Investigating the Mechanism of l-Valine in Improving the Stability of Gabapentin Combining Chemical Analysis Experiments with Computational Pharmacy

Abstract

The mechanism of l-Val on how to improve the stability of gabapentin (GBP) was described by the combination of chemical analysis experiments and computer simulations. Scanning electron microscope (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimeter (DSC), coupled with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), were used to identify β-GBP prepared by rapid solvent removal method. The reaction barriers on crystal planes, β-GBP (100) and β-GBP (10-1), are smaller than α-GBP and γ-GBP, reaching 276.65 kJ/mol and 299.57 kJ/mol, respectively. Thus, it was easier for β-GBP to form lactam, and the occurrence of β-GBP would lead the worse stability of α-GBP. The addition of neutral amino acids such as l-Val could improve the stability of α-GBP effectively. The adsorption energy of α-GBP (002) crystal plane with l-Val is larger than that of other crystal planes, reaching 42.17 kJ/mol. Hydrogen bond was the combination of l-Val and GBP main crystal planes, which could inhibit the crystal transformation of α-GBP. These results suggest that neutral amino acid protectants, such as l-Val, could improve the stability of α-GBP effectively, and inhibition of crystal transformation is one of the effective methods to improve the stability of polymorphic drugs.

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Funding

This work was supported by Shanghai Science and Technology Commission R&D Platform Special (18DZ2290500).

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Correspondence to Jiaxin Wang or Hansen Luan or Qiong Luo.

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Wang, J., Yang, L., Li, D. et al. Investigating the Mechanism of l-Valine in Improving the Stability of Gabapentin Combining Chemical Analysis Experiments with Computational Pharmacy. AAPS PharmSciTech 20, 114 (2019). https://doi.org/10.1208/s12249-019-1312-4

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KEY WORDS

  • Stability
  • Computational pharmacy
  • Hydrogen bond
  • Reaction barriers
  • Polymorphic drugs
  • Amino acid