Development and Scale-Up of a Crystallization Process To Improve an API’s Physiochemical and Bulk Powder Properties

Abstract

A revised crystallization process for TAK-117, a selective PI3Kα inhibitor currently in Phase 1b clinical trials, was developed that greatly improved the overall purity, recovery, and physiochemical and bulk powder properties of the isolated product. The original process afforded material that was prone to agglomeration during drying, resulting in significant product losses during sieving as well as issues with drug product manufacturability. Opportunities to explore a wide array of possible crystallization routes and solvent options were limited because TAK-117 is only sparingly soluble in most commonly used organic solvents apart from dimethyl sulfoxide (DMSO) and acidic systems. However, reasonable productivities were achieved using DMSO at elevated temperatures (100 °C), and the optimized process leveraged thermal cycling to improve the aspect ratio of the isolated crystals, minimize agglomeration during drying, and improve the powder’s bulk properties. The revised process was found to produce material of acceptable quality across a total of six batches at 15 and 30 kg scales.

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and In Situ Control of Downstream Production

“…Drying processes for pharmaceutical powders present a variety of challenges, often involving the formation of aggregates and decomposition of temperature-sensitive compounds. − Ciprofloxacin is prone to the formation of lumps during the drying process, especially during agitated drying at dry matter contents below 70 wt % and to dehydration for temperatures higher than 85 °C at 0.5 bar. , On top of that, drying times can fluctuate significantly depending on the starting dry matter content of the cake, which in turn is affected by fluctuations in pressure and filter resistance during the wash solvent deliquoring step. To ensure that the drug substance is consistently isolated as a dry powder and to prevent dehydration of the hydrate API, two feedback control systems were implemented in the drying process.…”

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

“…16 Crystallization process development involves selection of an appropriate solvent system, 17 a method to generate super-saturation (e.g., cooling, antisolvent addition, evaporation, or pH adjustment), 18−21 and tuning of process parameters (e.g., mixing intensity, cooling profile, antisolvent addition method and rate, and so forth) to achieve the desired crystal properties. 22,23 However, limited choices with solvent selection driven by upstream demands (e.g., compatibility with reagents) often result in difficulty in controlling the interplay of the various crystallization mechanisms (agglomeration, attrition, breakage, encrustation, etc.,). 24,25 To mitigate these issues, particularly, where drug product performance-related attributes (e.g., particle size and shape) cannot be delivered, alternative particle engineering strategies have been investigated, often using the application of external fields.…”

“…, cooling, antisolvent addition, evaporation, or pH adjustment), − and tuning of process parameters ( e.g. , mixing intensity, cooling profile, antisolvent addition method and rate, and so forth) to achieve the desired crystal properties. , However, limited choices with solvent selection driven by upstream demands ( e.g. , compatibility with reagents) often result in difficulty in controlling the interplay of the various crystallization mechanisms (agglomeration, attrition, breakage, encrustation, etc.…”

Evaluation of microflow configurations for scale inhibition and serial X-ray diffraction analysis of crystallization processes

“…We additionally show that nucleating agents that promote crystallization in the "bulk" of the droplet further reduce scaling and are an excellent system for studying with DMC-XRD. The seeding of crystallising solutions with a target material is of great importance in the pharmaceutical and chemical industries, [36][37][38][39] and has recently been recognized as a way to reduce the clogging of flow crystallisers. 40 The results presented here demonstrate that foreign material which promotes heterogeneous nucleation in solution can also reduce scale build-up on reactor surfaces.…”