Characterisation of polymorphic, pseudopolymorphic and amorphous forms of roxithromycin / Carine du Plessis
Du Plessis, Carine
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Roxithromycin is a relatively new, semisynthetic, macrolide antibiotic and an ether oxime derivative of erythromycin A, consisting of a 14-membered, macrocyclic, lactone ring. Roxithnrmycin has proven clinical efficacy in upper - and lower respiratory infections, ski - and soft tissue infections, urogenital - and orodental infections. Few literature was available on the physicochemical properties of roxithromycin during this study, whilst no documentation on polymorphism, pseudopolymorphism or amorphism of roxithromycin was found. The aim of this study therefore was to investigate the possibility of polymorphism, pseudopolymorphism, and amorphism within roxithromycin, and to identify and characterise those crystal forms being recrystallised during the study. Various solvents were hence used to crystallise different roxithromycin crystals, by means of two recrystallisation methods. These crystals were then characterised, using X-ray powder diffiactometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectrophotometry (IR) and thermomicroscopy (TM). The solubility of the various crystal forms were investigated in three media: phosphate buffer (pH 6), 0.1 N HCl and water. Dissolution studies were also performed in a phosphate buffer (pH 6) medium. The results that were generated from these studies clarified the hypothesis that roxithromycin does indeed exist in polymorphic, pseudopolymorphic and amorphous forms. Six different forms were identified and classified into two groups. Group I (true polymorphs): Form A (stable, high melting point crystal form), Form B (amorphous, low melting point form), Form C (stable, mid-melting crystal form), Form E (mixture of two crystal forms, i.e. a low melting point Form EL and a high melting point Form EH), and finally Form F (low melting point Form FL that transformed into a mid-melting point Form Fm, due to exposure to an increase in temperature, which further transformed into a high melting point Form FH with a further increase in temperature). Group II (pseudopolymorphic forms): Form D (amorphous, chloroform-solvated form). The solvents from which these forms were recrystallised were DMSO, ethyl acetate, THF, dichloromethane, acetonitrile and chloroform, respectively. The dissolution studies posed some difficulties during preparation of some of the samples. Gels formed during vortexing of some samples and no accurate results could be obtained, due to subsequent poor transferability into the dissolution vessels. The poor dissolution results necessitated the performance of solubility studies. The solubility results followed the same pattern throughout the study, i.e. phosphate buffer (pH 6) > 0.1 N HCl > water, except for Form EL, where the order was 0.1 N HCl > phosphate buffer (pH 6) > water. Since roxithromycin is a hydrophobic molecule, with no free hydroxyl groups, it explained its poor wettability and poor solubility in water. To conclude: Roxithromycin possesses the ability to recrystallise into polymorphic, pseudopolymorphic and amorphous forms. Six forms were identified and classified. Gel formation of roxithromycin during dissolution and its poor wettability should be duly considered during preformulation and manufacturing.
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