Solid Material Characterization of Freeze-Dried Gabexate Mesilate Containing D-Mannitol by Terahertz Spectroscopy

摘要

The purpose of the present study is to characterize polymorphic forms and intermolecular interactions of freeze-dried pharmaceuticals containing additives by terahertz (THz) spectroscopy as a, process analytical technology tool in the pharmaceutical industry. Freeze-dried gabexate mesilate/D-mannitol products containing 17-75 mol% gabexate mesilate were obtained using a conventional freeze-dryer. Freeze-dried products and physical mixtures of gabexate mesilate and mannitol with various drug contents were characterized by X-ray powder diffraction (XRD) analysis, differential scanning calorimetry (DSC) and THz. The XRD and DSC results indicated that freeze-dried mannitol was obtained as a mixture of β and δ forms of mannitol from a plain solution, but the freeze-dried product of the gabexate mesilate/mannitol mixture consisted of crystalline gabexate mesilate and the pure δ form of mannitol. Similar to the results of XRD and DSC, THz before the freezedrying of gabexate mesilate was almost the same as that after. In contrast, the THz of mannitol before freeze-drying had specific peaks due to the β form, but that after had peaks due to δ and β forms. To clarify the polymorphic forms of the freeze-dried products, the THz were analyzed by least squares regression. The calibration models used to predict the amounts of gabexate mesilate and mannitol had sufficient accuracy and linearity, respectively. Two decomposed THz in FGMs had specific peaks due to the δ form of mannitol or gabexate mesilate.