DOI: 10.1021/cg901002y
2009, Vol. 9 4208–4211
The Reemergence of Cocrystals: The Crystal Clear Writing Is on the Wall Introduction to Virtual Special Issue on Pharmaceutical Cocrystals
Introduction A virtual special issue on Pharmaceutical Cocrystals is presented herein by Crystal Growth & Design. Thirty-four invited or contributed manuscripts that have been published in Crystal Growth & Design as they were accepted are presented in an online table of contents (http://pubs.acs. org/page/cgdefu/vi/1) that links all the articles and presents them as a coherent body of work on the topic of cocrystals. The manuscripts illustrate how cocrystals have recently reemerged as a diverse and relevant research field within solid-state chemistry and pharmaceutical science. Manuscripts focus upon a broad range of subjects from traditional crystal engineering to structure-property relationships and illustrate how cocrystals are often studied through collaborations, both within academia and between academia and industry. This virtual special issue contains 34 contributions1-31 that reflect the reemergence of cocrystals in the past 5 years as exemplified by the frequency of cocrystal structures that have been archived in the Cambridge Structural Database (CSD)32 over the past 20 years (Figure 1). Cocrystals are a long-known but relatively little studied subset of solid-state chemistry. Quinhydrone, the prototypal cocrystal, was studied at least as far back as 1844 by Friedrich W€ ohler;33 yet, despite their ready accessibility and potentially great diversity, they represent only ca. 0.5% of the crystal structures that have been archived in the CSD. Recent interest in cocrystals can be attributed to both scientific and practical matters: crystal engineering34 means that cocrystals are amenable to design (i.e., CSD statistics, supramolecular synthons) in a way that other crystal forms such as polymorphs, solvates, hydrates are not; the realization by pharmaceutical scientists that physical properties of practical importance such as solubility and stability can be dramatically impacted or even controlled via cocrystal formation.28,35 The collection of invited or contributed manuscripts that is highlighted herein has been published in Crystal Growth & Design over the past year or so. Traditionally, a special issue prints all of the invited articles in a single printed issue. However, rather than imposing strict deadlines on the authors and holding up publication of the issue until all of *To whom correspondence should be addressed. (S.L.C.) Renovo Research, 1256 Briarcliff Road NE, Atlanta, GA 30306. E-mail:
[email protected]. (M.J.Z.) Department of Chemistry, CHE205, University of South Florida, Tampa, FL 33620. E-mail:
[email protected]. pubs.acs.org/crystal
Published on Web 08/31/2009
Figure 1. Frequency of occurrence of organic molecular cocrystals in the Cambridge Structural Database from 1988 to 2007. For the purposes of this graph, cocrystals are distinct from solvates, hydrates, and simple salts.
Figure 2. The author affiliation for each of the 34 manuscripts was categorized as follows: (1) all authors are from an academic institution, (2) all authors represent an industrial or private company, or (3) there are authors from both an academic institution and an industrial or private company. The percentage of papers in each category is indicated.
the manuscripts were finalized, each contribution was published individually after it was accepted in a printed issue. In this virtual special issue, we have collated these 34 contributions such that they will appear online as if in a single printed issue. As such, all articles are presented together in a virtual table of contents and there is even a cover illustration. Grouping these articles into a virtual collection highlights the related, often collaborative, work that ties the cocrystal community together: about 53% of the articles are from r 2009 American Chemical Society
Crystal Growth & Design, Vol. 9, No. 10, 2009
Editorial
4209
Figure 3. The 34 manuscripts in this virtual special issue can be grouped into nine categories. The number of manuscripts in each category is indicated in the graph.
