Combined wet milling crystallisation methods for particle engineering

Student thesis: Doctoral Thesis

Abstract

Recent advances in pharmaceutical manufacturing for consistent supply of medicines with the required physical properties has emphasised the need for robust crystallisation processes which is a critical separation and purification technique. Mechanical milling is employed post crystallisation as an offline unit operation usually in a separate dry solids processing facility for adjusting the particle size and shape attributes of crystalline products for downstream processing. An emerging and increasingly applied technology is high shear wet milling in crystalline slurries for inline size and shape modification during particle formation. This potentially avoids the need for multiple crystallisation trials and offline milling saving time, costs and powder handling. Similarly, sonication is a powerful particle engineering tool through immersing ultrasound probes directly in solution. This PhD project is focused on the investigation and process integration of wet milling and indirect ultrasound for enhancing crystallisation processes and engineering particle attributes. The experimental study combined a cooling and isothermal crystallisation (seeded & unseeded) process with wet milling and indirect sonication. Results from the combined method provides the ability to modify and selectively achieve a range of product outcomes including particle sizes with tight spans, equant shapes and low surface energies as well as increased nucleation rates.High shear from wet milling is also implemented as a seeding protocol configured to a mixed-suspension mixed-product removal continuous crystalliser which proved to be an adequate seed generation strategy.Deploying accurate quantitative analysis of size and shape attributes for solid particles is further explored. A multi-sensor measurement approach was employed using inline sensors, computational tools and offline techniques. The performance of these tools were vigorously tested for strengths and limitations which was proven to be beneficial for characterising the breakage of crystalline materials as well as overall process understanding and opportunities for process control.
Date of Award9 Oct 2019
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorAlastair Florence (Supervisor) & Jan Sefcik (Supervisor)

Cite this