Solid–Liquid Equilibrium Behavior and Solvent Effect of Gliclazide in Mono- and Binary Solvents

The solubility data of gliclazide in 10 mono-solvents (1,2-dichloroethane, 1,4-dioxane, 2-methoxyethanol, n-propyl acetate, isopropyl acetate, n-butyl acetate, pentyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and 2-butanone) and one kind of binary solvent (DMA + water) were measured between 278.15 and 323.15 K under atmospheric pressure by the gravimetric method. The Hansen solubility parameters and the KAT-LSER equation were used to investigate the solubility order and the influence of solvent effects on solubility. The experimental data were correlated by six thermodynamic models (the λh model, the Yaws model, the Apelblat model, the Jouyban model, the modified Jouyban–Acree model, and the Sun model). The results show that all of these models can correlate the experimental data well. Among them, the Apelblat model is the most suitable for correlating the solubility data of gliclazide in mono-solvents and binary solvents.


INTRODUCTION
Solution crystallization plays a significant role in separating and purifying products in pharmaceutical production, which determines the purity, particle size, and the final yield of products. 1 Crystal properties of drugs will significantly affect the bioavailability, release, metabolism, and excretion of drugs. 2,3 The solubility data of drugs are particularly important for the design and optimization of the crystallization process, which can provide the necessary parameters for crystallization process design. Meanwhile, solubility data are also of great significance for the selection of solvents in the crystallization process. 4−8 Gliclazide (CAS No. 21187-98-4, molecular formula: C 15 H 21 N 3 O 3 S, Figure 1) is a second-generation sulfonylurea oral hypoglycemic drug, which is a white crystalline powder and widely used in the treatment of type 2 diabetes mellitus. 9,10 There is no reported polymorph about gliclazide recently. 9,11 The mechanism of action of gliclazide is similar to that of toluene sulfonylurea, which selectively stimulates islet precursor cells to promote insulin secretion and release. 12,13 A lot of research has been reported on the synthesis and preparation of gliclazide, but few people pay attention to its crystallization process. Although gliclazide solubility data have been reported in some literature studies, 12,14 the solubility of gliclazide in some commonly used solvents is still not available.
In this work, the solubility data of gliclazide in 10 kinds of mono-solvents (1,2-dichloroethane, 1,4-dioxane, 2-methoxye-thanol, n-propyl acetate, isopropyl acetate, n-butyl acetate, pentyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and 2-butanone) and one kind of binary solvent (DMA + water) were measured between 278.15 and 323.15 K under atmospheric pressure by the gravimetric method. The solvents selected in this study are common solvents, which can be used to optimize the crystallization process of gliclazide and improve the product quality of gliclazide, such as crystal size distribution, yield, and whiteness. Six thermodynamic models, including the λh model, the Yaws model, the Apelblat model, the Jouyban model, the modified Jouyban−Acree model, and the Sun model, were used to correlate the experimental data. Hansen solubility parameters were employed to study the solubility order of gliclazide in mono-solvents and binary solvents. Furthermore, the KAT-LSER equation was used to study the influence of the solvent effects on the solubility of gliclazide.

THEORETICAL BASIS
In this research, the solubility data of gliclazide in 10 monosolvents were correlated by the λh model, Apelblat model, and Yaws model. The solubility data of gliclazide in DMA + water binary mixed solvents were correlated by the Apelblat model, the modified Jouyban−Acree model, and the Sun model. An opensource fitting software named 1stOpt (Professional Version 1.5, 7D-Soft High Technology Inc., China) was used in this investigation.
2.1. λh Model. The λh model 15−17 is a semiempirical model proposed by Buchowski, which is used for solubility fitting of a solute in individual solvents. The λh model can be expressed as follows: where λ and h are model parameters of the λh model, x 1 is the mole fraction solubility of a solute, T is the absolute temperature, and T m is the melting temperature of a solute.

Yaws
Model. The Yaws model 18,19 is also a semiempirical model to correlate the solubility data of a solute at different temperatures in mono-solvents. The equation is shown as follows where A 1 , B 1 , and C 1 are model parameters.

