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Minimising the impact of incomplete washing on active pharmaceutical ingredient (API) particle properties caused by drying; developing strategies to mitigate undesirable effects and a workflow to optimise isolation

Project Description

Poor API powder flow is often a cause of formulation challenges. In an ideal isolation process the characteristics of crystals produced during crystallization (PSD, morphology and polymorph etc.) are preserved. Purification is achieved by complete removal of mother liquor which contains dissolved impurities. Drying is accomplished by removal of residual solvent without any granule formation or other changes to the API particles such that the API flow properties are dominated by the primary particle attributes of aspect ratio, size distribution and surface character. This ideal situation is not usually achieved in practice; this PhD will deepen our fundamental understanding of the processes occurring and explore opportunities to improve the situation.

Inefficient washing during isolation leaves impurity molecules on the solvent wet crystal surfaces. Residual solvent in which the product has some solubility favours particle granulation during drying. Because the solvent evaporates from the cake surface this provides a transport mechanism carrying both dissolved API and impurities to the drying surface leading to inhomogeneous composition. Classically this may be addressed by agitation however agitation of solvent wet particles leads to particle breakage and can promote granulation and lump formation affecting bulk powder flow.

Although it is well known that drying performance may be affected by process, equipment and material parameters these effects are not typically investigated in detail during process development and alternative drying strategies are not usually explored.

The novel elements of this research are:

1. Measuring effect of residual solvent and surface impurities on the surface properties of a single crystal to gain fundamental insights which may explain some aspects of powder flow.

2. Characterising the processes by which inter-particle crystalline bridges leading to lumping.

3. Investigation of the migration of impurities during drying and their preferred final locations.

This PhD project will contribute towards the creation of an isolation work flow and diagnostic tools to help practitioners identify causes of drying issues and therefore to develop alternative drying strategies to achieve the required isolated material properties. The overall target will be to help deliver API powders with desirable powder flow properties to support consistency in formulation.

Project aims and methodology
1. Review the current pharmaceutical drying approaches and identify best practice and opportunities for improvement
Investigate drying processes at the single crystal level and identify causes of drying issues at this scale. Employ optical and Raman microscopy, TOF SIMS and AFM to examine particle surfaces.
2. Determine the effect of solute and impurity concentration in residual solution on the contact angle on specific crystal faces as a means to explain impurity location.
3. Investigate inter-crystal bridge formation at the microscopic level by monitoring and modelling the solution meniscus retreat and the size and strength of the inter crystal bridge formed as a function of face wettability and solute solubility in the residual solution. Use the insights gathered from this novel approach to identify causes and potential solutions to drying problems.
4. Take single crystal and small population findings and investigate the impact at the whole cake scale using Instron, powder texture analysis, microscopic examination and particle size / shape measurement instruments.
5. Consolidate mechanistic insights into a drying model which can simulate the effect of different drying starting points, material attributes and drying conditions on product properties. We anticipate developing a hybrid approach using DEM modelling tools to achieve this.
6. Develop procedures to quantify extent of agglomeration / lumping and of impurity migration during drying. Current bulk methods involve screening and weighing, whilst pragmatic this is effective. It will be augmented by individual lump testing using Instron to measure the required particle breaking force as a function of API particle attributes and drying conditions
7. Evaluate alternative analytical methods to determine impurity location and quantity.
8. Investigate alternative drying strategies /methodologies to avoid impurity migration and particle agglomeration, (static vs agitated, the role of pressure, heated nitrogen, vs conduction etc.)
9. Develop and test a strategy to minimise agglomerate formation and impurity migration. Evaluate this on multiple compounds to propose a work flow and diagnostic tools to help practitioners identify causes of drying issues in specific systems and to identify potential solution strategies.

In addition to undertaking cutting edge research, students are also registered for the Postgraduate Certificate in Researcher Development (PGCert), which is a supplementary qualification that develops a student’s skills, networks and career prospects.

Information about the host department can be found by visiting:

Funding Notes

This PhD project is initially offered on a self-funding basis. It is open to applicants with their own funding, or those applying to funding sources. However, excellent candidates will be eligible to be considered for a University scholarship. Tuition fees for 2018 for postgraduate research students at the University of Strathclyde are £4,330 for Home/EU students and £18,750 for international students. This does not include bench fees.

Students applying should have (or expect to achieve) a minimum 2.1 undergraduate degree in a relevant engineering/science discipline, and be highly motivated to undertake multidisciplinary research.

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