Organic Process Research & Development最新文献

Selecting the development form of an active pharmaceutical ingredient (API) in drug development is key to determining the final performance of the drug substance and drug product. Form selection requires an interdisciplinary approach involving a complex process to discover, monitor, and evaluate the solid-state characteristics, biopharmaceutical properties, stability, and processability of numerous forms. This Perspective discusses the importance of aligning critical material attributes with the desired quality target product profile to ensure drug safety and efficacy. It discusses how the form selection strategy is dependent on factors related to the administration route, dosage form, and therapeutic indication and provides an interdisciplinary framework with four prioritized sets of target attributes for oral delivery: solid-state properties, biopharmaceutical performance, stability, and processability. A classification system to guide form selection, particularly for immediate-release oral medications, is reviewed. The benefits of crystalline forms in terms of stability and processability are highlighted, emphasizing the role of solution crystallization in controlling their development. The interdisciplinary form selection process will be demonstrated through case studies highlighting how each set of target attributes were evaluated leading to the selection of ideal forms for development.

Enantioselective fluidized bed crystallization (FBC) presents an attractive process concept for the separation of chiral compounds due to its continuous operation, high productivity, and narrow size distribution achievable. Here, we report the application related to the amino acid dl-threonine, characterized by a needle-like crystal shape when crystallized from aqueous solution. After demonstrating successful chiral resolution via FBC, the impact of the system’s specific crystal growth kinetics on the FBC performance is studied at pilot plant scale. The coupling of the anisotropic crystal growth with size-classification and fragmentation in the seeding bypass enables the continuous production of compact pure enantiomer crystals with narrow size distribution. The optimization potential of the seeding strategy and the flow rate on separation performance, product crystal shape, and process robustness is investigated as well.

Novel approach is reported for highly efficient continuous mononitration of salicylic acid using confined impinging jet reactor (CIJR) with a vent. Initially, controlled semibatch reactions are optimized to achieve complete conversion and formation of mononitro products with very high selectivity for 5-nitrosalicylic acid (5-NSA). Further, the combination of computational fluid dynamics simulations and experiments is employed to optimize CIJR design and operating flow conditions, suitable to yield only mononitro products with excellent control over mixing, heat transfer, and liberation of fumes during continuous flow reaction. Detailed analysis of internal flow patterns, rate of heat generation, and concentration distribution inside the CIJR facilitated the optimization of present exothermic reaction in a safe manner. In less than a minute, complete salicylic acid (SA) conversion with good yield and better selectivity for 5-NSA is achieved using the CIJR. Safety and clogging issues are addressed effectively, even at a relatively lower mole ratio (1:5) of SA:acetic acid (AcOH). The present approach is quite scalable using the numbering-up strategy, with advantages viz. nonfouling, high throughput, and the small footprint of CIJR.

Process analytical technology (PAT) is increasingly being explored within pharmaceutical production and process development, with a particular emphasis in the vaccine and biologics space. PAT aims to provide increased process understanding and control through real-time monitoring of critical quality attributes and key process parameters as well as detection of process deviations. Downstream purification in pharmaceutical manufacturing processes can be complex and requires copious analytical characterization. Herein, we showcase the successful implementation of PAT for monitoring bioconjugation reactions related to both vaccine and biologic pharmaceutical manufacturing processes. Specifically, we explore a variety of PAT-based techniques and their utility for monitoring polysaccharide–protein and protein–small molecule bioconjugation reactions. PAT applications using at-line multiangle light scattering, in situ fluorescence spectroscopy, in situ viscosity, and at-line hydrophobic interaction chromatography are shown to each provide distinct, real-time analytical information to enhance the understanding and characterization of bioconjugation reactions.

The development of robust manufacturing processes for active pharmaceutical ingredients (APIs) is paramount to ensure a supply of safe and effective medications. Implementation of a holistic control strategy, including quality control of incoming raw materials, is a key element in meeting this goal. This paper describes several examples from recent Merck API manufacturing routes, in which impurities in raw materials affected the processes in various ways, including giving rise to new process impurities, jeopardizing process safety and causing damage to reaction vessels, and─sometimes unexpectedly and counterintuitively─suppressing formation of process impurities. In all of these examples, analytical characterization plays a critical role in identifying these impurities and enabling their control to ensure consistent process performance and product quality.