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during crystal form selection. Importantdesign strategies for making cocrystals aredescribed, along with some recent examples harmaceutical
physical properties. Cocrystal screeningand synthesis are also covered, particu-larly using solid-state grinding andsolvent-drop selective cocrystal synthesis.
Cocrystals: An
Solid-State Modifications of APIs
Polymorphs
Emerging Approach
A polymorph is “a solid crystalline phase of a given compound resulting from thepossibility of at least two different arrange-ments of the molecules of that compound to Physical Property in the solid state.”2Different polymorphs
of a given compound each possess aunique set of physicochemical properties,and many, if not most, compounds exhibit Enhancement
polymorphism to some extent.1,3,4 Somecompounds exist in more than ten crystalform modifications.5 At present, it is not William Jones, W.D. Samuel Motherwell, and generally possible to computationally pre-dict the number of observable polymorphs of even the simplest molecules,6 and as aresult, the use of high-throughput screen-ing methods to search for new polymor- Abstract
Pharmaceutical cocrystals are crystalline molecular complexes containing therapeutic molecules. They represent an emerging class of pharmaceutical materialsoffering the prospect of optimized physical properties. This article highlights important Hydrates and Solvates
opportunities and challenges associated with the design and synthesis of pharmaceutical cocrystals. Cocrystallization is first placed into context with the more established approaches to physical property optimization of polymorph, hydrate, and part of the crystal structure. Most solvents, salt selection. A directed, intermolecular-interaction-based approach to cocrystal however, are biologically toxic; as a re- design is described. The enhancement of specific physical properties, such as sult, most solvate-containing crystals are dissolution rate and physical stability, is illustrated by summarizing several recent reports. Synthetic approaches to cocrystallization are considered; in particular, the selectivity and screening-related opportunities afforded by solid-state grinding and solvent-drop grinding methods are discussed. Finally, an outlook on future pharmaceutical products.7,8 It has been es- developments summarizes the growth potential in this field, especially with regard to targeted, informatics-driven cocrystal screening approaches.
molecules are capable of forming hy-drates.9,10 As a result of process-induced Keywords: biomedical, crystal growth, crystalline.
stresses, such as changes in temperature,pressure, or relative humidity, hydratesoften convert into anhydrous crystal Introduction
anhydrate can result in significant changes crystallize on its own or it crystallizes into one or more crystal forms that possess un- major issues, for example, during storage, pharmaceutical product. Initial R&D ef- desirable physical properties. In either case, forts center on the identification of a suit- dosage form appearance and integrity.
Pharmaceutical Salts
structure of the active pharmaceutical in- ifications of an API, including polymorphs, gredient (API) of a drug substance is se- salts, solvates, and hydrates. In addition to modifying the properties of an API.11–13 lected to optimize therapeutic properties, these established crystalline API modifica- Salt formation is an acid–base reaction be- selecting the physical form of an API rep- tions, pharmaceutical cocrystals, or crys- resents a strategic opportunity for opti- substance. It is an attractive strategy, be- solubility, dissolution rate, hygroscopicity, possess either acidic or basic functionality, physical stability, and chemical stability.1 solid APIs exist in the crystalline form.
MRS BULLETIN • VOLUME 31 • NOVEMBER 2006
Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement
Pharmaceutical Cocrystals
variety of possible counter-molecules that may form cocrystals with a single API.
Allen et al. demonstrated a quantification of the “robustness” of a certain class of called motifs, or synthons) involving strong studies have directly addressed the real- hydrogen-bonded bimolecular ring motifs.
ization of physical property modification.
(CSD), a searchable repository containing volved cocrystals of several nontoxic C4 (four-carbon) 1,4-dicarboxylic acids with structures.18 They assessed the robustness itraconazole, an antifungal drug with very herent benefits as compared with salt for- of a motif in terms of its “formation prob- low aqueous solubility in its crystalline mation in at least two ways. The first is ability,” that is, the observed frequency of free base form.23 The cocrystals reportedly that, at least in theory, all types of mole- motif formation among all structures con- cules can form cocrystals, including weakly form screen of itraconazole, and the acids in the study were known to be biologically are traditionally considered to present a ity suggested a greater utility in a cocrys- higher risk in terms of physical property levels.15 Single-crystal data were reported for one of the cocrystals, a 2:1 itraconazole: limited or no capacity for salt formation.
succinic acid cocrystal (Figure 1), where toxicological reasons only 12 or so acidic or basic counterions are explored in a typical to the synthesis of new cocrystal materials.
