Solubility Determination for Carbamazepine and Saccharin in

Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

pubs.acs.org/jced

Solubility Determination for Carbamazepine and Saccharin in Methanol/Water Mixed Solvent: Basic Data for Design of Cocrystal Production by Antisolvent Crystallization Shoji Kudo* and Hiroshi Takiyama Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Nakacho, Koganei-shi, Tokyo 184-8588, Japan

ABSTRACT: In the pharmaceutical industry, selection of the crystal form of active pharmaceutical ingredients (APIs) is one of the ways for improvement of drug solubility. Recently, cocrystal form is attracting lots of attention, and production methods for cocrystalline particles are being studied. One of the production methods for cocrystal is solution cocrystallization method with antisolvent based on phase diagram. The objective of this present study is to obtain the basic data for the design of antisolvent cocrystallization operation. The system of carbamazepine (CBZ) and saccharin (SAC) in methanol/water mixed solvent at 303 K was selected. Equilibrium slurry with various compositions was prepared and analyzed to measure the phase diagram. The compositions of CBZ and SAC were determined by HPLC measurement, and the solvent composition of the equilibrium solutions were determined based on SAC and CBZ composition, and mass balance. By XRD measurement, CBZ III, CBZ dihydrate, SAC, and CBZ/SAC cocrystal I were observed as the solid phases coexisting with equilibrium solution. From these measurements, the concentration region in which cocrystal is stable was shown clearly. Therefore, the basic data for operation design of antisolvent cocrystallization operation was obtained for CBZ/SAC cocrystal in MeOH/water mixed solvent system at 303 K.

■

INTRODUCTION In the pharmaceutical industry, improvement of dissolution behavior of drugs is an important challenge. Selection of the crystal form of active pharmaceutical ingredients (APIs) is one of the ways to make the improvement. In terms of the crystal form, recently, cocrystals have been attracting a lot of attention because of the improved property, including dissolution behavior. Cocrystals are solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.1 Although many studies related to cocrystallization are for screening, there have been studies on cocrystallization methods for industrial cocrystal production.2,3 Considering the purity of the product crystals and use of the existing equipment, the solution method seems to be suitable for industrial process. Cooling crystallization4−6 and solid addition7 have been suggested as cocrystallization methods from solutions. The authors have also suggested a mixing two solutions method for cocrystal production of carbamazepine (CBZ)saccharin (SAC) from methanol (MeOH) solution at 303 K.8 Although there is a risk that undesired crystals, such as © XXXX American Chemical Society

single component crystals, deposit in the solution method, the cocrystallization methods mentioned above can overcome the risk by considering the ternary phase diagram to produce cocrystal selectively. Actually, according to the recent review about cocrystallization,3 if ternary phase diagram is well delineated, solution method is suitable for process. In the past several years, an antisolvent cocrystallization method has been suggested for high solid yield.9 In antisolvent crystallization, it is possible to set various crystallization conditions by changing the operation design, such as feed solution composition and mixing ratio. According to previous studies, antisolvent cocrystallization also has the deposition risk of the single component crystal depending on the crystallization conditions.9,10 However, these previous studies have indicated the effectiveness of phase diagram for selective production of cocrystalline particles by antisolvent cocrystallization although the investigated conditions of solution composition and mixing Received: October 23, 2017 Accepted: January 11, 2018

A

DOI: 10.1021/acs.jced.7b00920 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

