Solubility modelling and thermodynamic aspect of 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone in binary aqueous solutions of several alcohols

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Highlights

  • Solubility of propylthiouracil in four binary cosolvent mixtures were determined.

  • Solubility data was correlated and calculated by three solubility models.

  • Preferential solvation parameters of propylthiouracil by alcohols were determined.

  • Transfer properties were derived according to the determined solubility data.

Abstract

The equilibrium solubility of 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone in four neat solvents namely methanol, ethanol, n-propanol and isopropanol and co-solvent mixtures of methanol (1) + water (2), ethanol + water (2), n-propanol (1) + water (2) and isopropanol (1) + water (2) at temperature range from (278.15 to 333.15) K was reported. The experiment was carried out by the saturation shake-flask technique under atmosphere pressure (101.1 kPa). At the same composition of methanol, ethanol, n-propanol or isopropanol and temperature, the mole fraction solubility of 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone was highest in methanol (1) + water (2) mixtures, and lowest in isopropanol (1) + water (2) mixtures. By using the Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model, 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone solubility was well correlated obtaining RAD lower than 2.65% and RMSD lower than 1.85 × 10−4. The transfer Gibbs free energy (ΔtrG°), enthalpy (ΔtrH°), and entropy (ΔtrS°) were calculated, demonstrating that the solubilization capacity was more favorable with the increase in the alcohol concentration. Furthermore, quantitative values for the local mole fraction of methanol (ethanol, n-propanol or isopropanol) and water around the 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone were computed by using the Inverse Kirkwood–Buff integrals method applied to the determined solubility data. 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone was preferentially solvated by water for the four solvent mixtures in water-rich compositions; while in intermediate and co-solvent-rich composition for alcohol (1) + water (2) mixtures, 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone is preferentially solvated by the alcohol. The preferential solvation magnitude of 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone was highest in isopropanol mixtures than in the other three co-solvent mixtures.

Introduction

In later years, investigation upon the drugs’ solubility and its improvement has become a widely increasing topic in pharmaceutical fields. The drugs’ solubility in co-solvent mixtures is one of the most significant physicochemical properties [1], [2], [3], [4]. It is assessed significantly for the design of liquid dosage forms, raw material purification and understanding the mechanisms connecting the chemical and physical stability of solid dissolution [3], [5], [6]. They are considered as an essential factor to design the crystallization procedur, where the knowledge of solubility is required to control the particle size, supersaturation, yield and desired polymorphicform. In addition, cosolvency is an effective and optional solubilization method which is widely used to adjust the solid solubility, as aqueous co-solvent mixtures is essential for pharmaceutical and chemical industries since the mixtures may be employed as reaction medium or re-crystallization solvents in purification procedure of many compounds [1], [6]. Poor solubility in water may result in formulation difficulty or low bioavailability in the course of clinical development [1], [7]. Furthermore, drugs’ solubility in aqueous co-solvent mixtures allows one carrying out a thermodynamic analysis to deeply insight into the molecular mechanisms regarding the drug dissolution process and to evaluate the preferential solvation of a drug by solvent components in solutions [8], [9].

The compound 2,3-dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone (CAS Reg. No. 51–52-5, structure shown in Fig. 1), also named as propylthiouracil, is an useful medication used to treat hyperthyroidism [10], [11], [12]. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. However, propylthiouracil is poorly-soluble in water [13], [14], [15], [16], [17], [18], [19], [20]. The lower solubility is a key drawback in dosage design and significantly decreases its bioavailability. Cosolvency, surfactant addition, pH adjustment, complexation and changing crystalline forms are the most encountered pharmaceutical methods to solubilize drug candidates with low aqueous solubility [1], [2], [3], [5], [16], [17], [18]. Among them, the most effective and powerful tool for increasing solubility of poorly water soluble drugs is mixing a safe and miscible co-solvent with water [1], [2], [3], [5]. Solubility measurement of drugs in aqueous co-solvent mixtures offers useful data for better understanding of the solubility phenomenon in the media. However, despite the usefulness of this drug, it is completely devoid of information on physicochemical properties such as solubility of this drug in different solvents and solvent mixtures. A thorough literature view shows that only the propylthiouracil solubility in water at several temperatures is available in literatures [13], [14], [15], [19], [20]. However, the physicochemical property of allopurinol in neat organic solvent and solvent mixtures has not yet been investigated.

For co-solvency approach, solvent selection is an essential procedure. Practicable solvents should be nontoxic (environmentally safe), thermally stable, noncorrosive, and commercially available [1], [3], [5], [6]. Isopropanol is a colorless and flammable chemical compound with a strong odor. It is miscible with water, ethanol, ether and chloroform, and dissolves a wide range of non-polar compounds. Compared to alternative solvents, isopropanol is relatively non-toxic. It is used solely or in mixtures with other solvents for different purposes including in penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous applications [21], [22]. In general, ethanol is an environmentally-safe and common co-solvent to be used in the pharmaceutical industry due to its high solubilization capacity [23]. n-Propanol is green solvent [24] and miscible with water in all compositions. In addition, although n-propanol is not widely used as co-solvent for design of liquid medicines, it has been used as solvent in the pharmaceutical industry for resins and cellulose esters [25]. In addition, methanol is not used in developing liquid medicines due to its high toxicity. However it is used in drug purification [26] and is widely used as mobile phase in high performance liquid chromatography (HPLC) [27]. Considering these points-of-view, the main objective of this work is to report the equilibrium solubility of propylthiouracil in aqueous co-solvent mixtures of methanol, ethanol, n-propanol and isopropanol at temperatures ranging from 278.15 K to 333.15 K under atmospheric conditions in order to evaluate the respective thermodynamic quantities of the solution.

Section snippets

Theoretical consideration

The solubility models for describing the solubility of a solid in co-solvent mixtures have been reviewed by Jouyban [28]. Here, the Jouyban−Acree model [28], [29], a combination of the Jouyban−Acree model with van’t Hoff equation [29] and a combination of the Jouyban−Acree model with modified Apelblat equation [29] are employed to describe the propylthiouracil solubility in the aqueous co-solvent mixtures of methanol, ethanol n-propanol and isopropanol.

Materials

The propylthiouracil was provided by Sigma Chemical Co., Ltd, China with a mass fraction of 0.984. It was crystallized in methanol for three times. The final mass fraction of propylthiouracil used for solubility measurement was 0.997, which was confirmed by using a high-performance liquid chromatography (HPLC, Agilent 1260). The organic solvents namely methanol, ethanol, n-propanol and isopropanol were provided by Sinopharm Chemical Reagent Co., Ltd., China, the purities of which were all no

X-ray powder diffraction analysis

The patterns of the raw material as well as the solids equilibrated with liquid phase are shown in Fig. S1 of Supporting material. It can be seen that all the XRD patterns of solid phase of propylthiouracil equilibrated with its liquid phase have the identical characteristic peaks with the raw material. Therefore, the conclusion can be made that no polymorph transformation or solvate formation occurs during the experiment process.

Neat solvents

The determined mole fraction solubility (x) of propylthiouracil

Conclusion

The equilibrium solubilities of propylthiouracil in solvent mixtures of methanol (1) + water (2), ethanol (1) + water (2), isopropanol (1) + water (2) and n-propanol (1) + water (2) were determined experimentally by using the saturation shake-flask technique within the temperature range from 278.15 K to 333.15 K under atmospheric pressure (101.1 kPa). The mole fraction solubility of propylthiouracil was highest in (methanol + water) among the four mixtures at the same temperature and mass

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