Determination of the Solubility, Dissolution Enthalpy, and Entropy of

Feb 12, 2013 - Abstract: A novel racemic compound of pioglitazone hydrochloride is discovered 17 years after the FDA approval of the conglomerate...
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Determination of the Solubility, Dissolution Enthalpy, and Entropy of Pioglitazone Hydrochloride (Form II) in Different Pure Solvents Mengying Tao, Zhao Wang,* Junbo Gong, Hongxun Hao, and Jingkang Wang State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China S Supporting Information *

ABSTRACT: The solubility of pioglitazone hydrochloride (Form II) in N,N-dimethylacetamide, methanol, dimethyl sulfoxide, and acetic acid was determined at temperatures ranging from 283.15 to 323.15 K. The experimental data were correlated with the modified Apelblat equation, λh equation, van’t Hoff equation, ideal model, Wilson model, and nonrandom two-liquid model. Calculation results show that the λh equation, van’t Hoff equation, and the ideal model are more suitable in determining the solubility of pioglitazone hydrochloride (Form II) compared with the other three models. By using the van’t Hoff equation, the dissolution enthalpy, entropy, and molar Gibbs free energy of pioglitazone hydrochloride (Form II) are predicted in different solvents.

1. INTRODUCTION Pioglitazone hydrochloride (C19H20N2O3S·HCl, CAS Registry No. 112529-15-4), known as an oral antihyperglycemic agent, is useful in treating type II diabetes mellitus (chemical structure shown in Figure 1). Pharmacological studies show that

Figure 1. Chemical structure of pioglitazone hydrochloride.

pioglitazone hydrochloride can effectively improve sensitivity to insulin in muscle and adipose tissue and can inhibit hepatic gluconeogenesis. Pioglitazone hydrochloride improves glycemic control while reducing circulating insulin levels.1,2 Two different polymorphs of pioglitazone hydrochloride have been reported, namely, Form I and Form II.3 These two forms can be identified by using different X-ray powder diffraction patterns (Figure 2). Form I has characteristic peaks at 8.6, 17.4, and 20.8, whereas Form II has the peaks at 9.2, 10.4, 15.2, 16.4, 18.6, and 21.4.3 Solution crystallization is an important separation and purification process in many areas, particularly in the pharmaceutical industry. Crystal polymorphism has been the focus of much research in the pharmaceutical community.4−6 Although different crystal polymorphs have the same chemical composition, their crystal packing arrangements and molecular conformations may be different. Thus, crystal polymorphs may have different physicochemical properties (e.g., solubility). Identifying the solubility of the different polymorphs of pioglitazone hydrochloride is necessary to understand the transformation between these two polymorphs of the drug and to determine which of the two polymorphs has the better pesticide effect during crystallization. In our previous work,7 the solubility of pioglitazone hydrochloride (Form I) have been © 2013 American Chemical Society

Figure 2. X-ray power diffraction patterns of pioglitazone hydrochloride.

measured in methanol, ethanol, 1-propanol, acetic acid, and N,N-dimethylacetamide. Our previous results indicate that the solubility of pioglitazone hydrochloride (Form I) is related to the polarity of the solvents. However, until now, the solubility data of Form II are unavailable in literature. In this study, the solubility of pioglitazone hydrochloride (Form II) in N,N-dimethylacetamide, methanol, dimethyl sulfoxide, and acetic acid was determined at temperatures ranging from 283.15 to 323.15 K. The experimental data were correlated with the modified Apelblat equation, λh equation, van’t Hoff equation, ideal model, Wilson model, and nonReceived: Revised: Accepted: Published: 3036

December 24, 2012 February 8, 2013 February 12, 2013 February 12, 2013 dx.doi.org/10.1021/ie303588j | Ind. Eng. Chem. Res. 2013, 52, 3036−3041

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random two-liquid (NRTL) model. By using the van’t Hoff equation, we predicted the dissolution enthalpy, entropy, and molar Gibbs free energy of pioglitazone hydrochloride (Form II) in different solvents.

