ARTICLE pubs.acs.org/crystal
Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents Amjad Alhalaweh,† Anders Sokolowski,‡ Naír Rodríguez-Hornedo,§ and Sitaram P. Velaga*,† †
Department of Health Science, Lulea University of Technology, Lulea, S-971 87, Sweden ‡ Department of Pharmaceutical Chemistry, Uppsala University, Sweden § Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065, United States
ABSTRACT: The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacinsaccharin (INDSAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of INDSAC cocrystals was compared with that of indomethacinnicotinamide (INDNIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of INDSAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of INDSAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The INDNIC cocrystals were more soluble than the INDSAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior.
1. INTRODUCTION Cocrystals are structurally homogeneous crystalline phases with defined stoichiometry and contain two or more different neutral molecular components in a crystal lattice.1,2 Cocrystals have been described in the literature as molecular complexes, solid-state complexes, and molecular compounds.3 Although these solid-state complexes were observed in early solution complexation studies, their properties have not been studied in depth.35 Intermolecular interactions, known to be responsible for complexation in the liquid, are also key molecular recognition events in the formation of molecular complexes in the solid state, i.e. cocrystals.6 In recent years, cocrystals have been designed with an intent of improving material physical and biopharmaceutical properties.7 In fact, the physicochemical properties of drugs, such as the solubility, stability, and mechanical properties, can be engineered by changing the coformers used in cocrystallization, which could offer significant flexibility in drug formulation and product development.4,5 Knowledge of the solubility of the cocrystal components in a solvent used in crystallization is important for efficient cocrystal screening and scale-up.8 The equilibrium solubility of a substance is a function of the energy of interaction both within and between the solvent and solutes.9,10 Recent studies on the solubility behavior of cocrystals in organic and aqueous media have revealed the dependence of cocrystal solubility on the concentration of the coformer, analogous to the effect of common ions on the solubility of sparingly r 2011 American Chemical Society
soluble salts.1113 It has been shown that the drug concentration decreases as the coformer activity or concentration increases, in order to maintain the solubility product (Ksp). Therefore, the solubility of cocrystals can be given by Ksp, the activity or concentration product of cocrystal components. Solution complexation has been demonstrated to increase the solubility of a cocrystal to different extents, depending on the stoichiometry and strength of the complex. When the stoichiometry of solution complex is equal to that in the cocrystal, its solubility is increased by a constant value (product of Ksp and Kcomplex). The solubility of different cocrystals is a function of the solubility of the coformer used, but dependence on the crystal lattice structure and interaction energies in the cocrystal is still not clear.14 The cocrystals are congruently saturating if they are thermodynamically stable up on slurrying in a solvent; in other words, cocrystal components show the same or similar solubilities in that solvent. In contrast, an incongruently saturating cocrystal transforms to a less soluble solid form during slurrying; in other words, cocrystal components show extremely different solubilities in such a solvent. Mathematical models derived to describe the solubility behavior of cocrystals with different stoichiometries have been based on solubility product behavior and solution complexation.11,12 Received: April 22, 2011 Revised: July 10, 2011 Published: July 25, 2011 3923
