Case Study 2
2
Case Study 2: Optimisation of a Phase II Formulation Objectives Company A (undisclosed) contracted with Tillotts Services for the optimisation of a formulation of their active drug substance, API-162. Our customer also required the production of pilot batches of API-162 drug product within a hard gelatine capsule formulation for a Phase II clinical trial. Images A and B (Figure 1) show the microscopic appearance of the suspension before and after high shear homogenisation. The results clearly confirmed that after high shear homogenisation the particles of the active were well dispersed in the vehicle and the absence of agglomerates in the formulation. Results and Discussion The process development work undertaken by Tillotts Services focused on the solid state properties of API-162 in relation to defining the optimal particle size distribution and understanding the rheological properties of the suspension. This involved exploring different manufacturing parameters in order to achieve consistent and optimal content uniformity in the drug product. Our final process included a homogenisation step using a high shear mixing rotor/ stator homogeniser during the production of the highly concentrated suspension of the active. Figure 1. Light microscopy appearance of the suspension before and after rotor/ stator homogenisation. B: Suspension after rotor/ stator homogenisation A: Suspension before rotor/ stator homogenisation Background API-162 is a small molecule (M <500), characterised by a high aqueous solubility, especially in acidic media. The proposed formulation was a lipid based suspension in a macrogolglyceride of a vegetable oil. However, due to the high dose required for API- 162, the distribution of the active in the formulation was erratic and attributed to large agglomerates of particles in suspension. This resulted in inconsistent content uniformity within the filled capsules which required our investigation. r
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Tillotts Services Case Study 2 Optimisation of a Phase II Formulation
Transcript of Case Study 2
Case Study 2: Optimisation of a Phase II Formulation
Objectives
Company A (undisclosed) contracted with Tillotts Services for the optimisation of a formulation of their active drug substance, API-162. Our customer also required the production of pilot batches of API-162 drug product within a hard gelatine capsule formulation for a Phase II clinical trial.
Images A and B (Figure 1) show the microscopic appearance of the suspension before and after high shear homogenisation. The results clearly confirmed that after high shear homogenisation the particles of the active were well dispersed in the vehicle and the absence of agglomerates in the formulation.
Results and Discussion
The process development work undertaken by Tillotts Services focused on the solid state properties of API-162 in relation to defining the optimal particle size distribution and understanding the rheological properties of the suspension. This involved exploring different manufacturing parameters in order to achieve consistent and optimal content uniformity in the drug product. Our final process included a homogenisation step using a high shear mixing rotor/stator homogeniser during the production of the highly concentrated suspension of the active.
Figure 1. Light microscopy appearance of the suspension before and after rotor/ stator homogenisation.
B: Suspension after rotor/ stator homogenisation
A: Suspension before rotor/ stator homogenisation
Background
API-162 is a small molecule (M <500), characterised by a high aqueous solubility, especially in acidic media. The proposed formulation was a lipid based suspension in a macrogolglyceride of a vegetable oil. However, due to the high dose required for API-162, the distribution of the active in the formulation was erratic and attributed to large agglomerates of particles in suspension. This resulted in inconsistent content uniformity within the filled capsules which required our investigation.
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Conclusions
Tillotts Services successfully optimised the production process of our Customer’s formulation within the agreed timeframe.
As validated by our studies, a high shear rotor/stator homogenisation step was subsequently included in the production process.
The resulting formulation was a thixotropic suspension with no sedimentation during manufacture or after capsule filling.
Phase II production conducted in our liquid-fill GMP manufacturing facility, fully supported and project managed by Tillotts Services.
Figure 2 summarises the analytical data of samples taken from the top, middle and bottom of the suspension after rotor/stator homogenisation. Together with the rheological properties of the formulation, our results indicated the formation of a thixotropic system where the particles of the active are integrated within the vehicle matrix forming a network which avoids sedimentation after capsule filling (Table 1).
For further information on how Tillotts Services can help with your formulation development options, clinical drug product supply or commercial liquid-fill manufacture, please contact us at: E: [email protected] or W: www.tillotts.com
100.8 101.0 100.0
bottom(n=3) middle
(n=3) top(n=3)
0.0
120.0
100.0
80.0
60.0
40.0
20.0
% o
f API
in s
uspe
nsio
n
Figure 2. Homogeneity of the suspension after rotor/stator homogenisation Table 1. Content of API-162 in the final capsules
sampleAPI-162
(% per capsule)caps 1
mean 98.7
101.0caps 2 100.7caps 3 98.2caps 4 98.6caps 5 97.4caps 6 96.8caps 7 98.3
ww
w.tillotts.com
Copyright © Tillotts Pharma AG 2012
