(T1530-02-10) Spray Drying of Low Organic Solubility Pharmaceutical Compounds, a Vemurafenib Case Study

Purpose: Spray drying of amorphous solid dispersions (ASD) requires solubility of an active pharmaceutical ingredient (API) and polymer in an organic solvent system. As demand for compounds with low organic solubility increase, additional spray drying approaches are needed to reduce cost. Increasing a compounds organic solubility results in higher throughput, lower solvent usage and decreased production costs. Additionally, solvent choice is further limited due to environmental, health, and safety concerns. When APIs have insufficient solubility in typical solvent systems, novel approaches like high temperature spray drying can be used to enhance solubility (United States Patent No. US9248584B2, 2011). Using vemurafenib, a poorly soluble compound commercialized by a polymer co-precipitation method, this work aims to identify a suitable solvent for spray drying (Navit Sha, 2013). By screening a range of solvents and testing at elevated temperatures, two potential commercially viable spray drying approaches were identified, and used to produce small-scale amorphous solid dispersions.

Methods: Solubility of vemurafenib was measured in nine solvent mixtures at 25 °C. A single lead solvent was then selected to progress to heated process screening. Ambient Screening: 25 °C. API slurries were prepared in glass scintillation vials at 10 wt% solids in multiple organic solvent systems. The samples were held at 25 °C with constant stirring. After 2 hours and 24 hours, an aliquot was sampled into an Eppendorf tube, centrifuged, and added to a 70/30 acetonitrile/water mixture. The soluble fraction of the API was quantified using high performance liquid chromatography. Warm Screening: 15-60 °C. Vials were prepared at a range of API concentrations in the lead solvent system (90/10 acetone/water) and analyzed using Crystal 16 (Technobis). The vials were held at 15 °C for 30 minutes, heated to 54 °C at a rate of 0.5 °C/min, then held at temperature for 30 minutes. The material is visually observed during the 15 °C and 54 °C hold portions to check for solids. Solubility was determined by the clear point measured in the software. High Temperature Screening: 40-130 °C. API slurries were prepared at eight varied concentrations in pressure reaction vials (Synthware 1- mL vials). These were placed into an IKA heated dry block and visually assessed from 40-130 °C in 10 °C increments. Vials were equilibrated for 5 minutes at each temperature before observation. Solubility of the material was determined when the solution was visually clear. Spray Drying. Vemurafenib was spray dried using the same formulation as is commercially available, vemurafenib/HPMCAS-L (40/60). A custom lab-scale spray dryer with 35 kg/hour drying gas capacity was used to produce 10 g batches. Control formulations were sprayed from tetrahydrofuran (THF) to compare with those produced using super-heated solvent. Spray drying from heated 90/10 acetone/water was performed by feeding a suspension of undissolved API with dissolved polymer from a continuously stirred vessel to an in-line heat exchanger. Material was further dried in a vacuum oven at 40 °C with a nitrogen sweep to remove residual solvent. The amorphous state of the material was verified by powder x-ray diffraction using a Rigaku (MiniFlex 600). Material was placed in a 0.2 mm zero background holder and analyzed from 3-40 °2θ

Results: At ambient temperatures, vemurafenib was soluble in 95/5 THF/Water at 9.9 wt% and 90/10 acetone/water at 1.2 wt%. Additional solubility studies were conducted in 90/10 acetone/water at elevated temperatures. Warming the solution temperature but remaining below boiling point had minimal solubility enhancement. However, the solubility of vemurafenib increases significantly at super-heated temperatures, reaching 10.5 wt% at 130 °C. This provides an additional option for commercial-scale spray drying, utilizing a high temperature process. Formulations containing 40/60 Vemurafenib/HPMCAS-L SDD were successfully manufactured from both lead solvent systems. The SDDs appeared amorphous using x-ray diffraction and had no signs of degradation by HPLC. After secondary drying, spray dried materials were analyzed using gas chromatography to determine residual solvent content. Acetone was sufficiently removed from the powder, but THF remained at unacceptable levels. THF is an ICH class 2 solvent and has limit of 720 ppm, residual solvent was measured at 7260 ppm.

Conclusion: Using high temperature spray drying, vemurafenib was successfully manufactured as an amorphous solid dispersion out of a 90/10 acetone/water system. This provides a viable process with continuous manufacturing capabilities as an alternative to a co-precipitation batch process. While a THF/water solution also had sufficient solubility, uninhibited THF is not commercially available in large quantities, and it is difficult to secondary dry to safe levels. High temperature spray drying is a more complex technique but can be used to progress compounds that have been historically unsuitable for spray drying. By screening ambient and high temperature processes, the most efficient, sustainable, and commercially relevant technology can be nominated.

References: Ahmad Ziaee, A. A. (2019). Spray drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches. European Journal of Pharmaceutical Sciences, 300-318.
Millard, D. T. (2011). United States Patent No. US9248584B2.
Navit Sha, R. I.-J. (2013). Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorhpous Polymer Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipiration Process. Journal of Pharmaceutical Sciences, 967-981.

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Measured solubility of Vemurafenib at ambient temperature

Measured solubility of Vemurafenib with temperature increase