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Crystal Growth & Design The resulting phase solubility diagrams (PSDs) define the regions of thermodynamic stability for the cocrystals and their individual components, and have led to the development of the reaction crystallization (RC) method.15 The RC method has now evolved into a rational and efficient cocrystal screening method as well as a successful strategy for the scale-up crystallization of cocrystals.16,17 The transition or eutectic points are the concentrations at which two solid phases coexist in equilibrium with a liquid phase, regardless of the ratio of the two solid phases, at a fixed temperature and pH.14,18 Eutectic points can be used to estimate the solubility and to define the stability regions of the cocrystals in the phase diagrams.14,18 For unstable cocrystals, the eutectic point is demonstrated to be the nearest measurable equilibrium, from which its equilibrium solubility can be estimated. The molar ratio of cocrystal components in solution at the eutectic point is referred to as the eutectic constant (Keu). The Keu value of a cocrystal correlates with the thermodynamic stability and solubility ratio of the cocrystal and drug in a pure solvent.19 Keu has been previously applied to determine phase diagrams of racemic compounds and to the crystallization of enantiomers.20 In-depth studies of the phase solubility behavior of cocrystals in organic solvents are limited. Studies involving diverse cocrystals are essential for improving the understanding of cocrystal solution chemistry and solubility behavior. It is also important to evaluate the wider applicability/validity of previously proposed solubility prediction models and theories. Indomethacin is a typical model for poorly soluble biopharmaceutical classification system (BCS) class II drugs encountered today. The discovery and characterization of 1:1 indomethacinsaccharin (INDSAC) cocrystals and 1:1 indomethacinnicotinamide (INDNIC) cocrystals have been reported.21,22 The solubility behavior of 1:1 carbamazepinenicotinamide (CBZNIC) cocrystals has been investigated and was found to fit with the derived mathematical models.11 The aims of the current study were (1) to investigate the solubility behavior and solution chemistry of 1:1 INDSAC cocrystals in methanol, ethanol, and ethyl acetate; (2) to generate the PSDs for these cocrystals and validate relevant theoretical models; (3) to further evaluate the utility of eutectic constants in evaluating cocrystal solubility and stability in the solvents using INDSAC and INDNIC cocrystals as models; and (4) to investigate the impact of coformer properties on the solubility behavior and stability of cocrystals. The INDSAC and INDNIC cocrystals were prepared, and the phase purity was verified using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The solubility of the INDSAC cocrystals in methanol, ethanol, and ethyl acetate was measured as a function of coformer concentration (SAC). The eutectic points for INDSAC and INDNIC cocrystals were determined in the same solvents.
2. MATERIALS AND METHODS 2.1. Materials. Indomethacin (IND), saccharin (SAC), and nicotinamide (NIC) were purchased from Sigma-Aldrich (Stockholm, Sweden). Methanol and ethyl acetate of analytical grade were also sourced from Sigma-Aldrich. Ethanol (99.5% purity) was purchased from Kemetyl, Sweden. Milli-Q water was used in the study. All chemicals and solvents were used as received. 2.2. Preparation of Cocrystals. 2.2.1. Preparation of INDSAC Cocrystals. A mixture of IND (0.01 M, 3.578 g) and SAC (0.01 M, 1.832 g) was dissolved in 200 mL of ethyl acetate and heated to aid dissolution.22 The solution was left at room temperature (∼22 °C) in a controlled fume hood
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(air flow 0.54 m/s). The resulting crystals were filtered and dried in a desiccator over silica gel to ensure complete dryness. The crystals were milled gently using a mortar and pestle and were then passed through a 125 μm sieve (RETSCH). The powder thus obtained was verified by DSC and PXRD for phase purity. 2.2.2. Preparation of INDNIC Cocrystals. A 1:1 mixture of IND (0.7156 mg) and NIC (0.2442 mg) was placed in a 10 mL Retsch grinding jar, and two drops of methanol were added. The mixture was ground for 30 min in a Retsch grinder (Mixer Mill MM301, Retsch GmbH & Co.) at 30 Hz oscillations. The powder was then collected and dried at room temperature and the physical purity was verified by DSC and PXRD.
