Seeking Solutions in Solid-State Chemistry - Pharmaceutical Technology

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PharmTech Europe

Seeking Solutions in Solid-State Chemistry
Particle-engineering technologies, such as crystal design for crystallization and producting cocrystals, particle-size reduction, and amorphous solid dispersions, help to optimize delivery of a drug.

PTSM: Pharmaceutical Technology Sourcing and Management
Volume 8, Issue 11

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,


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