Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study

Abstract

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle−particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development

“…The inverse correlation between extent of agglomerate formed and the amount of washes done was explained by Ottoboni et al (2019 and 2020). 4 , 13 A more detailed explanation and the correlation of this factor with LOD is described in Section 4.4.3.…”

“…To improve the drying capability of CFD20 and to drive further improvements, which have been embodied in the subsequent CFD unit (AWL CFD25), a fast prototyping approach was followed to design and build the drying rig prototype created to study the CFD25 drying components. 13 …”

Exploring the Role of Anti-solvent Effects during Washing on Active Pharmaceutical Ingredient Purity

“…An alternative is selecting a solvent in which the API has similar solubility as that of the API in the mother liquor to prevent precipitation of material present within the mother liquor solution. 9 However, these approaches result in a reduction of yield from that obtained during the crystallization process. In addition, the final crystalline product obtained at the end of the drying process could have a different particle size distribution to the one obtained during crystallization.…”

A Novel Integrated Workflow for Isolation Solvent Selection Using Prediction and Modeling

“…The wash solvent selected should have a low boiling point and enthalpy of vaporization and high vapor pressure to favor the drying process reducing the constant and falling rate drying period. 31 Impurities dissolved in crystallization mother liquor should be removed by efficient washing. Impurities already incorporated into the API crystals or precipitated in their own right during the crystallization are not addressed in this workflow.…”

“…The wash solvent selected should have a low boiling point and enthalpy of vaporization and high vapor pressure to favor the drying process reducing the constant and falling rate drying period. 31 …”