CRYSTAL GROWTH & DESIGN
Making Co-CrystalssThe Utility of Ternary Phase Diagrams Renato A. Chiarella,*,† Roger J. Davey,‡ and Matthew L. Peterson† TransForm Pharmaceuticals, 29 Hartwell AVenue, Lexington, Massachusetts 02421 and UniVersity of Manchester, School of Chemical Engineering & Analytical Science, P.O. Box 88, SackVille Street, Manchester M60 1QD, U.K.
2007 VOL. 7, NO. 7 1223
ReceiVed March 5, 2007; ReVised Manuscript ReceiVed May 20, 2007
ABSTRACT: We describe the use of ternary, isothermal phase diagrams of co-crystal-forming systems as a basis for understanding current crystallization methodologies and for experimental design in the preparation of co-crystals. Multicomponent solid phases of active pharmaceutical ingredients (APIs) have become increasingly important in the drug-development process, primarily because they offer an alternative to the physical properties of neat API solid phases.1,2 Co-crystals are a subset of these and are defined as crystalline materials in which two or more components are neutral molecules and solids at room temperature.3,4 Previously referred to as binary compounds or complexes, cocrystals were first identified in the 19th century by melt crystallization.5-7 Currently, solution crystallization is the preferred method for co-crystal formation, particularly to obtain single crystals for structure analysis.8,9 However, its apparent failure in a number of cases10,11 has led to the use of solid-state grinding and more recently, so-called “solvent drop” grinding techniques as alternatives to solution crystallization.12-14 These latter, empirical process developments are not well-understood and their success has lent an air of mystery to the preparative methodology of co-crystal formation. Thus, for example, Shan et al.14 reported on the preparation of a number of co-crystals of cyclohexan-1,3cis,5cistricarboxylic acid by grinding and attempted to rationalize their results by invoking the concept of kinetic enhancements due to orientational and conformational freedom at interfaces, molecular collisions, and formation of tiny seed crystals resulting from solvent addition. Such published examples of co-crystal crystallization demonstrate the various challenges involved in adding a new component to a binary system15 and in rationalizing the experimental outcome. Given these difficulties and the current high level of interest in solvent drop-grinding experiments, we set out to shed further light on why solution experiments might sometimes fail and why solvent drop-grinding experiments might work. In this communication, we explore the thermodynamic perspective of these crystallization procedures. As a model material, we chose the 1:1 co-crystal formed between trans-cinnamic acid and nicotinamide (Scheme 1). trans-Cinnamic acid (C) has two known polymorphs, R and β (with melting points of 134 and 133 °C, respectively).16,17 The stable solid phase at room temperature is the R phase. Nicotinamide (N) has four known polymorphs, I-IV, with the room-temperature stable phase I melting at 127 °C.18 The binary phase diagram for this two-component system (reproduced in Figure 1) has been determined.19 This shows C and N to form two polymorphs of a 1:1 co-crystal. These forms, I and II, have congruent melting points of 98.5 and 96.5 °C respectively; that is to say, the co-crystals and their melts have identical composition. Our attempts to grow the co-crystal from solution yielded results that appear to typify the apparent mystery surrounding co-crystal preparation. For example, a 1:1 mixture of R C and N I slurried in methanol at 20 °C converted into form I of the co-crystal, whereas the same experiment in water yielded R C, as determined by powder X-ray diffraction. * Corresponding author. E-mail:
[email protected]. † TransForm Pharmaceuticals. ‡ University of Manchester.
Scheme 1.
Molecular Structures of trans-Cinnamic Acid and Nicotinamide
Evaporation at room temperature of an undersaturated equimolar solution of C (0.03 mol fraction) and N (0.03 mol fraction) in methanol gave pure co-crystal I. Evaporation at room temperature of an undersaturated equimolar solution of C (0.0007 mol fraction) and N (0.0007 mol fraction) in water gave a mixture of R C, cocrystal I, and N I. Additionally, cooling of an undersaturated C (0.001 mol fraction) and N (0.001 mol fraction) solution in water from 105 to 20 °C gave pure R C. Solvent drop-grinding experiments of R C (0.1 mol fraction) and N I (0.1 mol fraction) in methanol, and R C (0.06 mol fraction) and N I (0.06 mol fraction) in water all yielded the co-crystal I. Recent work has shown that co-crystal solid-liquid equilibria can be described in terms of the solubility product and solution complexation of the components.20 This approach, however, was limited to half the co-crystal solubility curve and as a result does not help in the current context. Instead, we resolved to measure the essential phase equilibria and began by visualizing the effect of adding a solvent to the C and N co-crystal system through construction of the three-component phase diagrams in both water and in methanol. We note that C and N have similar solubilities in methanol but very different solubilities in water, where C is only sparingly soluble. The solubility curves of each solid phase were determined by allowing slurries with varying C to N ratios to equilibrate with stirring at constant temperature. All slurries were seeded with each solid phase, namely R C, N I, and co-crystal form I. Once the samples equilibrated, the solid phases were characterized using powder X-ray diffraction, and the concentrations of C and N in solution were determined using HPLC.21 The three-component phase diagrams for the C and N co-crystal system in methanol at 20 °C and in water at 50 °C are shown in Figures 2 and 3, respectively. In both cases, region 1 comprises undersaturated solutions and is bounded by the solubility curves of R C (a to b), the co-crystal (b to c), and N I (c to d). Thus, R C is the stable solid phase in region 2, the co-crystal is the stable solid phase in region 3, and N I is the stable solid phase in region 4. Regions 5 and 6 are invariant regions in which mixtures of the co-crystal and R C and the co-crystal and N I exist, respectively. Any mixture with total composition in regions 5 and 6 would be in equilibrium with the invariant points b and c, respectively, thus providing a quick way to determine the eutectic compositions (see Table 1).
