Solubility and dissolution thermodynamics of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide in PG + water co-solvent mixtures at (298.15 to 338.15) K

Highlights

• Solubility of isoniazid analog in various PG + water mixtures was measured.

• The solubility was observed highest in pure PG.

• Experimental solubilities were correlated well with Apelblat and Yalkowsky model.

• Solubilities were increased with increase in temperature and mass fraction of PG.

Abstract

The objective of present investigation was to measure the solubility and dissolution thermodynamics of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide [isoniazid (INH) analog] in various propylene glycol (PG) + water co-solvent mixtures from (298.15 to 338.15) K. The experimental solubilities of INH analog were correlated with Apelblat and Yalkowsky models. The root mean square deviations were found to be (1.13–3.98)% and (1.45–5.73)% for Apelblat equation and Yalkowsky model, respectively. Good correlation was observed between experimental and calculated solubilities of INH analog with correlation coefficients in the range of 0.995–0.999. The mole fraction solubility of INH analog was found to be highest and lowest in pure PG (7.38 × 10⁻³ at 298.15 K) and pure water (5.17 × 10⁻⁷ at 298.15 K), respectively. The results of dissolution thermodynamics indicated endothermic and non-spontaneous dissolution of INH analog.

Introduction

Solubilization methods have very important role in different area of pharmaceutical industries such as drug purification, crystallization, separation and the most important drug formulation design [1], [2]. Development of liquid oral dosage forms of poorly water-soluble drugs is a great challenge at all stages of formulation development processes [1]. Nevertheless, the addition of permissible amount of a co-solvent is an effective means to overcome solubility problems of poorly water-soluble drugs [2], [3]. Ethanol, propylene glycol (PG) and polyethylene glycol 400 (PEG 400) are the commonly used co-solvents for solubility enhancement of poorly water-soluble drugs in liquid oral dosage forms [3], [4], [5], [6]. Isoniazid (INH) is the most popular drug for the treatment of tuberculosis (TB) caused by Mycobacterium tuberculosis [7], [8]. The doses and adverse effects of anti-TB drugs including INH are very frequent, therefore various analogs of INH have been investigated as potential drug candidates in order to eliminate their adverse effects [9], [10], [11], [12]. The IUPAC name of INH analog used in this study is N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide (C₁₃H₁₁ClN₄OS; molar mass 306.77 g mol⁻¹) and its molecular structure is presented in Fig. 1 [13]. INH analog has been characterized and investigated for potential antifungal activity [12]. It has been reported as poorly water-soluble compound (mole fraction solubility of 5.17 × 10⁻⁷ at 298.15 K) in literature [13], [14]. Apelblat equation and log-linear model of Yalkowsky are the commonly used models for correlation of experimental solubilities with calculated ones and to investigate the influence of temperature and co-solvent mixtures on solubility of drugs, respectively [15], [16], [17], [18]. The solubilities and dissolution thermodynamics of INH analog in Transcutol + water and PEG 400 + water co-solvent mixtures from (298.15 to 338.15) K have already been reported in literature [13], [14]. However, the solubilities and dissolution thermodynamics of INH analog in PG + water co-solvent mixtures are not reported in literature. Therefore, in present report, the solubilities and dissolution thermodynamics of INH analog in various PG + water co-solvent mixtures from (298.15 to 338.15) K were measured. The experimental solubilities of INH analog were measured using the shake flask method as it is the commonly used method for this purpose. The generated solubility data of INH analog were correlated with Apelblat and Yalkowsky models.