The physico-chemical properties and recrystallisation kinetics of selected amorphous active ingredients
During the last two to three decades the application of amorphous solid-state forms within the pharmaceutical industry gained much interest. The rationale for this heightened interest is the increased aqueous solubility, increased dissolution rate and subsequent possible improved bioavailability offered by the amorphous form of a drug. Although amorphous solid-state forms of drugs are not considered something new within the pharmaceutical industry, thorough reviewing of current and older literature on this topic, shows that much is still to be discovered, learned and understood about this very interesting field within the solid-state chemistry of drugs. In order to gain a better understanding of amorphous solidstate behaviour, three structurally unrelated active pharmaceutical ingredients, namely zopiclone, sulfadoxine and roxithromycin have been selected for this study. In the first study, zopiclone was investigated for glass-forming ability. The well-known method of quench cooling of the melt proved to be somewhat of a challenge for the preparation of amorphous zopiclone. The purchased crystalline anhydrate form of zopiclone melted at ± 177°C, followed by the rapid degradation of the drug. Therefore, an additional step was added to the preparation method of amorphous zopiclone. A dihydrated form (Form B, already described in literature) was recrystallised from toluene. This form was subsequently dehydrated to form an anhydrous form with a lower melting point (± 150°C). Therefore, a lower melting temperature was used to obtain molten zopiclone. Although amorphous zopiclone was successfully prepared through a quench cooling of the melt method, it was determined that this method produced a fragile amorphous form with poor physical stability. The stability of this amorphous form was influenced by temperature, moisture as well as physical agitation. Further studies focused on successfully stabilising the amorphous form of zopiclone, this lead to the formulation of an amorphous solid dispersion. The advantage of the amorphous solid dispersion lies within the improved dissolution rate, as well as the inhibition of the recrystallisation of the amorphous zopiclone. In the second study an amorphous form of sulfadoxine was successfully prepared through quench cooling of the melt. The study illustrated that in contrast to literatures’ dictation that good glass-forming ability and strong strength parameters infer good stability, is not always the case. The recrystallisation behaviour was studied isothermally by applying the Johnson-Mehl-Avrami model and non-isothermally by applying the Kissinger model. The study illustrated that the nucleation and crystal growth rate is temperature dependent and that the presence of crystal seeds significantly decreases the amount of activation energy that is necessary for the re-crystallisation process to start. The physical stabilisation of the amorphous form was investigated using physical mixtures of amorphous sulfadoxine with polyvinylpyrrolidone-25 (PVP-25). This proved that a drug: polymer physical mixture of 1 : 4 inhibited the thermally induced recrystallisation of amorphous sulfadoxine completely. From this it was deduced that in some instances the preparation of amorphous solid dispersions to stabilise the metastable amorphous form of a drug is not always necessary. A mere physical mixture of the amorphous drug with a stabilising agent could suffice. In the third study, the complex and highly controversial concept of the existence of “polyamorphism” within pharmaceutical compounds have been addressed. The influence of different preparative techniques on the thermodynamic and morphological properties of amorphous roxithromycin was investigated. The outcome of this study showed that the preparation route has a pronounced effect on the thermodynamic and morphological properties of the resulting amorphous solid-state forms. Subsequently, such differences have a mentionable effect on the drug performance, either during pharmaceutical processes or after patient administration. Findings and results of other studies on the topic of “polyamorphism” were correlated with this study and it was concluded that different amorphous forms of the same drug do indeed exist. However, it was evident from other literature reviews and original research that a well-defined definition for this phenomenon is still being evasive. Through a combination of this study on different amorphous forms of roxithromycin as well as other studies on an array of other drugs, the proposed terms of pseudo-polyamorphism or atypical polyamorphism were explored. Forthcoming from the first study on amorphous zopiclone, the fourth study developed. During the initial investigation of zopiclone dihydrate, recrystallised from toluene, it became apparent that the dihydrate easily dehydrates to form an anhydrous form with a lower melting point as that of a commercially available anhydrate form of zopiclone. This prompted the investigation of the dehydration kinetics of zopiclone dihydrate (Form B). The dehydration kinetics was investigated by applying two model-free methods, namely the Kissinger and the Ozawa-Flynn-Wall methods. The application of both methods correlated very well with one another. It was deduced that zopiclone Form B dehydrates relatively easy and that disruption of the crystal structure is not necessary for the dehydration process to complete.
- Health Sciences