10.1021/cg070218y CCC: $37.00 © 2007 American Chemical Society Published on Web 06/14/2007
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Communications
Figure 1. Two-component phase diagram for C and N.
Figure 2. Three-component phase diagram for C and N in methanol at 20 °C (mol fraction).
In methanol, the co-crystal undergoes congruent dissolution, and the solubility curve (b to c) of the co-crystal crosses the co-crystal component stoichiometric ratio line (e to f). This means that it is possible to crystallize the co-crystal by evaporating an undersaturated solution containing 1:1 stoichiometric amounts of C and N in solution (in Figure 2, this would involve moving from region 1 to region 3 away from the solvent apex on the dashed vertical line). Likewise, the co-crystal will also crystallize from a supersaturated methanol solution of 1:1 stoichiometric amounts of C and N. The equivalent ternary phase diagram measured using water as a solvent is shown in Figure 3. Here, it is evident that the region 3, in which the co-crystal is the stable phase, is skewed toward the N axis because of the wide difference in aqueous solubilities of R C and N I. This leads to the situation in which the co-crystal solubility curve does not cross the 1:1 stoichiometric ratio line, resulting in incongruent dissolution. The maximum co-crystal
solubility therefore does not lie at the co-crystal component stoichiometric ratio as in methanol. This means that the co-crystal is not stable when in contact with an aqueous solution having the 1:1 stoichiometic ratio. In changing the solvent from methanol to water, the co-crystal goes from a situation in which it dissolves congruently to one in which it dissolves incongruently. Because the co-crystal melts congruently at 98.5 °C and dissolves incongruently in water at 50 °C, there must be a temperature between the melting point and 50 °C at which this transition in behavior occurs. Above this temperature, it should be possible to crystallize pure co-crystal; however, below this temperature, pure co-crystal cannot be obtained. As shown in Figure 3, evaporative crystallization of a solution having 1:1 stoichiometry at 50 °C will result in the initial formation of R C followed by concomitant crystallization of the co-crystal as the system passes from region 2 to 5. Similarly, a supersaturated solution with 1:1 amounts of C and N at 50 °C would
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Crystal Growth & Design, Vol. 7, No. 7, 2007 1225
Figure 3. Three-component phase diagram for C and N in water at 50 °C (mol fraction). Table 1. Eutectic Compositions (as mol fraction) of C, N, and Solvent Determined by Equilibration in the Invariant Phase Diagram Regions solvent and temperature
xC
xN
xsolvent
solid phases in equilibrium
methanol at 20 °C methanol at 20 °C water at 50 °C
0.079 0.039 0.030
0.034 0.072 0.283
0.886 0.888 0.686
R C + co-crystal Ia co-crystal I + N I co-crystal I + N I
The R C + co-crystal I eutectic in water at 50 °C was not determined using this method but by the interception of the R C and co-crystal I solubility curves. a
yield either pure R C or a mixture of R C and the co-crystal depending on the amount of solvent relative to the other two components (regions 2 and 5 in Figure 3). Given that these thermodynamic data typify the possible behavior of co-crystal/solvent systems, the challenges and observed problems of co-crystal crystallization from solution may be rationalized. It is clear that crystallization from solutions of appropriate stoichiometry will not lead a priori to the appearance of co-crystals. Indeed, the range of compositions chosen in the search for co-crystals in any particular system must be dictated by the relative solubilities of the two components, with success being more likely in a solvent in which the solubilities of both components are similar. This clearly rationalizes our inability to crystallize the C and N co-crystal from water. The success of solvent drop-grinding experiments can now been seen to be due to the low solvent mole fractions, which dictate that crystallization takes place in a region in the phase diagram in which the co-crystal is more likely to be the stable solid phase (as this approximates toward the binary system); whether these can be reproduced in solution or not is still debatable. In three-component systems such as these, the way in which the eutectic points originating in the binary system (e1 and e2 in Figure 1) change with the addition of solvent is of key importance. If one of these points crosses the co-crystal stoichiometric ratio line (point b in Figure 3), then the kind of behavior observed from C and N in water will occur. If neither crosses, then the system will behave similarly to C and N in methanol. An idea of whether congruent
or incongruent dissolution will occur can be obtained from the relative solubility of the components: if they are similar, then it is quite likely that congruent dissolution will occur, whereas if they differ largely, then incongruent dissolution is likely. That is to say, the difference in solute-solvent interactions between each co-crystal component should be considered when selecting a solvent system. Note Added after ASAP Publication. This communication was released ASAP on June 14, 2007 with incorrect author affiliations. The corrected version posted on June 26, 2007.