Jouyban
where x 1 is the mole fraction of a solute, α and β terms are the model constants, and Abraham solvation parameters (AP i ), Hansen solubility parameters (HP i ), and Catalan parameters (CP i ) were used as the solute−solvent interaction terms.

Apelblat
Model. The Apelblat model 21,22 is widely used to fit the solubility data. It can be described as follows where A 2 , B 2 , and C 2 are model parameters of the Apelblat model and x 1 is the mole fraction of a solute. 2.5. Modified Jouyban−Acree Model. The Jouyban− Acree model 23 is used to describe the effects of temperature and the fraction of each component in the binary solvent on solubility. The Jouyban−Acree model can be expressed as eq 5.
where x 1 is the mole fraction of a solute; x 2 ′ and x 3 ′ are the mole fractions of each mono-solvent in the binary solvents (without a solute); J i is the model constant; and N represents the composition of the solvent. The Jouyban−Acree model can be combined with the Apelblat model to obtain the modified Jouyban−Acree model, which is shown as follows The above equation can be simplified as where A 1 to A 9 are model parameters of the modified Jouyban− Acree model.

Sun
Model. The Sun model 24,25 is shown in 8, which is used to correlate the solubility data at temperature and solvent composition in binary solvents. where D 1 to D 7 represent the model parameters of the Sun model and x 2 ′ is the mole fraction of good solvent in binary solvents.

Hansen Solubility Parameters.
HSPs (Hansen solubility parameters) are widely used to predict the solubility order of a solute in solvents, which were proposed by Hansen in 1967. 26,27 In this research, the effect of the interaction of gliclazide with 10 different mono-solvents and one kind of binary solvent was analyzed by Hansen  Values of parameters (δ d , δ p , and δ h ) can be calculated by the group contribution method. 28−30 The equation is as follows 12) where i represents the structural group of the substance, F di is the group contribution to the dispersion forces, and F pi and E hi are the contribution of polarity force and hydrogen bonding energy of the structural group i, respectively.
The difference in total solubility parameter (Δδ t ) can be obtained from the following equation where δ t1 and δ t2 are total Hansen solubility parameters of gliclazide and solvents, respectively.
Δδ is used to evaluate the difference in the HSP between them. It can be expressed as follows There is a concept of a thermodynamic relationship between δ d and δ p , which is used in miscibility investigations. It can be expressed as follows The degree of miscibility between the two substances can be calculated by 21 and 22. The Hansen solubility parameters (δ d , δ p , and δ h ) of each solvent selected in this study can be obtained from the literature. 31,32 2.8. Data Correlation. To evaluate the fitting level of each model, the relative average deviation (RAD) and root mean square deviation (RMSD) were selected to evaluate the fitting degree of each model where n represents the number of experimental points, and x 1 exp and x 1 calcd are the experimental and calculated solubility data, respectively. Figure 2 (which take the results of T = 323.15 K and x 2 ′ = 0.6 of gliclazide residual solids, for instance), there is no obvious difference in the position of the main peaks among the raw material and the residual solids at all experimental temperatures. The main characteristic diffraction peaks are at 2θ = 10.50, 14.92, 17.88, 20.78, and 21.10°. The XRPD patterns are similar to the literature. 12,14 It indicates that there is no crystal transformation of gliclazide during the dissolution process. The value of the melting point (T m ) of gliclazide was obtained from the literature. 14 The calibration (i.e., zero drift, baseline drift, indication error of heating, temperature indication error rate, accuracy, and repeatability) was performed before the measurement.

