Experimental solubility evaluation and thermodynamic analysis of biologically active D-tryptophan in aqueous mixtures of N,N-dimethylformamide and several alcohols

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Highlights

  • Solubility of D-tryptophan in four solvent mixtures was reported and correlated.

  • Preferential solvation of D-tryptophan was studied by method of IKBI.

  • KAT-LSER model was employed to investigate solvent effect.

Abstract

The D-tryptophan solubility in aqueous solutions of methanol, ethanol, isopropanol and N,N-dimethylformamide (DMF) was measured by the saturation shake-flask method at temperatures ranging from 283.15 K to 333.15 K. The maximum solubility was found in water for alcohol (1) + water (2) mixtures, and in neat DMF for DMF (1) + water (2) mixture. When the same temperature and mass fraction of the water is given, the highest mole fraction solubility of D-tryptophan was found in (DMF + water). The solid phases were tested by X-ray powder diffraction (XPRD) showing no polymorphic transformation, solvate formation or crystal transition. Three solubility models, i.e. the Jouyban-Acree, van’t Hoff-Jouyban-Acree and Apelblat-Jouyban-Acree were employed to correlate the experimental solubility values so as to obtain thermodynamic parameters. The RAD and RMSD data were no more than 1.65% and 9.40 × 10−5, respectively. Linear solvation energy relationship analysis based on Kamlet-Taft parameters indicated that the variation of D-tryptophan solubility depended on π∗ for methanol (ethanol, isopropanol) (1) + water (2), and cavity term for DMF (1) + water (2). The preferential solvation parameters (δx1,3) for methanol, ethanol, isopropanol and DMF derived by means of the inverse Kirkwood–Buff integrals were negative in the four solvent mixtures with intermediate and alcohol-rich compositions, which indicated that D-tryptophan was preferentially solvated by water. The higher solvation by water could be explained in terms of the higher acidic behaviour of the solvents interacting with the Lewis basic groups of the D-tryptophan. However D-tryptophan is preferentially solvated neither by water nor by DMF in DMF + water mixture.

Introduction

As is well-known to us, amino acids are recognized to be essential building blocks of proteins in a variety of food, agriculture and bioscience areas that can be existed in either L- or D-isomer except for the glycine [1], [2]. It is reported that D-type amino acids can be employed in inhibiting microbial attachment onto solid surfaces and leading to the separation of mature bio-membrane in the low concentration [2], [3]. As one of the non-protein active amino acid found in naturally produced peptides, D-tryptophan (CAS Reg. No. 153-94-6, structure shown in Fig. 1, IUPAC name (R’)-α-Amino-3-indolepropionic acid) has abundant application value in the fields of food, agriculture and medical industries with special physiological properties [4], [5], [6].

The solubility and related thermodynamic parameters of the amino acids like Gibbs energy of transfer are essential in exploring the mechanism of interactions between solvent molecules with bio-macromolecules [7]. In some cases thermodynamic parameters are found to be helpful in characterizing the conformational changes of macromolecules like proteins in solution. This opens a field of investigation on the studies of solvation of amino acids in different solvent systems. Size, shape, charge, hydrogen bonding capability, hydrophobicity, hydrophilicity, zwitterionic character, chemical reactivity, etc., of an amino acid are seen to govern it in solution which is why a lot of studies are performed to correlate their structural aspects with their solvation individuality [8]. In this way, the knowledge of the thermodynamic properties of proteins as well as amino acids in different solution is necessary. Although many solubility results of several amino acids in neat solvents and solvent mixtures are available in the literatures, a new addition in this area would definitely enrich the region which still remains to be explored. The literatures research discussed the effect of 3rd component (additive) on the water structure around tryptophan [9], [10], [11], [12]. The increase in the solubility of tryptophan in water upon addition of various organic compounds was explained on the basis of the following mechanism: such a 3rd component comes in contact with the hydrophobic moiety of tryptophan to result in a simultaneous structural change of the iceberg around that moiety, accompanying an increase of its affinity to water. It was demonstrated that the more hydrophobic the drug, the more it was adsorbed by carbon black from aqueous solution. Although physicochemical properties relating solubility of L-tryptophan and DL-tryptophan in aqueous solutions have been extensively studied [9], [10], [11], [12], [13], the physicochemical properties of neat D-tryptophan in aqueous and organic solutions have not been studied so far. So this work tries to give an idea about the relative stabilization of D-tryptophan in aqua-organic mixtures with respect to water and the complex solute–solvent and solvent–solvent interactions therein.

In addition, due to the good market prospects, many investigators endeavor to study the production of D-tryptophan. D-tryptophan is usually produced from L-tryptophan by racemization under the basic condition. Obviously, it is rather necessary to separate the two optical isomers of D- and L-tryptophan type by means of efficient methods in order to realize further application. In the cost of D-tryptophan production, the separation and purification hold a large proportion and has become a bottleneck problem. The crude D-tryptophan must be purified via recrystallization in aqueous solutions of alcohols and other organic compounds [5], [6], [14]. However, to design an optimized process of crystallization, it is necessary to study the thermodynamics the crystallization first. The obtained solubility data enables us to find the most suitable solvent systems to purify various drugs by means of solvent crystallization.

