Achieving desired bioavailability

PTE: Can you be specific in terms of achieving desired bioavailability/solubility of the resulting product, stability of the resulting product, the ease and/or scalability of the manufacturing process, and other process conditions that are important in deciding which approach to use?

Bend Research: As mentioned previously, both spray drying and HME can be used effectively to manufacture amorphous dispersions. A formulation produced by either process would be expected to yield similar bioavailability and physical stability as long as both processes yield a homogeneous amorphous dispersion with appropriate final-powder particle size, which generally requires milling for HME. If either of the processes fails to produce a homogeneous amorphous dispersion, the resulting formulation will likely underperform. This situation is most common when a compound fails to completely dissolve during the hot-melt-extrusion process due to either the high melting temperature of the compound, or the low solubility of the compound in the molten polymer, resulting in crystallisation or phase separation when the melt cools.

Recent advances

PTE: On an industry level, can you highlight recent advances in HME with respect to improvements in the manufacturing process and its application to different types of APIs?

Bend Research: HME is a technology that has been widely used in pharmaceutical and nonpharmaceutical industries for decades. Recent advances in HME include efforts to reduce processing temperatures by including plasticisers and reduce the residence time of the compound and polymer during processing. Numerous research groups are looking at nonvolatile plasticisers, such as vitamin E or triethyl citrate, to reduce processing temperatures. Others have reported the use of volatile excipients, such as supercritical carbon dioxide, to avoid decreases in the final dispersion's glass-transition temperature that occur with traditional plasticisers. There have also been recent reports of the use of equipment that has significantly reduced residence time. Professor McGinity's research group at the University of Texas has developed a process called Kinetisol to make amorphous dispersions. It is based on equipment that was developed to recycle plastics, which can reduce the residence time of the API and polymer at processing temperatures from minutes to tens of seconds.

PTE: On an industry-wide level, can you highlight recent advances in spray drying with respect to improvements in the manufacturing process and its application to different types of APIs?

Bend Research: While spray drying is a well-established process, innovations in formulation approaches and process equipment are occurring. In formulation, there is an increasing need for a third component in the dispersions to help deliver challenging compounds aimed at novel biological targets. Often, a surfactant is added to help increase the dissolution rate or dispersion-particle wetting or to provide an alternate micelle source to enhance drug solubility in vivo.

Equipment advances include novel spray-dryer and cyclone designs to collect the dispersion particles more efficiently. This is especially significant for particle-engineering applications such as inhalation, which requires the manufacture and collection of particles with a narrow particle-size distribution for delivery to the lung. As part of the effort to formulate compounds with low solubility in organic solvents, Bend Research has developed a "hot process," which allows a drug suspension to be heated to high temperatures—often well above the ambient-pressure boiling point of the solvent—in a heat exchanger to dissolve the drug immediately before it is introduced into the spray dryer. This decreases solvent use and results in a more scalable process.