2.3. Solubility of Cocrystals and Cocrystal Components in Organic Solvents. The equilibrium solubility of INDSAC cocrystals in the absence and presence of SAC (0.0050.1 M) in methanol, ethanol, and ethyl acetate was determined at 25 ( 0.5 °C. The experiments were conducted by adding an excess of INDSAC cocrystal solid phase to solutions in 10 mL glass vials. The suspensions were magnetically stirred for 24 h. Samples were withdrawn and filtered through a syringe filter, 0.2 μm (cellulose acetate membrane) or 0.45 μm (polypropylene membrane), and the aliquot was diluted as required. Solubility of the samples was tested after 72 h, and the solubility data was found to be similar to that at 24 h. The concentrations were measured by HPLC as described below. The equilibrium solubility of IND, SAC, and NIC was measured in pure solvents under similar conditions in a similar manner. Solid phases, at equilibrium, were filtered, dried, and analyzed by PXRD. Note that IND in methanol converts to IND methanol solvate, as confirmed by PXRD. 2.4. Transition Point or Eutectic Point Determination. The eutectic point for the INDSAC cocrystals was accessed by either suspending IND in a near-saturated SAC solution or by adding INDSAC cocrystals to an IND suspension. The eutectic point for INDNIC cocrystals was determined by adding INDNIC cocrystals to a suspension of IND until both solid forms coexisted in equilibrium for at least 24 h. The equilibrium concentrations of IND and SAC or NIC at the eutectic points at 25 °C ( 0.5 were measured by HPLC. The existence of drug and cocrystal solid forms at equilibrium was examined and confirmed by PXRD.
2.5. High-Performance Liquid Chromatography (HPLC) Methods. Solutions were analyzed by HPLC (series 200 binary LC pump and 200 UVvis detector, TotalChrom software, Perkin-Elmer, Wellesly, MA). IND, SAC, and NIC were separated over a C18 column (Dalco Chrometch, 5 μm, 150 mm 4.6 mm). The HPLC analysis was conducted at room temperature with a flow rate of 1 mL/min. For IND, UV detection at 319 nm was used and the mobile phase was 0.2% w/v phosphoric acid and MeOH, in proportions of 25:75.23 SAC was detected at 254 nm and the mobile phase consisted of 20% v/v acetic acid adjusted to pH 3 by adding a saturated solution of sodium acetate.24 NIC was detected at 260 nm and the mobile phase was a mixture of water and methanol (6:4) containing 0.1% trifluoroacetic acid. Mobile phases were degassed for 30 min before use. 2.6. Differential Scanning Calorimetry (DSC). Thermal analyses of the samples were performed on a DSC Q1000 (TA Instruments) which was calibrated for temperature and enthalpy using indium standard. Samples (13) were crimped in nonhermetic aluminum pans and scanned at a heating rate of 10 °C/min under a continuously purged dry nitrogen atmosphere (flow rate 50 mL/min). The instrument was equipped with a refrigerated cooling system. Samples were scanned over the range 30250 and 30180 °C in case of INDSAC and INDNIC, respectively. The melting point of INDSAC cocrystals is 183.3 ( 0.1 °C, while that of INDNIC cocrystals is 126.9 ( 0.3 °C. The heat of fusion of INDSAC and INDNIC cocrystal were 153.5 ( 3.9 and 116.9 ( 1.3, respectively (n = 4). 2.7. Powder X-ray Diffraction (PXRD). PXRD patterns were recorded on a Siemens D5000 powder diffractometer with Cu KR radiation 3924
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Figure 2. Total concentration of IND in equilibrium with INDSAC cocrystals as a function of inverse total SAC concentration in methanol (2), ethanol (9), and ethyl acetate ([).
