Amorphism and polymorphism of azithromycin
Odendaal, Roelf Willem
MetadataShow full item record
Azithromycin, an azalide and member of the macrolide group, is a broad spectrum antimicrobial, representing one of the bestselling antimicrobials worldwide. It is derived from erythromycin and exhibits improved acidic stability as a result of its structural modifications. The stable solid form of azithromycin is its dihydrate, although it also naturally occurs in its metastable forms, i.e. the monohydrate and anhydrate. Because azithromycin is poorly soluble in water, its absorption from the gastro-intestinal tract is negatively influenced, which ultimately affects its bioavailability following oral administration (37 %). Polymorphic (monohydrates and dihydrates) and anhydrous forms of azithromycin were screened and investigated. One anhydrous form also proved to be amorphous, which shifted the focus of this study from polymorphism to amorphism. An amorphous glassy azithromycin was subsequently prepared and fully characterised to present its solid state profile. The stability of this amorphous glassy form was established at a high temperature and relative humidity over a period of four weeks. Exposure to increased relative humidity (up to 95 %) and increased water content (up to 50 %) also served as stability indicating tests. Its solubility in various aqueous media was determined. A solid dosage form (tablet), containing the azithromycin glass, was prepared, whereafter these tablets were subjected to dissolution studies in different aqueous media. The stability of azithromycin glass in tablet form was determined over a period of three months. The permeability of azithromycin glass across excised pig intestinal tissue was further established at various pH values. This amorphous glassy form of azithromycin (AZM-G) proved to be very stable at high temperature and relative humidity, whilst also remaining stable after prolonged exposure to 95 % of relative humidity, as it only adsorbed moisture onto its surface. Water content (up to 50 %) had no plasticising effect on azithromycin glass. It demonstrated a significantly higher water solubility (339 % improvement) in comparison with the commercially available azithromycin dihydrate and was it also 39 % more soluble in phosphate buffer (pH 6.8) than its dihydrate counterpart. The prepared azithromycin glass tablets showed a promising dissolution profile in water, due to the improved water solubility of this glass form. The transport of azithromycin glass at higher pH values (6.8 and 7.2) across the membrane proved to be significantly higher than that of azithromycin dihydrate, thus also illustrating its pH dependence for its transport across pig intestinal tissue. The improved water solubility of the azithromycin glass, together with its faster dissolution rate, its superior stability and its increased permeability, may ultimately result in a higher azithromycin bioavailability following oral administration. These research outcomes hence give rise to the need for investigating the effect of administering lower dosages of azithromycin and to determine whether the same antimicrobial efficacy would possibly be achieved, due to maintaining the same tissue concentration levels at these lower dosages.
- Health Sciences