2. EXPERIMENTAL SECTION 2.1. Materials. Pioglitazone hydrochloride (Form II) was prepared according to literature procedures.3 Pioglitazone hydrochloride was characterized as Form II by X-ray powder diffraction and the purity of pioglitazone hydrochloride was analyzed by high-performance liquid chromatography (Agilent 1100, Agilent Technologies, USA). The mass fraction purity was >0.99. Pioglitazone hydrochloride was dried under vacuum at 318.15 K for 24 h and then stored in a desiccator. N,NDimethylacetamide, methanol, dimethyl sulfoxide, and acetic acid (Tianjin Kewei Chemical Reagent Co. Ltd., China) were of analytical reagent grade; the mass fraction of these solvents was >0.995. 2.2. Apparatus. 2.2.1. Differential Scanning Calorimetric (DSC) Measurements. The melting temperature Tm1 and enthalpy of fusion ΔfusH1 of pioglitazone hydrochloride (Form II) were measured using DSC (DSC 1/500, Mettler-Toledo, Switzerland) under a nitrogen atmosphere. The sample size was approximately 5 mg, and the heating rate was 10 K/min. The measurement uncertainty was estimated to be less than 2%. 2.2.2. X-ray Powder Diffraction. Data collection was performed on Rigaku D/max-2500 (Rigaku, Japan) using Cu Kα radiation (1.5405 Å) in the 2-theta range of 2° to 40° and scanning rate of 1 step/s. 2.3. Solubility Measurements. The solubility of pioglitazone hydrochloride (Form II) in different solvents was tested by using the synthetic method.8 The measuring principle and setup using in this study are similar to those described in the literature.7 The temperature of the jacketed vessel was controlled by a thermostatical water bath (type 501A, Shanghai Laboratory Instrument Works Co., Ltd., China) with ±0.05 K uncertainty. Concentrations were determined by using a balance (type AB204, Metler Toledo, Switzerland) with ±0.0001 g uncertainty. A laser monitoring system, which includes a laser generator, a photoelectric transformer, and a light intensity display, was employed to determine the dissolution rate of pioglitazone hydrochloride (Form II) in different solvents at fixed temperature. The same experiment was repeated three times, and the average values were utilized to calculate the mole fraction solubility. The estimated uncertainty of the solubility values is dimethyl sulfoxide > acetic acid > methanol. The polarity of the solvents obeys the following order: N,N-dimethylacetamide < dimethyl sulfoxide < acetic acid < methanol.25 Benzene, pyridine ring, and a large number of low-level fatty chain structures comprise the molecular structure of pioglitazone hydrochloride (Form II); therefore, pioglitazone hydrochloride (Form II) has poor polarity and has solubility behavior in accordance with the empirical rule “like dissolves like”. The parameters and AADs of the six models are presented in the Supporting Information. Compared with the other three models, the λh equation, van’t Hoff equation, and ideal model are more suitable in describing the solubility of pioglitazone hydrochloride (Form II). The value of λ in the λh equation denotes the nonideality of solution systems. The ideal solution

(8)

(9)

On the basis of the activity coefficient method, the equilibrium solubility of the compound may be expressed by the following simplified equation:18 ln x1 =

⎛ Δλ ⎞ ⎛ λ − λ 22 ⎞ ν1 ν ⎟ = 1 exp⎜ − 21 ⎟ exp⎜ − 21 ⎝ ⎝ RT ⎠ RT ⎠ ν2 ν2

where

In the liquid−solid system, the fugacity of the compound in the liquid phase can be expressed by the following activity coefficient of solute γ1: x1γ1(T , P , x1)f1l (T , P) = f1s (T , P)

