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Process analytical technology (PAT) applications pertaining to Pfizer's Flexible API Supply Technology (FAST) initiative.

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.

A highly scalable combined modular and 3D-printed falling film crystallization device is developed and demonstrated herein; the device uses a small, complex, printed overflow-based film distribution part that ensures formation of a well-distributed heated liquid film around a modular, tubular residence time/crystallizer section, enabling extended residence times to be achieved. A model API (ibuprofen) and impurity (ibuprofen ethyl ester) were used as a test system in the evaluation of the novel crystallizer design. The proposed crystallizer was run using three operational configurations: batch, cyclical batch, and continuous feed, all with intermittent removal of product. Results were suitable for intermediate purification requirements, and stable operation was demonstrated over multiple cycles, indicating that this approach should be compatible with parallel semicontinuous operation for intermediate purification and solvent swap applications in the manufacture of drugs.

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...

A low-cost, modular, robust, and easily customisable continuous liquid-liquid phase separator has been developed that uses a tubular membrane and annular channels to allow high fluidic throughputs while maintaining rapid, surface wetting dominated, phase separation. The system is constructed from standard fluidic tube fittings and allows leak tight connections to be made without the need for adhesives, or O-rings. The units tested in this work have been shown to operate at flow rates of 0.1 – 300 mL/min, with equivalent residence times from 80 to 4 seconds, demonstrating the simplicity of scale-up with these units. Further scale-up to litre per minute scales of operation for single units and tens of litres/minute through limited numbering up should allow these low cost concentric annular tubular membrane separators to be used at continuous production scales for pharmaceutical applications for many solvent systems. In principle this approach may be sufficiently scalable to be utilized in-line, in batch pharmaceutical manufacturing also, through further scale-up and numbering up of units. Several solvent systems with varying interfacial tensions have been investigated, and the critical process parameters affecting successful separation have been identified. An additively manufactured diaphragm based back pressure regulator was also developed and printed in PEEK, allowing highly accurate, adjustable, and chemically compatible pressure control to be accessed at low cost. Enterprise Ireland European Commission - European Regional Development Fund Science Foundation Ireland

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO...

Continuous crystallization has gained interest in the pharmaceutical sector as part of the drive toward the transition from exclusive batch manufacturing to integrated continuous manufacturing in this industry. As a result, the design and operation of continuous crystallization processes for the preparation of pharmaceutical materials has been featured strongly in recent scientific literature. This review is an effort to gather together all of the published understanding on continuous crystallization with a pharmaceutical focus and to benchmark progress to date in realizing the potential benefits of transitioning this stalwart pharmaceutical unit operation from batch to continuous configurations.

Chemically resistant parts for flow chemistry, with integrated mixing elements have been produced using the 3D printing process of fused filament fabrication, from poly(etheretherketone). Poly(etheretherketone) has greater chemical resistance than common fused filament fabrication materials such as acrylonitrile butadiene styrene, polypropylene, or even high-performance plastics like poly(etherimide), in addition to having superior thermal resistance and excellent mechanical strength. Printed reactors were demonstrated to be suitable for liquid–liquid extraction and flow chemistry and to be capable of withstanding pressures of at least 30 bar allowing superheated solvents to be used. Burst tests in simple geometries of 20 minute duration have indicated that increased operating pressures of up to 60 bar could be accommodated in future reactor designs. The ability to use fused filament fabrication for these reactors allows highly customisable, cost effective flow reactors and equipment to be fabricated on relatively inexpensive benchtop scale printers. X-ray microcomputed tomography was utilised to non-invasively image and verify the internal structure of the prints to ensure fidelity in reactor fabrication. This non-invasive method of equipment validation shows potential in helping to demonstrate regulatory compliance for bespoke additively manufactured components, for example in continuous pharmaceutical manufacturing where the methods and printer used in this work should be sufficient to produce, (continuous) manufacturing scale equipment. Enterprise Ireland Science Foundation Ireland Pfizer Inc.

A leading method for the crystallization of pharmaceutical compounds is to rapidly mix an antisolvent with a solvent saturated with the desired drug. Compared to cross-flow mixers, coaxial nozzles have negligible buildup of crystalline material on their surfaces and are less likely to plug. Rather than requiring moving parts, the inlet velocities of the input solvent and antisolvent streams provide the necessary mechanical energy for turbulent mixing. Computational fluid dynamics (CFD), micromixing modeling, and the population balance equation (PBE) are coupled in the simulation of coaxial nozzle crystallization of lovastatin-saturated methanol by intense mixing with the antisolvent water. The simulations show that flow rates of inlet streams have a profound effect on crystal size distribution (CSD), which is caused by different degrees of inhomogeneity in the supersaturation and nucleation and growth rates. Other important process parameters are pipe length of pipe downstream of the injection point and the inner and outer pipe diameters. To the authors' knowledge, this is the most detailed simulation study on coaxial crystallizers reported to date. The simulation results show the feasibility of tailoring a specific crystal size distribution by adjusting the operating conditions (such as inlet stream velocities) of the coaxial crystallizer.

