DOI: 10.1021/cg100361y
Cocrystal Formation from Solvent Mixtures
2010, Vol. 10 3237–3241
Timo Rager* and Rolf Hilfiker Solvias AG, Department for Solid-State Development, WRO-1060, Mattenstrasse 22, 4002 Basel, Switzerland Received March 19, 2010; Revised Manuscript Received May 17, 2010
ABSTRACT: Solvent mixtures can be used to thermodynamically suppress solvate formation as a competing reaction in solution-based cocrystallization experiments. This has been demonstrated successfully for the cocrystallization of carbamazepine and saccharin in the presence of up to nine different solvate-forming solvents and was further tested by cocrystallization experiments with 18 other known cocrystal formers of carbamazepine. It was found that the chances of success of this approach increase with the number of solvents in the mixture. It was additionally observed that solvent mixtures can be used to level out the solubility differences between different compounds.
Introduction Cocrystallization experiments in ternary systems of the two cocrystal components and a solvent have become increasingly popular for the preparation of pharmaceutical binary compounds.1-8 In particular, suspension equilibration of the drug substance in a saturated solution of the cocrystal former1b,4 provides a number of advantages in cocrystal screening: (a) the presence of a liquid phase accelerates the transformation, (b) thermal stress on the components is avoided, (c) the solubilities of the components are taken into account in the experimental design even without necessarily knowing them exactly, (d) there are almost no restrictions with respect to the choice of the solvent (e.g., with regard to its boiling point), (e) there is a maximum driving force for cocrystal formation due to a maximum activity of the cocrystal components in solution, (f) the formation of a thermodynamically stable solid state is favored (an inherent property of suspension equilibration experiments),9,10 (g) the method is tolerant with respect to unexpected stoichiometries of the binary compound, and (h) the evaluation of the experiments is particularly simple because any change of the precipitate relative to the thermodynamically stable form of the pure drug substance is indicative for the formation of a binary compound (i.e., the interpretation is not complicated by the presence of the solid cocrystal former as a mechanical admixture). In principle, one such suspension equilibration experiment should be sufficient to decide whether a stable cocrystal of the two components exists or not. A major risk in limiting the experiments to one single solvent is—apart from kinetic hindrance—the possible competition with solvate formation of one of the components or the binary compound. Solvate formation (in analogy to any other formation of multicomponent compounds) depends on the solvent activity,3 which correlates (although not necessarily linearly) with the concentration of the solvent in solution. Thus, the risk of solvate formation can be reduced by keeping the solvent concentration low. This is more or less synonymous
with choosing a solvent with a high solubility of the cocrystal former.4,11 In addition to this, utilizing solvent mixtures should lower as well the risk of solvate formation with any of the solvents in the mixture because the activity of each solvent is further decreased (Scheme 1). Solvent mixtures provide an additional advantage for crystallization experiments in that they may also improve the transformation kinetics. It has been shown experimentally for a few solvent combinations that the nucleation rate in solvent mixtures is generally higher than that in the pure solvent with the lowest nucleation rate.9 This can also be justified by theory: it has been argued that the nucleation is favored by a high solubility and hindered by strong, directed interactions between solvent and solute.9 Mixed solvents will generally provide a larger number of less dominant interactions. Therefore, the activation energy for nucleation should be overcome more easily. Also, practical experience tells that with the greatest probability the solubility in a solvent mixture will be above the solubility in the poorest solvent. Scheme 1. Concept of Cocrystallization from Solvent Mixtures To Prevent Solvate Formation
The concept of cocrystal formation in mixed solvents is tested here with the model compound carbamazepine (CBZ), which is known to form a number of cocrystals and solvates.4,12-16 Cocrystal formation with saccharin (SAC) and 18 other compounds is investigated in the presence of solvate-forming solvents. Experimental Section
*To whom correspondence should be addressed. E-mail: timo.rager@ solvias.com.
Chemicals. Carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide, 236.27 g/mol) was obtained from Acros Organics (99% purity, crystalline form III).17 Saccharin (1,1-dioxo-1,2-benzothiazol-3-one, 183.18 g/mol), all other cocrystal formers (typically with g99% purity), and all solvents (puriss. p.a. quality) were purchased from Fluka. All chemicals were used without further purification.
r 2010 American Chemical Society
Published on Web 06/03/2010
pubs.acs.org/crystal
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Table 1. Solvates of CBZ solvent no.