by unique carboxylic acid and imide dimer synthons interconnected by weak hydrogen bonds.22 The cocrystals were readily formed in ethyl acetate, ethanol, and methanol using the solvent evaporation method. The solubilities of INDSAC cocrystals as a function of SAC concentration in the various solvents are shown in Figure 1ac. This cocrystal is congruently saturating and its solubility decreases nonlinearly with increasing concentration of SAC in all the solvents. A similar behavior in the solubility of CBZNIC cocrystals has been reported earlier with increasing NIC concentrations; this behavior was explained by the solubility product equations.11 Cocrystals with other stoichiometries have also been found to have similar behavior.12,13 Previously derived mathematical models based on the solubility product and solution complexation for 1:1 cocrystals were employed for predicting the solubility behavior of INDSAC cocrystals. The derivations of these models are presented and discussed in detail in the earlier study.11 However, specific equations for INDSAC cocrystals are presented here. The equilibrium reaction for 1:1 INDSAC cocrystals when they dissociate to their components in solution without solution complexation can be given as Ksp
INDSACsolid T INDsolution þ SACsolution Figure 1. Solubility of INDSAC cocrystals at 25 °C as a function of total SAC concentration in (a) methanol, (b) ethanol, and (c) ethyl acetate. The solid gray lines represent the predicted cocrystal solubility according to eq 8, using values for Ksp and K11 given in Table 3. The dotted lines represent the predicted solubility of IND according to eq 9, with K11 values calculated from the cocrystal solubility data in Table 3. Open symbols are experimental solubility values for IND (methanol solvate or γ-form) in neat solvents. The dashed lines represent the 1:1 stoichiometric composition of IND and SAC. (1.540 56 Å). The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence slit and antiscattering slit settings were variable for the illumination of the 20 mm sample size. Each sample was scanned over a range of 2θ between 5° and 40° with a step size of 0.02° and a time per step of 1 s. The instrument was previously calibrated using a silicon standard.
3. RESULTS AND DISCUSSION 3.1. Solubility Behavior of INDSAC Cocrystals and Evaluation of Models. The INDSAC cocrystals are characterized
ð1Þ
Ksp can be given as Ksp ¼ ½IND½SAC
ð2Þ
and the cocrystal solubility can be written as ½INDtotal ¼
Ksp ½SACtotal
ð3Þ
if the total concentrations are equal to the free concentrations in eq 2. Thus, eq 3 predicts that the plot of [IND]total versus 1/[SAC]total is linear, with a slope given by Ksp. This was found to be the case for INDSAC cocrystals (Figure 2); the equations of the lines are presented in Table 1. Subsequently, the Ksp was determined for INDSAC cocrystals in every solvent; these are presented in Table 2. The linear regression analysis indicates that the y-intercepts were not significantly different from zero in ethyl acetate but were significantly different from zero in methanol and ethanol. Thus, eq 3 accurately predicted the experimental data in ethyl acetate but not in methanol and ethanol, where the model 3925
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When K11 Ksp , [SAC]total, the equation can be simplified to
underestimated the cocrystal solubility (data not shown). Obviously, this model does not consider solution complexation, which has been shown to have significant effects on the fit of the model.11 The equilibrium of the solution in the presence of a 1:1 solution complex can be written as Ksp
INDSACsolid T INDsolution þ SACsolution
½INDtotal ¼
K11
ð5Þ
where K11 is the binding constant for the 1:1 complex formed in the solution. K11 can be given as K11 ¼
½INDSAC ½INDSAC ¼ ½IND½SAC Ksp
ð6Þ
and the cocrystal solubility can be expressed as ½INDtotal ¼
Ksp þ K11 Ksp ½½SACtotal K11 Ksp
ð7Þ
½INDtotal ¼ ½INDo þ
R2
and y-intercept)
value
solvent methanol
y = 1.12 10
3
3
((0.05 10 )x +
0.98
2 103 ((0.8 103) ethanol
y = 0.61 103 ((0.02 103)x +
0.99
1.97 103 ((0. 56 103) ethyl acetate
y = 1.40 103 ((0.07 103)x
0.98
0. 61 103 ((1.24 103)