This article describes a systematic approach used to streamline the process for the isolation of bosutinib monohydrate, a promiscuous solvate former. A thorough understanding of the complex solid form landscape was garnered, and this knowledge was used to develop a process that routinely delivered the correct solid form and excellent purity at the end of the last bond-formation step, without the need for additional recrystallization and/or solid form conversion steps.

The impact of hydrodynamics on agglomeration during the crystallization of an active pharmaceutical ingredient (API) was investigated. The type of agglomerate formed was experimentally observed to correlate with agitation level at the laboratory and kilo-lab scales. It was hypothesized that differences in agglomerate type were related to differences in the collision rate of primary crystals, caused by differences in the local degree of agitation (e.g., the local values of fluid turbulence dissipation rate, e). Spatial distributions of e were determined from computational fluid dynamics (CFD) models at process scales ranging from laboratory (200 mL) to commercial scale (875 L). Higher values of e were calculated for conditions shown to result in the formation of rounded, compact agglomerates, while at the lower values of e, looser agglomerates of flakelike particles were observed. Predictions for pilot-plant- and commercial-scale crystallization operating conditions were made using local e values as the sc...

We describe the synthesis, chromatographic purification, and isolation of the epothilone–folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10–30 g) of cGMP quality BMS-753493.

The process development and the kilogram-scale synthesis of BMS-688521 (1) are described. The synthesis features a highly efficient telescoped sequence which utilizes previously described spirocyclic hydantoin (4b) to produce the final intermediate via an SNAR reaction. A final deprotection step affords BMS-688521 (1) in high quality with an overall yield of 65% from the key intermediate, spirocyclic hydantoin (4b).

The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

A study of the process−property−performance relationship of a Bristol-Myers Squibb drug substance led to successful development of crystallization and drying processes that produce crystals with desired and consistent physical properties. A controlled crystallization technique was developed to obtain well-defined, large crystals with a narrow particle size distribution. This crystallization process provided a less compressible filter cake for effective cake washing and deliquoring and afforded an easily dried product with desired powder properties. To preserve the quality of the crystals during drying, a drying protocol using low shear agitation was developed. This protocol prevented crystal attrition during drying, which was shown to adversely affect the formulation process and, thus, drug product performance. API crystals prepared by this method consistently resulted in excellent formulation processing and drug product performance.

One of simplest Langmuir-Blodgett films is a stack of fatty acid layers bridged together by divalent cations. A certain fraction of fatty acids remain protonated, an amount dictated by aqueous subphase conditions during film deposition; these films are thus comprised of two components with different solubilities in organic solvents. We investigated the so-called skeletonization process that occurs when behenic acid multilayers are immersed in benzene. In particular, we used a quartz crystal microbalance to measure the loss of film mass and found that it agrees well with the amount of protonated acid in the original film. We also used the quartz crystal microbalance to investigate the equilibrium vapor sorption properties of unmodified films and compared them to those of skeletonized films. Both types of films take in nearly the same amount of water but absorb distinctly different amounts of selected organic vapors.

The properties and stability of confined Langmuir–Blodgett multilayers made of arachidic acid were investigated using the surface forces apparatus. Two different types of confined films were studied: one formed by bringing two separate LB films into molecular contact, the other formed by bringing one LB film into direct contact with mica. The measured thickness of confined material depends solely on the total number of trapped molecular layers (28 A/layer). The force required to separate the substrates, however, depends on the type of contact made. More force (equivalent to a work of adhesion of 36 mJ/m2) is required to separate an LB film from mica than from another LB film (28 mJ/m2). Applied stress impacts the integrity of the LB multilayers; the films are particularly vulnerable to the combination of shearing and tensile stresses. Microscopic changes in film structure are sufficient to generate anomalous behavior at the macroscopic level, namely pinning of the contact region despite changes in load exerted on the deformable interacting bodies.

The relationship between the mass uptake and the swelling of arachidic acid Langmuir-Blodgett (LB) films exposed to water vapor was investigated. Combining sorption data from the quartz crystal microbalance with swelling data from the surface forces apparatus (SFA), it was found that films exposed to water vapor ( approximately 75% RH) absorb 0.22 moles water/mole LB film with an associated swelling of 0.2 Å/film layer. This degree of film swelling is less than that predicted if the water taken up exhibits the molar volume of bulk liquid water. The configuration of the films in the SFA, where they are trapped between impermeable surfaces, makes possible the measurement of the lateral diffusion coefficient of water in these layered materials. This was found to be 1.5 x 10(-10) cm(2)/s, which is at least 100 times faster than diffusion normal to the layers as measured with the microbalance. Copyright 1999 Academic Press.