academic institutions; 26% are from industrial/private companies; 21% represent academic/industrial collaboration (Figure 2). It is not by chance that almost half of the articles list at least one author from an industrial or private company. The role that the pharmaceutical industry has played in the development of this field has been beneficial to the academic community by providing funding as well as a practical application that fits well with the goals of the academic community and graduate student training. The pharmaceutical industry has benefitted because it is not practical to perform the fundamental R&D required to develop a field such as pharmaceutical cocrystals. Thus, it is unsurprising that a significant amount of industrial research and collaborative industrial/academic research appears in this issue. In lieu of any statistical evidence, we make the assumption that the amount of industry involvement (and private funding of R&D) in this field is more extensive than most other academic niches. There are 18 manuscripts (53%) for which all of the authors are from a single group or the same department within an institution. The remaining 16 manuscripts (47%) represent collaborations between at least two different groups (e.g., different institutions or different departments within a single institution, without regard to academic or industrial affiliation). The high degree of collaboration reflects the multidisciplinary nature of the current body of work and indicates a healthy and maturing field of study. The 34 manuscripts in this virtual special issue can be grouped in to nine categories based on the focus of the manuscript (Figure 3). These different categories reveal the current topics of interest in the field of pharmaceutical cocrystals. Perspectives The manuscripts in this virtual special issue on Pharmaceutical Cocrystals begin, appropriately, with a historical perspective of cocrystals. Stahly1 presents an interesting historical perspective as he reviews the cocrystal literature published before 2000. A second perspective article by Nangia and Rodriguez-Hornedo2 highlights a bilateral United States-Indian conference that was held in Mysore, India, in February 2009. Crystal Engineering Manuscripts addressing the fundamentals of crystal engineering were submitted by a group of authors that are familiar names in the field: Nangia, Aaker€ oy, Bernstein, and Desiraju.
These authors carefully considered the role of specific intermolecular interactions between the cocrystal formers and how the manipulation of these interactions can be used as a tool to direct a system toward a targeted multicomponent molecular assembly. Nangia3 investigated the effect of π-π stacking in cocrystal stabilization as well as the role of the cocrystal former as an additive that can influence the polymorphic form of the primary molecule in the experiment when cocrystal formation does not occur. Aaker€ oy4 investigated an interaction that does not receive as much attention in the literature - the halogen bond. They demonstrated that the halogen bond, while not as reliable as the hydrogen bond, can still be used in a secondary role along with a more traditional hydrogen bond to yield a predictable supramolecular motif. Bernstein5 reported a cocrystal between urea and imidazolidone that contains an unusual structural motif and takes advantage of graph set analysis to evaluate this peculiar motif. Desiraju6 evaluated five crystal structures of multicomponent crystals containing either lamivudine or zidovudine (anti-HIV drugs) in order to compare the ability to predict or target rational cocrystals of a given drug compound with a more empirical approach to discovering cocrystals based on screening experiments. Salts and Cocrystals There has been considerable discussion in the literature concerning the distinction and relationship between cocrystals and salts since at the very least there is a continuum between cocrystals and salts.36 This topic was addressed in two manuscripts in this special issue. Nangia7 continues his ongoing investigation of salts and cocrystals with a contribution that focuses on the motifs that result when carboxylic acid, pyridine, amine, and hydroxyl groups are all present in a multicomponent system. Tocher and Price8 evaluate the interactions of pyridines and carboxylic acid groups. Of particular interest are the computational results presented indicating that the structure can be more accurately modeled when the correct location of the acidic proton is used. Cocrystal Synthesis and Experimental Methods With the increased interest in cocrystals, it is not surprising that the experimental methods used to synthesize them have become more evolved. Zaworotko9 reported 17 new cocrystals containing acid-pyridine and hydroxyl-pryidine interactions and compared the formation of these and other previously reported cocrystals using solvent drop grinding
4210
Crystal Growth & Design, Vol. 9, No. 10, 2009
and slow evaporation techniques. Rades10 focused on the formation of carbamazepine-nicotinamide cocrystals via cogrinding using an array of initial conditions and evaluated the stability of the product. Friscic and Jones11 contributed a comprehensive review on the topic of cocrystal formation through grinding and present a discussion on the current understanding of the mechanisms of mechanochemical cocrystallization. This work is featured on the cover of this special issue. Although cocrystal formation by grinding has been very successful for a number of groups, there have also been considerable advances in the understanding of cocrystal formation in solution. ter Horst and Cains12 reported the use of saturation temperatures of the components to determine the appropriate concentration regions where cocrystals are expected to form in solution. Puel and colleagues at Sanofi Aventis13 used in situ ATR-FTIR spectroscopy to investigate the kinetics of cocrystal formation in solution. This kind of methodology is essential to the successful formation and/or processing of cocrystals on an industrial scale. Cocrystal Screening and Characterization Results As Desiraju has noted,6 cocrystal screening is an important part of the overall process of investigating multicomponent structures. Three contributions were studies in which a compound of interest was screened against a variety of cocrystal formers in order to discover new cocrystals and then the resulting cocrystals were characterized. Hilfiker and Blatter14 reported the successful screening of the active pharmaceutical ingredient (API) piracetam. Crystal structures for five of the cocrystals are reported and discussed. Bernstein and Hickey15 collaborated to screen benzo-[18]crown-6 against urea and thiourea plus their derivatives and characterized the resulting cocrystals. MacGillivray and Zhang16 screened caffeine against an array of structural isomers of aromatic carboxylic acids using an advanced solvent-mediated phase transformation technique and discovered and characterized nine new caffeine cocrystals.