API salt screen,12,15 there are many poten- In the future, automated searches for for- tial counter-molecules that may be used in mation probabilities pertaining to the mo- profile as compared with itraconazole free lecular structure of an API of interest will may be defined as the species cocrystallized profiles of the cocrystals approached that with the API.) The U.S. Food and Drug Ad- ministration manages several lists of sub- had been developed for the specific aim of Pharmaceutical Cocrystals and
enhancing the dissolution rate of the API.
gredients (e.g., the FDA’s GRAS list, a list Physical Property Enhancement
safe”), with the total amount of substances cocrystal screening in addition to imple- significantly.19 In 2002, Oswald et al. demon- increased scope of cocrystals is a benefit strated cocrystallization of the analgesic the itraconazole:succinic acid cocrystal, in that it suggests a greater likelihood of profile for an API physical form, it also which was capable of acting as a hydrogen- than with the most basic site on the drug Zaworotko and co-workers reported cocrys- tals of the APIs ibuprofen, flurbiprofen, and ceptors.21 These examples served as early cocrystal design and more efficient cocrys- proof that a series of cocrystals with com- boxylic acid chain lengths other than C4 , Synthon Approach to Cocrystal
point data, however, these reports focused including malonic (C3), glutaric (C5), and essentially on structural features without adipic (C6) acids, were reportedly unsuc- addressing the functional properties that cessful. Until it becomes possible to confi- these cocrystals might offer. Additionally, will form cocrystals with a given API, high- of tremendous value to this research field.
proposed several “hydrogen-bond rules,” including the observations that (1) all good co-workers reported on a series of cocrys- of the API fluoxetine, the active ingredient tals of the API carbamazepine, a drug used in the antidepressant drug Prozac.24 This typically pairs with the best acceptor in a in the treatment of epilepsy, with a variety of different counter-molecules, including several that are biologically nontoxic, in- cluding acetic acid, nicotinamide (vitamin analysis17) assisted Etter and co-workers acid (HCl) salt of fluoxetine, generating in implementing rational cocrystal design charin.22 The report brought to light the three novel cocrystals of salts. For example, MRS BULLETIN • VOLUME 31 • NOVEMBER 2006
Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement
Figure 1. Crystal packing diagram and corresponding unit cell of the 2:1 itraconazole:succinic acid cocrystal.23 Carbon atoms are large andgray, hydrogen atoms are small and white, nitrogen atoms are blue, oxygen atoms are red, and chlorine atoms are green. addressed using caffeine as a model API.
with succinic acid to form a succinic acid cocrystal of the fluoxetine:HCl salt, with a physical instability as a function of rela- 2:1 caffeine:oxalic acid cocrystal, Figure 2), stoichiometry of 2:2:1 fluoxetine:chloride: was physically stable at all RH conditions succinic acid (see Structure 1). Significant
polymorph undergoes conversion to a crys- and all time points across the study. This talline hydrate upon exposure to high RH, rates of each of the three cocrystals were and the hydrate loses water below a criti- upon slurrying in water. The stability of observed, such that individual cocrystals cal RH and reverts to the anhydrate. This the caffeine:oxalic acid cocrystal is partic- were found to exhibit rates above, below, ularly remarkable given that both caffeine and comparable with that of the crystalline known to convert to crystalline hydrates.
cocrystals (and cocrystals of salts) with limited salt-forming capacity attributable The reason for this stability is currently to its weak basicity (its conjugate acid has of the wide supramolecular diversity that a reported pKa of 3.6), meaning that it is may be achieved via cocrystal design.
capable of forming salts only with strong Supramolecular Synthesis via
Solid-State Grinding
able salt of caffeine had been reported in Solid-state grinding is the act of mixing, the CSD, a caffeine HCl salt that existed as pressing, and crushing materials manually to obtain a series of cocrystals of caffeinethat could be measured with regard to RHstability.25 A strategy was devised wherebycaffeine cocrystallization was attemptedwith several pharmaceutically acceptabledicarboxylic acids of various chain lengths.
