(568d) Preventing Agglomeration and Controlling the Psd of API Particles Via Reverse-Addition Crystallization
AIChE Annual Meeting
2021
2021 Annual Meeting
Separations Division
Advances in Separations Technologies
Thursday, November 18, 2021 - 2:10pm to 2:35pm
Fast crystallization kinetics of API molecule result in the agglomeration and formation of particles
larger than 500 μm when isolated via commonly used forward-addition antisolvent crystallization
techniques. Controlling the particle properties and accessing d90 < 100 μm are needed to meet the
drug substance target material profile. A recrystallization step was therefore implemented to
control the particle size with a quality by design approach. We first demonstrated the use of a
terminal wet milling and thermal cycling process to access the desired particle properties. We then
designed an above-surface reverse-addition crystallization to remove the wet milling requirements
and reduce cycle time. A DoE was conducted to map the design space, and ability to change the
particle size from 500 μm to 60 μm has been demonstrated by simply altering crystallization
temperature, charge time, and seed loading. We found that the overall concentration, seed size,
and mixing do not significantly impact the particle size. The center point conditions determined
from the DoE studies provide a wide parameter operating window to ensure consistent access to
the target material properties. The newly developed reverse-addition crystallization process offers
a simple and robust control over the particle size while giving >94% yield, and has been
demonstrated at kilograms-scale API synthesis.
larger than 500 μm when isolated via commonly used forward-addition antisolvent crystallization
techniques. Controlling the particle properties and accessing d90 < 100 μm are needed to meet the
drug substance target material profile. A recrystallization step was therefore implemented to
control the particle size with a quality by design approach. We first demonstrated the use of a
terminal wet milling and thermal cycling process to access the desired particle properties. We then
designed an above-surface reverse-addition crystallization to remove the wet milling requirements
and reduce cycle time. A DoE was conducted to map the design space, and ability to change the
particle size from 500 μm to 60 μm has been demonstrated by simply altering crystallization
temperature, charge time, and seed loading. We found that the overall concentration, seed size,
and mixing do not significantly impact the particle size. The center point conditions determined
from the DoE studies provide a wide parameter operating window to ensure consistent access to
the target material properties. The newly developed reverse-addition crystallization process offers
a simple and robust control over the particle size while giving >94% yield, and has been
demonstrated at kilograms-scale API synthesis.