DOI: 10.1021/cg900885n
Co-Crystallization in the Caffeine/Maleic Acid System: Lessons from Phase Equilibria
2010, Vol. 10 268–273
Kun Guo,*,† Ghazala Sadiq,‡ Colin Seaton,‡ Roger Davey,‡ and Qiuxiang Yin† †
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China, and The Molecular Materials Centre, School of Chemical Engineering and Analytical Sciences, The University of Manchester, P.O. Box 88, Manchester, UK M60 1QD
‡
Received July 28, 2009; Revised Manuscript Received October 12, 2009
ABSTRACT: Previous studies of the cocrystallizing system caffeine-maleic acid has shown the existence of 1:1 and 2:1 cocrystals together with a new polymorph of maleic acid. In this current work, we have attempted to rationalize this behavior through measurement of the binary and ternary phase diagrams.
Introduction The formation of cocrystals is currently receiving increased attention since they represent a class of materials with potential for exploitation to improve the physical or chemical properties of active pharmaceutical ingredients.1,2 While the uses of dry grinding, solvent drop grinding, and solvent crystallization have been reported as key preparative techniques,3-8 determination of the ternary phase diagram is likely to be an important aspect of the development of rational, large-scale preparative procedures using solution crystallization.9-12 In addition, such phase information can provide insights into the existence of metastable states and potential dissolution pathways. The work described in this paper was motivated by two factors. First, we have been aware of a number of reports in the literature in which, while searching for the occurrence of cocrystals workers have serendipitously discovered a new polymorph of one of the potential coformers. Thus, for example, Thallapally et al. discovered a new polymorph of 1,3,5-trinitrobenzene while attempting to prepare cocrystals with trisindane;13 Vishweshwar et al. reported the occurrence of a second polymorph of aspirin while performing crystallization experiments in 1:1 mixtures with levetiracetam;14,15 Wenger and Bernstein found two new sesquihydrates of oxalic acid while attempting to prepare 1:1 cocrystals of oxalic acid with glutamine and asparagine.16 Mei and Wolf utilized a similar idea in the preparation of new polymorphs of acridine in the presence of high loadings of dicarboxylic acids.17 Of particular interest in this context was the work of Day et al. in which a new polymorph of maleic acid was discovered during studies of the cocrystallizing system maleic acid and caffeine.18 In this case, a 2:1 cocrystal was prepared by grinding and dissolving in chloroform and upon evaporation the new polymorph of maleic acid appeared. It was noted that this outcome could not be repeated. A second motivating factor of our current work was an earlier paper from Trask et al.19 which provided more details of the preparation of both 1:1 and 2:1 cocrystals of maleic acid and caffeine. The 1:1 material was obtained by drop grinding with methanol and by evaporative crystallization from dichloromethane, although the authors noted that, like the maleic acid polymorph, this was *To whom correspondence should be addressed. pubs.acs.org/crystal
Published on Web 10/30/2009
not repeatable and indeed most solutions of 1:1 stoichiometry did not yield the cocrystal. Preparation of the 2:1 material appeared yet more complicated and was achieved either by dissolution of the components in chloroform/hexane solutions and adding n-hexane to effect a drown-out crystallization or through cogrinding. The authors confirmed the stoichiometry of this phase with NMR and reported a unit cell for the structure but were unable to obtain a full structure solution. Overall, it appeared difficult to effect controlled crystallization in this system with both stoichiometry and solvent affecting the balance of 1:1 and 2:1 cocrystals obtained. This cocrystallizing system thus seemed a suitable case for further work on two counts - first the unexpected appearance of a new polymorph of one of the coformers and second the apparently serendipity of the preparative methods for isolating the cocrystals. Hence, we set out confidently with the simple idea that if we determined the binary and ternary phase diagrams of caffeine/maleic acid/solvent we would be able to rationalize the stability regimes of the three solid phases: Form II of maleic acid and the 1:1 and 2:1 caffeine-maleic acid cocrystals. Experimental Section Materials. Maleic acid (99% chemical purity) and caffeine (99%) were sourced from Sigma-Aldrich and were used as received. Both compounds were initially characterized by X-ray powder diffraction (XRPD). Acetone (99%, purchased from VWR