Table 2. INDSAC Cocrystal Solubility Products, Ksp, and Solution Complexation Constants, K11, in Organic Solvents Ksp (M2)
K11 (M1)
methanol
1.12 103 ((0.05 103)
1.82 ((0.75)
ethanol
0.61 103 ((0.02 103)
3.25 ((0.9)
ethyl acetate
1.40 103 ((0.07 103)
0
solvent
K11 ½INDo ½SACtotal 1 þ K11 ½INDo
ð9Þ
where [IND]o is the intrinsic solubility of IND in a neat solvent.6 The measured solubility of IND in neat solvents and the dependence of the predicted IND solubility on the concentration of SAC are presented in Figure 1. The solubility of IND has slightly increased with increasing concentration of SAC, and at the transition point or eutectic point, the solution is saturated with both IND and cocrystal (Figure 1). Obviously, solution complexation results in an increase in the intrinsic solubility of the drug with increasing concentration of the coformer. Saccharin has shown weak solution complexation tendency with number of pharmaceuticals and organic compounds in aqueous solutions.25 For example, the study of carbamazepinesaccharin cocrystal in ethanol and 2-propanol showed that solution complexation is not significantly different from zero in ethanol and is 1.7 M1 in 2-propanol.26 There was only a small or insignificant degree of solution complexation between IND and SAC in the solvents studied, in line with earlier studies. The determination of PSDs is an important part of cocrystal scale-up operations, since they provide an insight into rational
Table 1. Linear Regression Analysis According to eq 3 or 8 equation of line ((standard error of slope
ð8Þ
This equation predicts that, when there is solution complexation, the INDSAC cocrystal solubility will be greater, by a constant value (the product of Ksp and K11), than when there is no solution complexation. K11 values calculated from the intercept of the linear equation are presented in Table 2. The Ksp values, the solubility of the cocrystals, and the solubilities of their components were lower in ethanol than in methanol and ethyl acetate (Table 3a). In contrast, the K11 value was higher in ethanol than in methanol or ethyl acetate. In fact, it has been observed previously that the tendency to form solution complexes is greater when the solubility of cocrystal components and cocrystals is low.11 This is possibly due to the preferred solute solute interaction taking place over a solutesolvent interaction. Further, the K11 determined from the above relationships can be used to predict the increase in the solubility of IND in the presence of SAC, according to the following equation:
ð4Þ
INDsolution þ SACsolution T INDSACsolution
Ksp þ K11 Ksp ½SACtotal
Table 3. Mean Value of Concentrations at 25 °C of Drug and Coformer in Pure Solvents and at the Eutectic Point, the Solubility Ratio of Coformer to Drug, and the Observed Keu Values for (a) INDSAC Cocrystal and (b) INDNIC Cocrystal in Different Solvents a solvent
[SAC] (M)
(a) INDSAC [SAC]/[IND] [IND SAC]d (M)
methanol
0.047 ( 0.002
b
0.247 ( 0.008
0.032 ( 0.001
ethanol
0.054 ( 0.001c
0.153 ( 0.004
0.025 ( 0.000
ethyl acetate
0.102 ( 0.005c
0.181 ( 0.001
0.037 ( 0.001
solvent
a
[IND] (M)
[IND] (M)
[NIC] (M)
methanol ethanol
b
0.047 ( 0.002 0.054 ( 0.001c
1.682 ( 0.078 0.735 ( 0.009
ethyl acetate
0.105 ( 0.005c
0.073 ( 0.001
[SAC]eu (M)
observed Keu
4.70
0.053 ( 0.003
b
0.025 ( 0.004
0.472 ( 0.060
2.82
0.059 ( 0.000
0.014 ( 0.001
0.232 ( 0.011
1.77
0.099 ( 0.003
0.015 ( 0.000
0.149 ( 0.008
[IND]eu (M)
(b) INDNIC [NIC]/[IND]
[IND]eu (M)
[NIC]eu (M)
observed Keu
31.89 13.52
b
0.064 ( 0.006 0.065 ( 0.000
0.594 ( 0.037 0.215 ( 0.019
9.298 ( 0.441 3.299 ( 0.191
0.72
0.130 ( 0.004
0.041 ( 0.001
0.319 ( 0.004
Standard deviation is presented in parentheses, n = 3. b IND methanol solvate. c IND γ-form. d Measured solubility of INDSAC cocrystals. 3926
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Figure 3. Phase solubility diagram of INDSAC cocrystals in ethyl acetate. The blue line is the cocrystal solubility as a function of the SAC concentration, evaluated using eq 3. The pink point is the eutectic point, and ] and 0 represent the solubility of IND and SAC, respectively, in neat ethyl acetate. The dashed lines represent the 1:1 stoichiometric composition that crosses the solubility curve for the cocrystal at (b).
