| In recent decades, supramolecular chemistry and crystal engineering theory have been developing rapidly. A series of new materials by molecular self-assembly between the molecules, and the formation of new substances in terms of physical and chemical properties have significant changes. Therefore, the field has received more and more attention from researchers. The development of pharmaceutical cocrystal is the result obtained by the application of supramolecular chemistry and crystal engineering theory to the structural modification of active pharmaceutical ingredients(API). Pharmaceutical cocrystals formed by noncovalent bond between the active pharmaceutical ingredients and co-formers. Pharmaceutical cocrystals which is a good modification for the physical and chemical properties of active pharmaceutical ingredients is not changed the molecular structure of the API, for example, melting point, stability, solubility, dissolution rate and bioavailability and so on. The preparation of pharmaceutical cocrystal is an effective method to reduce the technological difficulty and improve the quality of pharmaceutical preparations.Preparation methods of pharmaceutical cocrystals include solvent method, grinding method, melting method, ultrasonic method and suspension method and so on. Single crystal diffraction, Powder diffraction, DSC, Raman spectroscopy and Fourier transform infrared spectroscopy detection is usually employed to characterize the cocrystal.Ezetimibe is the first selective cholesterol absorption inhibitor, which is the only one used in clinical by far. log(octanol/water) partition coefficient(log P) of ezetimibe is 4.5, and ezetimibe has poor water solubility(0.012 mg/m L at 23 °C). The biological availability of the existing dosage forms is low(35-65%), and the physical and chemical properties can not be improved by salt formation. In this paper, ezetimibe is selected as a pharmaceutical active ingredient, and nicotinamide, maleic acid and nicotinamide were selected as coformers after a series of screening tests, which formed pharmaceutical cocrystals with ezetimibe by liquid assisted grinding.Characterization of cocrystals of EZE were analyzed by X-ray powder diffractometry(XRPD), Differential scanning calorimetry(DSC), Fourier transform infrared spectroscopy and scanning electron microscopy(SEM). The dissolution rate and the light stability of the three drugs were further studied. There was a obvious improvement for cocrystals in dissolution comparing pure EZE, and the cocrystals needs to be placed under the shading condition because of it were a little effect for a long time illumination.In addition, there are two accidental discoveries in the process of cocrystal screening. First, ezetimibe was placed in exposure with anhydrous solvent, and ezetimibe monohydrate crystal was separated out. It explained that ezetimibe may be traces of water in the air. The crystal structure of monohydrate crystal was characterized by X-ray single crystal diffractometer. a=6.2461(9), b=15.4893(2),c=22.3602(4), α=90.00(5) °, β=90.00(2) °, γ=90.00(5) °, and belongs to orthogonal,space group P212121. Then, when the urea was used as the coformer to prepare ezetimibe cocrystal by solution method, ezetimibe occurred rearrangement reaction in anhydrous ethanol and anhydrous methanol solvent under room temperature. The crystal structure of cyclizate ether impurity was characterized by X-ray single crystal diffractometer. The results present that the cell parameters a=6.1407(4), b=7.6603(5),c=11.1455(7), α=72.497(5) °, β=99.535(2) °, γ=85.538(5) °, and belongs to triclinic,space group P1.In the study, ezetimibe is employed in active pharmaceutical ingredients, and the cocrystals of ezetimibe were obtained by liquid assisted grinding. The preparation method is quick and simple, and is readily accessible to industrialization. The cocrystal in physical and chemical properties is significantly improved. |
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