solvents with specific compositions were prepared initially. Sample slurry was prepared by adding SAC, CBZ, and MeOH/ water mixed solvent to the flasks at the predetermined composition ratios. According to the observation of cocrystallization by Horst and Cains,12 cocrystal nucleates from the solution when cocrystal deposition is involved by solvent mediated transformation. In addition, according to the previous study for CBZnicotinamide (NCT) cocrystal by Gagniere et al.,7 the trajectory of solution composition shows the deposition of cocrystal having fixed composition of CBZ and NCT (cocrystal composition) during the cocrystal deposition by solvent mediated transformation. Based on these previous studies, the authors decided it was not necessary to prepare the equilibrium slurry from the clear solution. Therefore, the initial slurry was not prepared from clear solution in which all four components were dissolved. Eleven kinds of the MeOH/water mixed solvents with different water compositions (mixed solvent composition, wwater,solv. = 0, 0.1, 0.2, ..., 0.9, 1) were examined. Considering the outline of phase diagram based on the previous studies (e.g., Horst and Cains12), it is necessary to measure at least the following four points in order to determine the solubility of each solid phase as a phase diagram: (i) solubility of only CBZ, (ii) solubility of only SAC, (iii) polysaturated point of CBZ and cocrystal, and (iv) polysaturated point of SAC and cocrystal. In addition, to determine the solubility curve of each solid phase, some additional points are necessary. Based on these considerations, the range of CBZ and SAC mass in each fraction of binary solvent mixture was selected. In the actual experiment, the total mass range of the slurry was around 10 g for each run number. The slurry was stirred for at least 16 h at 303 ± 0.05 K. After stirring, the solid phase and solution were sampled from the slurry and analyzed, respectively. The solid samples were characterized by XRD measurement (X-ray Diffractometer Ultima IV or MiniFlex, Rigaku, Japan) immediately after sampling. The solute (SAC and CBZ) compositions of the equilibrium solutions were determined by high-performance liquid chromatography (HPLC) measurement. HPLC measurement was carried out by using the HPLC system of Shimadzu Corporation equipped with column oven (CTO-10ASVP), degassing unit (DGU-12A), solvent delivery unit (LC-10ADVP), UV−vis detector (SPD-10AVP), and auto sampler (SIL-20A) and chromatpac integrator (C-R8A). An Inertsil ODS-SP column (4.6 mm × 250 mm, 5 μm) (GL Sciences Inc., Japan) was used for chromatographic separation. Separation was carried out isocratically at 45 °C with a

ratio were limited. Therefore, it seems to be important to perceive the total image of the phase diagram for the investigation of the variety of the antisolvent cocrystallization’s condition. It is also important to provide the basic data which enables the design of various operations for antisolvent cocrystallization. In antisolvent cocrystallization, the system consists of four components: two kinds of cocrystal components, good solvent, and antisolvent. Therefore, the objective of this present study is to obtain the basic data (as the quaternary phase diagram) for operation design of antisolvent cocrystallization. Previously, study on the solubility determination of CBZ-nicotinamide cocrystal in binary mixed solvent was conducted.11 In this present study, the system of CBZ and SAC in MeOH/water mixed solvent at 303 K was selected. For both of CBZ and SAC, MeOH and water are a good solvent and an antisolvent, respectively.

2. EXPERIMENTAL SECTION In order to determine the phase diagram for CBZ and SAC in MeOH/water mixed solvent at 303 K, equilibrium slurry with various compositions of the four components were prepared and analyzed. For the equilibrium solutions, the solid phases in the equilibrium solutions were characterized by XRD measurement, and the compositions of CBZ and SAC were determined by HPLC measurement. The solvent composition of the equilibrium solutions were determined based on SAC and CBZ composition and the mass balance. 2.1. Materials. The following reagents were used to prepare the slurry: Anhydrous carbamazepine (anhydrous CBZ), > 97.0% purity; saccharin (SAC), > 98.0% purity; and methanol (MeOH), > 99.8% purity. In addition, for HPLC measurement, the following reagents were also used: nicotinamide, > 98.0% purity; phosphoric acid, 85% concentration; dipotassium phosphate, >99.0% purity; and MeOH for HPLC grade, > 99.7% purity. These reagents were purchased from Wako Pure Chemical Industries, Ltd., except phosphoric acid, which was purchased from Kanto Chemical Co., Inc. Anhydrous CBZ was also purchased from Kanto Chemical Co., Inc. Further purifications for these reagents were not carried out. Deionized water was used as pure water. The information about chemical samples is summarized in Table 1. 2.2. Procedure. 2.2.1. Preparation of the Equilibrium Slurry and Measurement. In order to investigate the equilibrium solution composition and coexisting solid phase with the solution, sample slurry was prepared. MeOH/water mixed Table 1. Chemical Sample Table molar mass [g/mol]