Λ 21 =

2 ⎤ ⎡ τ21G21 τ12G12 ⎥ ln γ1 = x 22⎢ + (x 2 + G12x1)2 ⎦ ⎣ (x1 + G21x 2)2

Assuming the solution is an ideal solution (γ1 = 1), then eq 7 can be expressed as follows: a ln x1 = +b (7) T where a and b are the model parameters, and x1 is the mole fraction of solubility at system temperature T. 3.2.5. Local Composition Model. At a given temperature and pressure, the fugacity of the compound in the liquid and solid phases should be the same at phase equilibrium. f1l (T , P , x l) = f1s (T , P)

⎛ Δλ ⎞ ⎛ λ − λ11 ⎞ ν2 ν ⎟ = 2 exp⎜ − 12 ⎟ exp⎜ − 12 ⎝ ⎝ RT ⎠ RT ⎠ ν1 ν1

Here, Δλ12 and Δλ21 are the cross interaction energy parameters that can be fitted by experimental solubility, and ν1 and ν2 are the mole volumes of the solute and solvent, respectively. NRTL Model. The NRTL model can be expressed in the following binary form:22

where ΔH1, Ttp,1, ΔCp,1, Ptp,1, and γ1 are the mole enthalpy of fusion, triple-point temperature, difference of heat capacities between subcooled liquid and solid, triple-point pressure, and activity coefficient for solid component, respectively; x1 is the solid solubility of the component at the system temperature T and pressure p, and R is the universal gas constant. The above equation is generally simplified by replacing the triple-point temperature Ttp,1 with the normal melting temperature Tm1. The last two terms on the right-hand side of the equation are canceled such that pressure correction would become negligible. The contribution of heat-capacity difference is often minor, and no solid-to-solid conversion ranging from T to Ttp exists. Equation 5 may be rewritten as follows: ln x1γ1 =

Λ12 =

(10)

The activity coefficient, melting temperature, and enthalpy of fusion should be determined to calculate the solubility of the solute via eq 10. Two well-established activity coefficient models, namely, the Wilson model19 and the NRTL model,20 were used for the calculations in this study. Wilson Model. The Wilson model can be expressed in the following binary form:21 ⎞ ⎛ Λ12 Λ 21 ln γ1 = −ln(x1 + Λ12x 2) + x 2⎜ − ⎟ x 2 + Λ 21x1 ⎠ ⎝ x1 + Λ12x 2 (11)

where 3038

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Gibbs energy of solution can be calculated by the following equations:26 ΔGd = ΔHd − T ΔSd

(17)

The calculated dissolution enthalpy, entropy, and the Gibbs energy are presented in the Supporting Information. Results show that the ΔHd of pioglitazone hydrochloride (Form II) in each solvent in the experimental temperature range is endothermic (ΔHd > 0), which explains the increasing solubility of pioglitazone hydrochloride (Form II) with increasing temperature. Dissolution is an endothermic process because the interactions between pioglitazone hydrochloride molecules and solvent molecules are more powerful than those between the solvent molecules. The positive ΔHd and ΔSd in N,Ndimethylacetamide, methanol, dimethyl sulfoxide, and acetic acid denote that the processes involved in dissolving pioglitazone hydrochloride (Form II) in these four solvents are all entropy-driven.27 Based on the data, the values of the Gibbs energy of solution are positive, and decrease with the increasing temperatures in all the solvents. Low ΔHd values correspond to higher solubility, which means more favorable dissolution. These results are critical for the optimization of the dissolution and crystallization processes of pioglitazone hydrochloride (Form II).