name
CBZ/solvent (mol/mol)
ref
1 2 3 4 5 6 7 8 9
H2O ethylene glycol formic acid acetic acid DMSO sulfolane DMF acetone dioxane
1:2 1:2 1:1 1:1 1:1 1:2 1:1 1:1 1:0.5
14 12 12 12 15 12 15
Differential Scanning Calorimetry. Measurements were performed with a 20 K/min heating rate on a Perkin-Elmer DSC 7. Corrected peak temperatures are reported. Raman Spectroscopy. A Bruker RFS100, Nd:YAG laser with a 1064 nm excitation wavelength, 100 mW nominal laser power, and Ge detector was used. The samples were prepared on Al sample holders. Spectra were measured with 64 scans and a resolution of 2 cm-1. Thermogravimetry. A TA Instruments TGA Q5000 was used. The samples were placed in Al crucibles and heated up in a flow of N2 at a rate of 10 K/min. UV/Vis Spectroscopy. A Hewlett-Packard 8453 spectrophotometer with a diode array detector and cuvettes with a 1 cm path length were used. X-ray Powder Diffraction. Experiments were performed on a Bruker D8 Advance, using Cu KR radiation (λ = 1.54180 A˚), 40 kV/40 mA, and a LynxEye detector. The samples were prepared on silicon single crystal sample holders with a 0.1 mm depth. Solubility Determinations and Solvate Formation. An excess of either CBZ or the cocrystal former was added to 0.5-2 mL of solvent or solvent mixture. The suspensions were agitated at 25 °C for several days, and the solid was filtered off through a PTFE centrifuge filter (Millipore). In the case of CBZ and SAC, a weighed aliquot of the solution was diluted with MeOH to a defined volume, and the concentration was determined by UV/vis spectroscopy (ε(CBZ, 285 nm) = 11.8 103 L/(mol cm), ε(SAC, 285 nm) = 0.7 103 L/(mol cm)). The solubility of all other cocrystal formers was determined gravimetrically either from the difference of added and recovered solid or by evaporation of an aliquot of the saturated solution. The accuracy of these solubility determinations is estimated to be on the order of a factor of 2. The crystalline solids of CBZ were analyzed by Raman spectroscopy and thermogravimetry as well as X-ray diffraction in the case of the solvates with ethylene glycol and sulfolane. Cocrystallization Experiments. An excess of CBZ was added to a saturated solution of the cocrystal former in the appropriate solvent or solvent mixture. The suspension was treated with ultrasound for a few minutes and was then agitated at 25 °C for several days. The solid was filtered off by centrifuge filtration and analyzed by Raman spectroscopy and by additional methods if needed.
Results and Discussion Nine stable solvates of CBZ (Table 1) have been investigated in this study as possible competitors to cocrystal formation. Most of these solvates have already been reported previously in the literature. To the best of our knowledge, this is not the case for the 1:2 solvates with ethylene glycol and sulfolane. The crystallinity of these solvates was confirmed by XRPD (Figures 1 and 2), and their stoichiometry was derived from TGA measurements. Prior to each cocrystallization experiment with CBZ and SAC, the equilibrium solubilities of the two components in the solvent or solvent mixture were determined. These values are summarized in Table 2 and are additionally represented in Figure 3. A clear trend toward more similar solubilities of both cocrystal components in mixed solvents is observed, which may be attributed to an averaging of more and less favorable interactions between solute and solvent.
Figure 1. X-ray powder diffractogram of the ethylene glycol solvate of CBZ.
Figure 2. X-ray powder diffractogram of the sulfolane solvate of CBZ.
The competition between cocrystal and solvent formation was studied by adding an excess of CBZ (relative to the solubility in the binary CBZ/solvent system) to a saturated solution of SAC in each solvent or solvent mixture (Table 2). After equilibration for several days, the solid was isolated and characterized by Raman spectroscopy (and additional methods if necessary). A first set of experiments was performed with pure solvents. Three of these experiments provided a 1:1 cocrystal of CBZ and SAC with a sharp mp at 180 °C with ΔH = 59.1 kJ/mol. Experiments in acetone and dioxane initially resulted in clear solutions and subsequently in the formation of a different solid state form of the cocrystal with an mp of ca. 170 °C with ΔH = 55.4 kJ/mol. Fast transformation into the first cocrystal form was observed in DSC, and 1H NMR confirmed the same 1:1 stoichiometry for both forms. The Raman spectra (Figure 4) and X-ray diffractograms (Figure 5) of the two forms are in good agreement with the known polymorphic forms I and II of the cocrystal.12,16 A mixture of hydrate and cocrystal form I was isolated from water, which is attributed to an insufficient amount of SAC in the solution. A complete suppression of cocrystal formation by solvate formation was found in formic acid, acetic acid, and sulfolane (Table 2). Further experiments were thus performed with mixtures of the most critical solvents, i.e., water, formic acid, acetic acid, and sulfolane, and finally with a mixture of the complete set of solvate-forming solvents. Equimolar portions of the solvents were mixed, which is based on the consideration that in an ideal system the solvent activities in a mixture are given by their mole fractions and on the intention to decrease all solvent activities to the same extent. As long as the solvent activities in the mixture are not known in more detail, ideality is considered to be a sensible assumption. It turned out that the thermodynamic stability of the hydrate and the sulfolane solvate is rather low, as indicated by the fact that their formation was not observed in any of the cocrystallization experiments with solvent mixtures.
