Example – Case Study 1
Increase understanding of API crystallisation and improve consistency of PSD for a commercial product:
- 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.
Provide recommendations for on scale manufacturing
JMP software used:
|Experiment||Seed Type||Seed Loading w/w%||Age Time Post-Seeding hr||Anti-solvent addition rate hr||Cool Down Time hr||Seed Temperature °C|
|DoE 1||Unmilled bimodal||0.01||0||2.25||4||50|
|DoE 2||Unmilled bimodal||0.01||0||2.25||4||50|
|DoE 3||Unmilled bimodal||0.001||0||10||4||48|
|DoE 4||Milled unimodal||0.001||0||10||4||48|
|DoE 5||Unmilled bimodal||0.04||0.25||10||10||48|
|DoE 6||Milled unimodal||0.04||0.25||10||10||52|
|DoE 7||Unmilled bimodal||0.04||16||10||4||52|
|DoE 8||Milled unimodal||0.04||0||2.25||10||48|
|DoE 9||Milled unimodal||0.001||0||10||10||52|
Example – Case Study 2
Determine proven acceptable range (PAR) for micronisation of a product to meet customer requirements
- 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
- 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
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.
- Fine hair-like needles observed post nucleation
- Material blinding filter cloth → very long deliquoring times.
- Limited development space for a filed commercial product.
- Proposed the introduction of temperature cycles to the cooling step (Ostwald Ripening) to promote growth of material.
- Proof of concept experiment completed to demonstrate benefits.
- Consultation with process team and engineer followed by repeat experiment optimised for plant conditions.
- 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
- 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
Presence of fines
- 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.
- 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