Investigation of the physico-chemical properties of amorphous solid-state forms of azithromycin
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Azithromycin is chemically modified from the macrolide, erythromycin and thereby shows improved efficacy and has more advantages above other macrolides. Azithromycin is currently the most prescribed and used macrolide antibiotic worldwide with much less frequent oral administration required. The biggest disadvantage of azithromycin is its poor water solubility. Poor water solubility of an active pharmaceutical ingredient (API) is seen as a critical factor, which can have a detrimental effect on not only the bioavailability of the API, but also the effective treatment of patients. A complete physico-chemical characterisation is extremely important for an API as it may exist in different solid-state forms which can display different physico-chemical and thermodynamic properties. Stability, solubility, dissolution rate, bioavailability, particle morphology, powder flow, powder colour and tableting behaviour are all properties that can be influenced by these differences. The better the dissolution rate of an API, the better is the absorption from the gastrointestinal tract (GIT), leading to improved bioavailability of the API. Preparing an amorphous solid-state form of an API is an effective and easy way to improve the aqueous solubility. However, the inherent instability of these solid-state forms is usually detrimental. Preparation methods such as quench cooling of the melt, slow cooling of the melt, hot-air melting, ambient solvent evaporation, rapid solvent evaporation and spray-drying, all with different intermediary states (melt or solution), were identified and selected for the preparation of amorphous azithromycin. The possibility of solution-mediated, solvent-mediated and solid-solid phase transformations of amorphous azithromycin was also investigated. The principal goal was to investigate the impact and to illustrate the effect of the different preparation methods on the physico-chemical characteristics of each obtained amorphous solid-state form of azithromycin. XRPD and FTIR positively characterised the amorphous habit of the different preparation techniques in this study showing that each mentioned preparation method can indeed create amorphous forms of azithromycin. The thermodymic properties of all the preparation techniques reflected a fragility index (m) lower than 75 and a high strength parameter (D), meaning that a lower free energy is present that will lead to a higher physical stability. Two amorphous forms prepared from a solution intermediary state showed significantly higher temperatures of zero mobility making them more physically stable during ambient storage conditions. The amorphous form prepared from a spray-drying technique showed the lowest activation energy for structural relaxation, thereby contradicting the temperature of zero mobility finding of this amorphous form. The stability of amorphous forms can also be influenced by means of solid-solid phase transformation, solvent-mediated phase transformation and solution-mediated phase transformation (SMPT). Vapour sorption experiments proved that the different amorphous forms are not influenced by solvent-mediated phase transformations. Dissolution was used to investigate the possibility of SMPT of the amorphous forms. The rates of SMPT differed and in some instances the transformation was not visible from dissolution data, proving that the rate of SMPT was too rapid. Through investigation of the recrystallisation behaviour of amorphous quench cooled azithromycin, it became evident that the recrystallisation process followed a first-order reaction rate. An 8-fold solubility enhancement in comparison with the solubility of crystalline azithromycin was determined by applying a Nogami plot. This study proved that it is possible to prepare different amorphous forms of the same API and that these different amorphous forms differ substantially in terms of particle morphology, physical stability and ultimately in terms of dissolution rates.
- Health Sciences