International), ethanol (analytical reagent grade, from Fisher Scientific), methanol (HPLC grade, from Fisher Scientific), and distilled deionized water were used with no further purification. Grinding Experiments. Dry grinding and drop grinding were performed with a Retsch MM200 Mixer Mill, equipped with two 10 mL stainless steel grinding jars and two stainless steel grinding balls. All grindings were performed at a rate of 30 Hz. Single Crystals. Single crystal X-ray diffraction data for the 1:1 cocrystal was collected on Bruker SMART CCD diffractometer. The selected crystal was mounted on the tip of a glass pin using Paratone-N oil and placed in the cold flow produced with an Oxford Cryocooling device. X-ray Powder Diffraction (XRPD). XRPD patterns were recorded on a Rigaku Miniflex X-ray powder diffractometer using Cu KR radiation (λ = 1.5406 A˚). Data were collected from 5° to 40° at a continuous scan rate of 0.03°/min. Differential Scanning Calorimetry (DSC). In order to determine the binary phase diagram, DSC data for the pure components, r 2009 American Chemical Society
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Table 1. The Solubilities of Maleic Acid and Caffeine in Five Solvents at 25°C solvent methanol ethanol acetone water chloroform
solubility of maleic acid g/100 g of solvent
solubility of caffeine g/100 g of solvent
g104.8 g105.2 33.4 (25.0% w/w) >120 ∼0
1.23 1.48 1.51 (1.48% w/w) ∼0 very high, not measured
physical mixtures of the components, the 1:1 cocrystal and 2:1 cocrystal were collected on a Mettler DSC 30. The heating rates used were in the range 1-10 °C/min under a nitrogen atmosphere. Solubility Determination. The solubility data of maleic acid and caffeine at 25 °C were measured using a gravimetric method. Slurries of maleic acid and caffeine in 30 mL of acetone were stirred for 3 days at 25 °C to ensure a state of equilibrium was achieved. After this time, samples of the saturated liquid phase were decanted from the slurries into Petri dishes of known mass and weighed. The samples were then evaporated to dryness and reweighed. Optical Microscopy. Crystallization of 1:1 stoichiometry was studied in a 3 mL covered cell. Optical micrographs were recorded using a Zeiss Axioplan 2 polarizing microscope and Linksys image capture software.
Results and Discussion Solvent Selection. In determining the phase diagram of the maleic acid-caffeine system the choice of solvent is an important variable. In this study, we investigated five solvents: methanol, ethanol, acetone, water, and chloroform. It is preferable to find a solvent in which both components have similar, measurable solubilities. Thus, we were looking for a solvent that would allow us to use a gravimetric method for solubility measurement and which would avoid extreme asymmetry in the ternary diagram. Unfortunately, the solubilities of maleic acid and caffeine show, not surprisingly, large differences in all solvents as seen in Table 1 ; the dicarboxylic acid is soluble in polar solvents while caffeine is not. In their studies of caffeine-dicarboxylic acid cocrystals, Trask et al. (presumably) avoided this problem by use of chloroform/methanol mixtures having ratios from 30:1 to 3.5:1. Crystallization was then induced either by evaporation or the addition of hexane as an antisolvent. We decided to avoid such two and three component solvent mixtures in our work and hence selected acetone as the solvent of choice, it offering the closest solubility of the components of the solvents tested. We then proceeded to check that we could make the known 1:1 and 2:1 cocrystal phases from acetone solutions. Preparation of Solid Phases 1:1 Caffeine/Maleic Acid Cocrystal. Caffeine (0.01 mol) and maleic acid (0.07 mol) were added to 30 mL of acetone at 25 °C and stirred for 5 min to dissolve the majority of the solid and create a mixture having the overall composition (4.51% caffeine, 22.99% maleic acid, 72.50% acetone) lying in region 4 of the ternary diagram (Figure 5). The stirring was stopped and after 1 h needle-like crystals of suitable size for single-crystal XRD were obtained. The unit cell parameters were found to be a = 6.7565(2), b = 12.4860(3), c = 15.7929(5) A˚, R = 90.00, β = 93.998(3), γ = 90.00, volume = 1329.07 A˚3, which agreed well with those reported previously by Trask et al. for the 1:1 cocrystal. Powder samples could also be prepared in this way, but in addition were made by both dry and solvent drop grinding. Dry grinding of maleic acid (1 mmol) and
Figure 1. XRPD patterns of all the compounds, from bottom to top: maleic acid, caffeine, 1:1 caffeine/maleic acid cocrystal, simulated 1:1 caffeine/maleic acid cocrystal, 2:1 caffeine/maleic acid cocrystal.
