Case Studies2020-05-06T20:49:11+00:00

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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