CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 8 3339–3341
PerspectiVes Indo-U.S. Workshop on Pharmaceutical Cocrystals and Polymorphs Ashwini Nangia*,† and Naı´r Rodrı´guez-Hornedo*,‡ School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India, and Department of Pharmaceutical Sciences, UniVersity of Michigan, Ann Arbor, Michigan 48109-1065 ReceiVed May 22, 2009
An Indo-U.S. bilateral meeting on Pharmaceutical Cocrystals and Polymorphs was jointly sponsored by the Indo-U.S. Science and Technology Forum (IUSSTF) and the U.S. National Science Foundation. This workshop meeting was held in the historic Mysore city, located about 150 km from Bangalore, on February 8-10, 2009. The American and Indian delegations, which included editors of Crystal Growth & Design,1 assembled at the Indian Institute of Science campus on the morning of February 8. Scientific discussion and cultural exchange started right away in the 4 h bus ride to Mysore. Apart from about a dozen or so speaker delegates from each side, the meeting provided a rare opportunity for about 20 Indian graduate students and a few scientists from pharmaceutical R&Ds to attend an international level meeting at a low cost. Organizers from both sides, Ashwini Nangia and Gautam R. Desiraju (India) and Naı´r Rodrı´guez-Hornedo and Michael J. Zaworotko (USA), decided on a format in which two 30 min talks were to be followed by a 30 min Q&A session. In the informal atmosphere of a small group this format worked out very well, with many questions and comments throughout the meeting. Ashwini Nangia (University of Hyderabad) outlined rational heterosynthon-based approaches to cocrystal design and engineering in model compounds and for APIs and GRAS coformers. Reliable guidelines that influence the formation of neutral cocrystal or ionic salt based on pKa differences between acid and base is still an open question. The difficulty becomes more acute in multifunctional cocrystal systems. Naı´r Rodrı´guezHornedo (University of Michigan) quickly moved the discussion from structure to properties of cocrystals and the importance of solution chemistry, namely, our ability to modify and control solubility. It is possible to fine-tune the cocrystal-pH solubility dependence and for cocrystals to achieve solubilities as high as 150 times the solubility of the parent drugs. Eutectic points for cocrystals were shown to parallel cocrystal solubilities, and a * To whom correspondence should be addressed. † University of Hyderabad. ‡ University of Michigan.
good rule of thumb for cocrystals to be more soluble than API is to use coformers whose solubility is 10-fold higher than the API. Scott Childs (Renovo Research) brought in the phase diagram for optimizing drug and coformer components using four different experimental methods: reaction crystallization, sonic-slurry, high-throughput evaporative, and liquid-assisted grinding. Ram Jetti (Matrix Laboratories) gave case studies and examples of property enhancement of APIs in cocrystals, for ¨ rn example, hygroscopicity, solubility, and bioavailability. O Almarsson (Alkermes Inc.) highlighted the itraconazole-succinic acid (2:1) cocrystal prototype showing enhanced solubility comparable to Sporanox beads formulation of the amorphous phase. The cocrystal platform is ideally suited for waterinsoluble and poorly orally bioavailable APIs; however, dissolution and conversion dynamics of cocrystals during oral transit in the gastrointestinal tract is a challenge for future studies. Guru Row (Indian Institute of Science Bangalore) presented the charge density method for understanding intermolecular interactions and hydrogen bonds, a quantitative approach that could be useful to distinguish between the neutralsalt continuum, that is, for acid · · · pyridine O-H · · · N to pyridinium · · · carboxylate N+ H · · · O- states. Peter Stephens (SUNY Stony Brook) elaborated on powder X-ray diffraction fingerprint and quantitative characterization of new solid-state materials. In the absence of single crystal data, which can happen often enough with pharmaceutical solids, structure determination from powder data by Rietveld refinement is an excellent technique for polymorphic and cocrystal samples. Vishweshwar Peddy (Dr. Reddy’s Laboratories) illustrated case studies of heterosynthons for cocrystal design and engineering of APIs and polymorphism in cocrystals. Apart from the traditionally wellknown salts, hydrates and solvates of drugs, cocrystals between API and GRAS coformer present a new approach to solid form management. The concluding lecture of day 1 was by Stephen Byrn (Purdue University) on a Quality by Design (QbD) solubility enhancement platform for fast development of a “home run” solid. Thanks to 505(b)(2) regulation, it is possible to reformulate cocrystals in an accelerated time line of 52 weeks IND application.
10.1021/cg900554h CCC: $40.75 2009 American Chemical Society Published on Web 07/02/2009
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Crystal Growth & Design, Vol. 9, No. 8, 2009
Figure 1. A few of the students and speaker delegates at the Indo-U.S. workshop (L to R): Rajesh Goud, Surya Narayan, Palash Sanphui, Lalit Rajput, Jagadeesh Babu, Ranjit Thakuria, Bipul Sarma, Naı´r Rodrı´guezHornedo, Ashwini Nangia, Scott Childs, Ram Jetti, Anil Kumar, Kumar Biradha, and Vishweshwar Peddy.
