Solubility modelling, solvent effect and preferential solvation of 6-chloropurine in several aqueous co-solvent mixtures between 283.15 K and 328.15 K

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Highlights

  • 6-Chloropurine solubility in four co-solvent mixtures was determined and correlated.

  • Solvent effect were investigated using KAT-LSER model.

  • Preferential solvation of 6-chloropurine was investigated by IKBI method.

Abstract

The mole fraction solubility of 6-chloropurine in aqueous mixtures of methanol, ethanol, N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA) was measured by a saturation shake-flask method over the temperature range of (283.15–328.15) K at pressure of 101.2 kPa. The solubility of 6-chloropurine increased positively with increasing temperature at a given solvent composition and decreased with increasing mass fraction of water in each binary system. The maximum solubility was found in neat methanol, ethanol, DMF and DMA. Given the same temperature and mass fraction of the organic solvent, the solubility of 6-chloropurine was greater in (DMF + water) than in the other three solvent mixtures. The X-ray power diffraction (XPRD) analysis showed that no polymorphic transformation, solvate formation or crystal transition took place during the experiments. Linear solvation energy relationships concept was used to describe the variation in the solubility based on the solvent effect. The preferential solvation parameters were derived from their thermodynamic solution properties using inverse Kirkwood–Buff integrals. The preferential solvation parameters (δx1,3) for methanol, ethanol, DMF and DMA were negative in the four solvent mixtures with water-rich compositions, which indicated that 6-chloropurine was preferentially solvated by water. Temperature has little effect on the preferential solvation magnitudes. The higher solvation by water could be explained in terms of the higher acidic behavior of the solvents interacting with the Lewis basic groups of the 6-chloropurine. Furthermore, several mathematical cosolvency models were adopted to correlate the measured solubility values. The relative average deviation and root-mean-square deviation were no more than 2.36% and 1.026 × 10−3, respectively.

Introduction

In recent years, study on the drugs’ solubility and its improvement has been a widely increasing subject in pharmaceutical areas. Aqueous solubility is an important physicochemical property that plays a significant role in various physical and biological processes. Poor aqueous solubility is likely to result in low bioavailability or formulation difficulty during clinical development [1], [2]. Therefore evaluation of solubility at early stages of lead optimization and candidate selection is necessary during the drug discovery process. The solubility of drugs in solvent mixtures as a function of composition and temperature is evaluated importantly for the purposes of raw material purification, design of liquid dosage forms, and understanding of the mechanisms relating to the physical and chemical stability of pharmaceutical dissolutions [3], [4], [5], [6], [7]. Alternatively, drug solubility in solvent mixtures allows performing a thermodynamic analysis to insight into the molecular mechanisms regarding the drug dissolution process and the preferential solvation of the solute by the solvent components [8], [9].

6-Chloropurine (C5H3ClN4, CAS Reg. No. 87-42-3, chemically named 6-chloro-7H-purine, structure shown in Fig. 1) is classified by the one of some bioactive purine derivatives which has been widely exploited in medical chemistry, pesticide and agricultural chemicals fields [10], [11], [12], [13]. From structural viewpoint, 6-chloropurine is the most ubiquitous nitrogen-containing heterocycle in nature. However, 6-chloropurine is only slight soluble in water. The mole fraction solubility of 6-chloropurine in water is reported by Bendich as 6.402 × 10−4 at 297 K [14] and by Albert as 6.473 × 10−4 at 293 K [15]. The lower solubility would be a key drawback in dosage design and significantly decreases its bioavailability. Cosolvency, pH adjustment, surfactant addition and complexation are the most commonly encountered pharmaceutical approaches for solubilizing drug candidates with low aqueous solubility [5]. Among them, the most powerful and effective tools for increasing solubility of poorly water soluble drugs is mixing a safe and miscible co-solvent with water [3], [4], [5]. Solubility determination of drugs in water−co-solvent mixtures provides useful data for better understanding of the solubility phenomenon in these media. However, despite the usefulness of this drug, it is completely devoid of information about physicochemical properties such as solubility of this drug in different solvents and solvent mixtures. A thorough literature search shows that only the solubilities of 6-chloropurine in water at 293 K or 297 K are available [14], [15]. In order to study the physicochemical properties of 6-chloropurine in neat solvents and solvent mixtures, it is essential to determine systematically the solubility for pharmaceutical systems.

