Article pubs.acs.org/IECR
Modeling and Simulation of Thermodynamic Properties of L‑Alanyl‑L‑Glutamine in Different Solvents Guan Wang,† Yongli Wang,†,‡ Jie Zhang,† Qinghua Luan,† Youguang Ma,† and Hongxun Hao*,† †
School of Chemical Engineering and Technology, and ‡Tianjin Key Laboratory of Modern Drug Delivery and High-Efficiency, Tianjin University, Tianjin 300072, China S Supporting Information *
ABSTRACT: The solubility of L-alanyl-L-glutamine (Ala-Gln) in pure water and ethanol−water mixed solvents was measured using a synthetic method from 283.15 to 313.15 K. Molecular dynamics simulation was carried out to explain the effect of ethanol content on the solubility of Ala-Gln. The radial distribution function was used to evaluate the interactions between solute molecules and solvent molecules. The solubility data was correlated by four thermodynamic models, including the hybrid model, Wilson model, NRTL model, and UNIQUAC model. It was found that the NRTL model could give better correlation results than the other models. The dissolution properties of Ala-Gln solutions, including the free Gibbs energy, the dissolution enthalpy, and the dissolution entropy, were calculated by using the modified van’t Hoff equation.
1. INTRODUCTION The study on the solubility of crystalline solids in different solvents is of great practical interest for most engineering researchers. Although many thermodynamic models, such as the Apelblat model, Jouyban−Acree model, local composition models and so on, have been developed to describe or predict the solubility behavior of solute in pure or mixed solvents, the molecular mechanism of the dissolution process of solute which is important for understanding the process was still not clear. Given this situation, it is necessary to investigate the thermodynamic properties of the solute (shown in Figure 1) in different solvents by using the molecular simulation methods. L-Alanyl-L-glutamine (Ala-Gln, CAS Number: 39537-23-0) is an active pharmaceutical ingredient (API) used for vein nutritional injection. Unlike glutamine which is insoluble in water, Ala-Gln (shown in Figure 1) is soluble and stable in aqueous solution.1,2 It has good therapeutic effect on parenteral metabolic disease and immunodeficiency syndrome.3−6 During the manufacturing of Ala-Gln, the crystallization process is the final step. The level of the design and operation of crystallization process will directly affect the final quality of the Ala-Gln product. Therefore, as basic data for the crystallization process, the solubility of Ala-Gln is essential for the design and optimization of crystallization process. However, no solubility data of Ala-Gln can be found from literatures. In this paper, the solubility of Ala-Gln in pure water and ethanol + water mixed solvents was experimentally determined at temperature range of 283.15−313.15 K by using a synthetic method. The obtained experimental solubility data was correlated by using four thermodynamic models, including a hybrid Jouyban-Acree model and three local composition models (Wilson, NRTL, and UNIQUAC). To understand the influence mechanism of solvent content on solubility, molecular dynamics simulation was carried out to investigate the effect of ethanol content on the solubility of Ala-Gln. The radial distribution function (RDF) was used to evaluate the © 2014 American Chemical Society
Figure 1. Molecular structure and partial numbering of (a) Ala-Gln, (b) ethanol, and (c) water.
interactions between solvent molecules and solute molecules. Moreover, the thermodynamic properties (free Gibbs energy, enthalpy and entropy) for the dissolution process of Ala-Gln were predicted by using the modified van’t Hoff equation. Received: Revised: Accepted: Published: 3385
December 2, 2013 January 26, 2014 February 3, 2014 February 3, 2014 dx.doi.org/10.1021/ie404081c | Ind. Eng. Chem. Res. 2014, 53, 3385−3392
Industrial & Engineering Chemistry Research
Article
COMPASS force field in Materials Studio (Accelrys Software Inc., US). Then the cubical boxes, based on the real composition of Ala-Gln solution, were created using Amorphous Cell. After energy minimization of the simulation boxes, a 300 ps run in NVT ensemble using Nose10 for thermostat was applied first for equilibration. Since an external or artificial thermostat would cause an inevitable error of dynamics,11 the last frame of NVT simulation was simulated in the NVE ensemble for 500 ps. The time step used is 1.0 fs. The group based summation method12 was used to describe nonbond interaction in periodic system. The trajectory files from the simulation were analyzed for radial distribution function g(r). Based on the definition of g(r), the larger the value of g(r) was, the higher the possibility of the appearance of the interactions between solute molecules and solvent molecules was, which was related to the solubility of the solute. The partial labeling of molecules used in the simulations for the purpose of molecular recognition was shown in Figure 1.
2. EXPERIMENTAL SECTION 2.1. Materials. Ala-Gln was supplied by Hubei Haosun Pharmaceutical Co., Ltd. (Hubei, China). Ethanol was purchased from Tianjin Kewei Chemical Co., Ltd. (Tianjin, China). Distilled deionized water (conductivities
