(130d) Heat Exchanger Model for Predicting Temperature and Dissolution of API for a High-Throughput Temperature Shift Spray Drying Process

The temperature-shift spray-drying process enables high-throughput, commercially relevant manufacturing of poorly soluble active pharmaceutical ingredients (APIs) in organic solvents by increasing API solubility by at least 10-fold relative to room temperature operation. In the temperature-shift technique, an in-line tube-in-tube heat exchanger rapidly increases the temperature of a spray suspension to fully dissolve an API immediately before entering the spray dryer. API dissolution kinetics are a key factor when designing the process and optimizing operating parameters. The temperature and residence time must be selected to create an operating space to allow for full dissolution without causing API degradation. A first-principles model was developed to provide guidance on the heat and mass transfer requirements to aid in experimental design. Temperatures of the solution flowing through the heat exchanger were measured, and the model was found to accurately predict the heat transfer. Additional experiments were done with a model compound to assess the dissolution model and were also found to be in good agreement. This tool will help improve thermal shift spray drying process development and process parameter optimization to achieve the desired product quality more efficiently.

Methods:

A scale-independent model to describe both heat and mass transfer was developed using first principles approaches. To develop a heat transfer model, we employed an energy balance across the heat exchanger and then evaluated typical heat transfer correlations and dimensionless numbers. These correlations from literature were found to be applicable to our physical situation. This approach allowed calculation of the temperature profile of both the hot and cold sides of the tube-in-tube heat exchanger as a function of length.

Dissolution of an API was modeled using the Noyes Whitney Equation. By knowing the temperature profile of the heat exchanger, the concentration of dissolved drug was determined based on the changing solubility of the API as a function of temperature. Additionally, fundamental parameters like the diffusion coefficient and solution viscosity were also allowed to vary as a function of temperature leading to a good approximation of the physical properties of the suspension during dissolution in the heat exchanger.

An experimental set-up was fabricated to measure the temperature of the inlet and outlets of both the hot and cold streams. Initial trials were completed testing ranges of temperatures, flowrates, and heat exchanger geometries using water as a test fluid. To further test the heat transfer model, placebo spray drying experiments using the dispersion polymer HPMCAS were conducted on a clinical scale dryer with a water-acetone mixture. HPMCAS was tested at two solids loadings to see how solution temperatures with different viscosities were predicted by the model.

To evaluate the dissolution of an API through the heat exchanger, Riboflavin was used as a model compound. An in-line UV probe was used to determine the effective concentration in solution as a function of heat exchanger residence time across a range of flowrates.

Results:

The temperatures of the tube side are predicted with less than 5% error compared to experimental data spanning small scale feasibility to large commercial scale for water, solvent, and polymer solutions. Dissolution of Riboflavin in water was predicted with good accuracy over the flowrates tested at small scale.

Conclusions:

The model was found to accurately describe the heat and mass transfer for this novel rapid heating spray drying process. This can be used for better designing DOE studies to understand the operating space with respect to drug dissolution and degradation. Future work will focus on better understanding this sensitivity of API dissolution kinetics during the temperature shift process.