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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.

The final chemical transformation and isolation in the synthesis of an active pharmaceutical ingredient (API), referred to as the Pure Step, is often chemically simple but scientifically, operation...

Crystallization is the primary process used to purify synthetic drug substances and intermediates as well as to control bulk properties, including particle size, surface area, and flowability. Acco...

For drug substance manufacturing, it is necessary to have a robust crystallization process that can isolate quality active pharmaceutical ingredients with the desired crystal size distribution (CSD...

Amorphous solid dispersions are a promising option for managing compounds with poor aqueous solubility. However, for compounds with high melting points, thermal stability limitations, or poor solubility in volatile solvents, conventional routes of hot melt extrusion or spray drying may not be viable. Co-precipitated amorphous dispersions (cPAD) can provide a solution. For the material studied in this paper, the cPAD material that was seemingly identical to spray dried material in terms of being single phase amorphous (as measured by DSC and XRD ) but showed slower dissolution behavior. It was identified that physical properties of the cPAD material could be improved to enhance wettability and improve dissolution performance. This was achieved by incorporating the cPAD material into a matrix of water soluble excipients generated via evaporative isolation routes. Importantly, this approach appears to offer another route to further increase the drug load in final dosage units and is significant as increased drug loading generally results in slower or incomplete release. Results showed successful proof of concept via in vitro biorelevant dissolution and confirmatory canine pharmacokinetic studies yielding comparable exposure for capsules comprised of conventional spray dried material as well as capsules with elevated drug load comprised of cPAD hierarchical particles.

Direct compression offers a simple route to generate pharmaceutical dosage units and is core to the growing arena of continuous manufacturing. However, direct compression can be untenable for some active materials. This paper will outline three specific challenges API's can present to direct (active pharmaceutical ingredients) compression. The first involves API's having exceedingly high aspect ratio ("needles") or small particle size resulting in low bulk density and poor flow properties. Two additional cases are relatively newer challenges to direct compression driven by the growing need for solubility enhancing formulations, and involve nano-crystalline materials and spray dried amorphous dispersions. Multiple approaches for managing high aspect ratio or micronized API's have been implemented during the crystallization process or via particle coating downstream from API isolation. Fewer options have been reported for the successful conversion of nano-crystalline materials or spray dried amorphous dispersions into materials amenable to direct compression as these materials offer another specific set of challenges. One route that has not been explored that stands to allow continuous drug product processing across a broader product portfolio involves evaluating opportunities at the drug substance/drug product interface. Here, the options achieved through targeted introduction of excipients to the drug substance processing steps during product precipitation and/or isolation from a product slurry are discussed. This approach introduces new opportunities for designing multicomponent particles through productive and inherently continuous processes. This also offers a longer-term potential route to integrate across continuous drug substance processing to continuous drug product processing.

A shift in particle size distribution toward smaller particle sizes has been observed in batches of Compound A Triethanolate, an isolated intermediate of a commercially available active pharmaceutical ingredient, leading to poor deliquoring of the filter cake and longer filtration times, which compromised the overall process cycle time. In the most extreme case, product breakthrough during filtration was observed, leading to significant yield loss. Compound A Triethanolate is crystallized through antisolvent addition/distillation/cooling crystallization in ethyl acetate/water/ethanol. Laboratory experiments were carried out using representative product streams in order to identify the cause for the shift in particle size distribution, which could be attributed to excessive secondary nucleation at an early stage of the process caused by the use of seed particles that have been previously dried under agitation. While statically dried particles exhibit a smooth surface, the surface of particles dried under a...

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.

Rotor–stator wet mills are commonly used in the pharmaceutical industry to reduce particle size and normalize API physical properties as a means to facilitate downstream drug product operations and...

An automated crystallization platform enabled by FTIR and FBRM in combination with automation and chemometrics has provided a versatile tool for efficient crystallization process development. This system allows users to perform a “walkup” operation for routine process evaluation and also execute automated feedback control of crystallization based on a preset supersaturation profile via cooling and/or antisolvent addition. The concept, procedure, and benefits of the PAT-enabled crystallization platform are presented in general terms and then illustrated through several case studies where feedback control is applied to cooling, antisolvent addition, and “fed batch” (hot batch solution charged to lower-temperature seed bed) crystallization.

It is critical to consistently achieve the desired crystal form for an active pharmaceutical ingredient (API) because crystal form may affect the compound’s chemical stability, bioavailability, and pharmaceutical processing performance. The extent to which a crystallizing system is driven by growth vs nucleation is dependent upon the level of supersaturation, defined as the difference between solution concentration and solubility. We describe a method for the accurate measurement of real-time supersaturation, which enabled us to develop and optimize an API crystallization via a feedback-control loop based on concentration measurement with online FTIR. In this contribution we discuss a novel extension of the published work [Zhou, G. X.; et al. Cryst. Growth Des. 2006, 6, 892−898] which ensured robust isolation of the thermodynamically most stable crystal form of an API. The system of interest is a monotropic polymorphic system with overlapping metastable zones. In order to ensure exclusive isolation of the...