chemical Name anhydrous CBZa

236.27

SACb

183.18

MeOHc

32.04

nicotinamide

122.13

phosphoric acid

97.99

dipotassium phosphate water

174.18

a

18.02 b

c

source Wako Pure Chemical Industries, Ltd. Kanto Chemical Co., Inc. Wako Pure Chemical Industries, Ltd. Wako Pure Chemical Industries, Ltd. Wako Pure Chemical Industries, Ltd. Wako Pure Chemical Industries, Ltd. Wako Pure Chemical Industries, Ltd. our laboratory

initial mass fraction purity

purification method

0.970

none

0.970 0.980

none none

0.998

none

0.997 (HPLCd grade) 0.980

none none

0.85 (concentration)

none

0.990

none

distilled and deionized

none

final mass fraction purity

analysis method

d

Carbamazepine. Saccharin. Methanol. High-performance liquid chromatography. B



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Figure 1. Schematic diagram of distribution of mass from prepared slurry to equilibrium slurry when the solid phase is CBZ·dihydrate (Case (i)).

Figure 2. Schematic diagram of distribution of mass from prepared slurry to equilibrium slurry when the solid phases are CBZ·dihydrate and cocrystal (Case (ii)).

2.2.2. Estimation of Solvent Compositions. When only CBZ dihydrate is the coexisting solid phase in the slurry (Case (i)), the total mass amount of each component in slurry and the mass of the components distributed into equilibrium slurry (solid phase and solution phase) are shown in Figure 1.

mobile phase comprised of 65 mass% methanol, 34 mass% water, and 1 mass% phosphate buffer (40 mM, pH = 7, prepared from phosphoric acid and dipotassium phosphate). The flow rate was 0.9 mL/min. The solute (CBZ and SAC) concentrations were measured by internal reference method for sample solutions from equilibrium slurry. In the measurement, sample solutions were diluted by solvent having the same composition with the mobile phase, and nicotinamide (NIC) was used as the internal standard. The injection volume was 10 or 20 μL. CBZ, SAC, and NIC eluted from the column were detected by UV−vis detector set at 230 nm of wavelength. For MeOH and water, the composition in the equilibrium solutions were estimated by using the equilibrium composition of CBZ and SAC, and the overall composition of the slurry based on mass balance. The mixed solvent composition of equilibrium solution which is free of solute components is the same as those of initial mixed solvent when the solid phases are not solvate. However, according to the previous studies,9,10,13 it is possible that CBZ deposits as dihydrate when mixed solvent has a high water composition. The mixed solvent compositions of the equilibrium solutions are different from the initial compositions if CBZ dihydrate deposits. Therefore, it is necessary to estimate the solvent composition in the case of deposition of CBZ dihydrate. According to the previous studies dealing with phase diagram for cocrystal components and solvent system,9,10 the following two cases are predicted: (i) only CBZ dihydrate is the coexisting solid phase in the slurry, and (ii) CBZ dihydrate and CBZ/SAC cocrystal are coexisting. The equations based on the mass balance were solved for these two cases.

Figure 3. XRD peak patterns from database (a−d) and the typical XRD peak patterns obtained in this study (e−k): (a) CBZ III;14 (b) CBZ dihydrate;15 (c) SAC;16 (d) 1:1 CBZ/SAC cocrystal I;17 (e) Run 1; (f) Run 3; (g) Run 4; (h) Run 7; (i) Run 9; (j) Run 90; and (k) Run 91. Cu Kα radiation was used. For the condition of run number refer to Table 2. C



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Table 2. Overall Composition of Slurry Used During Measurement of Quaternary Phase Diagram, Corresponding Solution Compositions and Phases at 303.15 K under 0.1010 MPaa overall composition, wov. (mass fraction) run no. 8