X-ray Powder Diffraction (XRPD) and DSC. As shown in
3.2. Solubility Results. The mole fraction solubility data of gliclazide are listed in Table 1 and shown in Figure 3. In monosolvents, the mole fraction solubility of gliclazide increased with the increase of temperature. The maximum solubility was obtained in DMSO at 323.15 K, and the minimum solubility was obtained in isopropyl acetate at 278.15 K. When the temperature is 298.15 K, the solubility order of gliclazide in the selected 10 mono-solvents is DMA > DMSO > 1,2dichloroethane > 1,4-dioxane > 2-butanone, 2-methoxyethanol > n-propyl acetate > n-butyl acetate > pentyl acetate > isopropyl acetate. When the temperature is above 313.15 K, the solubility of gliclazide in the solvent of DMSO is greater than that in DMA. Solubility results showed that gliclazide was easily soluble in DMSO and DMA and soluble in 1,2-dichloroethane, 1,4dioxane, 2-methoxyethanol, n-propyl acetate, isopropyl acetate, n-butyl acetate, pentyl acetate, and 2-butanone. The polarity order of these mono-solvents is 2-methoxyethanol (66.7)> DMSO (44.4) > DMA (40.1) > 1,2-dichloroethane (32.7) = 2butanone (32.7) > n-butyl acetate (24.1) > 1,4-dioxane (16.4). 33 Obviously, the solubility order of gliclazide is different from the sort of solvent polarity, which means that the dissolution of gliclazide is affected not only by the polarity of the solvent but also by other factors, such as viscosity, steric effects, and solute− solvent interaction.
The experimental solubility of gliclazide in DMA + water solvent mixtures is shown in Figure 4 and listed in Table 2. The  , and x 1 Apelblat represent the calculated mole fraction solubility by the λh model, Yaws model, Jouyban model, and Apelblat model, respectively. The standard uncertainty of temperature is u(T) = 0.05 K, and the relative standard uncertainty of pressure is u r (P) = 0.05. The relative standard uncertainty of mole fraction solubility is u r (x 1 ) = 0.04. and x 2 ′ = 0.9) is about 380 times greater than that at the lowest temperature and lowest DMA content (T = 278.15 K and x 2 ′ = 0.3). The solvent system involved in this study is an important solvent for gliclazide crystallization purification, especially the DMA + water system. This information would be meaningful in the process of purification and recrystallization of gliclazide.
The Hansen solubility parameters were used to analyze the solubility capable of gliclazide in this investigation. HSPs of gliclazide were calculated by the group contribution method, and the results are shown in Table 3. The HSP values are listed in Table 4. The results of δ d , δ p , and δ h of gliclazide are 20.81, 18.87, and 7.48 MPa 1/2 , respectively. As shown in Table 4, the solubility data of gliclazide were basically negatively correlated with the values of Ra(v) except for the solvents of 2-butanone and pentyl acetate. For each mono-solvent, solubility data were basically negatively correlated with the values of Δδ t and Δδ. For DMA + water binary solvents, as the DMA mole ratio increases, the value of Δδ t decreases, which is consistent with the tendency of gliclazide solubility to increase with an increasing positive solvent mole ratio except x 2 ′= 0.3. Meanwhile, as the DMA mole ratio increases, the value of Δδ t decreases, which is basically negatively correlated with the solubility data.
where π* is the dipolarity/polarizability of the solvent; α and β represent the acidity and basicity of hydrogen bonding of the solvent, respectively; and V s and δ H are the molar volume of gliclazide and solubility parameter of Hildebrand of the solvent, respectively. The constant c 0 is the intercept value at π* = α = β =   Table 5.
The solubility of gliclazide in 10 mono-solvents at 298.15 K was calculated by the KAT-LSER model, and the result is as follows where R 2 and RSS represent the squared relative coefficient and residual sum of squares, respectively. The values of the regression coefficient of π*, β, and V s δ H 2 /(100RT) are positive, indicating that the solubility of gliclazide is positively correlated with dipolarity/polarizability, hydrogen bond alkalinity, and self-cohesiveness. The values of the regression coefficient of α are all negative, indicating that the solubility of gliclazide decreases with the increase of hydrogen bond acidity of the solvent. In addition, the proportions of hydrogen bond acidity, hydrogen bond basicity, dipolarity/polarizability, and the Hildebrand solubility parameter in the total solvent effect were 14.34, 36.63, 12.61, and 36.42%, respectively, indicating that the hydrogen bond basicity and Hildebrand solubility parameter play an important role in the solubility of gliclazide. , and x 1 Apelblat represent the calculated mole fraction solubility by the modified Jouyban−Acree model, Sun model, and Apelblat model, respectively. x 2 ′ is the mole fraction of DMA in the DMA + water binary solvents (without solute). The standard uncertainty of temperature is u(T) = 0.05 K, and the relative standard uncertainty of pressure is u r (P) = 0.05. The relative standard uncertainty of mole fraction solubility is u r (x 1 ) = 0.04. The relative standard uncertainty of the solvent composition is u r (x 2 ′) = 0.0008.

