PTE: What factors determine particle size? What are the differences in particle size achieved through jet-milling, wet polishing,
and nanoparticle generation?
Minchom: Particle-size reduction is not a simple phenomenon. The mechanism of generating the material of the prescribed particle size
has a profound effect upon a range of physical properties that may have a significant effect on the resulting pharmaceutical
behaviour. The final particle size of a material subjected to a comminution process is dictated by particle attributes, such
as crystal hardness, morphology and original crystal size, as well as the size-reduction method and energy applied. Jet-milling
and wet polishing may generate materials with equivalent median particle sizes; however, the resulting span from jet-milled
material is likely to be wider than the wet-polished material. Amorphous material and highly reactive surfaces also may result
from jet-milling while a higher level of crystallinity is maintained with wet polishing.
Dry methods, such as jet-milling, tend to be more cost-effective (mainly because they do not require sophisticated isolating
techniques), but they are more aggressive, less reproducible and more limited in terms of the achievable size reduction.
Amorphous solid dispersions
PTE: What factors determine which method (i.e., spray-drying, HME, spray-congealing and inclusion-complexation generation) to
use to produce the amorphous solid dispersion?
Minchom: Amorphous solid dispersions represent a tremendous opportunity for solubility enhancement of oral drugs. The resulting supersaturation
levels (and hence bioavailability) and the physical stability of the final dosage form, however, depend on the manufacturing
method applied. Many approaches are available to generate amorphous solid dispersions.
Spray-drying, being a solvent method, is the most versatile technique to obtain solid dispersions due to its gentle process
conditions and much wider formulation options. Spray-drying is a technology that works well in nearly every compound. Another
advantage of spray-drying is that it can be effectively operated using much smaller quantities of drug substance, thereby
making it the most cost-effective option during early-stage development.
Melt methods, such as HME and spray-congealing, on the other hand, are more cost effective at the larger scale manufacturing
and have the additional advantage of being solvent-free techniques. To use these methods, however, the compound needs to be
soluble in the polymer/matrix and physically stable complexes need to be created. These methods are also limited to drug substances
that can sustain relatively high heat loads. All these techniques are relatively well-established within the pharmaceutical
industry, although spray-drying is a step ahead in terms of maturity.
While challenging at a very small scale, the rationale design of an HME formulation is viable when the API is available in
pilot-scale quantities. Where an API has low solubility in all preferred spray-drying solvents or retains extensive solvent
following drying, HME may represent the best way forward for the development of a stable amorphous solid dispersion. Spray-congealing
can uses a number of lipophilic excipients, which are useful in formulating poorly water-soluble compounds that will form
self emulsifying drug-delivery system (SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on administration, as
well as the polymers commonly used in spray-dried amorphous solid dispersions.