Thesis
Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2023
- Thesis identifier
- T16684
- Person Identifier (Local)
- 201765867
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- In the pharmaceutical industry, the final drug substance (active pharmaceutical ingredients (API)), and the key synthetic intermediates are mostly isolated as crystalline solids. A considerable amount of effort is spent in the crystallisation process to produce a crystalline solid with the requisite chemical quality together with the right physical properties (filterability, product size, uniformity, etc.), for isolation and further downstream processing to manufacture the drug product. Whilst carefully designed upstream processes may attain the desired crystal properties in suspension, these are often compromised during the isolation of the API by filtration, washing and drying. These isolation processes pose significant challenges to the production of crystals with the desired physical properties; avoiding granulating, or breaking the crystals, or precipitating dissolved product and impurities. Washing is a key step in pharmaceutical isolation to remove the unwanted crystallisation solvent and dissolved impurities (mother liquor) from the API filter cake to ensure the purity of the product whilst maximising yield. The aim of this thesis is to understand how the physiochemical properties of crystallized material and the wash solvent can affect the characteristic of the API product at the end of the washing process. Strategies for optimal wash solvent selections are explored to help minimise dissolution of API product crystals while preventing precipitation of product or impurities. This is done by taking solubility measurement of commonly used binary solvent mixtures of; paracetamol API, crystallisation solvent and wash solvent. The results of these solubility measurements are presented together with a methodology to analyse anti-solvent effect of different solvent combinations. The data from these results are used for selection of wash solvent to avoid both these phenomena which can be challenging but is essential to maintain yield, purity, and particle characteristics throughout the isolation process. A major objective of this work aims to improve pharmaceutical product quality, increase sustainability, and reduce manufacturing cost. Constant rate filtration/washing is employed that allows for collection of separate aliquots during all stages of filtration, washing and deliquoring of the API cake. This enables a wash profile to be obtained, as well as providing an overall picture on the mass of API lost during isolation and so can assist in optimizing the washing strategy. This constant rate methodology was tested using paracetamol API together with blue dye used as an impurity to allow for visualization of washing process of a filtered API cake. Analysis of the filtrate collected during this study was found to be useful in determining the endpoint of washing, the amount of API lost during the washing process and the likely extent of agglomeration occurring during washing to be evaluated. Further work looks at employing particle size distribution measurement techniques to quantify agglomerate formation caused during the washing process. Several different lab-based particle size distribution techniques were employed to analyse washed API cake, however, none of them were found to be successful in providing conclusive results. This work highlighted some of the challenges of characterising API particles obtained from a multi-component system at the end of the washing process. This demonstrates that sizing wet clumped material is even more challenging than sizing dried but agglomerated product. The final component of this work was the development of a wash process workflow to assist with design and optimisation of an API washing process. This workflow collates all the learning developed throughout the different studies in this PhD project to produce a workflow which provides an optimum strategy for designing of washing processes in pharmaceutical isolation of APIs. This workflow was validated using an industrial compound from AstraZeneca with the constant rate methodology successfully used to investigate optimum washing process parameters for the investigated compound.
- Advisor / supervisor
- Lue, Leo
- Price, C. J. (Chris J.)
- Resource Type
- DOI
关系
项目
| 缩略图 | 标题 | 上传日期 | 公开度 | 行动 |
|---|---|---|---|---|
|
|
PDF of thesis T16684 | 2023-08-30 | 公开 | 下载 |