Automated Lab Reactors and In-situ Sampling for Data-Rich Experiments
Jurica, J. A., & McMullen, J. P. (2021). Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development. Organic Process Research & Development, 25(2), 282–291.
This article presents a compelling case for using data-rich experimentation (DRE) to fully characterize reactions while mitigating the effect of potentially competing objectives in later stages of pharmaceutical development. DRE uses available technologies that provide extensive, real-time analytical data paired with modeling tools to thoroughly define reactions and processes. Because reactions often proceed non-linearly, collecting time-referenced analytical data across the duration of an experiment provides a more accurate view of reaction progress. Automated, in-situ sampling eases the experimental burden, enabling scientists to easily obtain this data and maximize the amount of knowledge gained from each experiment.
In this study, an automated benchtop reactor (EasyMax 102 synthesis workstation) with accompanying autosampler (EasySampler 1210) was used to support late-stage process characterization studies of a cyclization reaction. The data-rich experiments were structured according to a 24 full factorial design of experiment (DoE), with 12 reaction samples taken at equal time intervals over the course of each 22-hour experiment. While EasyMax provided precise control over reactor conditions, EasySampler automatically extracted, quenched, and diluted reaction samples for HPLC analysis. The information obtained was then used to generate dynamic response surfaces for each response variable as well as model time-dependent competing conditions and trade-offs necessary for achieving both high yield and reaction stability. Using this combination of dynamic response surface methodology and DoE-driven data-rich process characterization allowed the authors to easily and quickly scan a large temporal design space, resulting in significant improvements in efficiency and experimental reproducibility when compared to conventional methods.
In-Situ FTIR Speeds Kinetic Analysis and Process Understanding
Yang, C., Feng, H., & Stone, K. (2021). Characterization of Propionyl Phosphate Hydrolysis Kinetics by Data-Rich Experiments and In-Line Process Analytical Technology. Organic Process Research & Development, 25(3), 507–515.
Enzymatic phosphorylation using propionyl phosphate (PrP) as a phosphate donor is a key step in the synthesis of an important active pharmaceutical ingredient (API). Using PrP as a phosphate donor offers benefits for downstream biocatalytic processing. However, it also presents challenges. Without careful process control, PrP hydrolysis can compete with the desired enzymatic reaction. The hydrolysis reaction is also temperature-dependent and cannot be easily stopped, making scale-up and monitoring via traditional offline analytic tools, such as HPLC, difficult. FTIR-based process analytic (PAT) technology offers a viable alternative and has been successfully used to monitor hydrolysis reactions in-situ.
In this study, in-situ FTIR spectroscopy of a repeated temperature scanning (RTS) experiment was used in conjunction with computational modeling to develop a cost-efficient, robust approach to characterizing propionyl phosphate hydrolysis reaction kinetics. ReactIR was used to monitor the extent of a single PrP hydrolysis reaction carried out in an EasyMax 102 advanced thermostat system. Offline NMR analysis of seven samples taken during the reaction was used to calibrate the rich in-situ FTIR dataset (~3000 data points). The resulting concentration profiles and temperature data were then fit to a first-order kinetic model using Dynochem modeling software, reporting two key kinetic parameters for PrP hydrolysis for the first time. The activation energy at near neutral pH was found to be 107.2 kJ/mol, and apparent rate constant at 33 °C was 0.0721 h−1. Dynochem was further used to simulate reaction performance and aid in developing process control strategies to mitigate risk. The authors conclude by stating that data-rich experimentation (DRE) using a modified RTS method and real-time, in-situ PAT reaction monitoring can provide the information required to produce quantifiable reaction kinetics and speed process understanding in a single well-designed experimental run.
In-Situ Raman, FTIR, FBRM and Particle Size Image Analysis Provide the Information to Optimize Crystallizations
Gao, Y., Zhang, T., Ma, Y., Xue, F., Gao, Z., Hou, B., & Gong, J. (2021). Application of PAT-Based Feedback Control Approaches in Pharmaceutical Crystallization. Crystals, 11(3), 221.
Precise control of crystallization processes regulates polymorphs, crystal shape, size, and size distribution of the final crystal product. Process analytical technology (PAT) has become an important platform for enabling data-driven process development for the control of crystallization processes. This article summarizes the recent development of PAT in the crystallization field with a particular focus on the application of model-free feedback control based on information collected by online monitoring technologies.
The authors provide a detailed discussion of several different model-free strategies using real-time PAT that have been applied to various crystallization processes resulting in improved particle size distribution, polymorph control, and product quality. These include:
- Supersaturation control (SSC)/concentration feedback control (CFC) for cooling and dissolution of crystals on lab and manufacturing scales using FTIR-ATR and UV/Vis – ATR
- Direct nucleation control (DNC) based on particle count in solution via FBRM
- Polymorph concentration control (PCC) applying in-solution, Raman-based polymorph measurement
- Image analysis based direct nucleation control (IA-DNC) to monitor particles in solution
- SSC-DNC combined with the mass-count (MC) method is performed using ATR-FTIR and FBRM
- Active polymorphic feedback control (APFC) using Raman and ATR-UV/Vis spectroscopy in combination
PAT Provides In-Situ Analysis in Integrated Continuous Manufacturing System
Testa, C. J., Hu, C., Shvedova, K., Wu, W., Sayin, R., Casati, F., Halkude, B. S., Hermant, P., Shen, D. E., Ramnath, A., Su, Q., Born, S. C., Takizawa, B., Chattopadhyay, S., O’Connor, T. F., Yang, X., Ramanujam, S., & Mascia, S et al. (2020). Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study. Organic Process Research & Development, 24(12), 2874–2889.
