In most cases, organic materials exist in the solid phase as polymorphs, solvatomorphs or
amorphous forms. Physico-chemical properties in the solid-state are all affected primarily in
terms of dissolution, solubility, bioavailability, stability and processability. Therefore
investigation into the polymorphic behaviour of APIs has become a mandatory part of drug
characterisation studies by pharmaceutical companies (Giron, 2001).
The influence polymorphism has on bioavailability and the need for the development of
drugs in the amorphous form have instigated regulatory bodies such as the FDA to require
solid-state characterisation of pharmaceuticals (Strachan et al., 2005). Subsequently a
study was conducted to determine the physico-chemical properties of two poorly watersoluble
macrolides; clarithromycin and spiramycin. Characterisation methods included:
XRPD, IR, TGA, DSC, SEM, Karl Fischer titration, solubility and stability studies.
Recrystallisations of spiramycin from various solvents indicated that this API mainly exists in
the amorphous form. The DSC proved to be of little value in the characterisation of this
particular macromolecular antibiotic, since wide inter-sample variations were mostly
obtained. TGA results showed higher solvent uptake than expected. This was ascribed to
the amorphous, sponge-like character of this drug.
For the sake of reproducibility and quality of the results, characterisation of spiramycin was
more reliant on spectroscopic and crystallographic methods. Samples generated from 2-
butanol, chloroform, ethyl acetate, 1.4-dioxane, methanol, n-propanol, iso-propanol and
tetrahydrofuran showed characteristic peaks in the range of 2000-2400 cm-1 that were not
present in the IR spectrum of the raw material. Conversely, the XRPD patterns were all identical, exhibiting a characteristic “halo” pattern with no detectable Bragg diffraction peaks.
A solubility assessment showed no significant differences between the raw material and the
recrystallisation products. In fact the raw material seemed to be the form with the highest
solubility, albeit it only by a small margin.
According to the literature, clarithromycin exists in five forms. Form 0 exists as a solvate,
form I is a metastable form, form II is the stable form (Liu & Riley 1998; Deshpande et al.,
2006), form III is a solvate of acetonitrile (Liu et al., 2003; Liang & Yao, 2008) and form IV is
a hydrate (Avrutov et al., 2003). The stable form II is used in formulations currently on the
market.
A follow-up study was done relating to a study performed by De Jager (2005). The raw
material (form II) was recrystallised from acetonitrile, chloroform and ethyl acetate.
Two new crystal forms were prepared from chloroform and acetonitrile. With the necessary
driving force, both of these crystals forms are able to convert to the thermodynamically
stable form II. In addition, a solvate recrystallised from chloroform together with its
corresponding desolvate, showed a 4 and 1.5 fold respective increase in solubility when
compared to the raw material.
The recrystallisations from ethyl acetate delivered crystals with an XRPD pattern similar to
form II. This proved that clarithromycin can be recrystallised directly from this solvent
without the need of an additional conversion step, as was the case in the study done by De
Jager (2005). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2013
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/10860 |
| Date | January 2012 |
| Creators | Van Eeden, Rodé |
| Source Sets | North-West University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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