1 2 38 48 58 68 78 8 98 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

wwater,solv. (mass fraction) 0

0.1

0.2

0.3

0.4

0.5

SAC (1)

CBZ (2)

0 0.00576 0.02484 0.02982 0.04000 0.05330 0.08964 0.08033 0.08042 0 0.00493 0.02511 0.0348 0.0397 0.0426 0.0569 0.09220 0.0913 0.0882 0 0.00540 0.01824 0.02569 0.03556 0.02743 0.04053 0.06654 0.06854 0.07069 0 0.00358 0.01859 0.02529 0.02546 0.02331 0.03118 0.05781 0.05044 0.05552 0 0.00312 0.01434 0.01150 0.01641 0.01595 0.02191 0.04140 0.04209 0.04328 0 0.00281 0.01488 0.0119 0.01614 0.01044 0.02001 0.05014 0.04204

0.14720 0.12797 0.14954 0.08958 0.05220 0.03992 0.02992 0.01035 0 0.12033 0.11830 0.12024 0.0947 0.0517 0.0548 0.0436 0.0355 0.0095 0 0.1022 0.1032 0.1214 0.06625 0.04588 0.03480 0.03318 0.02225 0.00495 0 0.06923 0.07077 0.09289 0.05016 0.03275 0.03032 0.02312 0.01877 0.00324 0 0.05380 0.05949 0.05530 0.02628 0.02123 0.02294 0.01989 0.01270 0.00309 0 0.05329 0.05541 0.05471 0.02830 0.02110 0.02135 0.01905 0.00959 0.00229

MeOH (3) water (4) 0.85280 0.86626 0.82562 0.88060 0.90781 0.90677 0.88044 0.90932 0.91958 0.79147 0.78886 0.76897 0.7835 0.8179 0.8124 0.8096 0.7852 0.8094 0.8208 0.7181 0.7130 0.6881 0.7263 0.7347 0.7503 0.7411 0.7291 0.7413 0.7435 0.6515 0.6480 0.6220 0.6472 0.6593 0.6628 0.6623 0.6467 0.6627 0.6614 0.5675 0.5622 0.5580 0.5771 0.5772 0.5765 0.5747 0.5658 0.5712 0.5723 0.4736 0.4711 0.4654 0.4801 0.4816 0.4840 0.4804 0.4701 0.4777

0 0 0 0 0 0 0 0 0 0.08820 0.08790 0.08569 0.08690 0.09071 0.09013 0.08982 0.08710 0.08979 0.09106 0.1797 0.1784 0.1722 0.1817 0.1839 0.1875 0.1852 0.1822 0.1852 0.1858 0.2792 0.2777 0.2666 0.2774 0.2825 0.2836 0.2834 0.2767 0.2836 0.2830 0.3787 0.3752 0.3724 0.3851 0.3852 0.3847 0.3835 0.3801 0.3837 0.3844 0.4731 0.4707 0.4650 0.4797 0.4811 0.4842 0.4806 0.4702 0.4779

equilibrium solution composition, weq (mass fraction) SAC (5)

CBZ (6)

0 0.0059 0.0120 0.0145 0.0269 0.0405 0.0625 0.0647 0.0629 0 0.0052 0.0099 0.0114 0.0221 0.0232 0.0378 0.0532 0.0522 0.0517 0 0.0058 0.0083 0.0106 0.0184 0.0191 0.0293 0.0432 0.0422 0.0418 0 0.0037 0.0066 0.0089 0.0139 0.0142 0.0225 0.0338 0.0327 0.0329 0 0.00327 0.0051 0.0068 0.0096 0.0090 0.0128 0.0252 0.0232 0.0243 0 0.00291 0.00379 0.00382 0.0061 0.0044 0.0093 0.0172 0.0171

