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

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 atten...

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Published inAAPS PharmSciTech Vol. 20; no. 3; p. 114
Main Authors Wang, Jiaxin, Yang, Lixiang, Li, Daixi, Xu, Ying, Yang, Li, Zhao, Hong, Zhu, Zhuangzhi, Luan, Hansen, Luo, Qiong
Format Journal Article
LanguageEnglish
Published Cham Springer International Publishing 01.04.2019
Subjects
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Pharmacology/Toxicology
Pharmacy
Research Article
Stability
Amino acid
Reaction barriers
Computational pharmacy
Hydrogen bond
Polymorphic drugs
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Summary: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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ISSN:1530-9932
1530-9932
DOI:10.1208/s12249-019-1312-4