The strategy relied upon a caffeine-acidhydrogen-bond interaction that satisfiedthe hydrogen-bond rules, forming a motif Structure 1. Hydrogen-bond arrangement
Figure 2. Hydrogen bonding in a 2:1 that exhibited a good degree of robustness in the crystal structure of succinic acid caffeine:oxalic acid cocrystal. Carbon cocrystal of fluoxetine:HCl salt; taken atoms are large and gray, hydrogen atoms Six caffeine:dicarboxylic acid cocrystals are small and white, nitrogen atoms are were reported, and the results of storing MRS BULLETIN • VOLUME 31 • NOVEMBER 2006
Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement
cle size reduction, solid-state grinding may The ability of solid-state grinding to re- cocrystal material after significantly re- rials to induce covalent or supramolecular reactivity. In the context of pharmaceutical cocrystals, solid-state grinding has emerged to enable selective polymorphic synthesis recently as a viable synthetic alternative to transformations can bring disastrous con- solution-based crystallization methods. In cocrystals (Forms I and II).31 The two poly- synthesis by solid-state grinding offers en- cocrystals with caffeine and several mono- differed primarily in terms of the stacking of solution crystallization. Moreover, the carboxylic acids, solid-state grinding gen- of sheets, were first found to precipitate erated crystal forms which were initially concomitantly from solution. In an effort inaccessible from solution. In experiments involving caffeine and trifluoroacetic acid, tion in cocrystal screening efforts.
cocrystal material synthesis was initially found to be possible only via grinding.
found that solid-state grinding of caffeine demonstration of the application of solid- state grinding to pharmaceutical cocrystal nantly Form I and that solvent-drop grind- synthesis in a study of six cocrystals of the upon the quantity of starting material in sulfa drug sulfadimidine with various car- hexane, and heptane) also produced Form I boxylic acids, including anthranilic acid in the absence of Form II. Alternatively, (AA) and salicylic acid (SA).26 Addition- seeds obtained by grinding, cocrystal ma- the grinding of starting materials in the strated for one particular cocrystal, the presence of more polar solvents (acetoni- sulfadimidine:AA cocrystal. In a grinding trile, chloroform, and water). A possible method was used to obtain a single crystal factor that may have had a role in this ob- SA cocrystal, for which the crystal struc- for one of the structures, which confirmed served selectivity was the observation of a the initial PXRD structure solution of that been reported of stoichiometric selectivity Enhanced Supramolecular
Selectivity via Solvent-Drop
In addition to the ability of solvent-drop Grinding
based their explanation for the preference stoichiometric selectivity in cocrystalliza- on the relative strengths of hydrogen bond- ing in the ingoing homomeric acid crystals.
supramolecular selectivity in certain cocrys- strated as a way of interconverting crystal In extending these results to pharmaceuti- tal systems. Termed “solvent-drop” grind- ing, this method allows for stoichiometric acid.32 In the case of succinic acid, grind- might be used to assess the stability of a given pharmaceutical cocrystal material in grinding of two materials together, as with the presence of excipients (i.e., substances solid-state grinding, but with the addition of a minor quantity of solvent (typically a crystallize only at high temperatures. AA, few tenths of one equivalent of solvent per be encountered in the course of a formula- mole of starting material). The added sol- versions between the three different poly- catalytic role, in that the quantities em- described in the previous section, whereas ployed are small and the solvent is not a single crystals were obtained by solution component of the final cocrystal product.
growth, it was reported that most cocrys- tals could also be prepared by grinding to- gether the reactants in a ball mill. This application with regard to crystalline salt system involving several cocrystals of ni- trogenous bases with a cyclohexanetricar- screening is an important aspect of physi- boxylic acid derivative, all of which were cal property optimization, as well as intel- cocrystals. Solid-state grinding was often initially prepared by solution growth. It lectual property protection, for many API candidates. Much effort, increasingly using of preparing cocrystal materials for the in- readily prepared by solid-state grinding, high-throughput robotics, is expended in re- vestigation of hydrogen-bond preferences.
vealing all potential salts (and polymorphs cocrystal content after grinding together of salts) to ensure that the salt selection is they reported that certain cocrystal modi- starting materials for a significant time.