0.103 0.1025 0.107 0.0700 0.0362 0.0241 0.0164 0.0107 0 0.0881 0.0890 0.0909 0.0686 0.0296 0.0290 0.0173 0.0135 0.0101 0 0.0685 0.0711 0.0725 0.0490 0.0238 0.0237 0.0147 0.0103 0.0054 0 0.0495 0.0504 0.0513 0.0316 0.0180 0.0182 0.0111 0.0073 0.00332 0 0.0312 0.0316 0.0319 0.0204 0.0126 0.0138 0.0083 0.00467 0.00318 0 0.0180 0.0179 0.0176 0.0176 0.0083 0.0138 0.0050 0.00259 0.00238

D

MeOH (7) water (8) 0.8972 0.8916 0.8815 0.9155 0.9369 0.9354 0.9211 0.9246 0.9371 0.8205 0.8150 0.8091 0.8281 0.8536 0.8532 0.8506 0.8402 0.8440 0.8536 0.7450 0.7383 0.7352 0.7522 0.7660 0.7658 0.7650 0.7573 0.7620 0.7666 0.6654 0.6621 0.6595 0.6717 0.6777 0.6776 0.6768 0.6715 0.6751 0.6773 0.5811 0.5789 0.5776 0.5835 0.5865 0.5861 0.5871 0.5803 0.5839 0.5852 0.4913 0.4899 0.4895 0.4895 0.4930 0.4908 0.4927 0.4900 0.4902

0 0 0 0 0 0 0 0 0 0.0914 0.0908 0.0902 0.0918 0.0947 0.0946 0.0944 0.0932 0.0936 0.0947 0.1865 0.1848 0.1840 0.1883 0.1917 0.1913 0.1911 0.1892 0.1904 0.1915 0.2852 0.2838 0.2826 0.2879 0.2904 0.2900 0.2896 0.2874 0.2889 0.2899 0.3877 0.3863 0.3854 0.3893 0.3913 0.3911 0.3918 0.3898 0.3897 0.3905 0.4908 0.4894 0.4891 0.4890 0.4926 0.4910 0.4929 0.4902 0.4903

coexisting solid phase CBZ III CBZ III CBZ III + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC SAC CBZ III CBZ III CBZ III + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC SAC CBZ III CBZ III CBZ III + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC SAC CBZ III CBZ III CBZ III + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC SAC CBZ III CBZ III CBZ III + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC SAC CBZ III CBZ III CBZ III + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC

Ib

Ib

Ib

Ib

Ib

Ib



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Table 2. continued overall composition, wov. (mass fraction) run no.

wwater,solv. (mass fraction)

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

0.6

0.7

0.8

0.9

1

SAC (1)

CBZ (2)

0.04878 0 0.001188 0.01200 0.01982 0.02192 0.02008 0.02198 0.02807 0.02426 0.02383 0 0.001513 0.00505 0.007054 0.007934 0.01296 0.01251 0.01628 0.02023 0.02099 0 0.000670 0.00491 0.01165 0.01580 0.01428 0 0.01287 0.01590 0.01647 0 0.00368 0.00543 0.00997 0.00761

0 0.03191 0.03266 0.03987 0.02823 0.02564 0.02020 0.01986 0.01209 0.00106 0 0.01482 0.01630 0.01665 0.008184 0.007912 0.01204 0.01219 0.00504 0.000299 0 0.01672 0.01671 0.02337 0.01034 0.00775 0 0.00984 0.01646 0.00496 0 0.00305 0.00502 0.00394 0.00232 0

equilibrium solution composition, weq (mass fraction)

MeOH (3) water (4) 0.4755 0.3872 0.3865 0.3792 0.3808 0.3810 0.3839 0.3833 0.3839 0.3899 0.3905 0.2960 0.2951 0.2940 0.2959 0.2957 0.2924 0.2925 0.2935 0.2937 0.2936 0.1965 0.1963 0.1942 0.1956 0.1953 0.1972 0.09910 0.09715 0.09799 0.09843 0 0 0 0 0

