(130e) Advancing Spray Drying Process Capabilities for Low Solubility Drug Compounds By Leveraging Temperature-Shift Solubility Enhancement: A Case Study with Alectinib

Purpose: Amorphous solid dispersions can provide bioavailability enhancement to active pharmaceutical ingredients with low aqueous solubility, which enables oral delivery. A spray drying process is a scalable technique for manufacture of amorphous solid dispersions. Manufacturing spray dried dispersions (SDDs) provides opportunities for particle engineering to optimize quality attributes such as flowability, compactibility, dissolution rate and drug release profiles that can be essential to drug product development. One of the limiting factors that can impact the SDD formulation and process is a drug’s solubility in organic solvents. Low drug solubility in organic solvents can have several process and product impacts that can make an SDD challenging as a lead formulation technology, including: low throughput, large batch size and non-optimal powder properties (e.g. particle size and bulk density). One novel technique to overcome the organic solubility limitation is to take advantage of the temperature-shift solubility enhancement. Achieving rapid drug dissolution from short term heating of a spray drying solution requires consideration to the drug’s chemical stability and modification of the processing equipment to solubilize the drug in an inline heat exchanger followed by flash atomization, which utilizes vaporization and solvent cavitation for droplet formation. Here, we discuss the technical considerations of developing such a process for an SDD of Alectinib, a BCS class II oral dosage oncology drug.

Methods: The solubility of Alectinib was first determined as a function of temperature. Two small-scale techniques were compared: 1) High temperature NMR, and 2) thermogravimetric analysis (TGA). The solubility improvement at the selected temperature was then investigated using a high pressure solution vessel with a sight glass to visually confirm solubility. Lastly, two internally-developed models were used to optimize a PSD-1 spray drying process: 1) an in-line heat exchanger model to tune flow rate and temperatures required for heat and mass transfer and 2) a spray drying thermodynamic model to predict drying gas inlet and outlet temperatures. The temperature-shift SDD was then characterized using DSC, XRPD and dissolution testing to compare the performance relative to crystalline drug. A control SDD was manufactured by a standard spray drying process using a dilute, ambient-temperature spray solution for further comparison.

Results: High-throughput solubility screening using a TGA method at 25°C and 37°C showed that a 90/10 methanol/water solvent system provided the highest temperature-shift advantage with a thermodynamic solubility of 0.4wt% at 25°C and 0.5wt% at 37°C. High temperature NMR enabled solubility measurements up to 120°C and demonstrated an increase to 1.2wt% solubility at that temperature. Extrapolating the two-point TGA method to higher temperatures with the van’t Hoff relationship resulted in excellent agreement with the NMR solubility measurements in the anticipated operating range of 100-130°C, which was also confirmed by using a larger volume pressurized solution vessel. Improvements to the NMR solubility was also observed with the addition of dissolved HPMCAS-H. Successful manufacture of amorphous SDDs was achieved on a PSD-1 spray dryer through a model-based process optimization strategy and demonstrated a 6x increase in API throughput using the temperature-shift process. Dissolution in gastric and intestinal media with varying micelle concentrations showed significant dissolution rate, extent and AUC improvements against pure crystalline material. No performance difference was observed between SDD manufactured using the inline heating process when compared to a dilute solution sprayed at room temperature

Conclusion: Utilizing the described temperature-shift process with a challenging low organic solubility drug compound provided significant throughput improvements while reducing spray drying energy requirements by enabling higher spray solution concentrations and reducing batch sizes. Further application of this process can provide continued cost reduction in the spray drying manufacturing process while promoting the advancement of research in critical areas including atomization, drying kinetics and drug/polymer interactions.