caffeine (1 mmol) for 90 min produced the 1:1 cocrystal and some residual caffeine, while solvent drop grinding (with 5 drops of acetone) of the same stoichiometry of maleic acid and caffeine produced pure 1:1 cocrystal. 2:1 Caffeine/Maleic Acid Cocrystal. Samples of the 2:1 caffeine/maleic acid cocrystal were prepared by dry grinding maleic acid (1 mmol) and caffeine (2 mmol) or, alternatively, from maleic acid (1 mmol), caffeine (2 mmol), and 5 or 10 drops of acetone ground for 90 min. It was observed that the 1:1 cocrystal would appear first (after about 1 min), and only after 30 min could the 2:1 cocrystal be found. A final mixture of 2:1 cocrystal and residual caffeine was obtained by dry grinding, but the addition of minor quantities (5 or 10 drops) of acetone reduced the amount of residual caffeine as judged by the absence of the 2θ = 12° peak in the XRPD. Attempts to prepare a single crystal by solvent crystallization from acetone solutions of 2:1 stoichiometry were unsuccessful. Powder patterns of the 1:1 cocrystal prepared by solvent crystallization in acetone and the 2:1 cocrystal obtained by acetone drop grinding are shown in Figure 1. They are compared with the XRPD of the starting materials and the calculated 1:1 XRPD. The XRPD of our 2:1 material is identical with that of Trask et al., see ref 19, Figure 6b. These data confirm that we were able to prepare the known cocrystal forms using a combination of solution mediated and grinding methodologies with acetone as a solvent. Form II of Maleic Acid. It proved impossible to obtain polymorph II of maleic acid using either the method reported by Day et al.18 or recrystallization of a 2:1 stoichiometry using acetone as a solvent. Even during the measurement of the ternary phase diagram it was never observed. Ostwald et al. recently demonstrated the crystallization of Form II from aqueous solutions at elevated pressure.20 It is evident that at the pressure above 0.5 GPa it is the stable phase but that it reverts to form I when the pressure is released. The Binary Maleic Acid/Caffeine Phase Diagram. The DSC curves of maleic acid, caffeine, 1:1 cocrystal, and 2:1 cocrystal are shown in Figure 2. The melting points of maleic acid, caffeine, 1:1 cocrystal, and 2:1 cocrystal are 138.7, 234.5, 104.1, and 118.4 °C, and their melting enthalpies are 26.9, 24.8, 30.4, 26.8 kJmol-1, respectively. It is noted that above its melting point maleic
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Figure 2. The DSC curve of pure and binary phases, from top to bottom: maleic acid, caffeine, 1:1 caffeine/maleic acid cocrystal, and 2:1 caffeine/maleic acid cocrystal (contaminated with a small amount of 1:1).
Figure 3. The ideal binary phase diagram and the measured points of maleic acid, caffeine, and the cocrystals (b). The measured eutectic temperatures are also indicated (9).