0.4757 0.5809 0.5797 0.5689 0.5712 0.5715 0.5758 0.5749 0.5759 0.5848 0.5857 0.6891 0.6871 0.6843 0.6889 0.6884 0.6826 0.6828 0.6852 0.6857 0.6854 0.7868 0.7863 0.7776 0.7824 0.7811 0.7886 0.8911 0.8735 0.8811 0.8851 0.99695 0.99129 0.99063 0.98771 0.99239

SAC (5)

CBZ (6)

0.0171 0 0.00123 0.00308 0.00312 0.00490 0.0066 0.0083 0.0114 0.0114 0.0114 0 0.0015 0.0025 0.0026 0.0031 0.00434 0.00393 0.00700 0.00690 0.00687 0 0.00069 0.00207 0.00408 0.0054 0.0054 0 0.00183 0.00423 0.00422 0 0.00171 0.00246 0.00353 0.00354

0 0.0067 0.0068 0.0070 0.0068 0.00353 0.00244 0.00183 0.00129 0.00106 0 0.00250 0.00254 0.00258 0.00238 0.00173 0.00104 0.00117 0.00054 0.000275 0 0.00093 0.00095 0.00097 0.000361 0.000249 0 0.000384 0.000401 0.000118 0 0.000169 0.000177 0.000098 0.0000579 0

MeOH (7) water (8) 0.4913 0.3989 0.3984 0.3973 0.3960 0.3966 0.3964 0.3959 0.3949 0.3950 0.3955 0.3003 0.2999 0.2995 0.2990 0.2990 0.2983 0.2984 0.2976 0.2977 0.2978 0.2001 0.1999 0.1998 0.1991 0.1989 0.1989 0.1002 0.0999 0.0996 0.0997 0 0 0 0 0

0.4915 0.5944 0.5935 0.5926 0.5940 0.5950 0.5946 0.5939 0.5924 0.5925 0.5932 0.6972 0.6960 0.6955 0.6960 0.6961 0.6963 0.6965 0.6948 0.6951 0.6953 0.7989 0.7984 0.7972 0.7964 0.7955 0.7957 0.8994 0.8979 0.8960 0.8961 0.9998 0.9981 0.9974 0.99641 0.99646

coexisting solid phase SAC CBZ dihydrate CBZ dihydrate CBZ dihydrate + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC + cocryst. Ib SAC SAC CBZ dihydrate CBZ dihydrate CBZ dihydrate + cocryst. cocryst. Ib cocryst. Ib cocryst. Ib cocryst. Ib SAC+ cocryst. Ib SAC SAC CBZ dihydrate CBZ dihydrate CBZ dihydrate + cocryst. cocryst. Ib SAC + cocryst. Ib SAC CBZ dihydrate CBZ dihydrate + cocryst. SAC + cocryst. Ib SAC CBZ dihydrate CBZ dihydrate + cocryst. cocryst. Ib SAC + cocryst. Ib SAC

Ib

Ib

Ib

Ib

Ib

a u(T) = 0.05 K, u(p) = 0.0004 MPa. The relative uncertainties of the overall compositions, ur (wov.,SAC) = 0.006, ur (wov., CBZ) = 0.02, ur (wov., MeOH) = 0.009, ur (wov., water) = 0.001. The relative uncertainties of the equilibrium solution, ur (weq,SAC) = 0.03, ur (weq,CBZ) = 0.03, ur (weq,MeOH) = 0.04, ur (weq,water) = 0.04. b1:1 CBZ/SAC cocrystal I.17

When CBZ dihydrate and CBZ/SAC cocrystal are coexisting (Case (ii)), the total mass amount of each component in slurry and the mass of the components distributed to equilibrium slurry (solid phase and solution phase) are shown in Figure 2. Considering Cases (i) and (ii), the mass balances can be written as follows: mCBZ

