Roxithromycin is a semi-synthetic, macrolide antibiotic, derived from
erythromycin A. It acts as a bacteriostatic drug at low concentrations and a
bactericidal drug at high concentrations. It binds to the 50S subunit of the 70S
ribosome, which causes the reversible inhibition of RNA-dependent bacterial
protein synthesis.
It is well known that active pharmaceutical ingredients (APIs) may exist in
numerous solid states. Differences in the solid state significantly influence the
physical and chemical properties of an API. The in vivo performance of a
dosage form will also be influenced by the solid state properties of a given
pharmaceutical active. The amorphous characteristics of APIs have a
significant impact on their performance and thus offer the potential for exciting
new pharmaceuticals. Whilst amorphous forms of poorly soluble APIs are more
soluble than their crystalline counterparts, they tend to be physically unstable,
which makes their formulation into solid dosage forms quite challenging.
Roxithromycin has only 50% oral bioavailability due to its poor aqueous
solubility and for this reason, its potential for optimal therapeutic effect are
limited. Poor solubility is thus an important obstacle in formulation
development.
During this study, amorphous forms of roxithromycin were prepared via quench
cooling, and desolvation of chloroform- and ethyl acetate solvates. These
amorphous forms were characterised by means of several techniques, whilst
their solubilities and stabilities were also investigated.
The outcomes of the solubility studies illustrated the complexity of this API and
its amorphous forms with regards to their interactions with water. Solubility studies confirmed the superior solubility of the roxithromycin glass (prepared
through quench cooling) and amorphous forms (desolvation of solvates) over
the roxithromycin monohydrate in water. The solubility in water improved in the
order of roxithromycin monohydrate < roxithromycin glass < roxithromycin glass
powder < amorphous chloroform desolvate.
The roxithromycin monohydrate, as well as the amorphous forms of
roxithromycin demonstrated stability over a one-month period of exposure 40°C
and relative humidity (RH) of 75%. The roxithromycin glass powder tended to
revert to the more stable crystalline monohydrate after week 3 of stability
testing. The roxithromycin glass at lower temperatures of 25°C and 30°C (both
at 75% RH) tended to transform into the more crystalline form at week 4 of the
study. These transformations were, however, not as significant as during the
40°C / 75% RH study. The conclusion could therefore be made that this
transformation into the crystalline form was more temperature – than moisture
dependant. At a higher temperature (at identical humidity conditions), the
transformation into the crystalline form was much faster.
Stability studies on the two roxithromycin desolvates were also performed in
order to determine whether these amorphous forms, would differ, with regards
to their stability, from the glass prepared through heating and cooling. It was
determined that the desolvates were more stable than the roxithromycin glass. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/8390 |
| Date | January 2011 |
| Creators | Van Niekerk, Elzet |
| Publisher | North-West University |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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