Thermodynamic and molecular investigation into the solubility, stability and self-assembly of gabapentin anhydrate and hydrate

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Highlights

  • Solubility of gabapentin anhydrate/monohydrate in alcohol-water mixtures was experimentally determined.

  • Molecular dynamics simulations were carried out to explore the effect of solvent composition on the solubility.

  • Critical water activity and the transition temperature of gabapentin anhydrate/hydrate were determined.

  • Ternary phase diagram of (gabapentin-ethanol-water) at 293.15 K was built.

Abstract

Solubility of gabapentin anhydrate/monohydrate in alcohol-water mixtures was experimentally determined. An interesting trend of the solubility was found, which showed both maximum and minimum solubility with different solvent compositions at one temperature. Molecular dynamics simulations were carried out to explore the effect of solvent composition on the solubility, indicating that the water association played an important role. Critical water activity and the transition temperature of gabapentin anhydrate/hydrate were also determined, and a relationship between them was established to investigate the factors influencing the hydration. Furthermore, the ternary phase diagram of (gabapentin-ethanol-water) at 293.15 K was built by slurry experiments for further understanding of the crystal form transformation, which confirmed the stability regions of anhydrate/monohydrate and verified the above established relations. Then the dehydration/hydration process in the solution can be predicted and controlled, thus obtaining the desired product.

Graphical abstract

In alcohol-water system, gabapentin anhydrate can transform to monohydrate with the increasing of water, which is influenced both by temperature and water activity. The solubility of anhydrate/hydrate have strange trend, especially existing a minimum in water rich region. Molecular dynamics simulations show the water association and solvent-solute interactions are the key factors.

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Introduction

Gabapentin (GBP), chemically called 1-(aminomethyl) cyclohexaneacetic acid (C9H17NO2, CAS Registry No. 60142-96-3), is a derivative of c-aminobutyric acid (GABA). The chemical structure of gabapentin is shown in Fig. 1. It possesses abilities to cross the blood-brain barrier and increase GABA content of some brain regions [1]. Being famous as an antiepileptic drug, GBP has extended its applications to anxiety disorders, restless legs syndrome, hot flashes, and neuropathic pain (such as diabetic neuropathy, peripheral neuropathy and trigeminal neuralgia) [2], [3]. Furthermore, this substance is tolerated by patients and has few side effects in the cardiovascular system. In those applications, GBP is usually employed as a solid and it addresses interest to explore occurrence of polymorphism or solvate formation. Four crystal forms (I-IV) were previously reported, in which form I is a monohydrate and forms II-IV belong to anhydrates [4], [5], [6], [7]. Different solid forms may have significantly dissimilar properties and, in this case, the efficacy of the drug would also be affected.

Hydrate, the most commonly identified solvate, forms when water is incorporated into the crystal lattice. The presence of water molecules may allow stronger interactions within the hydrate crystal and a more efficient packing [8], [9]. As a result, a hydrate has a lower Gibbs energy and is more thermodynamically stable than anhydrate when water activity is high enough for hydrate formation [10], [11], [12], [13]. Hydration has altered pharmaceutically important properties (e.g., solubility, physical and chemical stability) [14], [15], [16]. According to the Noyes-Whitney equation, hydrates even have lower dissolution rates based on solubility [13]. But crystal shape and particle size distribution should also be considered. On account of the desired product performance, either the anhydrate or the hydrate can be selected as the final drug form. During manufacturing of the drug product in aqueous solution (e.g., solution crystallization), a solvent-mediated transformation of the anhydrate/hydrate phase might occur, determined by surrounding environment, such as water activity, temperature, etc. [16], [17], [18]. Therefore, the evaluation and control of their tendency to hydrate or dehydrate is of particular importance.

Alcohol-water mixtures are often favoured in chemical industry considering safety and economy. Alcohol forms hydrogen bonds with water, the structure and properties of the alcohol-water mixture behave quite differently from the pure components. When a solute dissolves in alcohol-water binary solvents, the structure and molecular interaction of molecules will be more complicated, which can cause different solubility phenomenon [19], [20]. Molecular dynamics (MD) computer simulation can achieve studies for local structures, hydrogen bond pairs and dynamical properties over the entire composition range [21], [22], [23], [24], [25]. Borin and Skaf1 [21] studied molecular association between water and dimethyl sulfoxide in solution by MD simulations. Gereben [22] performed the simulation in ethanol-water mixtures for detailed investigation of hydrogen-bonded network and complete ring analyses. Based on results from MD simulations, the radial distribution function (rdf) and coordination number get widely used since they accurately reveal distribution of atoms or molecules [26], [27].

A key objective of this work is to achieve better understanding of the phase behaviour and relative thermodynamic stability of the anhydrate/hydrate system. GBP has been selected as the model compound, and single crystal structure of its anhydrate (form II) and monohydrate (form I) was obtained and fully analysed. Optical microscopy, powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA) were used to characterize the solid forms. The solubility and stability of GBP anhydrate and monohydrate was investigated in alcohol-water mixtures. To explore effects of solvent composition on solubility changes, MD simulations were conducted and then intermolecular energy and hydrogen bonds were calculated. The transition points between GBP anhydrate and hydrate were obtained based on the solubility. The relationship between temperature and critical water activity was established. Through slurry experiments, isothermal triangular phase diagram was applied for analysing the phase equilibrium of the GBP-ethanol-water system.

Section snippets

Materials

Raw material of GBP anhydrate was supplied by Zhejiang Chiral Medicine Chemicals Co., Ltd., China. PXRD pattern identifies it as GBP form II [7]. The crystals of hydrate were prepared by cooling crystallization in water. Based on PXRD pattern and TGA trace, the crystals obtained were confirmed as monohydrate and have been considered as GBP form I in the previous literature [7]. Methanol and ethanol were purchased from Tianjin Jiangtian Chemical Technology Co., Ltd. Water required for all

Crystal packing

The crystal structures, considered to be standard definition of crystal forms, for GBP anhydrate (form II) and monohydrate are shown in Fig. 1 and Table 2.

Both of the structures are consistent with literature reported by Ibers [5]. In GBP anhydrate, each unit cell contains four gabapentin molecules. It exists extensive hydrogen bonding between the NH3+ and COO- groups of neighbouring molecules. All hydrogen bonds propagate along both directions ([1 0 0] and [0 1 0] directions) and they are located

Conclusions

In this study, we reported solubility and relative stability of GBP anhydrate and monohydrate in alcohol-water mixtures. The single crystal structures show that water molecules of GBP monohydrate interact with GBP molecules and change the crystal packing. In alcohol-water binary mixtures, the solubility of GBP anhydrate increases with water content, and there is a maximum with a certain composition. For the monohydrate, the solubility decreases with water content, and there is a minimum at

Acknowledgments

The authors are grateful to the financial support of National Natural Science Foundation of China (NNSFC 81361140344 and NNSFC 21376164), National 863 Program (2015AA021002), Major Science and Technology Program for Water Pollution Control and Treatment (NO.2015ZX07202-013) and Tianjin Science and Technology Project (15JCZDJC33200).

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