For those that did not proceed to completion MRS BULLETIN • VOLUME 31 • NOVEMBER 2006
Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement
techniques, which are most common in cur- 9. S.R. Vippagunta, H.G. Brittain, and D.J.W.
rent polymorph and salt screens, require a Grant, Adv. Drug Deliv. Rev. 48 (2001) p. 3.
10. A.L. Gillon, N. Feeder, R.J. Davey, and R.A.
Storey, Cryst. Growth Des. 3 (2003) p. 663.
to cover variables such as solvent system 11. P.L. Gould, Int. J. Pharm. 33 (1986) p. 201.
12. L.D. Bighley, S.M. Berge, and D.C.
choice, concentration, and heating or cool- Monkhouse, in Encyclopedia of Pharmaceutical Technology, Vol. 13, edited by J. Swarbrick and such as solid-state grinding, as well as the J.C. Boylan (Marcel Dekker, New York, 1996).
13. R.J. Bastin, M.J. Bowker, and B.J. Slater, Org. grinding, appear to offer a highly efficient Process Res. Dev. 4 (2000) p. 427.
alternative for offering evidence of whether 14. P.H. Stahl and C.G. Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Verlag Helvetica Chimica Acta, Zurich, 2002).
anthranilic acid (AA) polymorphs via the melt using techniques such as thermal 15. P.H. Stahl and C.G. Wermuth, Eds., Mono- graphs on Acids and Bases, in Handbook of Phar- maceutical Salts: Properties, Selection and Use (Verlag Helvetica Chimica Acta, Zurich, 2002).
nity to screen for cocrystals with minimal 16. M.C. Etter, J. Phys. Chem. 95 (1991) p. 4601.
Conclusions and Outlook
17. M.C. Etter, Acc. Chem. Res. 23 (1990) p. 120.
18. Allen, F. H., Acta Crystallogr. B58 (2002) p. 380.
cocrystallization will be of increasing im- 19. Ö. Almarsson and M.J. Zaworotko, Chem. solid form selection in the near future.
20. I.D.H. Oswald, D.R. Allan, P.A. McGregor, by targeted, efficient cocrystal screening W.D.S. Motherwell, S. Parsons, and C.R. Pul-
ham, Acta Crystallogr. B58 (2002) p. 1057.
21. R.D. Bailey Walsh, M.W. Bradner, S. Fleisch- man, L.A. Morales, B. Moulton, N. Rodriguez- that indicate the ability of cocrystals to Hornedo, and M.J. Zaworotko, Chem. Commun. ble counter-molecules that may be consid- ered in a cocrystal screen with an API is a 22. S.G. Fleischman, S.S. Kuduva, J.A. McMa- significant benefit of this approach, but hon, B. Moulton, R.D.B. Walsh, N. Rodriguez- offers challenges in terms of screening ef- Hornedo, and M.J. Zaworotko, Cryst. Growth portant for the successful implementation Des. 3 (2003) p. 909.
of cocrystallization in the pharmaceutical 23. J.F. Remenar, S.L. Morissette, M.L. Peterson,B. Moulton, J.M. MacPhee, H.R. Guzmán, and to be explored in a given cocrystal screen, Ö. Almarsson, J. Am. Chem. Soc. 125 (2003)
especially if ternary systems are to be con- sidered (e.g., three-component cocrystals Acknowledgments
24. S.L. Childs, L.J. Chyall, J.T. Dunlap, V.N.
and cocrystals of salts). Current crystal Smolenskaya, B.C. Stahly, and G.P. Stahly, J. Am. Chem. Soc. 126 (2004) p. 13335.
25. A.V. Trask, W.D.S. Motherwell, and W.
Jones, Cryst. Growth Des. 5 (2005) p. 1013.
26. M.R. Caira, L.R. Nassimbeni, and A.F.
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MRS Materials Connections
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cocrystal screening efforts. Solution-based MRS BULLETIN • VOLUME 31 • NOVEMBER 2006

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