- Title
- Formulation of methyldopa 250 mg tablets by direct compression using a quality by design approach
- Creator
- Baguma, Murungi Isaac
- Subject
- Pharmaceutical chemistry
- Subject
- Tablets (Medicine)
- Date Issued
- 2022-04
- Date
- 2022-04
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10948/58575
- Identifier
- vital:59929
- Description
- Various pharmaceutical materials are known to take up moisture during both storage and manufacture. This phenomenon, termed hygroscopy, can result in unacceptable levels of moisture, potentially having deleterious effects on product quality, and consequently product efficacy and safety. Drug inefficacy specifically can result in life-threatening complications for the pregnant mother with uncontrolled blood pressure. Marketed as immediate release tablets, methyldopa is an antihypertensive drug commonly used in South Africa to treat hypertensive disorders of pregnancy. Despite being in use for over 50 years, the physicochemical challenges posed by methyldopa remain ever present. Methyldopa is not only significantly hygroscopic, but also prone to oxidative and hydrolytic degradation that can be accelerated by moisture. Poor compression behaviour, another limitation of methyldopa, leaves the formulation scientist with a constellation of formulation hurdles that must be faced, understood and overcome. This is a task that can be tackled using elements of the Quality by Design (QbD) approach. Using this approach, the impact of these phenomena on tablet quality can be better understood and controlled. This study was aimed at using this approach to develop a formulation of methyldopa 250 mg tablets. Direct compression, a simple and moisture-free process, was selected for the manufacture of methyldopa tablets. After careful review of literature and consultation with experts, excipients were selected for the candidate formulation and preliminary concentrations established for each. Similarly, settings for mixing and compression variables were established. Adopted from the QbD framework, the risk posed to tablet quality by these factors was qualitatively analysed using Preliminary Hazard Analysis (PHA) and quantitatively evaluated using Failure Modes and Effect Analysis (FMEA). Eight (8) factors determined to be high risk were further investigated in a preliminary experiment that followed a 12-batch Plackett Burman design. Data from this experiment was used to draw statistical relationships between the aforementioned factors and tablet quality attributes, thus shedding light on excipients and process parameters with practically significant impact on methyldopa tablet quality. Multivariate Analysis of Variance (MANOVA) of the response data reported SSG concentration, citric acid monohydrate xxvii concentration and mixing speed as key factors (p<0.05), demonstrating the need to control these factors for quality targets to be met. These three factors underpinned the 16-batch definitive experiment that followed, conceived using a Box Behnken design (BBD) including four batches prepared at the centerpoint values in the region of experimentation. The optimal methyldopa tablet formulation was achieved at the following settings: 1.0 % m/m magnesium stearate, 1.0 % m/m colloidal silica, 3.9 % m/m sodium starch glycolate, 1.7 % m/m citric acid monohydrate, mixing speed of 101 rpm, 6 minutes of pre-lubrication mixing, 2 minutes of lubrication and compression speed of 20 rpm. These settings were included in the design space and subsequent control strategy. It was learned that, within the design space, the risk to tablet quality and, by extension, the patient, was insignificant. This demonstrated that, using the QbD approach, challenges to pharmaceutical development can be effectively overcome.
- Description
- Thesis (MA) -- Faculty of Science, School of Environmental Sciences, 2022
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (xxvii, 414 pages)
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Faculty of Science, School of Environmental Sciences
- Language
- English
- Rights
- Nelson Mandela University
- Rights
- All Rights Reserved
- Rights
- Open Access
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | Baguma, MI.pdf | 5 MB | Adobe Acrobat PDF | View Details Download |