crystallization pathways. 11 Figure 3 shows the PSD for 1:1 INDSAC cocrystals in ethyl acetate. The stability regions for the different solid phases were established and are labeled using Roman numbering in Figure 3. In region I, the cocrystal is undersaturated with respect to the drug (i.e., more soluble) and only the drug is supersaturated. Both the drug and the cocrystals are supersaturated in region II, and both are undersaturated in region III. The solubility of the cocrystals is lower than that of the drug in region IV, and only cocrystals are supersaturated in this region. Therefore, a scale-up crystallization process in region IV is reasonable. Knowledge of PSDs has also been invaluable in the design of screening experiments for cocrystals.15 Figure 3 also demonstrates that the cocrystal has the highest solubility at the point where the stoichiometric line crosses the cocrystal solubility line, i.e., the stoichimetric solubility of the cocrystal. When one of the cocrystal components is in excess in the solution, the cocrystal solubility decreases. Therefore, cocrystal has the lowest equilibrium solubility at the eutectic points. 3.2. Eutectic Concentrations of INDSAC and INDNIC Cocrystals. In crystallization processes, knowledge of both eutectic points (cocrystaldrug, cocrystalcoformer) is necessary. However, a relevant and easily accessible eutectic point in cocrystal research is where cocrystal and drug coexist in equilibrium with the solution, for the reason that the drug is often less soluble than the coformer. This is true in case of incongruently saturating cocrystals such as INDNIC cocystal in methanol and ethanol. The presence of both IND and cocrystal phases at the eutectic points was confirmed by PXRD for the studied systems, as shown in Figure 4a,b. The concentrations of the drug and the coformers, as measured by HPLC, are presented in Table 3a,b. Under ideal solution behavior, the intrinsic (stoichiometric) solubility of the cocrystals can be predicted from the concentrations of the cocrystal components at the eutectic points as follows: qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ð10Þ Scocrystal ¼ ½drugeu ½cof ormereu The calculated solubilities of INDSAC cocrystals using eq 9 in different solvents were close to the measured cocrystal solubilities in the pure solvent. The proposed model is found
Figure 4. Powder X-ray diffraction patterns (PXRD) for different solid phases. IND and (a) INDSAC cocrystals and (b) INDNIC cocrystals in equilibrium with the solutions in MeOH = methanol, EtOH = ethanol, and EtOAc = ethyl acetate at 25 °C.