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Table 2. Cocrystal Formation between CBZ and SAC in Solvate-Forming Solvents and Equimolar Solvent Mixtures solubilityc Mwb
composition of the suspensions in saturated SAC solutionsc
solid-state form of the precipitate
(g/mol)
CBZ (mol/mol)
SAC (mol/mol)
CBZ (mol/mol)
SAC (mol/mol)
in the absence of SAC
in the presence of SAC
1 2 3 4 5 6 7 8 9 1þ3 1þ4 1þ6
18.02 62.07 46.03 60.05 78.13 120.17 73.09 58.08 88.11 32.02 39.04 69.10
0.00001 0.005 0.019 0.004 0.029 0.010 0.037 0.005 0.015 0.001 0.002 0.033
0.0004 0.009 0.007 0.004 0.374 0.052 0.290 0.048 0.084 0.003 0.006 0.039
0.0008 0.009 0.028 0.009 0.058 0.018 0.077 0.014 0.030 0.002 0.004 0.055
0.0004 0.009 0.007 0.004 0.352 0.051 0.267 0.048 0.082 0.003 0.005 0.037
hydrate þ cocrystal form I cocrystal form I formic acid solvate acetic acid solvate cocrystal form I sulfolane solvate cocrystal form I cocrystal form II cocrystal form II formic acid solvate acetic acid solvate cocrystal form I
3þ4
53.04
0.019
0.007
0.040
0.007
3þ6 4þ6 1þ3þ4
83.10 90.11 41.37
0.039 0.017 0.007
0.023 0.031 0.006
0.069 0.034 0.016
0.021 0.030 0.006
1þ3þ6 1þ4þ6 3þ4þ6 1þ3þ4þ6 1-9
61.41 66.08 75.42 61.07 67.08
0.023 0.010 0.031 0.018 0.048
0.016 0.022 0.019 0.015 0.076
0.041 0.022 0.057 0.035 0.068
0.015 0.021 0.018 0.014 0.071
hydrate ethylene glycol solvate formic acid solvate acetic acid solvate DMSO solvate sulfolane solvate DMF solvate acetone solvate dioxane solvate formic acid solvate acetic acid solvate hydrate þ sulfolane solvate acetic acid solvate þ formic acid solvate formic acid solvate acetic acid solvate acetic acid solvate þ formic acid solvate formic acid solvate acetic acid solvate acetic acid solvate acetic acid solvate acetic acid solvate
solvent no.a
a
acetic acid solvate formic acid solvate acetic acid solvate acetic acid solvate formic acid solvate acetic acid solvate acetic acid solvate acetic acid solvate cocrystal form I
For solvent numbers, cf. Table 1. b Average values in the case of mixtures. c Concentrations in mole fractions of the total mixture.
Figure 3. Solubilities of CBZ (black) and SAC (gray) in pure solvents and equimolar solvent mixtures at 25 °C. The numbers refer to the solvents in Table 1.
However, whenever formic acid or acetic acid was present, a solvate of either one of these dominated. The highest stability is indicated for the acetic acid solvate, which still prevailed over the SAC cocrystal in a quaternary solvent mixture. The acetic acid solvate of CBZ was even observed in an equimolar mixture of all nine solvate-forming solvents. However, its thermodynamic stability was sufficiently reduced under these conditions so that the solvate could be superseded by the CBZ/SAC cocrystal. Several solvents or solvent mixtures exhibited a lower molar solubility for SAC as compared to CBZ, and a significant excess of CBZ relative to SAC was added in some cases
Figure 4. Comparison of the Raman spectra of the two polymorphic forms of the CBZ/SAC cocrystal.
