Advantages and disadvantages of each technique
PharmTech:
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 plasticizers 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.
PharmTech:
What are the advantages/disadvantages of using spray drying compared with HME to 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.
Achieving desired bioavailability
PharmTech:
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 HME process due to either
the high melting temperature of the compound, or the low solubility of the compound in the molten polymer, resulting in crystallization
or phase separation when the melt cools.
Spray drying and HME are readily scaled. Commercial-scale equipment is available at many pharmaceutical organizations and
several contract research organizations.
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