to predict the equilibrium solubilities of INDSAC cocrystal with sufficient accuracy in congruent solvents. In case of incongruent systems, the equilibrium solubility is inaccessible. Thus, the model can be used for the estimation of the equilibrium solubility of cocrystals in incongruent solvents, an outcome which is not possible to achieve experimentally as compared to congruent cocrystals.14 However, eq 9 assumes that the activity coefficients of a drug and coformer are equal to unity, which may result in inaccurate solubilities for cocrystals undergoing solution complexation or ionization.14 The Keu has been shown to be a good indicator of cocrystal solubility and stability.19 Keu (observed) can be calculated from the measured concentrations of the coformer and the drug at the eutectic point as follows: Keu ¼
½cof ormereu ½drugeu
ð11Þ
It has been shown that 1:1 cocrystal systems with Keu < 1 are congruently saturating while those with Keu > 1 are incongruently saturating in respective solvents.19 For INDSAC cocrystals, Keu was ethanol > ethyl acetate (Table 3a). While the rank order of Keu values for INDNIC cocrystal follows methanol > ethanol > ethyl acetate (Table 3b). Indeed, these rank orders are in line with the rank orders of solubility ratio of SAC to IND and NIC to IND, respectively, in different solvents (Figure 5a,b). These results reinforce the idea that Keu values, and therefore cocrystal solubility, follow the solubility ratio of the coformers to drug in different solvents. They also provide an indication of the effect of solvents on the solubility behavior and stability of cocrystals. Again, this knowledge is very important for the selection of optimal cocrystals for further development, as well as for synthesis or scale-up of cocrystals.19,27 Indeed, it has been suggested that the solubility of cocrystals follows the component solubilities.14 According to Figure 5, the solubility of SAC was lower than that of NIC in ethanol and methanol, resulting in lower Keu values for the INDSAC cocrystals in these solvents. However, this trend did not hold in ethyl acetate, where the solubility of INDSAC cocrystals (and thus the Keu value) was still lower than that of INDNIC cocrystals, even though SAC was more soluble than NIC. IND is highly solubilized by NIC ([IND]eu > [IND]) in ethyl acetate as a
Keu 1 100 Keu þ 1
ð13Þ
xsb for the INDSAC cocrystals was 0 in methanol and ethanol. This can be explained by the fact that the cocrystals were more soluble than the drug in the respective solvents, which means that excess coformer was needed to stabilize the cocrystals at the eutectic point. Further, a greater excess is needed for more soluble cocrystals, correlating with higher coformer solubility in the respective solvents. In these cases, a nonstoichiometric composition would be needed to stabilize the cocrystals. A similar observation was made for a number of cocrystals in a previous study.19 In summary, the concepts presented in this paper are of direct relevance to cocrystal screening and scale-up. Besides evaluating solubility models proposed earlier, we have demonstrated once again the importance and practical applications of eutectic point and Keu in cocrystal research using two new cocrystals. The eutectic point (and Keu model) determination is a simple and material-sparing approach and provides valuable insights on the stability and solubility of cocrystals and their stability domains of different phases in the phase solubility diagram. In the case of incongruently saturating cocrystals, which are very relevant in practice, eutectic points are the nearest measurable equilibrium.
4. CONCLUSION This study presents the solubility behavior of 1:1 INDSAC cocrystals in methanol, ethanol, and ethyl acetate. Relevant mathematical models that describe the solubility of this system were evaluated. The eutectic constants of cocrystals of IND with SAC or NIC were determined in various organic solvents and used to evaluate the effects of coformer and solvent on the solubility and stability of the cocrystals. The solubility of INDSAC cocrystals decreased as the concentration of SAC increased in the solution. This behavior was explained by the solubility product and solution complexation. The eutectic constant was found to be a function of cocrystal and drug solubility. The eutectic constant for INDNIC cocrystals was higher than that for INDSAC cocrystals in all the solvents studied. This was explained by the greater solubility of NIC and its greater tendency for solution complexation compared to SAC. INDSAC cocrystals were congruently saturating in all the 3928
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Crystal Growth & Design solvents studied, whereas INDNIC cocrystals were congruent in ethyl acetate and incongruent in methanol and ethanol. Cocrystal behavior can be expressed in terms of the solubility product. Eutectic constants can be used to select the optimum coformer and solvent in scale-up and formulation development studies.
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(26) Bethune, S. J. Ph.D. Thesis, University of Michigan, Ann Arbor, MI, 2009. (27) Huang, N.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2010, 10, 2050–2053. (28) Lim, L.; Go, M. Eur. J. Pharm. Sci. 2000, 10, 17–28.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT A.A. and S.P.V. thank the Kempe Foundation (Kempestiftelserna) for an instrumentation grant. S.P.V. is also grateful for the project grant from the Swedish Research Council (Vetenskapsradet). ’ REFERENCES
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