The Challenge and background
The recrystallization of Pregabalin in Isopropyl Alcohol (IPA) and Water is complex and does not follow a normal linear relationship. Pfizer circumvented this problem by elaborate azeotropic distillations to change solvent ratios post dissolution but this introduced extra complexity and cost. The challenge presented to SSPC for this project was to develop a cost-effective process to overcome these complexities.
The Solution
SSPC Principal Investigator Prof. Pat Frawley and post-doctoral researcher Brian De Souza used a combination of accurate design space determination combined with process modelling to identify a ‘sweet spot’ in the commercial process. The team worked collaboratively, utilising the equipment and software developed in-house for determining the design space and were able to work with the Pfizer team to use their kilo lab for validation.
The innovative solution developed was divided into two parts:
The first part of the solution involved changing from a complex four step crystallization procedure using a modified solvent matrix to a single cool down procedure. This provided considerable benefits, in terms of time, throughput, solvent costs and Particle Size Distribution.
The second part of the solution focused on maximising yield. This was realised by pressure recrystallization thus increasing the solvent boiling point and allowing for a higher solubility at the process start. It is important to note that the improvements described could be applied either individually or synergistically in combination.
A lack of uniformity in particle size distribution can have consequences for downstream processes such as filtering and drying. The pressurisation approach has the advantage of preserving the benefit of a monomodal PSD. Pressure recrystallisation, as a means of improving yield, has been championed in the University of Limerick using several commercially available API’s including paracetamol. A novel test rig, developed in the University, allows for non-intrusive high temperature / high-pressure measurements, which could not be obtained using the standard gravimetric approach.
The Impact
This project has led to the development of a new manufacturing process which delivers a 3% increase in yield, improved efficiencies, a reduction in solvent use and complexity, improvements in throughput and better particle consistency.
This process now formally named the DeSouza process will be incorporated into a new next generation Pregabalin process now complete, that has been developed by the PDC.
The commercial impact of this research emanates from:
(1) Manufacturing productivity impacts, including reduction in solvent usage, time savings in production processes, and reduction in environmental waste costs leading to Greener process. There is an increase in yield and particle size distribution control.
(2) The candidate API selected for optimisation, Pregabalin known by the brand name Lyrica, was and remains one of Pfizer’s biggest multi billion euro selling APIs. Significant economic benefits will be derived from this research.
Publication
Solubility of (S)-3-(Aminomethyl)-5-Methylhexanoic Acid in Pure and Binary Solvent Mixtures, J. Chem. Eng. Data, DOI: 10.1021/acs.jced.5b00736.
“An application that has significantly impacted a manufacturing process within the pharmaceutical sector.” Prof Liam Tully, Pfizer Global Process Development Centre (RIP).
