Micronization

Micronization is the process of reducing the average diameter of a solid material's particles. Traditional techniques for micronization focus on mechanical means, such as milling and grinding. Modern techniques make use of the properties of supercritical fluids and manipulate the principles of solubility.

The term micronization usually refers to the reduction of average particle diameters to the micrometer range, but can also describe further reduction to the nanometer scale. Common applications include the production of active chemical ingredients, foodstuff ingredients, and pharmaceuticals. These chemicals need to be micronized to increase efficacy.

Traditional techniques

Traditional micronization techniques are based on friction to reduce particle size. Such methods include milling, bashing and grinding. A typical industrial mill is composed of a cylindrical metallic drum that usually contains steel spheres. As the drum rotates the spheres inside collide with the particles of the solid, thus crushing them towards smaller diameters. In the case of grinding, the solid particles are formed when the grinding units of the device rub against each other while particles of the solid are trapped in between.

Methods like crushing and cutting are also used for reducing particle diameter, but produce more rough particles compared to the two previous techniques (and are therefore the early stages of the micronization process). Crushing employs hammer-like tools to break the solid into smaller particles by means of impact. Cutting uses sharp blades to cut the rough solid pieces into smaller ones.

Modern techniques

Modern methods use supercritical fluids in the micronization process. These methods use supercritical fluids to induce a state of supersaturation, which leads to precipitation of individual particles. The most widely applied techniques of this category include the RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method (Particles from Gas Saturated Solutions). These modern techniques allow for greater tuneability of the process. Supercritical carbon dioxide (scCO2) is a commonly used medium in micronization processes.[1] This is because scCO2 is not very reactive and has easily accessible critical point state parameters. As a result, scCO2 can be effectively used to obtain pure crystalline or amorphous micronized forms.[2] Parameters like relative pressure and temperature, solute concentration, and antisolvent to solvent ratio are varied to adjust the output to the producer's needs. Control of particle size in micronization can be influenced by macroscopic factors, such as geometric parameters of the spray nozzle and flow rate, and molecular level changes due to adjustments in state parameters. These adjustments can lead to the nucleation of particles of varying sizes by redistributing conformational equilibria and polymorphic transformations.[3][4][5] The supercritical fluid methods result in finer control over particle diameters, distribution of particle size and consistency of morphology.[6][7][8] Because of the relatively low pressure involved, many supercritical fluid methods can incorporate thermolabile materials. Modern techniques involve renewable, nonflammable and nontoxic chemicals.[9]

RESS

In the case of RESS (Rapid Expansion of Supercritical Solutions), the supercritical fluid is used to dissolve the solid material under high pressure and temperature, thus forming a homogeneous supercritical phase. Thereafter, the mixture is expanded through a nozzle to form the smaller particles. Immediately upon exiting the nozzle, rapid expansion occurs, lowering the pressure. The pressure will drop below supercritical pressure, causing the supercritical fluid - usually carbon dioxide - to return to the gas state. This phase change severely decreases the solubility of the mixture and results in precipitation of particles.[10] The less time it takes the solution to expand and the solute to precipitate, the narrower the particle size distribution will be. Faster precipitation times also tend to result in smaller particle diameters.[11]

SAS

In the SAS method (Supercritical Anti-Solvent), the solid material is dissolved in an organic solvent. The supercritical fluid is then added as an antisolvent, which decreases the solubility of the system. As a result, particles of small diameter are formed.[8] There are various submethods to SAS which differ in the method of introduction of the supercritical fluid into the organic solution.[12]

PGSS

In the PGSS method (Particles from Gas Saturated Solutions) the solid material is melted and the supercritical fluid is dissolved in it.[13] However, in this case the solution is forced to expand through a nozzle, and in this way nanoparticles are formed. The PGSS method has the advantage that because of the supercritical fluid, the melting point of the solid material is reduced. Therefore, the solid melts at a lower temperature than the normal melting temperature at ambient pressure.

Applications

Pharmaceuticals and foodstuff ingredients are the main industries in which micronization is utilized. Particles with reduced diameters have higher dissolution rates, which increases efficacy.[9] Progesterone, for example, can be micronized by making very tiny crystals of the progesterone.[14] Micronized progesterone is manufactured in a laboratory from plants. It is available for use as HRT, infertility treatment, progesterone deficiency treatment, including dysfunctional uterine bleeding in premenopausal women. Compounding pharmacies can supply micronized progesterone in sublingual tablets, oil caps, or transdermal creams.[15] Creatine is among the other drugs that are micronized.[11]