Data
where c, e, s, a, b, and v are the Abraham solvation parameters; δ d , δ p , and δ h are Hansen solubility parameters; and SP, SdP, SA, and SB are Catalan parameters. For mono-solvents, the Apelblat model, Jouyban model, and Yaws model correlate the experimental solubility better than the λh model by comparing the average value of RAD (0.0078). For DMA + water binary solvents, the Apelblat model is better than the other two models in correlating the experimental solubility, with maximum RAD and RMSD values of 0.0112 and 0.00031, respectively. The R 2 of all of the models was larger than 0.997.    The maximum values of RAD and RMSD of all selected models are no larger than 0.0591 and 0.000806. In general, all selected models give satisfactory results.

Materials.
The active pharmaceutical ingredient (API) gliclazide (mass percentage 99.5%) was obtained from Shouguang Fukang Pharmaceutical Co., Ltd. Information of all of the materials used in this research are listed in Table 12. All organic solvents selected in this study (i.e., 1,2-dichloroethane, 1,4-dioxane, 2-methoxyethanol, n-propyl acetate, isopropyl acetate, n-butyl acetate, pentyl acetate, DMSO, 2-butanone, and DMA) were of analytical grade obtained from Sinopharm Chemical Reagent Co., Ltd. The deionized water was prepared   in our laboratory (Advance EDI, Sartorius, Germany). All of the chemicals were used without further purification.

X-ray Powder Diffraction
Analysis. X-ray powder diffraction (XRPD) was selected to evaluate the gliclazide raw materials and the residual solids obtained from different temperatures in each solvent to ensure that there was no crystal transformation during the equilibrium process. All tests were conducted by an X-ray diffractometer (PANalytical B.V. X'Pert PRO MPD, Netherlands). The experiment was performed by Cu Kα radiation at a scan speed of 10°min −1 , and the data were gauged from 5 to 50°(2θ). The tube voltage and the current were 40 kV and 30 mA, respectively. All of the measurements were carried out at room temperature (298.15 K) and atmospheric pressure (0.1 MPa).

Solubility Determination.
The gravimetric method was selected to measure the solubility of gliclazide in both monosolvents and binary solvents at temperatures ranging from 278.15 to 323.15 K (at intervals of 5 K) under atmospheric pressure. The experimental details and the validation of the system have been mentioned in our previous work. 12,14 The experimental process is described as follows. Excess solids of gliclazide were placed in a jacketed reactor, which contains a certain amount of solvent. The specified temperature was maintained through a thermostatic water-circulating bath (CF41, Julabo, Germany). The uncertainty of temperature is ±0.05 K. The solution was stirred for more than 10 h through a magnetic stirrer to ensure that solid−liquid equilibrium was reached, which was confirmed by concentration analysis every 0.5 h. After stopping the stirrer, the solution was allowed to stand for about 6 h. About 5 mL of supernatant was sampled and filtered by a 0.22 μm pore size filter membrane (all syringes and filter membranes used in the experiment were heated to the corresponding temperature in advance) and evaporated in a vacuum drying oven at 40°C for 12 h to ensure that the weight does not change (the weight was confirmed every 0.5 h in the preliminary experiment to ensure that 12 h was enough for the drying process). The balance (model AL204, Mettler Toledo, Switzerland) with a precision of ±0.0001 g was used to measure the mass of all samples. The test was repeated three times at each temperature, and the average was taken as the final result. The mole fraction solubility of gliclazide in 10 different monosolvents and a binary solvent mixture (DMA + water) was calculated according to 21 where x 1 represents the mole fraction solubility of gliclazide;, x 2 ′ is the mole fraction of good solvent (DMA) in the binary solvent (DMA + water); m 1 , m 2 , and m 3 represent the masses of gliclazide, good solvent, and antisolvent, respectively; and M 1 ,