Session 1: Smarter Solid Form & Pre-formulation Studies Archives - Pharma Crystallization Summit

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264): A Solid-State Chemistry Perspective

wpadm — Tue, 16 Jun 2020 02:36:49 +0000

Alfred Y. Lee Department of Analytical Research & Development Merck & Co., New Jersey USA Keywords: Green Manufacturing, Gefapixant Citrate, Solid-State Chemistry, crystal structure prediction Gefapixant citrate (or MK-7264) is a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. It has demonstrated significant efficacy in recent Phase 3 clinical trials in reducing the frequency of cough in patients with refractory chronic cough after 12 weeks of treatment compared to placebo. A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate. The newly developed commercial process features many advantages including low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced active pharmaceutical ingredient (API) costs. This presentation provides a solid-state chemistry perspective on the development of a commercial manufacturing process for gefapixant citrate. Key innovations that will be discussed are: (1) exploitation of a cocrystal that enabled chemical purification and enhance the physical properties of a regulatory starting material; (2) utilization of crystal structure prediction (CSP) across the chemical synthesis to ensure that products are launched with the best chemical processes; (3) manipulation of a physical form for crystallization selectivity to purge chemical impurities; (4) a novel salt metathesis approach to consistently deliver the correct API salt form in high purity; and (5) navigation of a complex solid form landscape through knowledge of a process phase diagram.

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What Solid Form Should I Choose?

wpadm — Tue, 16 Jun 2020 02:35:30 +0000

Ann Newman Pharmaceutical Consultant Seventh Street Development Group The solid form of an active pharmaceutical ingredient (API) used in development has become an important aspect of drug development based on possible issues with manufacturability, solubility, bioavailability, and stability differences between materials. A variety of solid forms can be investigated in screening studies, including polymorphs, salts, cocrystals, amorphous, and amorphous dispersions. The next step after finding the forms is collecting relevant data to choose the best form for the targeted dosage form and development plan. This usually includes more in-depth experiments with solubility, physical and chemical stability, and possible process induced transformations during API crystallization or formulation. This talk will discuss properties to consider when choosing a form, as well as methods used in the industry for comparison. Case studies that illustrate the selection process will be presented, and examples of using different forms in various types of formulations for lifecycle management will also be discussed.

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Understanding and Controlling the API Form/Powder Property Risks in Drug Substance and Product Processes

wpadm — Tue, 16 Jun 2020 02:34:31 +0000

Dr. Shawn Yin Scientific Director, Materials Science and Engineering, Drug Product & Development Bristol-Myers Squibb Co. Abstract It is well known that some key drug substance physical properties, like crystal form, crystallinity, size, morphology, etc., can be altered during drug substance and/or product processes, and potentially during the product shelf life. Therefore, acquiring a good knowledge of how both the DS and DP process impacting on these critical product quality attributes is one of the key development activities, aiming at ensuring a success product development and bringing a robust product to the market. This presentation described, via real development/manufacturing examples, several risk factors including regulatory risk of DS/DP process induced API physical changes. These risks are assessed based on physical characteristics of material single crystal structures, surface/bulk physical characterizations and their relevant biopharmaceutical properties. The impacts of these risks on DS/DP CMC activities, product quality and patients are also discussed.

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Absolute Structure Determination of API Molecules by MicroED analysis of Cocrystals formed based on Cocrystal Propensity Prediction Calculations

wpadm — Tue, 16 Jun 2020 02:33:14 +0000

Chandler Greenwell Applications Scientist XtalPi Harsh Shah Senior Scientist J-Star) Jessica Bruhn Principal Scientist NanoImaging Services Of the 35 small molecule drugs approved in 2020, 43% were chiral compounds formulated as enantiopure products. For most chiral small molecule drugs, only one enantiomer is biologically active, while the other enantiomer can potentially lead to unwanted side-effects/toxicity (e.g. thalidomide). Therefore, it is critical that researchers establish ways to purify only the desired enantiomer and use structural characterization techniques to understand which enantiomer is biologically active. Historically, single crystal X-ray diffraction (scXRD) has been the gold standard for establishing the absolute configuration of active pharmaceutical ingredients (APIs), either directly from the measured intensities or by co-crystallization with a chiral probe. Unfortunately, this technique is limited by the need to grow suitably sized crystals, which can be challenging for many APIs. Here, we present a method for obtaining absolute configuration from chiral co-crystals that are too small for scXRD by using microcrystal electron diffraction (MicroED). In order to streamline this approach, we have also employed computational methods to guide co-crystal formation. These computational methods combine a conductor-like model for realistic solvents (COSMO-RS), machine learning (ML) and pKa considerations to virtually screen a large list of potential co-formers. The top co-former hits were then employed in cocrystal screens and potential co-crystals were characterized by light microscopy, X-ray powder diffraction and NMR. Crystalline material was then sent for MicroED structure determination without the need to optimize for the growth of large crystals, resulting in a rapid structure determination and establishment of the absolute configuration of the API. This strategy was employed to determine the absolute configuration of two pharmaceutical compounds: Finafloxacin and Ipragliflozin.

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