Figure 4. A schematic ideal binary phase diagram.
acid appears to decompose. This proved a serious issue in trying to establish the melting point of caffeine in the
presence of maleic acid and vice versa since once the eutectic temperature was reached the composition of the system
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Figure 5. The ternary phase diagram caffeine-maleic acid-acetone at 25 °C in mass%. (1) liquidus, (2) caffeine þ liquid, (3) caffeine þ 1:1 cocrystal þ liquid, (4) 1:1 cocrystal þ liquid, (5) maleic acid þ 1:1 cocrystal þ liquid, (6) maleic acid þ liquid. The hatched region describes the approximate zone in which the metastable 2:1 cocrystal appears. The data points for this figure are provided in the Supporting Information.
Figure 6. (a-f) The crystallization of the 1:1 cocrystal.
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changed due to decomposition. These thermal data, together with the equations of Schroeder-van Laar and PrigogineDefay,21 were thus used to construct the ideal binary phase diagram shown in Figure 3. The measured points for the pure phase materials and the eutectics have been included. The two calculated liquidus curves for the 1:1 and 2:1 cocrystals are indicated, and it can be seen that these are consistent with the measured eutectic temperatures. Since the calculated ideal liquidus curves of pure maleic and caffeine do not intersect those of the cocrystals in Figure 3, it appears from this ideal calculation that either the cocrystals are metastable states, which is not borne out by the DSC data or, more likely, the true liquidus curves, particularly for caffeine-rich liquids, deviate strongly from ideality due to liquid phase intermolecular interactions. Thus, Figure 4 shows a schematic binary phase diagram in which the liquidus curves of pure maleic acid and caffeine have been drawn to intersect those of 1:1 and 2:1 cocrystals, respectively. The two cocrystals’ liquidus curves also intersect giving, in total, three eutectic points. Comparison of Figures 3 and 4 now reveals the significant extent of nonideality which must exist on the caffeine-rich side of the binary system. The Ternary Maleic Acid/Caffeine/Acetone Phase Diagram. Figure 5 shows the caffeine-maleic acid-acetone
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phase diagram at 25 °C. It contains six regions and two eutectic points. Region 1 is the solution phase region where all materials are dissolved and the solutions are undersaturated. Regions 2 and 6 are the stability regimes of pure solid caffeine and maleic acid, respectively. The solubilities of caffeine and maleic acid in pure acetone are 1.48% (w/w) and 25.0% (w/w), respectively. The presence of maleic acid in acetone increases the solubility of caffeine to 4.28% (w/w), suggesting complexation of the two components in these dilute solutions, a feature which is consistent with the noted non ideality in the binary phase diagram of Figure 3. In contrast, the solubility of maleic acid is unchanged by the addition of caffeine in the more concentrated region of the phase diagram implying little change in relative strengths of the intermolecular interactions, again consistent with the binary system. Presumably, since caffeine is so weakly solvated by acetone, the presence of an H-bonding second solute can have a significant effect. Maleic acid on the other hand is already well solvated by acetone so that the addition of caffeine makes little difference. In region 3 crystals of pure caffeine and the 1:1 cocrystal are in equilibrium with a solution of invariant composition E1, while region 4 describes the stability zone of the 1:1 cocrystal. Its skewed nature is indicative of the problems encountered in using solvent evaporation to crystallize the 1:1 cocrystal.19 The hatched area in Figure 5 shows the region where the 2:1 cocrystal appeared. The data points shown represent the compositions of dry and drop grinding experiments (one with 5 drops and one 10 drops of acetone), which gave the 2:1 cocrystal in around 50% of experiments. This cocrystal could not be accessed by solvent crystallization in acetone. On the other hand if acetone is added to solid 2:1 cocrystal, a mixture of 1:1 cocrystal and caffeine can be found. With further addition of acetone, it is possible to put the overall mixture in domain 2 resulting in a suspension of pure caffeine and its saturated solution. These observations suggest