust particles, leading, in turn, to difficulties in terms of achieving reliable crystallization control. In addition, there is also another aspect associated with nucleation reflecting the poor ability of many active pharmaceutical ingredients (API) to spontaneously nucleate at low to moderate solution supersaturation leading to a small particle size.2 Seeding is often used as a source of secondary nuclei to control nucleation either through contact with seed surfaces or by contact breeding of nuclei swept away from the seed surfaces through hydrodynamic forces.3 However, seeding can suffer from many problems associated with irreproduci-
*To whom correspondence should be addressed. E-mail: ana.kwokal@ pliva.hr. pubs.acs.org/crystal
Published on Web 08/26/2009
bility due for example to variation of the seed surface area, roughness, and quality. Interest on the impact of the surface chemistry and nanoscale topology on heterogeneous crystallization is rapidly increasing4-7 owing to the fact that understanding the subtle interaction of molecules at the surface is often crucial for determining the nucleation mechanism needed for predicting the crystallization outcome. Crystallization is often referred to as an art rather than science, reflecting the fact that the detailed mechanistic behavior associated with practical heteronucleation is still not all that well understood. The development of modern techniques for surface characterization at the molecular level and new achievements associated with this offer the promise, in principle, of being able to achieve process understanding and, hence, improve the control of crystallization and related phenomena.8 In the latter respect, surface assembled monolayers (SAMs) offer a potentially unique way to provide controllable surface templates for both nucleation promotion and the direction of the structural organization of nucleation clusters. SAMs have become important in recent years reflecting their potential use in different fields, mostly molecular electronic devices 9,10 but also as a template for crystallizing materials with defined structural units.8,11-14 A range of well-defined surfaces have been examined for crystallization studies, for example, SAMs of thiol-based molecules,13-16 Langmuir monolayers,17 single crystals,4,18,19 polymer substrates,20-22 r 2009 American Chemical Society
Article
Crystal Growth & Design, Vol. 9, No. 10, 2009
4325
Figure 1. The molecular structure of Entacapone (left) together with details of the intermolecular packing (right) of its form A. In this, the red shadow area represents the location of the (010) crystal plane.
monolayers of twisted binaphthyls,23 or SAMs of aromatic compounds on silica.24 Ward and co-workers4,18,19 have shown the template-directed crystallization of selected organic crystal polymorphs on single crystal surfaces, yielding the concept of organic crystal polymorphism by surface control and hence opening up new possibilities for the existence of “a library of organic seeds which can be used to either control polymorphism or to search for unknown polymorphs”. Since then, there have been rather few papers regarding the crystallization of organic crystals by surfaces templating. However, inorganic crystals especially CaCO322,24-27 crystallized on templated surfaces have been found to result in different polymorphs having a variety of interesting crystal shapes. The comprehensive work of Hiremath et al.15 about controlling the crystal polymorphism of 1,3-bis(m-nitrophenyl) urea by the use of SAMs of substituted 40 -X-mercaptobiphenyls has shown how changing of just one functional group can change intermolecular interactions and dipole moment orientation which consequently change the molecular ordering within this crystallization system. Cox et al.28 have selectively grown the anhydrous and monohydrate forms of theophylline on functionalized SAMs. Other examples include the formation of metastable polymorphs of a steroid molecule on the specific face of a stable polymorph29 and the crystallization of a cocrystal onto one of its component subphases.30 However, these experiments have been mostly carried out on crystals grown on a template surface directly.22,25-27 To the authors’ knowledge, there have been no studies, so far, which have shown the influence of surface templates on crystallization within the bulk solution and within a representative reaction vessel size. This paper seeks to address the latter issue through detailed studies of the effect of a self-assembled layer, SALE of the pharmaceutical compound Entacapone, (E)-2-cyanoN,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl) propenamide (Figure 1), on its subsequent crystallization behavior. Entacapone is a selective and reversible inhibitor of catecholO-methyltransferase and is used for the treatment of Parkinson0 s disease31 and is marketed commercially in form of tablets under the name COMTan (Novartis). There are six known polymorphic forms of Entacapone, named A,31 D,32 (R, β, γ, δ),33 but only one of these has a fully solved and published crystal structure, namely, form A.31 Polymorph screening of Entacapone from about 50 different solvents and their mixtures mostly gives forms A and D and mixtures of them with small amount of forms R and δ.34 Form A which is known to be the most stable phase34 crystallizes from acetone solvent with morphologies ranging from needles to thin plate-shaped crystals, while form D has been found to
crystallize as a very thin needles. Neither of these particle morphologies are desirable in the terms of processability of API and its resultant solid dosage forms. No solid conversion between forms A and D is observed before melting. However, after melting, form D has been found to convert to form A under specific heating conditions.34 In this study, the nucleation and crystal growth of Entacapone in the presence and absence of a SALEs adsorbed onto Au (100) single crystal surfaces is examined. The Au (100) surface was chosen due to its ability to adsorb most organic molecules without any chemical interaction as well as its ability of being renewable and reproducible in terms of its surface structure. 2. Materials and Methods 2.1. Materials. Entacapone form D obtained from PLIVA Croatia, with more than 99.9% purity was used for all solution crystallization studies using a solvent of 88% distilled water and 12% acetone (Acros Organic, for residue analysis), hereafter 12A88W. This mixture was chosen to provide an optimal solubility for crystallization studies. An Au (100) single crystal (Goodfellow Ltd.) in a form of cylindrical disk (having a diameter of 0.5 cm; thickness of 1 mm; orientation of (3°; purity
