According to label claims, in commercial solid dosage forms, azithromycin (AZI) exists either as a monohydrate (MH) or as a dihydrate (DH). Although these two forms are known to be relatively stable in the solid state, AZI sesquihydrate (SH) was observed in a drug product. This was believed to be a consequence of a processing-induced phase transformation. Our goal was to prepare and characterize AZI SH and map its solid-state transition pathways with other AZI phases. When dehydrated at temperatures <80°C, DH yielded an isomorphic dehydrate, whereas dehydration at ≥80°C yielded SH. Heating SH to 100 °C or holding at 0% RH at room temperature, yielded an amorphous product through an intermediate isomorphic dehydrate, isostructural to SH. On the other hand, dehydration of MH (at ≥60 °C) resulted in amorphization with no intermediate crystalline anhydrate. Diagnostic XRD peaks of AH, MH, SH, and DH enabled their unambiguous identification. However, the presence of crystalline excipients hindered active pharmaceutical ingredient characterization in drug product. Pattern subtraction method was used to selectively remove the contribution of the crystalline excipients to the overall diffraction pattern, thereby facilitating the physical characterization of AZI in the drug product.
Bibliographical noteFunding Information:
The work was partially supported by Ranbaxy Laboratories Limited and the William and Mildred Peters endowment fund. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through MRSEC program. The authors thank Meena Rani, PhD for her contributions.
©2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
- Crystal structure
- Physical characterization
- Thermal analysis
- Water sorption
- X-ray powder diffractometry