Polymorph Selection and Process Intensification in a Continuous Crystallization–Milling Process: A Case Study on l-Glutamic Acid Crystallized from Water

Abstract

The continuous crystallization of L-glutamic acid from water is studied in a single stage mixed suspension mixed product removal crystallizer that is coupled to a milling loop. We show that the stable β polymorph can be obtained in the presence of milling at operating conditions that would lead to the metastable α polymorph without milling. The effect is first shown through a series of experiments carried out at different residence times, feed concentrations and in the absence/presence of milling. The experimental observations are rationalized through the use of a population balance equation model. We conclude that the observed effects result from fines generation and the corresponding increase in crystal surface area. Using the model, we obtain a map of polymorphic outcomes and process productivity in dependence of operating conditions. It is shown that the combined milling/crystallization process exhibits higher productivity and an enlarged region of operating conditions where the stable polymorph of L-glutamic acid can be reliably obtained in comparison to a conventional crystallization process.

Investigation of Wet Milling and Indirect Ultrasound as Means for Controlling Nucleation in the Continuous Crystallization of an Active Pharmaceutical Ingredient

“…This generated a rapid increase in total counts from 0 to 50 min due to enhanced secondary nucleation which leveled off after 200 min as the supersaturation is depleted (Figure 10a). The initial strategy was to operate in a continuous singlepass mode without recirculation by feeding an undersaturated solution (70 mg/mL) through the ultrasound flow cell at different temperatures and hence supersaturations (35,40, and 45 °C corresponding to supersaturation values of 2.6, 2, and 1.6, respectively). This would allow for the flow cell to be positioned between the feed tank and the first stage of a multistage MSMPR crystallizer effectively separating nucleation from growth.…”

“…On the other hand, high-shear rotor-stator wet milling devices have found widespread use in pharmaceutical manufacturing owing to their ease of use and broad availability. They can be applied either immersed into the reactor or through a recirculation loop to perform size reduction, − shape manipulation, − polymorphic selection, , conglomerate separation in full-scale manufacturing, , or seed generation. , In continuous manufacturing, a key driver for applying wet milling is to control nucleation for APIs possessing wide metastable zone widths (MSZWs) and thus exhibiting slow nucleation kinetics. Its use has also been shown to reduce the process startup and time to reach the steady state .…”

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

“…The design space study elucidated the fact that the fines generation from milling increased the available crystallization surface area, which enhanced the yield and widened the attainable region of product quality attributes vs. the crystallization process alone. Köllges and Vetter (2019) designed a single MSMPR crystallizer coupled with milling to attain the stable β-polymorph of l-glutamic acid from aqueous solution, mapping the attainable process productivities vs. polymorphic regions ( Figure 8) [58]. The authors showed that only via addition of a milling process to the crystallization process allowed for attainment of the β-polymorph, whereas the crystallizer alone could only produce the metastable α-polymorph.…”

Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing

“…In addition to improved productivity, continuous crystallization has a number of distinct advantages over batch operation. Being able to reach a steady state during the crystallization process (something not possible in batch) results in greater reproducibility and consistency in the crystalline material and shows some advantages compared to batch in terms of control of polymorphic form and engineering of particle size distribution, in addition to a significant increase in productivity [ 8 , 9 , 10 ]. In addition, competitive steady states in continuous crystallizers have recently been demonstrated to provide a robust mechanism to produce both stable and metastable polymorphs at scale [ 11 , 12 , 13 , 14 ].…”