that the stability region for the 2:1 cocrystal is metastable and submerged within region 3. These results indicate that while the 1:1 cocrystal is a stable phase, the 2:1 complex is metastable, at 25 °C, explaining why solution crystallization has not been successful. Interestingly, it appears that this situation is not true at the melting points since in the binary phase diagram the 2:1 complex is a stable form. This raises the possibility that at higher temperatures in the ternary system the 2:1 cocrystal may be stable if a solvent of higher boiling point were used. The dissolution trajectory of a 1:1 cocrystal may also be inferred from the ternary diagram. If acetone is added to a sample of cocrystal, a solution phase of the same caffeine/ maleic acid stoichiometry will initially be obtained. However, with increased addition of acetone the tie line joining the 1:1 solid composition to the 100% acetone apex rapidly enters region 3 so that a phase change must occur giving a solution phase of composition E1 in equilibrium with a mixture of solid caffeine and 1:1 cocrystal. On further solvent addition, the system will enter region 2 giving a solution in equilibrium with solid caffeine. Given the asymmetry of the solubilities of the coformers, this behavior will be mirrored in all pure solvents. Growth of 1:1 Cocrystal in Acetone. Having explored the thermodynamic aspects of this system, the kinetic processes involved in formation of the 1:1 cocrystal are shown in Figure 5. Optical micrographs were taken of a caffeine/maleic
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acid/acetone mixture having a starting composition of 5.81% caffeine, 24.3% maleic acid, and 69.89% acetone lying in region 4 of the phase diagram. The higher solubility of maleic acid leads to its rapid dissolution so that Figure 6a shows mostly particles of caffeine with only a few residual maleic acid crystals. In Figure 6b, taken 10 min later, the needle-like 1:1 cocrystal forms very rapidly (actually with stirring it forms in only 5 min). In this solution-mediated process, as the cocrystals grow larger so the caffeine dissolves. After 44 min, the transformation to pure 1:1 cocrystal is complete as seen in Figure 6f. Conclusions The results of our study of the caffeine maleic acid system have been mixed. We have failed to rediscover polymorph II of maleic acid or to grow a single crystal of the 2:1 cocrystal. On the positive side, however, we have mapped out a consistent preparative route to the 1:1 cocrystal. Study of this system has been complicated by problems brought about largely by the physical characteristics of the starting components - disparity in solubility characteristics of the pure components and thermal decomposition of maleic acid. The metastability of the 2:1 form now seems clear, but an explanation for the appearance of maleic acid form II in the work of Day et al.18 has eluded us. We can only admire the astute and careful experimentation that brought this to light. Overall, we are left with the realization that outcomes resulting from serendipitous use of such techniques as grinding and mixed solvent crystallization are not necessarily easy to rationalize through measurement of phase behavior. This has very important implications for the transfer of state of the art laboratory chemistry into commercial practice since if we cannot, through thermodynamic measurements, map out possible process temperatures and compositions then we have serious problems. Acknowledgment. The authors would like to express their gratitude to AstraZeneca and Chinese Scholarship Council for funding of this study. We thank Chris Muryn for help with single crystal XRD and Keith Chadwick and Simon Black for helpful discussions. Supporting Information Available: The data points in Figure 5 are available free of charge via the Internet at http://pubs.acs.org.
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(17) Mei, X. F.; Wolf, C. Cryst. Growth Des. 2004, 4 (6), 1099–1103. (18) Day, G. M.; Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem. Commun. 2006, 54–56. (19) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013–1021. (20) Oswald, I. D. H.; Chataigner, I.; Elphick, S.; Fabbiani, F. P. A.; Lennie, A. R.; Maddaluno, J.; Marshall, W. G.; Prior, T. J.; Pulham, C. R.; Smith, R. I. CrystEngComm 2009, 11, 359–366. (21) Jacques J.; Collet A.; Wilen S. H. John Wiley & Sons: New York, 1981; Chapter 2, p 46.
