CrystEngComm PAPER Cite this: CrystEngComm, 2016, 18, 1118 Received 20th March 2015, Accepted 14th May 2015 DOI: 10.1039/c5ce00568j www.rsc.org/crystengcomm Polymorphism of vanillin revisited: the discovery and selective crystallization of a rare crystal structure† Padmini Kavuru, a Stephanie J. Grebinoski, a Mitulkumar A. Patel, a Lukasz Wojtas b and Keith Chadwick* a While polymer induced heterogeneous nucleation (PIHn) has been shown to be a powerful tool for crystallization control and polymorph screening the factors influencing PIHn, such as solvent selection, supersaturation and method of crystallization are not well understood. Herein, we report on the use of PIHn to selectively crystallize a new and rare crystal structure of vanillin. Nearly 65 years ago, Walter McCrone postulated vanillin to be trimorphic. However, only one crystal form, Form I, had been structurally characterized to this point. Form II crystallizes in the space group Pna2 1 with four molecules in the asymmetric unit. Achiral molecules exhibiting such crystal structures account for less than 0.008% of all organic entries in the Cambridge Structural Database. Polymorphic control by PIHn was observed to be highly dependent on the method of crystallization. In the presence of polyIJacrylic acid) and polyIJmethyl methacrylate) micro-particles the thermodynamically stable Form I was crystallized from isopropanol by quench cooling, while metastable Form II was obtained by slow evaporation. To our knowledge this is the first deliberate study to highlight the influence of crystallization method on PIHn. Introduction Polymorphism is the ability of a chemical entity to crystallize into different structures where the atoms, ions or molecules are packed differently within the crystal lattice. 1 For each polymorph the physicochemical properties, such as melting point, solubility and stability, are influenced by the differ- ences in crystal packing and/or structural conformation. 2,3 As a consequence, polymorphism is of great importance in the manufacture of products such as pharmaceuticals, where different crystal forms can significantly impact the bio- availability and/or manufacturability of a drug. 4,5 Therefore, conducting an effective screen during preformulation devel- opment in order to identify all polymorphs, including the most stable form, is considered critical in avoiding discovery during the later stages of manufacturing. 6 Additionally, poly- morphism can also have implications for intellectual property where crystal forms with superior properties can be patent protected. Numerous methods have been reported for both discovery and selective crystallization of polymorphs. 7–13 One of the most effective techniques is heterogeneous nucleation. 10–13 Heterogeneous surfaces with different chemistries, crystallo- graphic properties and/or topographies have all been shown to control crystal form. However, the rational design of a heterogeneous surface for the selective crystallization of a desired polymorph remains a key challenge as the mecha- nisms underlying heterogeneous nucleation are not well understood. Furthermore there is little understanding of how the properties of the solution phase in contact with the heterogeneous surface, such as solvent polarity, solute con- centration and supersaturation, and the method of crystalli- zation effect heterogeneous nucleation. Herein, we report on the selective crystallization and full structural characteriza- tion of a rare chiral crystal structure of vanillin (Form II), an achiral molecule. Selective crystallization was achieved through polymer induced heterogeneous nucleation on micro-particles of polyIJmethyl methacrylate) and polyIJacrylic acid). In addition to the chemistry of the polymer, the hetero- geneous crystallization of vanillin was also found to be highly dependent on the choice of crystallization method. Vanillin (Fig. 1) is a naturally occurring compound present in a wide variety of plants. The most common source is found in vanilla bean extract. However, it can also be synthet- ically produced as a by-product of the sulphite process for making wood pulp. 14 It is commonly used as a flavouring agent in the food, fragrance, beverage and pharmaceutical 1118 | CrystEngComm, 2016, 18, 1118–1122 This journal is © The Royal Society of Chemistry 2016 a Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA. E-mail: chadwick@purdue.edu; Fax: +765 494 6545; Tel: +765 496 2775 b Department of Chemistry, College of Arts and Science, University of South Florida, Tampa, FL 33620, USA † Electronic supplementary information (ESI) available: PXRD data and CIF file of Form II vanillin. CCDC 1055335. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ce00568j Published on 19 May 2015. Downloaded by Purdue University on 12/02/2016 15:28:15. View Article Online View Journal | View Issue