The batch-wise approach to manufacturing traditionally used in the pharmaceutical industry poses many challenges ranging from technical disadvantages to quality control issues to supply chain vulnerabilities. Integrated continuous manufacturing (ICM), which uses a series of integrated unit operations to streamline production, has gained recent interest as an alternative. ICM systems use control systems that are model-based and are equipped with various process analytical technology (PAT) capabilities. This work reports the development of an end-to-end ICM pilot plant that produces both active pharmaceutical ingredients (API) and tablets of a marketing generic drug.
PAT probes were installed to provide real-time testing and verify adherence to quality objectives in four out of processing six units. ParticleTrack (FBRM) and ReactIR in-situ probes were used in the reactive crystallizer to measure chord length distribution (CLD) and determine reactant concentration and reaction yield. FBRM and IR were similarly placed in the resuspension unit to determine API crystal chord length distribution and reactant/solvent content in the slurry. Other PATs in the system included near-IR probes to measure residual solvent contents after drum drying and determine content uniformity of the API in the polymer melt. Raman probes aided in determining crystal form/crystallinity in two different locations and a laser diffraction system measured API particle size distribution after drying.
The success of the pilot plant at production in specification API and tablets demonstrates how real-time PAT can be used in conjunction with integrated system control to improve efficiency, reduce energy consumption, decrease inventory levels and lead time, and lower capital investment (~90% in this example).
Calorimetry Ensures Reaction Safety and Improves Product Quality
Agosti, A., Panzeri, S., Gassa, F., Magnani, M., Forni, G., Quaroni, M., Feliciani, L., & Bertolini, G. (2020). Continuous Safety Improvements to Avoid Runaway Reactions: The Case of a Chloro-Thiadiazole Intermediate Synthesis toward Timolol. Organic Process Research & Development, 24(6), 1032–1042.
One of the most fundamental parameters that can be monitored and provide process-knowledge at all stages of development is temperature. While not often discussed in the context of process analytical technology (PAT), calorimetry provides valuable data and reaction understanding needed to safely and effectively design and control process thermodynamics. In this study, calorimetric investigation of an existing process revealed previously unknown safety concerns. Using the information gained, researchers were able to modify the process to reduce heat-related safety risks while simultaneously improving reaction yield and product quality.
The long-running procedure used to generate an intermediate in the synthesis of Timolol, a beta blocker introduced to the market in 1978 to treat glaucoma, presented several safety concerns. The protocol for converting 3,4-dichloro-1,2,5-thiadiazole (DCTDA) to a morpholine-adduct included exothermic reaction steps and was run neat (no additional solvent is used). To assess risk, the authors ran the reaction under conditions close to triggering a potentially dangerous runaway reaction. Differential scanning calorimetry was used to investigate the thermal stability of reagents and products and better define the level of risk. Preliminary reaction calorimetry experiments performed on a small scale in an EasyMax HFCal (100 mL) helped to identify at what point a loss of cooling would cause the reaction temperature to rise and trigger decomposition. The reaction proved to be highly exothermic in a cooling failure scenario. Additional experiments carried out on a larger scale in an OptiMax HFCal (1 L) provided further insight into potential decomposition and helped identify experimental parameters (e.g., stir rate, solvent environment, and order of reagent addition) that resulted in a more thermally stable reaction with higher product purity.
PAT Enables Azeotropic Drying Process to Scale-up to Production
Dance, Z. E. X., Crawford, M., Moment, A., Brunskill, A., & Wabuyele, B. (2020). Kinetics, Thermodynamics, and Scale-Up of an Azeotropic Drying Process: Mapping Rapid Phase Conversion with Process Analytical Technology. Organic Process Research & Development, 24(9), 1665–1674.
Distillation processes with multiple solid-state phases and changing liquid-phase compositions can be difficult to understand and scale up due to the complex thermodynamics and kinetics involved. Scientists will often avoid using the most efficient process because of challenges in gaining the necessary information required to reproduce it. This study reports the development and implementation of an efficient distillation drying process using process analytic technology (PAT), offline analytics, process modeling, and benchtop experiments to gain the knowledge needed to successfully translate to manufacturing scale.
2′-C-methyluridine is a pharmaceutical intermediate that crystallizes from water, yielding a dihydrate solid that undergoes phase conversion to a hemihydrate solid or the desired anhydrous solid as a function of distillation drying parameters. The desired anhydrous solid is not stable in ambient processing conditions, making the process difficult to measure using traditional offline methods. To better understand the kinetics involved, the authors performed the distillation drying process in an automated OptiMax lab reactor equipped with multiple in-situ PAT probes. An in-situ FTIR spectrometer (ReactIR) was used to monitor the water content in the system in real time and Raman spectrometer was used to analyze the solid-state form. The data-rich information gained allowed for the construction of a process phase map and characterization of the kinetics of the form transformations between the dihydrate, hemihydrate, and anhydrous phases. With the thermodynamic and kinetic understanding achieved, the authors were able to successfully transfer the distillation process to isolate the desired anhydrous intermediate from the gram scale in the lab to the hundreds of kilograms scale at a production facility.