Particle-size reduction
PharmTech:
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 behavior. 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
PharmTech:
What factors determine which method (i.e., spray-drying, HME,
spray-congealing, and inclusion-complex 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.
Although 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 systems
(SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on
administration, as well as the polymers commonly used in spray-dried amorphous
solid dispersions.
Patricia Van Arnum is executive editor of Pharmaceutical
Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830
tel. 732.346.3072, pvanarnum@advanstar.com
twitter@PharmTechVArnum.
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