Childs and Zaworotko
the characterization of cocrystals. Brittain21 submitted two manuscripts on the use of vibrational spectroscopy as a tool for investigating the formation of salts and cocrystals of benzylamine and benzoic acid and benzamide and benzoic acid. Gladden and co-workers at University of Cambridge22 reported on the use of terahertz time-domain-spectroscopy (THz-TDS) in order to distinguish isostructural cocrystals of APIs with chiral and racemic coformers. Calculations and Statistical Analysis A great deal of progress can be made in the field of cocrystals without stepping into a lab! Four manuscripts reported results based on data available in the Cambridge Structural Database (CSD), and one article focuses on the question of whether cocrystals can be computationally predicted. Zaworotko23 investigated the persistence of the familiar and iconic carboxylic acid-pyridine interaction when a hydroxyl group is also present in a structure through the use of CSD statistics and 15 new structures that were reported in the manuscript. The results indicated that supramolecular heterosynthons are generally favored over homosynthons but that hydroxyl groups can interfere with the carboxylic acid-pyridine interaction. Fabian24 calculated molecular descriptors for molecules in cocrystals extracted from the CSD and statistically determined that the strongest correlation that matched molecules most likely to cocrystallize involved shape and polarity. Steed25 reported that molecules that crystallize with Z0 > 1 are more likely to form cocrystals compared to molecules that form single component crystals with Z0 = 1. Childs and Wood26 reported the use of the Materials module of the computer application Mercury CSD to analyze 50 cocrystals containing the API carbamazepine. Price27 investigated the prediction of cocrystal formation by comparing the relative stability of the cocrystal and the pure components. Structure-Property Relationships
The discovery and understanding of cocrystals containing different stoichiometries of the components is a relatively recent topic in the current literature, and the three manuscripts submitted on this topic should attest to its importance. Peterson17 reported a novel solid solution of isonicotinamide with fumaric and succinic acids. The system was characterized by DSC and powder diffraction to indicate that the solid solutions were a single phase and not a mixture of phases. Seaton and Bladgen18 investigated the formation of 1:1 and 2:1 cocrystals of benzoic acid and isonicotinamide, and the results indicate that solvent plays a role in controlling the crystal form obtained. Rodriguez-Hornedo19 reported the investigation of 2:1 and 1:1 cocrystals of carbamazepine and 4-aminobenzoic acid, and the conditions that govern the stability of the cocrystals are reported in the context of the phase solubility and triangular phase diagrams.
In order to find practical application in the pharmaceutical industry, it is essential that cocrystals demonstrate improved properties that make them advantageous compared to other forms of the API. As the field is maturing, the focus is shifting from understanding cocrystals from a supramolecular perspective to the investigation of structure-property relationships in order to generate improved materials in a more reliable manner. Schultheiss and Newmann28 reviewed the physical property improvements based on cocrystals that have been reported in the literature in the last 10 years. Bak submitted two manuscripts29 that investigated the structure-property relationships in a large set of cocrystals of an API under development at Amgen. Zhao and Xiong30 investigated isotropic effects in a hydrated cocrystal system when water was substituted by deuterated water. Rodriguez-Hornedo31 published two articles on this topic. One revealed that cocrystal solubility is directly proportional to the component solubility in the systems that were studied. A second contribution on structure-property relationships by Rodriguez-Hornedo describes the relationship between solubility and pH in cocrystal systems.