Figure 4. Experimental and modeling the solubility (x) of pioglitazone hydrochloride (Form II) in different solvents: ■, N,N-dimethylacetamide; ●, methanol; ▲, dimethyl sulfoxide; ▼, acetic acid. The corresponding lines are calculated values based on the van’t Hoff equation.

can be given as λ = 1. On the basis of the correlated values of λ, it indicates that the larger the deviation of λ from 1 is, the more nonideal the solution system becomes. 3.4. Prediction of Dissolution Enthalpy, Entropy, And the Molar Gibbs Free Energy. The van’t Hoff equation relates the logarithm of the mole fraction of a solute as a linear function of the reciprocal of the absolute temperature, as shown in eq 4. ΔHd and ΔSd represent the dissolution enthalpy and entropy, respectively. From the experimentally obtained solubility data, a plot of ln x1 versus 1/T gives the values of enthalpy and entropy of dissolution from the slope and the intercept, respectively. Figure 5 shows the van’t Hoff plot of the logarithm of mole fraction solubility versus reciprocal absolute temperature. The

4. CONCLUSIONS The solubility data of pioglitazone hydrochloride (Form II) in N,N-dimethylacetamide, methanol, dimethyl sulfoxide, and acetic acid were obtained at temperatures ranging from 283.15 to 323.15 K. DSC was employed to determine the melting temperature Tm1 and the enthalpy of fusion ΔfusH1 of the compound. The solubility of pioglitazone hydrochloride (Form II) is a function of temperature. The order of the solubility of the compound is given as follows: N,Ndimethylacetamide > dimethyl sulfoxide > acetic acid > methanol. The experimental data were correlated with the modified Apelblat equation, λh equation, van’t Hoff equation, ideal model, Wilson model, and NRTL model. The calculation results show that the λh equation, van’t Hoff equation, and the ideal model are more suitable in determining the solubility of pioglitazone hydrochloride (Form II) compared with the other three models. By using the van’t Hoff equation, the dissolution enthalpy, entropy, and molar Gibbs free energy of pioglitazone hydrochloride (Form II) are predicted in different solvents.

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ASSOCIATED CONTENT

S Supporting Information *

Mole volumes of pure components, experimental solubility, optimized parameters for the models, and predicted values of the dissolution properties. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: 86-22-27405754. Fax: 86-22-27374971. E-mail: zhao_ [email protected].

Figure 5. van’t Hoff plot of logarithm mole fraction solubility of pioglitazone hydrochloride (Form II) in different solvents: ■,N,Ndimethylacetamide; ●, methanol; ▲, dimethyl sulfoxide; ▼,acetic acid.

Notes

The authors declare no competing financial interest. 3039

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ACKNOWLEDGMENTS The support from National Natural Science Foundation of China (No. 21206109) and China Ministry of Science and Technology for the key technology of preparation of edible pigment and industrialization project (No. 2011BAD23B02) are greatly appreciated.

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NOTATIONS a = empirical constant for the ideal model b = empirical constant for the ideal model A = empirical constant for the modified Apelblat equation AAD = average absolute deviation B = empirical constant for the modified Apelblat equation C = empirical constant for the modified Apelblat equation f = fugacity Δg12 = cross interaction energy parameter for the NRTL model (g12 − g22) (J/mol) Δg21 = cross interaction energy parameter for the NRTL model (g21 − g11) (J/mol) h = model parameter for the λh equation ΔHd = enthalpy of dissolution (J/mol) ΔfusH = enthalpy of fusion at the melting point (J/mol) N = number of experimental data P = pressure (Pa) R = the gas constant (8.3145 J/mol·K) ΔSd = entropy of dissolution (J/mol·K) ΔfusS = entropy of fusion at the melting point (J/mol·K) T = temperature (K) Tm = melting temperature (K) v = molar volume (cm3/mol) x = mole fraction in the solution

Greek Letters

α12 = nonrandomness parameter γ = activity coefficient λ = model parameter for the λh equation Δλ12 = cross interaction energy parameter for Wilson equation (λ12 − λ11) (J/mol) Δλ21 = cross interaction energy parameter for Wilson equation (λ21 − λ22) (J/mol) Subscripts

1 = solute (pioglitazone hydrochloride (Form II)) 2 = solvent (N,N-dimethylacetamide, methanol, dimethyl sulfoxide and acetic acid) Superscripts

calc = calculated data l = liquid s = solid

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REFERENCES

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