A strategy for the rapid, material-efficient development of crystallization processes centred around the use of process analytical technology (PAT) is presented and demonstrated on an active pharmaceutical ingredient (API) currently in development at Pfizer's Sandwich laboratories. PAT is implemented at scales as small as 1 mL in high-throughput equipment, enabling the early acquisition of key data to select the best crystallization approach. At a larger scale, PAT offers a window into process kinetics and, for the case study discussed in this contribution, highlighted vulnerabilities of the process arising from the formation of a labile solvate. A combination of online and off-line analyses provided the basis for a full assessment of the process.

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[reaction: see text] The enantiomeric excess of three different asymmetric catalyses has been predicted in excellent agreement with the experiments using a 3D-QSPR approach. In particular, GRid INdependent Descriptors generated from molecular interaction fields together with a simple partial least-squares method were found to be adequate to describe the enantioselectivity induced by these metal-ligand complexes.

The heat of reaction is an important parameter in the safe, successful scale-up of chemical processes. Reaction heat data is used to calculate the potential adiabatic temperature rise of the desired reaction, providing a worst-case scenario for rapid reaction of the entire batch with no heat loss to the surroundings. The data is used in parallel with information regarding the thermal stability of reaction mixtures/components and an intimate knowledge of the process to analyze the risk associated with running it on-scale. If the level of risk is judged to be unacceptable, the analysis can be used to make rational process changes in order to reduce the risk to an acceptable level. The Pfizer global process safety network provides a heat of reaction for all processes run in our kilo laboratories, pilot plant, and manufacturing facilities. In general, there are two methods used to determine reaction heats: (1) experimental measurement using some form of calorimetry, or (2) estimation techniques. Since experimental measurement is not always practical, accurate, or necessary, we set out to show that estimation techniques could be used reliably and efficiently to provide heat of reaction data for a wide range of chemistry. To gain confidence in our ability to accurately predict reaction heats, we carried out a comparative study of measured versus estimated values. The results of this study will be discussed in detail, including rationalization of any significant disparity through further analysis to more fully understand the limitations/advantages of both techniques. To help ensure consistent application of measurement/ estimation across the Pfizer global process safety network, we developed a decision tree to determine whether estimation or measurement should be considered for a particular reaction. In order to maximize the efficiency gain and to ensure accuracy in our estimations, we have created a heat estimation database that allows for (1) rapid archival/retrieval of model compounds, (2) calculation of reaction heat and adiabatic temperature rise, and (3) reporting/documentation of the results.