Perfecting solvent swap processes with refractive index trend data

This blog is first in a three-part series on how in-line process refractometers can optimize API processes.

The creation of Active Pharmaceutical Ingredients (APIs) is a critical part of pharmaceutical production. API formulation typically begins with loading chemicals into a reactor where chemical bonds are broken, and new bonds formed. After reaction, the active ingredient is separated through downstream purification steps, such as centrifugation and filtration. Typically, the API is recovered as a solid from the liquid phase and the solvent used is recovered in dedicated solvent recovery units.  Solvent recovery is important in the pharmaceutical industry because it helps to reduce costs and environmental impact. The final API solid is then dried before it can be used as an intermediate or to formulate the final drug product.

Developing and optimizing pharmaceutical manufacturing processes can be a complex and lengthy process, taking several years to complete. In order to streamline these processes and bring drugs to market faster, it is important for pharmaceutical companies to focus on creating efficient processes that are scalable and reproducible at a commercial scale. The implementation of the FDA’s Process Analytical Technology (PAT) framework, including the use of in-line measurement instrumentation, offers a valuable opportunity for pharmaceutical process development and scale-up through the collection and analysis of data for process understanding, design and optimization. PAT tools help to ensure quality is integrated into the design and that processes produce products of consistent quality that meet the required specifications. 

Using refractive index as part of PAT

Refractive index (RI) has proven to be a useful Process Analytical Technology (PAT) tool for the development, design, and continuous optimization of API manufacturing processes. Continuous, in-line measurement of RI provides data and process insight that aids in understanding and designing different manufacturing steps. The data allows for the creation of process profiles that can be used for detecting deviations and ensuring process equivalence. The Vaisala refractometer provides trend data with the high reliability and reproducibility required in pharma manufacturing. Refractive index measurements are not affected by the presence of gas bubbles, solid particles, or color of the liquid. These features of refractive index make it ideal for many applications in the API manufacturing process.  

Refractive index is a fundamental physical property of liquids and is generally not dependent on the quantity of the sample measured. This simplifies scaling up processes from lab to pilot, and then to full scale production.  

Trend data is obtained in real time and can be compared to the design process profile obtained by RI, which determines process equivalence and aids in evaluating and determining other critical process parameters, tolerances, and optimal operating conditions. Furthermore, process profiles from RI data have aid in identifying problems during scale-up and for continuous optimization of existing processes. 

Optimizing solvent swap

Solvent swap, a common step in API production, aims to replace the original solvent from reaction, with a solvent more suitable for the next processing step. Solvent swap is typically done by distillation. During distillation, RI measurements are used to monitor top (post-condenser) and bottom product liquid concentrations, e.g., to ensure the correct concentration of API or solvent is obtained, to identify the right point for more solvent addition, and to reduce overall solvent consumption. During process development, RI can also be used to obtain important data for design such as vapor–liquid equilibrium (VLE) data. 

In-line measurements are also useful to identify problems in the process. For example, in one customer case, trend data from the Vaisala refractometer was used during process scale-up to establish process equivalence from two facilities (one in US and one in Europe) and the lab process profile. Thanks to the in-line data from the refractometer, this customer discovered that the US plant was not behaving as designed and required an additional swap step to achieve the same purity achieved in the design in the lab and the EU pilot facility. In this case, the RI trend data was an invaluable troubleshooting tool that helped ensure they could achieve optimal operating conditions in all facilities. 

By using refractive index measurements, our customer identified deviations from lab to pilot. They were then able to take immediate corrective actions, which led to savings in solvent consumption and increased product yield. The customer had used refractive index measurements from early stage in the laboratory in order to study the mixture, obtain VLE data and a process profile, and to design the swap process. Scaling up from lab to pilot was simplified by in-line refractive index measurements.

Refractive index measurements are a powerful PAT tool for the design, monitoring, and optimization of solvent swap processes, as well as a valuable trending tool for process insight and troubleshooting.