(Table 2). Thus, an insufficient availability of SAC may have contributed to the prevalence of the solvate over the cocrystal in some experiments. However, except for the experiment in water, there was no indication from Raman spectroscopy for the presence of even trace amounts of the cocrystal in any of the crystallized solvates. (The limit of detection is estimated to be below 10% based on a well separated signal of the cocrystal at 1725 cm-1 or 1717 cm-1 depending on the polymorphic form.) This indicates that the cocrystal is indeed thermodynamically unstable in most solvent mixtures except for water/ sulfolane and a combination of all nine solvents.18 As an additional test, the same mixture of nine solvents was used to perform cocrystallization experiments of CBZ with
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18 other known cocrystal formers of this drug substance (Table 3).4,12,13 As before, the solubility of each cocrystal former in the mixture of nine solvents was determined in advance. It can be seen from Figure 6 that the molar solubility of all cocrystal formers varies by less than 1 order of magnitude. Contrary to this, the solubility of the same compounds in water varies by more than 3 orders of magnitude (data also included in Figure 6). This observation further supports the assumption that solvent mixtures tend to even out solubility differences between different compounds and solvents. As in the preceding set of cocrystallization experiments, in the next step, an excess of CBZ was added to saturated solutions of each cocrystal former. Up to three times the amount of CBZ was used, as compared to the solubility limit in the solvent mixture in order to generate a precipitate. For the majority of the cocrystal formers, a transformation of the precipitate was observed within one hour after addition of
CBZ; the rest of the samples recrystallized within 2-6 days at a maximum. Characterization of the precipitates by Raman spectroscopy indicated the formation of new crystalline solids for all samples except adipic acid and O-acetylsalicylic acid. In these two latter cases, the Raman spectrum perfectly matched the one of the acetic acid solvate of CBZ. However, in XRPD, even these two samples exhibited weak additional peaks, which provide an indication for partial cocrystal formation. Up to three different crystalline forms have been reported in the literature for some of the cocrystals in Table 3.4 Obviously, it will generally not be possible to gain this information from one single cocrystallization experiment. However, we consider identification of promising candidates for cocrystal formation to be the primary purpose of a screening experiment. Issues of polymorphism or variable stoichiometry of the cocrystal should be investigated in a subsequent step.
Figure 5. Comparison of the X-ray diffractograms of the two polymorphic forms of the CBZ/SAC cocrystal.
Figure 6. Solubilities of 19 cocrystal formers in an equimolar mixture of solvents 1-9 (b) and in water (O) at 25 °C.
Table 3. Cocrystal Formation between CBZ and 18 Different Cocrystal Formers in an Equimolar Mixture of All Nine Solvate-Forming Solvents from Table 1 composition of the suspensionsa cocrystal former
Mw (g/mol)
CBZ (mol/mol)
cocrystal former (mol/mol)
solid-state form of the precipitateb
O-acetylsalicylic acid adipic acid benzoic acid (þ)-camphoric acid fumaric acid glutaric acid glycolic acid 1-hydroxy-2-naphthoic acid maleic acid L-malic acid malonic acid nicotinamide oxalic acid 2-oxoglutaric acid salicylic acid succinic acid DL-tartaric acid L-tartaric acid
180.15 146.14 122.12 200.24 116.07 132.12 76.05 188.18 116.07 134.09 104.08 122.13 90.04 146.10 138.12 118.09 150.09 150.09
0.127 0.095 0.145 0.132 0.067 0.100 0.060 0.073 0.067 0.074 0.066 0.099 0.061 0.074 0.072 0.065 0.070 0.068
0.127 0.072 0.193 0.104 0.046 0.239 0.394 0.071 0.230 0.281 0.294 0.135 0.237 0.262 0.203 0.085 0.060 0.167
acetic acid solvate þ cocrystal acetic acid solvate þ cocrystal cocrystal acetic acid solvate þ cocrystal cocrystal form A cocrystal cocrystal cocrystal cocrystal cocrystal cocrystal form A cocrystal cocrystal cocrystal form A cocrystal cocrystal cocrystal form B cocrystal
a
Concentrations in mole fractions of the total mixture. b Assignment of crystalline forms based on XRPD according to ref 4.
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Crystal Growth & Design, Vol. 10, No. 7, 2010
Conclusions Solvate formation as a competing reaction to cocrystal formation can be suppressed by using solvent mixtures. However, the concentration of each solvent in the mixture may have to be decreased significantly, which means that a large number of solvents have to be combined. Crystallizations from a complex mixture of solvents may have disadvantages on an industrial scale, e.g., because of difficulties in controlling the correct composition of the solvent mixture over the whole process (including recycling) or because of toxicological problems. However, there seems to be no reason why complex solvent mixtures should not be used in smallscale screening experiments. An additional advantage of solvent mixtures is that they reduce the solubility differences between different compounds as compared to pure solvents. This predestines solvent mixtures for use as “universal” solvents with a reasonable (but not excessively high) solubility for a large number of different compounds. This property has the potential to further simplify the screening process. The solvent mixtures used in this study represent a worst case scenario in the sense that only solvate-forming solvents were included. Obviously, the composition of a “universal” solvent for a salt or cocrystal screening program based on suspension equilibration experiments would be selected along very different criteria, such as activity of each solvent in the mixture, solubility of the salt or cocrystal formers, chemical reactivity, volatility, viscosity of the mixture, or interference with analytical techniques. Acknowledgment. Discussions with Susan DePaul are gratefully acknowledged.
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