Day 2 opened with a lecture on the crystallization mechanism by Allan Myerson (University of Chicago). Statistical information on the nucleation of polymorphs is possible in highthroughput experiments (1000-3000 crystallizations and up to 10 000 trials) by applying the concepts of self-assembled monolayers and Raman and optical microscopy characterization on multipolymorphic systems such as ROY, sulfathiazole, mefenamic acid, and glycine. Different polymorphs competitively nucleate in solution and the probability of each form crystallizing depends on supersaturation conditions. A two-step nucleation mechanism, from an amorphous like critical size to the crystal nucleus, is proposed. In the case of amorphous states and poor quality crystals, solid-state NMR with cross-polarization and magic-angle spinning is the best spectroscopy to know structural information on cocrystals and polymorphs. The effects of differences in relaxation parameters and cross-polarization efficiencies to determine if the material is a mixture of crystalline and/or amorphous forms were presented by Eric Munson (University of Kansas). Solid-state NMR spectroscopy for the characterization of cocrystals, salts, and polymorphs was presented. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD), excellent complementary techniques for knowing the pharmaceutical solid, was the theme of Raj Suryanarayanan (University of Minnesota). In particular, pharmaceutical hydrates and manufacturing-induced phase transitions are monitored by pressure DSC and powder XRD. Two students gave oral presentations of 15 min each. Tejender Thakur (Universiy of Hyderabad) described crystal structure prediction of cocrystals using the synthon approach, and Lalit Rajput (Indian Institute of Technology Kharagpur) gave examples of remote substitution effects on hydrogen bonding and molecular packing in crystal structures. Narasimha Moorthy (Indian Institute of Technology Kanpur) argued that sterically hindered biphenyls and a rigid molecular scaffold are ideal for guest inclusion. Guest molecules can reside in three different regions of the host architecture illustrated by 40 host-guest examples. Leonard MacGillivray (University of Iowa) initiated a discussion on reactivity of cocrystals, as templates for [2 + 2] photochemical dimerization of olefins. The organization of reactive functional groups in finite supramolecular assemblies, synthesis of target molecules such as stereochemical control in cyclo-
Perspectives
phanes and long [n]-ladderanes were demonstrated. Srinivasan Natarajan (Indian Institute of Science Bangalore) talked about porous metal-organic frameworks and classical inorganic structures. Strategies for the stabilization of porous structures having Kagome, R-Po, and diamond lattice were exemplified. Robin Rogers (University of Alabama) showed how the noncrystalline phase of ionic liquids is a fertile area to explore for APIs as liquid salts. IL-APIs, which are related to salts and cocrystals, have interesting chemical and biological properties. The day ended with a holistic view of Indian culture, religion, and science as seen through the eyes of Gautam Desiraju (University of Hyderabad). He showed examples of cocrystals from his early research and linked them to more recent pharmaceutical cocrystals and polymorphs. Kumar Biradha (Indian Institute of Technology Kharagpur) presented the difficulties and challenges in crystal engineering of multifunctional molecules, illustrated by the amide, acid, pyridine, and halogen groups. Rodolfo Pinal (Purdue University) addressed a classic problem in chemical thermodynamics, that is, crystal stability and solubility in polymorphic systems. The stability of crystal systems is related to their stability, and hence solubility to geometric motifs in crystal structures. Parathasarathi Dastidar (Indian Association of Cultivation of Science Kolkata) addressed issues faced by a crystal engineer in a laboratory with directed goals to make cubic habit NaCl by the addition of urea modifier. He showed 1D gels and 2D and 3D networks in organic crystals. Anil Kumar (Institute of Life Sciences, Hyderabad) exemplified synergistic pharmaceutical cocrystals of fluoroquinolone antibiotics with nutraceutical coformers. There is significant improvement in the physicochemical and pharmacokinetic properties of ciprofloxacin and norfloxacin cocrystals compared to their marketed forms. Michael Zaworotko (University of South Florida) gave the concluding lecture on the potential of green chemistry through cocrystal controlled solid-state synthesis, or C3S3, of new biologically active molecules. A relook at natural products of therapeutic potential by making their cocrystals will surely improve solubility and bioavailability. A lively debate on nomenclature issues in crystal engineering, starting from what is a cocrystal, or co-crystal, to definition of terms such as pseudopolymorph, solvate, host-guest compounds, etc. kept the audience arguing for over an hour. The Indo-U.S. joint meeting dates and venue coincided with the 38th National Seminar on Crystallography being held at the University of Mysore campus on February 10-13, 2009. In this way CG&D editors were able to participate in this meeting and project the ACS journal to Indian crystallographers.1 Both these crystallography meetings highlighted the high level of work going on in X-ray diffraction, crystal engineering, macromolecular crystallography, and crystallography computing. The overall Indian contribution to world crystallography activity (both small-molecule and macromolecular) is quite impressive given the small size of the Indian crystallography community.2 Incidentally, almost 17% of papers published in CG&D are from Indian authors. The solid state is becoming important at a time when the pharmaceutical industry is in much need of expertise and talent in these very topicsspolymorphs, cocrystals, salts, hydrates and patenting of novel forms. The Indo-U.S. workshop sent a clear message that the timing is right for Indian academia and pharmaceutical R&Ds to reap dividends through scientific collaborations and business partnerships. The fact that the new drug molecule discovery pipeline has slowed down worldwide is an excellent opportunity for Indian scientists and industry to create novel intellectual property of pharmaceutical forms.
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The meeting ended with all participants clicking good-bye snaps on a sunny morning in Mysore, and some of them stayed on to catch a flavor of India’s rich history, culture, and art. The idea of another Indo-U.S. workshop on cocrystals and polymorphs was unanimously approved. Persons interested in organizing the next meeting should check out www.indousstf. org.
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References (1) Rogers, R. D. Crystal Growth & Design in India. Cryst. Growth Des. 2009, 9, 1639. (2) Desiraju, G. R. Crystallography in India. IUCr Newslett. 2007, 15 (4), 4–21.
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