Herein are described improvements in a discovery synthesis to enable a rapid scale up of 1 to support early phase clinical trials and formulation development studies. Process modifications included route redesign, simplifying a Mitsunobu reaction product's isolation, improving yields and impurity profiles for isolated intermediates, and removal of a chromatographic purification. Particle engineering studies identified a recrystallization protocol to produce 1 with enhanced solid-state properties. This improved process was scaled up to generate multikilogram quantities of drug substance with >99.8% area purity.

Three simple methods are presented for predicting particle size distribution (PSD) percentiles when subjecting a pharmaceutical crystallization wet-milled slurry to a single temperature cycle for two of Biogen’s drug substances. The methods are (I) a mathematical manipulation of the wet-milled PSD based on particle death during dissolution; (II) a linear empirical model fit of product PSD percentiles as a function of the wet-milled PSD percentiles and the amount of material dissolved; and (III) a nonlinear model fit to the change in PSD as a function of the amount of material dissolved and the particle surface area/volume ratio. The three methods were verified on production scale batches. Method II’s approach was also used for particle size control during manufacture by implementing a temperature solved from the model using the batch’s wet-milled particle size percentiles and a final target size. Method III was found to be the most accurate at prediction because it models particle surface area to volume ratio influencing crystal dissolution and growth rates. Method II was found to be not as accurate as method III; however, it was easily implementable during process control at the production scale. Method I provided the quickest estimate of final particle size using only the initial PSD and a solubility expression. Method III was recommended for best particle size prediction.

PURPOSE:To utilize a particle engineering strategy to improve the manufacturability of a cohesive and poorly compactable API at high drug loading for direct compression of mini-tablets.METHODS:A high-shear mixer was used for wet milling during the API manufacturing process to obtain target particle size distributions. The targeted particles were characterized and formulated into blends by mixing with excipients. The formulated blends were compressed directly into mini-tablets using a compaction simulator. The tablet hardness, weight variation, and friability of the mini-tablets were characterized and compared with mini-tablets prepared with hammer milled APIs.RESULTS:Compared to the hammer milled APIs, the wet milled APIs, had smoother surface, narrower particle size distributions and demonstrated a better flow properties. Moreover, the mini-tablets produced with the wet milled APIs exhibited better weight uniformity, robust tablet mechanical strength and ultimately better friability. In addition, unlike the hammer milled process, the wet milling process is controllable and easy to scale up.CONCLUSIONS:This study successfully implemented API particle engineering through a high shear wet milling process to produce particles suitable for robust drug product manufacturing.

Precompetitive collaborations on new enabling technologies for research and development are becoming popular among pharmaceutical companies. The Enabling Technologies Consortium (ETC), a precompetitive collaboration of leading innovative pharmaceutical companies, identifies and executes projects, often with third-party collaborators, to develop new tools and technologies of mutual interest. Here, we report the results of one of the first ETC projects: the development of a user-friendly population balance model (PBM)-based crystallization simulator software. This project required the development of PBM software with integrated experimental data handling, kinetic parameter regression, interactive process simulation, visualization, and optimization capabilities incorporated in a computationally efficient and robust software platform. Inputs from a team of experienced scientists at 10 ETC member companies helped define a set of software features that guided a team of crystallization modelers to develop software incorporating these features. Communication, continuous testing, and feedback between the ETC and the academic team facilitated the software development. The product of this project, a software tool called CrySiV, an acronym for Crystallization Simulation and Visualization, is reported herein. Currently, CrySiV can be used for cooling, antisolvent, and combined cooling and antisolvent crystallization processes, with primary and secondary nucleation, growth, dissolution, agglomeration, and breakage of crystals. This paper describes the features and the numerical methods of the software and presents two case studies demonstrating its use for parameter estimation. In the first case study, a simulated data set is used to demonstrate the capabilities of the software to find kinetic parameters and its goodness of fit to a known solution. In the second case study, the kinetics of an antisolvent crystallization of indomethacin from a ternary solvent system are estimated, providing a practical example of the tool.

This chapter describes the research program that led to the discovery of vixotrigine, a use-dependent voltage-gated sodium channel blocker designed to deliver an improved safety profile. The properties that led to the selection of this candidate molecule are discussed. The choice of initial synthetic strategy and the development of an early scalable synthesis are examined. Further development of a more efficient process and the incorporation of green chemistry principles to successfully prepare for commercial utility are described.

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 required to meet the supply needs for formulation optimization, phase 3 clinical trials, and registration stability batches (this is the expected commercial formulation). In this article, we describe how the process was streamlined from the early supply route (Giblin, G.; et al. Org. Process Res. Dev.2020, DOI: 10.1021/acs.oprd.0c00382) and a comprehensive control strategy was established. Process improvements included improving safety and scalability for a temperature-sensitive Grignard reaction, simplifying unit operations, removal of heterogenous conditions, and route redesign to afford a high yielding, one-pot sequential alkylation and amidation. Improvement in the salt formation step, combined with wet milling, resulted in improved particle properties with enhanced flow properties of the final active pharmaceutical ingredient. The process mass intensity was improved 65% while maintaining drug substance purity at more than 99.8%. This new process has been scaled up to generate metric ton quantities of drug substance.

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 properties of the drug substance highlights the importance of not only understanding the crystallization process and form landscape but also the ability to implement systematic characterization to identify key powder properties of drug candidates early in the drug development process.

Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D50 = 24 μm) and particle engineered wet milled API (D50 = 70 μm and 90 μm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ffc < 4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ffc > 10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized.

Enteric coated active pharmaceutical ingredient (API) particles can provide advantages in clinical and pre-clinical formulation development targeting intestinal drug release over traditional tablet and capsule formulations. The challenge with this approach is developing a robust coating process to achieve sufficient gastric protection and efficient intestinal release on micron sized particles. A Würster coating fluid bed process to directly produce enteric coated API particles was developed at a 650g scale and was scaled up to 20kg. Generating API with low 3-dimensional aspect ratio structure was critical for this process and was achieved through a wet milling process. The starting particle size had D50~90μm, and the D50 of the resulting coated particles could be as small as 180μm. Scanning electron microscopy imaging and dissolution testing were used to characterize the properties of the enteric layer on the API particles as a function of coating thickness. Coated API particles achieved up to 8h enteric protection in the gastric environment and rapid release in the intestinal environment.

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 degrees 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 mm. 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 the results of this study will be presented.