Techniques for Analysis of Cocrystals
Conclusions
As our understanding of cocrystals becomes more complex, the need for more sophisticated analysis techniques escalates. Four manuscripts focus on advanced cocrystal characterization techniques. Vogt20 published a comprehensive discussion on the application of solid-state NMR (SSNMR) for
An introduction to this special issue on pharmaceutical cocrystals would not be complete without addressing nomenclature and definitions. Most authors published in this special issue would agree with a statement such as “a cocrystal is a multicomponent crystal”. However, there is little agreement
Controlling Cocrystal Stoichiometry
Crystal Growth & Design, Vol. 9, No. 10, 2009
Editorial
concerning what the definition of a “component” might be. The opinions expressed in this special issue did little or nothing to resolve this conflict and even demonstrated that, if anything, the diversity of nomenclature surrounding this topic is increasing. For example, all of the following terms were used in this special issue to refer to a “cocrystal”: cocrystal, co-crystal, multicomponent crystal, molecular crystal, complex, molecular complex, multicomponent molecular complex, neutral molecular complex, multicomponent solid, mixed crystal, multi-component molecular crystal, multiple component crystal, molecular compound, heteromolecular crystal, and solid-state complex. A second example of nomenclature for which there disagreement exists is exemplified by the secondary component of the cocrystal, which was referred to as follows in this special issue: co-crystal former, ligand, coformer, cocrystal former, component, compound, molecular component, molecule, molecular species, organic compound, guest, and supramolecular reagent. A third such example of nomenclature is found in the variety of terms used in this special issue to describe the formation of cocrystals by grinding: grinding, mechanochemistry, mechanochemical synthesis, solvent drop grinding (or solvent-drop grinding or SDG), wetgrinding, liquid-assisted grinding, co-milling, neat grinding, dry grinding, solid-state grinding, co-grinding, and milling. There is a need to come to common ground on these matters since it would be beneficial and less confusing to readers if the community were able to agree on a more consistent set of terms. Fortunately, there were few cases, if any, for which it was unclear what the author meant. The matter of nomenclature tends to be primarily of academic interest and as noted by an industrial participant at a workshop on pharmaceutical cocrystals, “You can call them cabbages for all I care - what matters is whether or not they work”. Concerning the latter it seems clear that cocrystals can and do profoundly change physicochemical properties and thereby offer a degree of control over properties that is not feasible in a single compound crystal. Therefore, the proverbial “writing is on the wall” and cocrystals will surely continue to attract attention from solid-state chemists and pharmaceutical scientists because they offer such diversity in structure, composition, and properties.
References (1) Stahly, G. P. Cryst. Growth Des. 2009, published online, DOI: 10.1021/cg900873t. (2) Nangia, A.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 3339–3341. (3) Sarma, B.; Reddy, L. S.; Nangia, A. Cryst. Growth Des. 2008, 8, 4546–4552. (4) Aaker€ oy, C. B.; Schultheiss, N. C.; Rajbanshi, A.; Desper, J.; Moore, C. Cryst. Growth Des. 2009, 9, 432–441. (5) Deutsch, Z.; Bernstein, J. Cryst. Growth Des. 2008, 8, 3537–3542. (6) Bhatt, P. M.; Azim, Y.; Thakur, T. S.; Desiraju, G. R. Cryst. Growth Des. 2009, 9, 951–957. (7) Sarma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A. Cryst. Growth Des. 2009, 9, 1546–1557. (8) Mohamed, S.; Tocher, D. A.; Vickers, M.; Karamertzanis, P. G.; Price, S. L. Cryst. Growth Des. 2009, 9, 2881–2889. (9) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 1106–1123. (10) Chieng, N.; Hubert, M.; Saville, D.; Rades, T.; Aaltonen, J. Cryst. Growth Des. 2009, 9, 2377–2386. (11) Friscic, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621–1637. (12) ter Horst, J. H.; Deij, M. A.; Cains, P. W. Cryst. Growth Des. 2009, 9, 1531–1537. (13) Gagniere, E.; Mangin, D.; Puel, F.; Bebon, C.; Klein, J. P.; Monnier, O.; Garcia, E. Cryst. Growth Des. 2009, 9, 3376–3383.
