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 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.