References
  1. Franco, Paola; De Marco, Iolanda (2021-02-06). "Nanoparticles and Nanocrystals by Supercritical CO2-Assisted Techniques for Pharmaceutical Applications: A Review". Applied Sciences. 11 (4): 1476. doi:10.3390/app11041476. ISSN 2076-3417.
  2. Esfandiari, Nadia; Sajadian, Seyed Ali (October 2022). "CO2 utilization as gas antisolvent for the pharmaceutical micro and nanoparticle production: A review". Arabian Journal of Chemistry. 15 (10): 104164. doi:10.1016/j.arabjc.2022.104164.
  3. Hezave, Ali Zeinolabedini; Esmaeilzadeh, Feridun (February 2010). "Micronization of drug particles via RESS process". The Journal of Supercritical Fluids. 52 (1): 84–98. doi:10.1016/j.supflu.2009.09.006.
  4. Belov, Konstantin V.; Krestyaninov, Michael A.; Dyshin, Alexey A.; Khodov, Ilya A. (February 2024). "The influence of lidocaine conformers on micronized particle size: Quantum chemical and NMR insights". Journal of Molecular Liquids. 396: 124120. doi:10.1016/j.molliq.2024.124120. S2CID 267236654.
  5. Kuznetsova, I. V.; Gilmutdinov, I. I.; Gilmutdinov, I. M.; Sabirzyanov, A. N. (September 2019). "Production of Lidocaine Nanoforms via the Rapid Extension of a Supercritical Solution into Water Medium". High Temperature. 57 (5): 726–730. doi:10.1134/S0018151X19040138. ISSN 0018-151X. S2CID 213017906.
  6. Knez, Željko; Hrnčič, Maša Knez; Škerget, Mojca (2015-01-01). "Particle Formation and Product Formulation Using Supercritical Fluids". Annual Review of Chemical and Biomolecular Engineering. 6 (1): 379–407. doi:10.1146/annurev-chembioeng-061114-123317. PMID 26091976.
  7. Tandya, A.; Zhuang, H.Q.; Mammucari, R.; Foster, N.R. (2016). "Supercritical fluid micronization techniques for gastroresistant insulin formulations". The Journal of Supercritical Fluids. 107: 9–16. doi:10.1016/j.supflu.2015.08.009.
  8. Reverchon, E.; Adami, R.; Campardelli, R.; Della Porta, G.; De Marco, I.; Scognamiglio, M. (2015-07-01). "Supercritical fluids based techniques to process pharmaceutical products difficult to micronize: Palmitoylethanolamide". The Journal of Supercritical Fluids. 102: 24–31. doi:10.1016/j.supflu.2015.04.005.
  9. Esfandiari, Nadia; Ghoreishi, Seyyed M. (2015-12-01). "Ampicillin Nanoparticles Production via Supercritical CO2 Gas Antisolvent Process". AAPS PharmSciTech. 16 (6): 1263–1269. doi:10.1208/s12249-014-0264-y. ISSN 1530-9932. PMC 4666252. PMID 25771736.
  10. Fattahi, Alborz; Karimi-Sabet, Javad; Keshavarz, Ali; Golzary, Abooali; Rafiee-Tehrani, Morteza; Dorkoosh, Farid A. (2016-01-01). "Preparation and characterization of simvastatin nanoparticles using rapid expansion of supercritical solution (RESS) with trifluoromethane". The Journal of Supercritical Fluids. 107: 469–478. doi:10.1016/j.supflu.2015.05.013.
  11. Hezave, Ali Zeinolabedini; Aftab, Sarah; Esmaeilzadeh, Feridun (2010-11-01). "Micronization of creatine monohydrate via Rapid Expansion of Supercritical Solution (RESS)". The Journal of Supercritical Fluids. 55 (1): 316–324. doi:10.1016/j.supflu.2010.05.009.
  12. De Marco, I.; Rossmann, M.; Prosapio, V.; Reverchon, E.; Braeuer, A. (2015-08-01). "Control of particle size, at micrometric and nanometric range, using supercritical antisolvent precipitation from solvent mixtures: Application to PVP". Chemical Engineering Journal. 273: 344–352. Bibcode:2015ChEnJ.273..344D. doi:10.1016/j.cej.2015.03.100.
  13. Tanbirul Haque, A. S. M.; Chun, Byung-Soo (2016-01-01). "Particle formation and characterization of mackerel reaction oil by gas saturated solution process". Journal of Food Science and Technology. 53 (1): 293–303. doi:10.1007/s13197-015-2000-3. ISSN 0022-1155. PMC 4711435. PMID 26787949.
  14. wdxcyber.com >Progesterone - Its Uses and Effects Frederick R. Jelovsek MD. 2009
  15. project-aware > Managing Menopause > HRT > About Progesterone Page uploaded September 2002
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