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:
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
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.
- 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.

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

Dendritic-columnar crystals

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.
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



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