Capabilities: Case Studies

Example – Case Study 1

Project Objective

Increase understanding of API crystallisation and improve consistency of PSD for a commercial product:

Approach

• Identified success criteria for ideal API characteristics: D90 range, modality, crystal habit, filtration behaviour.
• Assessment of process using JMP software determined complex crystallisation with multiple factors interacting with each other.
• Fractional factorial design to generate parameter conditions for 9 experiments using JMP.
• Key findings used to implement recommendations for manufacturing on scale.
• Output measured using laser light scattering (Malvern), scanning electron microscopy, Morphologi G3 image analysis, leaf filtration.

Output

Provide recommendations for on scale manufacturing

JMP software used:

Example – Case Study 2

Project Objective

Determine proven acceptable range (PAR) for micronisation of a product to meet customer requirements

Approach

• Central composite experimental design investigating mill pressure and product feed rate
• Influence of input material assessed by performing confirmatory runs using different inputs at coarse and fine ends of PAR

Output

• Established PAR and operating parameter set points
• Determined input PSD has no impact on output

Case Study 3. Crystallisation Optimisation for Improved Deliquoring Rates in a Filter Dryer

Problem Statement

Variable bottleneck cycle times (97-161 hr, target is 91 hr) due to deliquoring rates during isolation of a commercial intermediate on a filter dryer. The process team requested that the crystallisation be investigated to determine if material with more suitable powder properties could be generated.

Outcome

• Filtration rates monitored in the lab using a pressurised leaf filter and analysed using SEM and light microscopy.
• Slurries were filtered at 1 bar gauge pressure with 10 mm filter cloth.
• Filtration reduced from > 40 seconds to 2-5 seconds via introduction of temperature cycles.
• Comparable material quality and losses to the mother liquor

Case Study 4. Improved Consistency of Unmilled API PSD

Problem Statement

• Variable PSD observed for unmilled API due to inconsistent nucleation and growth.
• Potential for dendritic growth resulted in dryer attrition and bimodal PSD.
• Modality and PSD observed using Morphologi-G3 and Malvern.

Attrition during extended crystallisation hold and agitated drying

• An increase in variability had been observed over time, therefore a project was initiated to understand cause of variability and improve consistency.
• A number of experiments performed using Radley’s AutoMATE reactor/RX10 with FBRM probe.

Factor investigated in the laboratory included:

• Powder properties of seed
• Temperature of solution on receipt to crystalliser
• Seeding temperature
• Anti-solvent addition time
• Cooling profile/time

Crystallisation solution was determined to be highly supersaturated leading to variability in desupersaturation. Allowing more time for material to desupersaturate resulted in less dendritic growth.

Recommendations included:

• Target temperature to be maintained during transfer of batch to the crystalliser.
• Adjustment of solvent matrix in seed slurry
• Recommended RPM for agitation in the crystalliser (based on CFD study)

Batch Temperature before and after transfer to crystalliser