4211
(14) Viertelhaus, M.; Hilfiker, R.; Blatter, F.; Neuburger, M. Cryst. Growth Des. 2009, 9, 2220–2228. (15) Wishkerman, S.; Bernstein, J.; Hickey, M. B. Cryst. Growth Des. 2009, 9, 3204–3210. (16) Bucar, D. K.; Henry, R. F.; Lou, X. C.; Duerst, R. W.; MacGillivray, L. R.; Zhang, G. G. Z. Cryst. Growth Des. 2009, 9, 1932–1943. (17) Oliveira, M. A.; Peterson, M. L.; Klein, D. Cryst. Growth Des. 2008, 8, 4487–4493. (18) Seaton, C. C.; Parkin, A.; Wilson, C. C.; Blagden, N. Cryst. Growth Des. 2009, 9, 47–56. (19) Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 889–897. (20) Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards, A. J.; Pham, T. N.; Watson, S. A. Cryst. Growth Des. 2009, 9, 921–937. (21) (a) Brittain, H. G. Cryst. Growth Des. 2009, 9, 3497– 3503. (b) Brittain, H. G. Cryst. Growth Des. 2009, 9, 2492–2499. (22) Parrott, E. P. J.; Zeitler, J. A.; Friscic, T.; Pepper, M.; Jones, W.; Day, G. M.; Gladden, L. F. Cryst. Growth Des. 2009, 9, 1452– 1460. (23) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2008, 8, 4533–4545. (24) Fabian, L. Cryst. Growth Des. 2009, 9, 1436–1443. (25) Anderson, K. M.; Probert, M. R.; Whiteley, C. N.; Rowland, A. M.; Goeta, A. E.; Steed, J. W. Cryst. Growth Des. 2009, 9, 1082–1087. (26) Childs, S. L.; Wood, P. A.; Rodriguez-Hornedo, N.; Reddy, L. S.; Hardcastle, K. I. Cryst. Growth Des. 2009, 9, 1869–1888. (27) Issa, N.; Karamertzanis, P. G.; Welch, G. W. A.; Price, S. L. Cryst. Growth Des. 2009, 9, 442–453. (28) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950–2967. (29) (a) Stanton, M. K.; Bak, A. Cryst. Growth Des. 2008, 8, 3856–3862. (b) Stanton, M. K.; Tufekcic, S.; Morgan, C.; Bak, A. Cryst. Growth Des. 2009, 9, 1344–1352. (30) Chen, L.; Zhao, H.; Ge, J.; Xiong, R.; Hu, H. Cryst. Growth Des. 2009, published online, DOI: 10.1021/cg900348x. (31) (a) Bethune, S. J.; Huang, N.; Jayasankar, A.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, published online, DOI: 10.1021/ cg9001187. (b) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 2252–2264. (32) Allen, F. H. Acta Crystallogr. 2002, B58, 380–388. (33) W€ ohler, F. Justus Lieb. Ann. Chem. 1844, 51, 153. (34) (a) Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647–678. (b) Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam, 1989. (c) Etter, M. C. J. Am. Chem. Soc. 1982, 104, 1095–1096. (d) Moulton, B.; Zaworotko, M. J. Chem. Rev. 2001, 101, 1629–1658. (35) Review articles that address the subject of pharmaceutical cocrys€ Zaworotko, M. J. Chem. Commun. 2004, tals: (a) Almarsson, O.; 1889–1896. (b) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499–516. (c) Shan, N.; Zaworotko, M. J. Drug. Discov. Today 2008, 13, 440–446. (d) Meanwell, N. A. Annu. Rep. Med. Chem. 2008, 43, 373–404. (e) Miroshnyk, I.; Mirza, S.; Sandler, N. Exp. Opin. Drug. Del. 2009, 6, 333–341. (f) Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617–630. (g) Blagden, N.; Berry, D. J.; Parkin, A.; Javed, H.; Ibrahim, A.; Gavan, P. T.; De Matos, L. L.; Seaton, C. C. New J. Chem. 2008, 32, 1659–1672. (h) Trask, A. V. Mol. Pharmaceutics 2007, 4, 301–309. (i) Cooke, M. W.; Stanton, M.; Shimanovich, R.; Bak, A. Amer. Pharm. Rev. 2007, 10, 54–59. (36) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323–338.
Scott L. Childs* Guest Editor Renovo Research/Triclinic Labs Michael J. Zaworotko* Associate Editor University of South Florida
