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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.

Selection of a diverse set of solvents is important for systematic investigation of polymorph landscape and quick identification of the stable polymorph. The diversity of selected solvents is usual...

This work studied a system of single stage mixed-suspension-mixed-product-removal (MSMPR) crystallization with particle breakage controlled by wet milling. Conventional single stage MSMPR crystallizer is limited by its degrees of freedom, which makes the process performance largely depend on steady state crystallization rate only tunable by residence time and supersaturation. Breakage brought by wet milling is demonstrated in this work as a supersaturation-independent variable to manipulate steady state conditions. The simulation results show that wet milling can act as a promising process intensification tool that increases process yield and broadens attainable region of particle size. Breakage model is adopted from dry milling and incorporated to high resolution finite volume population balance model. Four cases that cover a wide range of nucleation and growth rates have been tested, and the process yield and particle size are studied as functions of residence time and wet milling tip speeds.

The drying unit operation is used extensively in the pharmaceutical industry, but often a lack of understanding of the impact of the drying process parameters on active pharmaceutical ingredient critical quality attributes can create challenges during development. A working group within the Enabling Technologies Consortium identified common challenges in pharmaceutical drying development, including material constraints for scale-up studies and transferring to different equipment types and sizes. This manuscript surveys current practices within the industry for drying development related to chemical and physical stability, drying kinetics, and powder properties and highlights common development gaps for improving drying development workflows within the industry. The ultimate goal is to encourage further fundamental research and technological advancements for improving the drying development workflow.

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 convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

A practical, safe, and efficient process for the synthesis of PDE4 (phosphodiesterase type 4) inhibitors represented by 1 and 2 was developed and demonstrated on a multi-kilogram scale. Key aspects of the process include the regioselective synthesis of dihydrothieno[3,2-d]pyrimidine-2,4-diol 9 and the asymmetric sulfur oxidation of intermediate 11.

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and significantly improved the yield. To the best of our knowledge, this is the first example of flow iron-catalyzed Kumada cross-coupling reactions which addresses scale dependence issues which often plague Kumada reactions carried out in the traditional batch mode.

The IQ Consortium reports on the current state of process analytical technology (PAT) for active pharmaceutical ingredient (API) manufacturing in branded pharmaceutical companies. The article describes the application of PAT in manufacturing and provides representative examples in four common pharmaceutical unit operations: reaction and workup, crystallization, drying, and milling.

A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and initial mixing temperature are the critical parameters to minimize formation of byproducts and to get high reaction yield. Using a modular tubular flow reactor, the trans/cis-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate was obtained in 92% yield and isomerized under basic conditions to produce the trans-isomer in greater than 99% diastereomeric excess. Using this approach, the reaction yield was significantly increased compared to the batch process, and the robustness and reproducibility of this flow process was demonstrated for the synthesis of this key intermediate on a multikilogram scale.

A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig’s procedure.

A facile and economical five-step process for the synthesis of a sodium–hydrogen exchange type I inhibitor (NHE-1) was developed from readily available starting materials in 43% overall yield. Key transformations included a highly efficient copper-catalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts, a facile hydrogenation of 4-aryl dihydropyridines, a regioselective aromatic bromination, an efficient palladium-catalyzed carbonylation of aryl bromides, and a high-yielding acyl guanidine formation. A safe and scalable protocol for preparation of 2-trifluoromethyl phenyl Grignard reagent was developed, and a facile method for controlling the palladium content with N-acetyl-L-cysteine as the scavenger was demonstrated. Process issues in controlling the formation of a key diacylation side product during acyl guanidine formation are also addressed.

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C–H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

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.

In 2005, the American Chemical Society (ACS) Green Chemistry Institute (GCI) and global pharmaceutical companies established the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and engineering into the pharmaceutical industry. The Roundtable developed a list of key research areas in green chemistry in 2007, which has served as a guide for focusing green chemistry research. Following that publication, the Roundtable companies have identified a list of the key green engineering research areas that is intended to be the required companion of the first list. This publication summarizes the process used to identify and agree on the top key green engineering research areas and describes these areas, highlighting their research challenges and opportunities for improvements from the perspective of the pharmaceutical industry.

Pharmaceutical cocrystals could be used to improve the physicochemical properties of active pharmaceutical ingredients. Here, a practical solid form screen approach to identify pharmaceutical cocrystals in the early development stage is proposed. This approach first used a cogrinding screen to identify potential cocrystal former leads that could form cocrystals with the compound of interest, followed by a solvent-based screen to identify, evaluate, and generate the cocrystal candidates. This approach not only allows fast identification of the cocrystal candidates but also provides insights on their scalability. Using this approach for the development drug candidate, a glutaric acid cocrystal was identified that provided an improved intrinsic dissolution rate in comparison to that of the free form, and therefore this cocrystal is potentially a better solid form for development. The effects of solvents and structures of cocrystal formers on the cocrystal formation and the rationales for this approach are al...

