- Title
- Statistical optimisation of a terbinafine-containing cream
- Creator
- Strydom, Lana
- Subject
- Chemicals -- Physiological effect
- Subject
- Pharmaceutical chemistry Medical microbiology
- Date Issued
- 2019
- Date
- 2019
- Type
- Thesis
- Type
- Masters
- Type
- MSc
- Identifier
- http://hdl.handle.net/10948/44067
- Identifier
- vital:37101
- Description
- Terbinafine hydrochloride (TBH) belongs to the allylamine class of antifungals and displays a favourable dermatopharmacokinetic profile, being both lipophilic and keratinophilic. It has thus been included in a variety of topical dosage forms for the treatment of dermatomycoses, many of which have been the subject of optimisation studies, with the purpose of improving the product. Since a TBH-containing cream had not been found in literature to have been optimised before, the aim of this study was to optimise a TBH cream formulation. A TBH cream formulation, suitable for optimisation, was developed. Preformulation tests were undertaken, including active-excipient compatibility testing using a combined thermal method consisting of both differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), as well as isothermal stress testing (IST). With the confirmation of the suitability of the selected excipients, development of a suitable TBH cream took place largely by a trial-and-error approach. The choice of a suitable formulation was made based on the physical appearance and viscosity of the cream, for which a viscosity specification was set. The identified TBH cream formulation was evaluated for its physical appearance and physicochemical aspects to confirm its appropriateness for the purpose of further optimisation. Based on literature and observations from the preformulation and formulation stage, factors and responses for study during the optimisation stage were identified to study using a circumscribed central composite design (CCCD) at five levels (-1.612, -1, 0, +1, +1.612). Total percentage of surfactant (TPS), homogenisation speed (HS) and cooling rate (CR), were selected as factors to study their influence on cream viscosity, in vitro TBH release from the cream, as well as the chemical stability of TBH within the cream formulation. Following the application of stepwise multiple linear regression to the mathematical models, a suitable prediction model was only obtained for one response, cream viscosity at a shear rate of 20 s-1. A linear model was also found to fit the data for % in vitro TBH release after one hour, although a low R2 of 0.497 made the model unsuitable for prediction purposes. No mathematical model could be fit to the results for the response assessing the change in TBH concentration following seven days’ storage at accelerated stability conditions. The determination of the optimum TBH cream formulation was made chiefly on the basis of the results for cream viscosity and the optimised formulation was identified to have a predicted viscosity of 8.33 Pa.s and the factor settings to obtain this cream were a CR of 1.3 °C/min, HS set at 3400 rpm, and TPS of 4.2 %. Validation of the optimised TBH cream formulation was performed for cream viscosity at a shear rate of 20 s-1 and revealed that there was good agreement between the measured and predicted viscosity values. The optimised TBH cream underwent rheological characterisation and was compared to the innovator, Lamisil® cream, with both creams found to meet the desirable rheological profile. In vitro release testing (IVRT) was used to compare the release of TBH from the optimised TBH cream and Lamisil® cream, and the optimised TBH cream was found to show much greater TBH release over a six-hour time period than Lamisil® cream. Stability testing of the optimised TBH cream took place at accelerated stability testing conditions of 40 °C ± 2 °C and 75 ± 5 % relative humidity (RH). To assay the formulation and determine content uniformity over the three-month storage period, a suitable stability-indicating reversed-phase high performance liquid chromatography (RP-HPLC) method was developed and validated. Other cream properties which were tested included: qualitative aspects, viscosity, pH and microbial limits. At the end of the three-month stability testing period, the cream was found to meet most of the specifications set, except for cream homogeneity and viscosity. A TBH cream formulation was thus developed and optimised to meet a certain viscosity specification. Although this formulation was found to meet the viscosity specification on the day after its manufacture, the viscosity was found to increase on storage, such that it was outside the set viscosity specification range.
- Format
- xxxii, 417 leaves
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Science
- Language
- English
- Rights
- Nelson Mandela University
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NMU School of BioMolecular and Chemical Sciences
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | Lana Strydom - Final MSc Dissertation.pdf | 7 MB | Adobe Acrobat PDF | View Details Download |