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.

Alisertib sodium, an investigational oral oncology drug, posed some challenges toward developing a robust and scalable drying process employing an agitated filter dryer that manifested themselves during the technical transfer to a new manufacturing site. The API studied was a monohydrate that was found to readily dehydrate and agglomerate, impacting both drug product (DP) manufacture and in vitro dissolution. A scale down agitated filter dryer was designed that was used to study the drying unit operation and identify key process parameters. Through a combination of lab-and pilot plant-scale experiments, suitable drying conditions were developed that minimized agglomeration, eliminated dehydration, and produced API that behaved acceptably in downstream DP manufacture.

A revised Miyaura borylation process has been developed using tetrahydroxydiboron that avoids the use of bis(pinacolato) diboron and hence the need to hydrolyze the resulting boronic ester to its corresponding acid. The process was greatly simplified and successfully scaled-up in the pilot plant on a 65 kg scale, reducing plant cycle time and resulting in a 47% overall cost reduction. Furthermore, methodology for the study of the oxygen sensitivity of the process is reported that allowed for optimization of the amount of tetrahydroxydiboron and catalyst used. These studies also demonstrated an oxygen-induced decomposition of tetrahydroxydiboron.

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A modeling-based strategy is disclosed for identifying reaction conditions for the safe and effective scale-up of highly energetic hydrogenation reactions. The model was developed within Scale-up Systems’s DynoChem 2011 and takes under consideration the kinetics of the reaction, the reactor heat transfer capabilities, and the degree of mass transfer. Fourier transform infrared spectroscopy (FT-IR), heat flow, and H2 uptake data were used to determine the reaction kinetics that were found to be most accurately described by a Langmuir–Hinshelwood type model. The scale-up model was validated within our kilo-laboratory using a 5 L reactor.

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A material-sparing screening methodology has been developed for assessing the risk of particle size attrition of active pharmaceutical ingredients (APIs) during agitated drying using a single-ball mill process assisted by resonant acoustic mixing. This method requires only gram quantities of material and provides a critical particle fragility assessment that can be used to identify suitable agitation protocols that minimize attrition during at-scale manufacturing. The impact of initial particle size, as well as physical properties such as hardness, aspect ratio, and thickness, on particle breakage was assessed for both Takeda APIs and a range of commercially available compounds. Two models were developed and validated using both laboratory-scale and plant-scale agitated filter dryers, and a suitable workflow for the application of the developed methodology is proposed.

This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on particle size were experimentally investigated. A minimum d 50 of 27 and 36.8 μm was achieved when using the wet mill and ultrasound, respectively. The effectiveness of wet milling was demonstrated in a three-stage mixed suspension mixed product removal continuous crystallization of the API that was operated continuously for 12 h (eight residence times), achieving a steady state with minimal fouling. Strategies for improving the overall robustness of the setup in routine manufacturing are discussed.