MCBZ = m′CBZ + · mCBZ·dihyd. MCBZ + 2M water MCBZ + · mcocryst. MCBZ + MSAC

mSAC = m′SAC +

MSAC ·mcocryst. MCBZ + MSAC

m water = m′water +

2M water ·mCBZ·dihyd. MCBZ + 2M water

w′CBZ =

m′CBZ m′CBZ + m′SAC + mMeOH + m′water

(4)

w′SAC =

m′SAC + m′SAC + mMeOH + m′water

(5)

m′CBZ

For Case (i), the mass of water and CBZ in the equilibrium solution (m′water and m′CBZ) and CBZ dihydrate (m′ CBZ·dihyd.) in the solid phase were determined by solving the three equations (eqs 1,3, and 4) under mcocryst. = 0. For Case (ii), the mass of water, CBZ, and SAC in the equilibrium solution (m′water, m′CBZ, and m′SAC), and CBZ dihydrate and cocrystal in the solid phase (mCBZ·dihyd. and mcocryst.) were determined by solving the five eqs (eqs 1−5).

(1)

(2)

3. RESULTS AND DISCUSSION 3.1. XRD Measurement. According to the previous studies,8−10 it is possible that the following crystal forms can be observed in this experimental system: CBZ III, CBZ dihydrate,

(3) E



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stable was observed between two kinds of polysaturation regions: (i) CBZIII or CBZ dihydrate and CBZ/SAC cocrystal I, and (ii) SAC and CBZ/SAC cocrystal I. For wwater,solv. = 0.9, the region in which only cocrystal is stable was not observed under the examined condition. It is expected that the region exists between two kinds of polysaturated regions. When solid phase of CBZ is focused, it is predicted that there are polysaturated regions of CBZ III and CBZ dihydrated, the polysaturated region of cocrystal, CBZ III, and CBZ dihydrate from Table 2. When wwater,solv. ≥ 0.6, the outline of the phase diagram is different in the region in which CBZ composition is rich compared to that of SAC composition. If the outline of quaternary phase diagram would be depicted, it is necessary to determine the polysaturated region and the polysaturated point experimentally. However, the point of this study is to perceive the operation region for cocrystal production (region in which only cocrystal is stable). Now solid phase of cocrystal I is focused. In the cocrystal region, the compositions of SAC and CBZ in the equilibrium solution decreased with increase in water composition. This tendency means the solubility of the cocrystal I decreases with increase in water composition. Therefore, the antisolvent cocrystallization of CBZ/SAC cocrystal I is suitable in MeOH/water mixed solvent. These tendencies are clearly depicted in the ternary phase diagrams for SAC and CBZ in methanol/water mixed solvent for the range of the wwater,solv. = 0 to 0.5 (Figure 4a−f). Figure 4e is the same data as multicomponent phase diagram in the literature by Nishimaru et al.10 but shows solubility curves in more details.

1:1 CBZ/SAC cocrystal I, and SAC. Figure 3 shows the XRD peak patterns of these crystal forms from the database14−17 and the typical XRD peak patterns of the sample solid obtained in the present study (runs 1, 3, 4, 7, 9, 90, and 91). For the slurry conditions refer to Table 2. According to previous studies, the characteristic peaks for each crystal form were as follows: CBZ III, 2θ = 15°;18 CBZ dihydrate, 2θ = 8.9°;19 SAC, 2θ = 9.37° and 25.5°;20 and CBZ/SAC cocrystal I (P1(−)), 2θ = 6.88°.21 The crystal phase of the sample solid was identified based on the characteristic peaks and overall peak patterns for each/respective crystal phase. As expected, when CBZ dihydrate deposited, two cases were observed: (I) only CBZ dihydrate was the coexisting crystal form in the slurry, and (II) CBZ dihydrate and CBZ/SAC cocrystal were coexisting. The identification results of solid phase by XRD measurement are summarized with the slurry composition in Table 2. 3.2. Overall and Equilibrium Compositions of the Slurry and Solid Phases. Table 2 shows the summary of the overall compositions of slurry and the result of quantitative determination of the solution’s equilibrium composition. For the slurry, the maximum relative uncertainties of the overall compositions of SAC, CBZ, MeOH, and water were less than 2%. The maximum relative uncertainties of the compositions for the equilibrium solution (SAC, CBZ, MeOH, and water) were less than 4%. The compositions of SAC and CBZ in the equilibrium solution decreased with increase of water composition. When wwater,solv. was higher than 0.5, CBZ solid phase existed as CBZ dihydrate. In all of the examined mixed solvent compositions, except wwater,solv. = 0.9, the region in which only cocrystal is

