RESEARCH PROJECT MSc THESIS

Department of Chemical & Process Engineering

University of Strathclyde, Glasgow, UK
SOLVENT SELECTION FOR ISOLATION OF PHARMACEUTICAL PRODUCTS
Dr. Chris John Price
EPSRC Manufacturing Fellow & Director of Knowledge Exchange
Department of Chemical & Process Engineering
+ 44 (0)141 574 5303, chris.price@strath.ac.uk

"I propose to gather data linking loss of mass on drying with solvent selection for filtration
and washing, this in turn will be linked with the friability of the dried particles and this then
correlated with the solubility of the substrate in the selected wash solvent. The initial program
of work will be a wide selection of pure solvents, the substrate will be paracetamol, chosen to
be compatible with a larger program of work, this will allow the effect of particle size to be
explored as a categorical variable; micronized, typical crystalline and granular. If time allows
we will select a small group of solvent pairs and investigate the effect of making a solvent
switch between a primary solvent and secondary wash solvent on the tendency for the
particles to granulate on drying. This work fits into a bigger program of work on isolation
shown in the image below. The data gathered should form the basis of a paper on wash
solvent selection, it may not be a world changing publication but it will feed into a wash
solvent selection algorithm and so is likely to lead impact."

The proposed experimental work could comprise:

Filtration:
Prepare a defined quantity of saturated solution of paracetamol in a series of solvents at 20C.
The solvents will be selected to provide diversity of attributes and where necessary solubility
measurements will be made.
Suspend a defined quantity of a specific grade of paracetamol in the saturated solution.
Filter the suspension with a defined pressure driving force monitoring the volume of filtrate
collected against time.
Halt the filtration at the bubble point (the cake will be largely desaturated).
Determine the mass of filtrate collected and the wet cake mass.
Allow air to pass through the cake with a defined pressure drop for a defined time and
monitor the cake mass periodically.
The resulting damp filter cake will then be dried in a vacuum oven.
The filtration rate data will be plotted as filtration rate against volume of filtrate and the
specific cake resistance determined.

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Characterisation of the dry filter cake

Determine the dry cake mass.
Evaluate the extent of granulation of the cake (transfer dry solid onto a small nest of sieves
and determine hold up on each sieve).
Subject the product particles to shaking and re-determine hold up on each sieve.
Additional measurements:
Solution viscosity.
Investigation of washing with a different solvent:
Wash solvent selection will be informed by a solvent selection algorithm under development
at UoS.
In the case of washing two strategies will be evaluated:
1) Halting the filtration at dry land the point when the filter cake surface becomes exposed
and adding the wash without disturbing the cake such that displacement washing occurs.
2) Filtering to the bubble point and then adding the wash.
The product loss on washing will be determined and the ultimate impact on the properties of
the dried product will be assessed.
Correlation:
The combined impact of factors such as; the solubility of drug substance in the wash solvent,
the viscosity of the wash solvent and of the viscosity of the product saturated wash solvent,
the solution / solvent hold up in the wet filter cake etc will be evaluated in terms of the
tendency of the particles to agglomerate on drying, the robustness of resulting agglomerates
and the loss of yield as a result of washing.
This is really a starting suggestion. Short research program broadly along these lines will be
developed. I anticipate that the data gathered in this way will feed into several ongoing
research programs and will contribute to publications.
An example of a related research program is
http://remediesproject.com/research-2/project-structure/app-b/
By way of papers and publications, there is plenty of filtration literature but much less on the
impact of the combination of filtration, washing and drying on product powder attributes.
Understanding and Avoidance of Agglomeration During Drying Processes: A Case Study
by Melissa Birch and Ivan Marziano of Pfizer is a good example of the industrial perspective,
published in Org. Process Res. Dev., 2013, 17 (10), pp 13591366
http://www.bhs-filtration.com/A_Treatise_of_Filter_Cake_Washing_Mechanisms.pdf
provides a useful equipment vendors perspective.

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