Cosolvent effect on solubility of aripiprazole in mixed solvents and apparent thermodynamic analysis of dissolution process

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Highlights

Abstract

Due to different polymorphs demonstrate significant variations in the drug properties such as solubility, stability and dissolution rate. In this work, we study the shape of the solubility profile of form X0 (the thermodynamically stable form at room temperature) in two mixtures of (n-propanol + acetone) and (isopropanol + acetone) at T = 278.15–318.15 K. The solubility value is a function of temperature and solvent composition. It increases at first and then decreases with the increasing concentration of acetone in mass fraction, and the composition dependence of the solubility has a maximum around mass fraction of acetone w = 0.6 at all investigated temperatures. The Jouyban-Acree model and CNIBS/R-K model are applied to correlate the solubility, and CNIBS/R-K model is more suitable. The values of dissolution standard Gibbs energy (ΔGsolo) and dissolution standard entropy (ΔSsolo) are all positive which indicate that the dissolution is not only endothermic but also entropy-driving.

Introduction

Polymorphism of drugs in modern pharmaceuticals industry occurs more and more frequently because of their complex structural features [1]. Admittedly, polymorphism of drugs provides a possibility to obtain the required crystalline form with desired properties, but there are many instances where multiple forms of existence has created unexpected problems at all stages of drug development [2], [3]. According to the previous literature, Aripiprazole (APZ, the structure is shown in Fig. 1) exists in several distinct polymorphic, solvated, and amorphous forms [4], [5], [6], [7], [8]. In Braun and coworkers research, the existence of nine crystalline solid state forms (five polymorphs, a monohydrate, three solvates) besides the amorphous solid of APZ have been systematically studied [7], [8]. In the last few decades, the different crystal forms of APZ were named in various ways (such as Roman numerals, Latin capitals and Greek letters) in many patent applications. Various terminologies lead to great misleading for scientific researchers. Fortunately, Braun and coworkers have uniformly named the five polymorphs with Roman numerals (forms I, II, III, IV and X0) following the order of decreasing melting points. Moreover structural and thermodynamic features of those APZ polymorphs were characterized by Braun and coworkers with a variety of analytical techniques [7], [8].

APZ is a novel class of atypical antipsychotics, which has been marketed in the United States under the brand name Abilify [8]. Its mechanism of action is different from those of the currently marketed typical and atypical antipsychotics. APZ exhibits antagonist and agonist properties in animal models of dopaminergic hyperactivity and dopaminergic hypoactiv. Commonly, it is used to treat schizophrenia such as panic, obsessive-compulsive disorder, sleep disorder, sexual dysfunction, depression, anxiety or mania [9], [10]. Due to different polymorphs demonstrate significant variations in the drug properties such as solubility, stability and dissolution rate [11]. In particular, the solubility of polymorphic drug has attracted enough attention because it may influence bioavailability. In this work, we study the shape of the solubility profile of form X0 (the thermodynamically stable form at room temperature [8]) in mixtures of (n-propanol + acetone) and (isopropanol + acetone), and some apparent thermodynamic properties of dissolution are also evaluated.

Section snippets

Materials

Aripiprazole was purchased from Hubei YuanCheng SaiChuang Technology Co., Ltd (China). The sample had a purity of 0.997 in mass fraction, which was determined by high-performance liquid phase chromatograph (HPLC). The studied solvents with analytical grade were all purchased from Sinopharm Chemical Reagent Co., Ltd., China. Molecular sieve was added to the solvent to remove possible water. The detailed information of these materials was presented in Table 1.

X-ray diffraction investigations

The crystal form of APZ was analyzed

Results of PXRD

The results of PXRD patterns are shown in Fig. 2. From Fig. 2, we can find that all patterns of solid phase of APZ during experiment have the same characteristic peaks with the raw material. According to Ref. [8], form X0 can be produced by stirring a suspension of any APZ form in acetone, isopropanol and n-propanol, which does not form solvent adducts, below 338.15 K. Characteristic peaks of form X0 in Ref. [8] are the same as that of this work. In brief, it can be concluded that the

Conclusions

The solubility of aripiprazole in (acetone + n-propanol) and (acetone + isopropanol) was experimentally determined at T = 278.15–318.15 K. The solubility value is a function of temperature and solvent composition. It increases at first and then decreases with the increasing concentration of acetone in mass fraction, and the composition dependence of the solubility has a maximum around mass fraction of acetone w = 0.6 at all investigated temperatures. The Jouyban-Acree model and CNIBS/R-K model

Acknowledgment

The project was supported by College Students’ Science and Technology Innovation Project of XinZhou Teachers University, China (201707).

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