We characterize the effect of adsorbed hydrophobically modified polymers (hm-polymers) on the dynamics of surfactant bilayers by small-angle neutron scattering and neutron spin-echo spectroscopy. Two kinds of hm-polymers, (a) hydrophobically modified poly(acrylate) with tetradecyl (C-14) sidegroups randomly grafted to the poly(acrylate) backbone and (b) poly(PEG(6k)-lysine-stearylamide) with equally spaced hydrophobes, are added to bilayers of penta(ethylene glycol) dodecyl ether (C12E5) and hexanol. Both bare and polymer-doped membranes exhibit a stretched exponential relaxation in the form of S((q) over bar ,t) 2; S((q) over bar) exp[-(Gamma(q)t)(2/3)], where S(q) is the static structure factor and Gamma(q) is the relaxation rate. The relaxation rate depends subtly on the surface coverage of polymer. At high surface coverage, polymer slows down the relaxation by 20%, whereas at low surface coverage, polymer enhances the rate relative to that of the bare membranes. Hindered flow of solvent through the adsorbed polymer layer at high coverage appears to explain the retardation. The faster dynamics at low polymer coverage may be due to stiffening of the membrane or lateral diffusion of the dilute adsorbed polymer chains.

We study the effect of hydrophobically modified polymers (hm-polymers) on the phase behavior and membrane elastic properties of the lyotropic lamellar (Lα) phase of the nonionic surfactant penta(ethylene glycol) dodecyl ether (C12E5). The hm-polymer is a model comb-graft polymer with monodisperse PEG blocks (loops) of 6, 12, or 35 kg/mol connecting C18 stearylamide hydrophobes. The polymer is of interest because both its loops and hydrophobes are biocompatible. The membrane properties are extracted from the small-angle neutron scattering data based on the model of Nallet et al. The monophasic Lα region exists over a narrower membrane volume fraction range but to a higher polymer concentration for hmPEGs with larger PEG spacers. The rigidity of the membranes increases by 40% with decreasing PEG spacer size from 12 to 6 kg/mol or increasing polymer concentration. For hmPEG polymers with 2−3 loops, the effect of finite chain lengths plays a role on the phase behavior and membrane properties.

Effect of blade number on the structure of the trailing vortex around the Rushton turbine impeller is examined by analyzing the data of mean velocities, deformation rates, turbulent kinetic energy and energy dissipation rates for 2-, 4-, 6- and 8-straight blades disk turbine impellers in a baffled standard geometry stirred tank. The data of Sauter mean bubble diameter near the blade tip are combined with the turbulent characteristics around the vortex to discuss how the blade number and the strength of the vortex affect the performance of the gas dispersion around the Rushton turbines under a low gassing rate. The results of this analysis show that if power input per each blade is the same, the impeller having four blades not only has the strongest average mean deformation rates and the largest turbulent kinetic energy, but also disperses the smallest average bubbles under the same gassing rate. On etudie l'effet du nombre de pales sur la structure du vortex de traǐnee autour de la turbine Rushton en analysant les donnees de vitesses moyennes, de vitesses de deformation, d'energie cinetique turbulente et de taux de dissipation d'energie pour des turbines a disque a 2, 4, 6 et 8 pales droites dans un reservoir agite a contrepales classique. Les donnees du diametre de bulle moyen de Sauter pres de l'extremite de la pale sont combinees aux caracteristiques turbulents autour du vortex pour analyser comment le nombre de pales et la force du vortex influent sur la performance de la dispersion de gaz autour des turbines Rushton a une faible vitesse de gazage. Les resultats de cette analyse montrent que si la consommation de puissance pour chaque pale est la měme, la turbine a quatre pales non seulement a les plus grandes vitesses moyennes de deformation moyenne et la plus grande energie cinetique turbulente, mais egalement qu'elle disperse les plus petites bulles moyennes a la měme vitesse de gazage.

The effects of polymer concentration, polymer molecular weight, and hydrophobe substitution level of modified poly(acrylic acid) polymers on the formation, size, and viscoelastic properties of shear-induced multilamellar vesicles (onions) are studied by rheology and light diffraction. The onions are close-packed, space-filling vesicles formed by shearing aqueous lamellar phases of C12E5 surfactant to produce phases with sufficient order and size uniformity (O(1-3 microm)) to diffract light. The addition of hydrophobically modified polymers enhances the rate of formation, uniformity, and stability independent of hydrophobe substitution level. Onion size decreases with increasing shear rate as observed for pure surfactant onion systems, but the shear-rate dependence is changed by the polymer. The onion phase has a plateau modulus that increases with polymer concentration but is independent of hydrophobe substitution level or molecular weight. The model presented by Panizza et al. that relates the plateau modulus of the onion phase to membrane rigidity and the compression modulus is consistent with independent measurements of membrane properties from SANS.

We study the statics and dynamics of surfactant bilayers made of penta-(ethylene glycol) dodecyl ether (C12E5) and hexanol molecules and the effect of the addition of adsorbed hydrophobically modified (hm) poly(acrylate) with C14 sidegroups randomly grafted by small angle neutron scattering (SANS) and neutron spin echo (NSE) spectroscopy. The rigidity and layer compression modulus of the surfactant membranes increase with membrane volume fraction and the addition of hydrophobically modified polymers. The relaxation of the single bilayer depends on the membrane volume fraction that deviates from what single membrane theories predicted. Polymer doping slows down the membrane relaxation and the effect is more prominent for large Q in which the dynamics of the single bilayer is probed.