For cosolvency approach, solvent selection is a pivotal procedure. Practicable solvents should be thermally stable, nontoxic (environmentally safe), noncorrosive, and commercially available. The frequently used co-solvents in the pharmaceutical fields are methanol, ethanol, n-propanol, isopropanol, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMA), polyethylene glycol, dimethyl sulfoxide (DMSO) and so on [3], [5], [6], [7]. Generally, methanol is not used in developing liquid medicines due to its high toxicity. However it is used in drug purification [16] and is widely used as mobile phase in high performance liquid chromatography (HPLC) [17]. Ethanol is a safe and common co-solvent to be used in the pharmaceutical industry due to its high solubilization capacity [18]. DMF is a very interesting co-solvent to investigate the interrelation between drug solubility and medium polarity because it is aprotic and completely miscible with water [19]. N,N-dimethyl acetamide (DMA) is also a common co-solvent to alter the drug solubility efficiently and is widely used in pharmaceutical formulation [3], [5], [20]. Based on the considerations mentioned above, the main purpose of this work is to determine the equilibrium solubility of 6-chloropurine (3) in binary mixtures of {methanol (1) + water (2)}, {ethanol (1) + water (2)}, {N,N-dimethyl formamide (DMF) (1) + water (2)} and {N,N-dimethyl acetamide (DMA) (1) + water (2)} at temperatures ranging from (283.15–328.15) K under ambient conditions and to evaluate the respective thermodynamic quantities of the solution.

Section snippets

Theoretical aspects

Several mathematical models have been developed to describe the solubility of solid in solvent mixtures [3], [21], [22]. In this work, the solubility of 6-chloropurine in binary co-solvents of (methanol + water), (ethanol + water), (DMF + water) and (DMA + water) at different temperatures are correlated by Jouyban-Acree model [3], [21], [22], Apelblat-Jouyban-Acree model [21], [22] and van’t Hoff-Jouyban-Acree model [22].

Materials and apparatus

6-Chloropurine was purchased from Shanghai Bide Pharmatech Ltd. with a mass fraction of 0.980. It was purified three times via crystallization in methanol. The final content of 6-chloropurine employed for solubility determination was 0.996 in mass fraction confirmed by using a high-performance liquid chromatography (HPLC, Agilent-1260). Solvatochromic dyes including para-nitroaniline (PNA), para-nitroanisole (PNAS) and 2,6-diphenyl-4-(2,4,6-triphenylpyridinio) phenolate (RD) were purchased from

XPRD analysis

The patterns of the raw material 6-chloropurine and the solids equilibrated with liquor are plotted in Fig. S1 of Supporting Material. It is confirmed by XPRD pattern that all patterns of solid phase of 6-chloropurine in equilibrium with its solution have the same characteristic peaks with the raw material. Whilst the presence of amorphous phases cannot be ruled out, it can be concluded that there is possible no polymorph transformation or solvate formation during the entire experiment.

Neat solvents

The

Conclusions

The equilibrium solubilities of 6-chloropurine in co-solvent mixtures of (methanol, ethanol, DMF and DMA) + water with various composition were acquired experimentally via the saturation shake-flask method within the temperature range of (283.15 to 328.15) K under about 101.2 kPa. For all solvent mixtures, the mole fraction solubility of 6-chloropurine increased with increasing temperature and mass fraction of methanol, ethanol, DMF and DMA for the co-solvent solutions system, and the maximum

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