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As vixotrigine (1) entered a later clinical phase for trigeminal neuralgia (Zakrzewska, J. M.; et al. Lancet Neurol. 2017, 16, 291−300), the development of a sustainable late-stage process was requ...

We report the crystallization of a metastable small-molecule solvate and the effect of the isolation method on the physical and material properties of the resulting anhydrous material. The anhydrous crystalline products obtained from two different isolation routes using either a temperature-driven form change or a solvent-wash-mediated form change were analyzed by a suite of material-sparing characterization methods probing both physical form and material properties such as particle size distribution and powder flow behavior. The temperature-driven desolvation method was found to be time-consuming and undesirable. A relatively rapid desolvation approach was obtained using an ethyl acetate wash-mediated process. However, this method leads to powder with a broader particle size distribution, poorer flowability, higher interparticulate friction, and lower bulk density compared with the powder obtained by the temperature-driven desolvation process. The direct impact of the method of isolation on the material ...

The creation of the Enabling Technologies Consortium (ETC) is described. The ETC fosters precompetitive collaborations aimed at the development and evaluation of new enabling technologies for pharmaceutical research and development, with an initial focus on chemistry, manufacturing, and controls. An overview of the structure and function of the new organization, which will carry out its work while remaining mindful of antitrust compliance requirements, is herein presented along with a description of several ongoing development projects.

A series of case histories from IQ consortium member companies are presented in order to exemplify many of the different elements of drug substance control strategies that are required in order to ensure process performance and product quality. Control through process, method, and/or model design can combine to form a holistic control strategy that effectively manages risk and assures quality for the patient. A typical drug substance control strategy overview is presented, along with a number of detailed case histories that aim to demonstrate the use of process design and the development of methods and modeling to ensure control of critical quality attributes where appropriate, whether in the final drug substance or through upstream controls.

A number of strategies have been employed within the pharmaceutical industry in order to mitigate the risk of applying design space boundaries developed on the laboratory scale to commercial drug substance manufacturing. The following communication presents a number of case histories from members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the aim of exemplifying strategies used to confirm applicability of design spaces developed on the laboratory scale. The strategies presented have a common aim of ensuring that appropriate quality standards are developed, maintained, and enhanced during the product lifecycle whilst delivering rapid and cost-effective mechanisms for drug substance commercialization.

The formation and fate of monomethyl sulfate (MMS) and dimethyl sulfate (DMS) were studied by proton NMR for a sulfuric acid catalyzed esterification reaction in methanol. The kinetic rate constants for DMS and MMS were determined at 65 °C by fitting time-dependent experimental data to a model using DynoChem. In refluxing methanol, sulfuric acid was converted to monomethyl sulfate (MMS) in nearly quantitative yield within 45 min. Once formed, the MMS underwent a reversible esterification reaction to form DMS. Dimethylsulfate reacted with methanol to regenerate MMS and form dimethyl ether. A byproduct of the esterification reaction was water, which further consumed DMS through hydrolysis. On the basis of derived rate constants, in refluxing methanol, DMS would not be expected to exceed 4 ppm in the reaction mixture at equilibrium. In the presence of the carboxylic acid substrate, DMS was not detected in the reaction mixture. The reaction pathways of this system have been systematically investigated, and th...

A large-scale synthesis of denagliptin tosylate has been developed. The efficiency of the synthesis has been improved from the initially scaled route by changing the order of steps (performing a dehydration at a late stage). The key step of the synthesis is a single-step peptide coupling/dehydration, mediated by n-propanephosphonic acid cyclic anhydride. The challenges of developing this synthesis into a robust and practical manufacturing route are described.