| The existence of polymorphism and solvate of drugs has attracted people’s attention as solid forms that often appear in the crystallization process of solutions.This study used the antibacterial drug levofloxacin as the model substance.There are few studies on the polymorph and solvate of levofloxacin,and levofloxacin hemihydrate has very poor solubility in water,which is the commercial form of levofloxacin.In this research,levofloxacin polymorphs and solvates and their transformation processes were studied.Firstly,different solvent systems and crystallization methods were used to screen the crystal forms of levofloxacin.One anhydrous form and four solvates were obtained in the solvent systems of pure DMSO,n-propanol,isopropanol,ethylene glycol,and acetic acid,respectively.The single crystal structure of the anhydrous form α,npropanol solvate and ethylene glycol solvate were successfully obtained.Subsequently,X-ray powder diffraction,thermal analysis,morphology,and solid-state infrared were used to characterize the anhydrous form and solvates of levofloxacin.Since the anhydrous form α is extremely unstable at room temperature,its single crystal has not been available since 1995,when the research of levofloxacin form αbegan.This study is the first to obtain the crystal structure data of anhydrous form α by X-ray single crystal diffraction(SC-XRD)and it is found that the crystal structure data obtained by indirect methods(CSP,SDPD)in the previous literature have some errors.Based on the powder diffraction results,the cell parameters obtained by the SDPD method are consistent with the experimental data,but there are still several errors in the internal molecular morphology and hydrogen bonds.The most probable configuration predicted by CSP method which is based on molecular structure is far from the actual crystal structure,but some of the other predicted configurations of CSP method show a certain similarity to the actual crystal structure.For example,the unit cell parameters of the predicted Rank 2 configuration are very close to the actual data.In order to gain a deeper understanding of the anhydrous form α,this research also used MS software to simulate the crystal habit of levofloxacin anhydrous form α.For the three newly discovered levofloxacin solvates(N-propanol solvate,ethylene glycol solvate,acetic acid solvate),the single crystal structure results show that the solvent molecules of n-propanol solvate are trapped in the cell gap of the crystal,which indicate n-propanol solvate belongs to the van der Waals type solvate;while the solvent molecules of ethylene glycol solvate are linearly arranged in the crystal structure,which has properties similar to channel solvate,so desolvation of the ethylene glycol solvate will occur at low temperatures.We did not obtain the single crystal structure data of isopropanol solvate and acetic acid solvate,but X-ray diffraction results show that the PXRD diffraction peaks of n-propanol solvate and isopropanol solvate are highly coincident,so the two belong to isomorphic compounds.The studies find that the solubility,crystal habit,and product flowability of the acetic acid solvate are significantly better than those of the commercial form hemihydrate.This article studied the stability of levofloxacin in different solid forms.The variable temperature X-ray powder diffraction(VT-PXRD)studies show that the newly discovered solvates are directly transformed into anhydrous form γ after desolvation.Levofloxacin hemihydrate is suspended in different solvent systems to form anhydrous form α and various solvates.The solvates(including n-propanol solvate,acetic acid solvate,ethylene glycol solvate)and hemihydrate are first converted into anhydrous form γ during heating.When the anhydrous form γ continues to be heated,it will all be converted into the anhydrous form α before melting.Based on the crystal structure and thermal analysis data,the stability relationships of different solid forms of levofloxacin are established in this research. |
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