Figure 4. Ternary phase diagram for CBZ and SAC in MeOH/water mixed solvent at 303 K (wwater,solv. = 0−0.5): (a) wwater,solv. = 0; (b) wwater,solv. = 0.1; (c) wwater,solv. = 0.2;22 (d) wwater,solv. = 0.3; (e) wwater,solv. = 0.4; (f) wwater,solv. = 0.5. F



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Notes

For the range of wwater,solv. = 0 to 0.5, the depicting of the clear quaternary phase diagram is possible, and the 3-dimensional phase diagram is shown in Figure 5. According to Figure 5, the

The authors declare no competing financial interest.

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NOMENCLATURE mCBZ total mass of anhydrous CBZ in the slurry [g] mSAC total mass of SAC in the slurry [g] mMeOH total mass of MeOH in the slurry [g] mwater total mass of water in the slurry [g] m′CBZ mass of CBZ in the equilibrium solution [g] m′water mass of water in the equilibrium solution [g] mCBZ·dihyd. mass of solid CBZ dihydrate coexisting with the equilibrium solution [g] m′SAC mass of SAC in the equilibrium solution [g] mass of solid cocrystal coexisting with the mcocryst. equilibrium solution [g] w′CBZ mass fraction of CBZ in the equilibrium solution [-] w′SAC mass fraction of SAC in the equilibrium solution [-] wwater,solv. mass fraction of water in MeOH/water mixed solvent, i.e., mixed solvent composition [-] MCBZ molar mass of CBZ [g/mol] MSAC molar mass of SAC [g/mol] Mwater molar mass of water [g/mol] T temperature [K] p pressure [Pa]

Figure 5. Approximate 3-dimensional quaternary phase diagram for CBZ and SAC in MeOH/water mixed solvent at 303 K (mass fraction based, wwater,solv. = 0−0.5).

cocrystal region is between two kinds of polysaturated region; cocrystal and SAC in SAC rich side, and cocrystal and CBZ in CBZ-rich side. In addition, the cocrystal region narrows with increasing wwater,solv.. The concentration regions in which each solid phase is stable have been shown. In terms of production of cocrystalline particles, the operation point should be designed at least in the cocrystal region. The stable range of CBZ/SAC cocrystal I, namely, the range for antisolvent cocrystallization, was shown by Figures 4 and 5 clearly.

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CONCLUSIONS As a basic data for operation design of antisolvent cocrystallization of CBZ-SAC in MeOH/water mixed solvent at 303 K, solubility determination for CBZ and SAC in MeOH/water mixed solvent was carried out. CBZ III, CBZ dihydrate, SAC, and CBZ/SAC cocrystal I were observed as the solid phases coexisting with equilibrium solution, and deposition regions of these solid phases were perceived. CBZ dihydrate was observed when the water composition of the mixed solvent, wwater,solv., was higher than 0.5. The compositions of SAC and CBZ in the equilibrium solution decreased with increase in wwater,solv.. A stereoscopic quaternary phase diagram was depicted based on the data of equilibrium solution composition and the solid phase coexisting with the equilibrium solution partially (wwater,solv. = 0−0.5). The stable range of CBZ/SAC cocrystal I was shown by depicting the phase diagram clearly. The basic data which enables the design of various operations for antisolvent cocrystallization operation was obtained for CBZ/SAC cocrystal in MeOH/water mixed solvent system.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Tel: +81-42-388-7729. ORCID

Shoji Kudo: 0000-0002-6552-2622 Funding

This work was supported by a Grant-in-Aid for Scientific Research (No. 259943) from Japan Society for the Promotion of Science for financial support. G



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Solubility Determination for Carbamazepine and Saccharin in

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