References (1) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs, 2nd ed.; SSCI, Inc.: West Lafayette, IN, 1999. (2) Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O ¨ . J. Am. Chem. Soc. 2003, 28, 8456-8457. (3) Almarsson, O ¨ .; Zaworotko, M. J. Chem. Commun. 2004, 17, 18851896. (4) The term “pharmaceutical co-crystal” is defined as a crystalline material comprised of two or more unique solids at room temperature (22 °C), where at least one solid is an API and the co-crystal former is bound to the API via at least one hydrogen bond.22 (5) Miolati, A. Z. Phys. Chem. 1892, 9, 649-655. (6) Philip, J. C. J. Chem. Soc. 1903, 83, 814. (7) Kofler, L.; Kofler, A. Thermal Micromethods for the Study of Organic Compounds and Their Mixtures; Wagner: Innsbruck, Austria, 1952. (8) Bis, J. A.; Vishweshwar, P.; Middleton, R. A.; Zaworotko, M. J. Cryst. Growth Des. 2006, 6, 1048-1053. (9) Fleishman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.; Bailey Walsh, R. D.; Rodrı´guez-Hornedo, N.; Zaworotko, M. J. Cryst. Growth Des. 2003, 3, 909-919. (10) Trask, A. V.; van de Streek, J.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 2233-2241. (11) Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc. 1991, 113, 25862598. (12) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2004, 890-891. (13) Trask, A. V.; Haynes, D. A.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2006, 51-53. (14) Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 2372-2373.
1226 Crystal Growth & Design, Vol. 7, No. 7, 2007 (15) Henck, J.; Bernstein, J.; Ellern, A.; Boese, R. J. Am. Chem. Soc. 2001, 123, 1834-1841. (16) Groth, P. Chemische Kristallographie; Wilhelm Engelman: Leipzig, Germany, 1917. (17) Schmidt, G. M. J. J. Chem. Soc. 1964, 2014-2021. (18) Hino, T.; Ford, J. L.; Powell, M. W. Thermochim. Acta 2001, 374, 85-92. (19) Quehenberger, H. Monatsh. Chem. 1949, 80, 595-606. (20) Nehm, S. J.; Rodrı´guez-Spong, B.; Rodrı´guez-Hornedo, N. Cryst. Growth Des. 2006, 6, 592-600. (21) The equilibrium concentration of the components in solution was determined by allowing slurries of different C to N ratios to equilibrate. The slurries were magnetically stirred in 10 mL glass vials and maintained at constant temperature ((0.25 °C) using a circulating temperature bath (VWR Signature 1157). Aliquots were removed and filtered using a 0.2 µm GHP membrane filter (Pall Acrodisc 13) and diluted for HPLC analysis using methanol. Powder X-ray diffraction patterns were collected using a Bruker AXS D8
Communications Discover X-ray diffractometer with a Bruker AXS HI-STAR Area detector with CuKR radiation (λ ) 1.54 Å) at 40 kV and 40 mA; an automated x-y-z stage and a 0.5 mm collimator were used. The concentrations of C and N in solution were determined using an HPLC instrument (Waters 2695) coupled with a dual λ absorbance detector (Waters 2487) and used an Atlantis C18 4.6 × 150 mm, 5 µm. For C, the detection wavelength was setup at 273 nm, and a 10 min isocratic method with a mobile phase consisting of 60/40 water/ acetonitrile containing 0.1% trifluoroacetic acid was used. For N, the detection wavelength was setup at 225 nm, and a 5 min isocratic method with a mobile phase consisting of 97/3 25 mM potassium phosphate pH 3.0 in water/acetonitrile containing 0.1% trifluoroacetic acid was used. (22) Almarsson, O ¨ .; Hickey, M. B.; Peterson, M.; Zaworotko, M. J.; Moulton, B.; Rodriguez-Hornedo, N. Int. Pat. Appl. WO 2004/078163 A2, 2004.
CG070218Y
