Enhancing bioavailability can be achieved through hot-melt extrusion (HME) or spray drying.
PTE: One tool for bioavailability enhancement is to create amorphous solid dispersions through processes such as hot-melt extrusion (HME) or spray drying. What factors come into play to decide whether to produce the amorphous solid dispersions through HME or spray drying?
Bend Research: Both spray drying and HME can be used to produce amorphous dispersions that enhance the bioavailability of poorly soluble compounds. There are a number of factors that come into play when deciding to progress an amorphous dispersion. These include performance, projected dose, stability and manufacturability. When choosing which technology to employ for optimising the amorphous dispersion formulation's performance, two key factors are the physical-chemical properties of the API and the phase of development, which influences the amount of API available for formulation development.
Datacraft Co Ltd/GettyImages
Important physical–chemical properties include the solubility of the API in either a solvent (for spray drying) or polymer (for HME), the melting temperature of the API and the LogP value of the API. For spray drying, the solubility of the API in the solvent is crucial to ensure a readily scalable and viable process, whereas for HME, the solubility of the API in the polymer is crucial to ensure a thermodynamically stable system. The particle size of the API, which influences the dissolution rate during processing, can also be crucial for complete dissolution into the polymer melt.
The processing temperature is important for HME because the API must either melt to form a dispersion or dissolve through high shear forces into the molten polymer. If the processing temperature is too high, the compound or the polymer used in the formulation can degrade. Typically, 200 °C to 225 °C is regarded as the upper processing-temperature limit for an effective HME process. Although compounds can be extruded at higher processing temperatures, this physical situation often produces a partially crystalline formulation instead of an amorphous dispersion.
The phase of development is also an important factor in process selection. For example, for early-stage or discovery-support activities, API availability is often limited. This limited API availability tends to make spray drying the preferable process because its feasibility can be determined with as little as 50 to 100 mg of API, whereas several grams of API are typically required to develop an initial HME process. For APIs that are amenable to HME, typically after proof-of-concept clinical studies, when hundreds of grams of API are available, an initial spray-drying process can be converted from spray drying to HME.
PTE: What are the advantages and disadvantages of using HME compared with spray drying to produce the amorphous solid dispersion?
Bend Research: HME has two primary advantages. First, no solvents are used, so solvent cost and recovery are not a factor in cost-of-goods or environmental health and safety considerations. Second, the equipment footprint for HME is relatively small when the process is scaled up.
The primary disadvantage of HME is that the compound must be melted or dissolved in molten polymer at high temperatures. Thus, it is less applicable to compounds with higher melting temperatures or those that are thermally labile. This disadvantage can be partially remedied by including nonvolatile and volatile plasticisers in the formulation, which lower the temperatures required to produce an amorphous dispersion. Because an ideal amorphous dispersion is homogeneous at the molecular level, a second disadvantage is that the homogeneity of the final dispersion can be affected by process parameters such as temperature, screw configuration, screw speed and feed rates; this aspect, combined with the relatively large minimum batch size, results in cost and risk during early development.
PTE: What are the advantages and disadvantages of using spray drying compared with HME to produce the amorphous solid dispersion?
Bend Research: Spray drying offers the following advantages: it is applicable to a broader chemical space for the API and types of dispersion polymers that can be used (due to dissolution of the API in a volatile organic solvent), it does not expose the API to excessive heat during manufacture of the amorphous dispersion and it can be scaled down, requiring smaller quantities of API during formulation screening.
Spray drying has a few disadvantages as well: solvents are used and must be recovered, equipment footprints are larger, and capital and operating costs are higher. These considerations must be taken into account when designing later-stage or commercial processes and facilities, but they are not insurmountable—as evidenced by successful operation of Hovione's PSD-4 and PSD-5 spray-drying facilities and the fact that spray drying is used extensively outside of the pharmaceutical industry at large scales.
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.
Spray drying and HME are readily scaled and commercial-scale equipment is available at many pharmaceutical organisations and several contract research organisations.
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.