An empirical model of solvent effect has been developed by Kamlet and Taft et al. based on a classification of intermolecular interactions and considering their separate contribution to the free energy of solvent-effected change [15]. In this model, known as Kamlet and Taft linear solvation energy relationships, and abbreviated as KAT-LSER, the total energy changes arising from the solvent effect is expressed as a linear summation over all solute-solute, solute-solvent and solvent-solvent interactions. Intermolecular interactions are considered into two categories: non-specific interactions including dipole-dipole (Keesom), dipole-induced dipole (Debye) and instantaneous induced dipole-dipole (London dispersion), and specific interactions such as hydrogen bonding interactions. The solvent’s ability to participate in such interactions is characterized by introducing three solvatochromic parameters including π*, β and α to scale dipolarity/polarizability, hydrogen-bond basicity and hydrogen-bond acidity of solvent, respectively [15], [16], [17], [18]. Since these parameters are determined from direct measurement of energy changes induced by relating solute-solvent interactions, correlation analysis between them and the Gibbs energy of solvent-effected property such as the solubility in the framework of KAT-LSER gives quantitative information on their relative significance and thus on the nature of solvent effect [17], [18].

Although several semiempirical and theoretical models may be used to predict solubility of drug in mixed solvents, the availability of experimental solubility data is still fundamental for the pharmaceutical scientists [19]. In addition, solvent mixtures has been widely employed in pharmacies long ago [20]. Recently the mechanisms relating to the decrease or increase in drugs’ solubility start to be studied from a deep thermodynamic point of view, including the analysis of the preferential solvation of solute by the components in mixed solvents [21], [22], [23].

For co = solvency 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, isopropanol, N,N-dimethylformamide (DMF) and so forth [24], [25], [26], [27]. Methanol is not used to develop liquid medicines due to its high toxicity. However it is used in drug purification and is widely used as mobile phase in high performance liquid chromatography (HPLC) [28]. Ethanol is a safe and common co-solvent to be used in the pharmaceutical industry due to its high solubilisation capacity [29]. DMF is a very interesting solvent to investigate the interrelation between drug solubility and medium polarity because it is aprotic and completely miscible with water [30]. Isopropanol is a colorless and flammable chemical compound with a strong odour. It is miscible with water, ethanol, ether and chloroform, and dissolves a wide range of non-polar compounds. It is relatively non-toxic, compared to alternative solvents. Isopropanol is used solely or in mixtures with other solvents for different purposes including in penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous applications [31].

In terms of the considerations mentioned above, the main goal of this work is to report the equilibrium solubility of D-tryptophan (3) in neat solvents of methanol, ethanol, isopropanol, DMF and water, and liquid mixtures of {methanol (1) + water (2)}, {ethanol (1) + water (2)}, {isopropanol (1) + water (2)} and { DMF (1) + water (2)} at temperatures ranging from (283.15 to 333.15) K as well as solvent effect on the solubility and the preferential solvation of D-tryptophan by these organic solvents. This research expands the available solubility data about drug in neat organic solvents and solvent mixtures [24] and also allows the thermodynamic analysis of the respective dissolution and specific solvation process.

Section snippets

Materials

D-Tryptophan was purchased from Aladdin Industrial (Shanghai) Co., Ltd with a mass fraction of 0.980. It was purified three times via crystallization in ethanol. The final content of D-tryptophan employed for solubility determination was 0.995 in mass fraction confirmed by using a high-performance liquid chromatography (HPLC). In this work, all organic solvents (methanol, ethanol, isopropanol and DMF) used were provided by Sinopharm Chemical Reagent Co., Ltd., China with the mass fraction

XPRD analysis

The patterns of the raw material and the solids crystallized in neat solvents and solvent mixtures are plotted in Fig. S1 of Supporting information. It is confirmed by XRD pattern that all the XPRD patterns of solid phase of D-tryptophan 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 no possible polymorph transformation or solvate formation during the entire

Conclusion

The equilibrium solubility of D-tryptophan in aqueous solutions of methanol, ethanol, isopropanol and DMF with various compositions was acquired experimentally by means of the saturation shake-flask method in the temperature range of (283.15 to 333.15) K under atmospheric pressure. The maximum solubility of D-tryptophan is observed in neat water for the alcohol (1) + water (2) mixtures, and in neat DMF for DMF (1) + water (2) mixture. The dependence of D-tryptophan solubility on temperature and

Acknowledgements

The authors thank for the finical support from the National Natural Science Foundation of China (No. 21173188), Henan Province Science and Technology Key Project of China (No. 152102210322), and the Starting Fund for Talents of North China University of Water Resources and Electric Power (No. 003019).

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