Editing Micronization (section)

==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 (chemistry)|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 (scCO<sub>2</sub>) is a commonly used medium in micronization processes.<ref>{{Cite journal |last1=Franco |first1=Paola |last2=De Marco |first2=Iolanda |date=2021-02-06 |title=Nanoparticles and Nanocrystals by Supercritical CO2-Assisted Techniques for Pharmaceutical Applications: A Review |journal=Applied Sciences |language=en |volume=11 |issue=4 |pages=1476 |doi=10.3390/app11041476 |doi-access=free |issn=2076-3417}}</ref> This is because scCO<sub>2</sub> 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.<ref>{{Cite journal |last1=Esfandiari |first1=Nadia |last2=Sajadian |first2=Seyed Ali |date=October 2022 |title=CO2 utilization as gas antisolvent for the pharmaceutical micro and nanoparticle production: A review |journal=Arabian Journal of Chemistry |language=en |volume=15 |issue=10 |pages=104164 |doi=10.1016/j.arabjc.2022.104164|doi-access=free }}</ref> 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 polymorphic or amorphous transformations, as well as due to the characteristics of aggregation processes, which in some cases is accompanied by changes in conformational equilibria.<ref>{{Cite journal |last1=Hezave |first1=Ali Zeinolabedini |last2=Esmaeilzadeh |first2=Feridun |date=February 2010 |title=Micronization of drug particles via RESS process |url=https://linkinghub.elsevier.com/retrieve/pii/S0896844609003167 |journal=The Journal of Supercritical Fluids |language=en |volume=52 |issue=1 |pages=84–98 |doi=10.1016/j.supflu.2009.09.006|url-access=subscription }}</ref><ref>{{Cite journal |last1=Belov |first1=Konstantin V. |last2=Krestyaninov |first2=Michael A. |last3=Dyshin |first3=Alexey A. |last4=Khodov |first4=Ilya A. |date=February 2024 |title=The influence of lidocaine conformers on micronized particle size: Quantum chemical and NMR insights |url=https://linkinghub.elsevier.com/retrieve/pii/S0167732224001752 |journal=Journal of Molecular Liquids |language=en |volume=396 |pages=124120 |doi=10.1016/j.molliq.2024.124120|s2cid=267236654 |url-access=subscription }}</ref><ref>{{Cite journal |last1=Kuznetsova |first1=I. V. |last2=Gilmutdinov |first2=I. I. |last3=Gilmutdinov |first3=I. M. |last4=Sabirzyanov |first4=A. N. |date=September 2019 |title=Production of Lidocaine Nanoforms via the Rapid Extension of a Supercritical Solution into Water Medium |url=http://link.springer.com/10.1134/S0018151X19040138 |journal=High Temperature |language=en |volume=57 |issue=5 |pages=726–730 |doi=10.1134/S0018151X19040138 |bibcode=2019HTemp..57..726K |s2cid=213017906 |issn=0018-151X|url-access=subscription }}</ref> The supercritical fluid methods result in finer control over particle diameters, distribution of particle size and consistency of morphology.<ref>{{Cite journal|last1=Knez|first1=Željko|last2=Hrnčič|first2=Maša Knez|last3=Škerget|first3=Mojca|date=2015-01-01|title=Particle Formation and Product Formulation Using Supercritical Fluids|journal=Annual Review of Chemical and Biomolecular Engineering|volume=6|issue=1|pages=379–407|doi=10.1146/annurev-chembioeng-061114-123317|pmid=26091976|doi-access=free}}</ref><ref>{{Cite journal|last1=Tandya|first1=A.|last2=Zhuang|first2=H.Q.|last3=Mammucari|first3=R.|last4=Foster|first4=N.R.|title=Supercritical fluid micronization techniques for gastroresistant insulin formulations|url=https://www.researchgate.net/publication/282160941|journal=The Journal of Supercritical Fluids|volume=107|pages=9–16|doi=10.1016/j.supflu.2015.08.009|year=2016}}</ref><ref name=":0">{{Cite journal|last1=Reverchon|first1=E.|last2=Adami|first2=R.|last3=Campardelli|first3=R.|last4=Della Porta|first4=G.|last5=De Marco|first5=I.|last6=Scognamiglio|first6=M.|date=2015-07-01|title=Supercritical fluids based techniques to process pharmaceutical products difficult to micronize: Palmitoylethanolamide|journal=The Journal of Supercritical Fluids|volume=102|pages=24–31|doi=10.1016/j.supflu.2015.04.005}}</ref> Because of the relatively low pressure involved, many supercritical fluid methods can incorporate thermolabile materials. Modern techniques involve renewable, nonflammable and nontoxic chemicals.<ref name=":2">{{Cite journal|last1=Esfandiari|first1=Nadia|last2=Ghoreishi|first2=Seyyed M.|date=2015-12-01|title=Ampicillin Nanoparticles Production via Supercritical CO2 Gas Antisolvent Process|journal=AAPS PharmSciTech|volume=16|issue=6|pages=1263–1269|doi=10.1208/s12249-014-0264-y|issn=1530-9932|pmc=4666252|pmid=25771736}}</ref>

=== RESS ===
In the case of RESS (Rapid Expansion of Supercritical Solutions), the supercritical fluid is used to [[Solvation|dissolve]] the solid material under high pressure and temperature, thus forming a [[Homogeneity and heterogeneity|homogeneous]] supercritical [[Phase (matter)|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.<ref>{{Cite journal|last1=Fattahi|first1=Alborz|last2=Karimi-Sabet|first2=Javad|last3=Keshavarz|first3=Ali|last4=Golzary|first4=Abooali|last5=Rafiee-Tehrani|first5=Morteza|last6=Dorkoosh|first6=Farid A.|date=2016-01-01|title=Preparation and characterization of simvastatin nanoparticles using rapid expansion of supercritical solution (RESS) with trifluoromethane|journal=The Journal of Supercritical Fluids|volume=107|pages=469–478|doi=10.1016/j.supflu.2015.05.013}}</ref> 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.<ref name=":3">{{Cite journal|last1=Hezave|first1=Ali Zeinolabedini|last2=Aftab|first2=Sarah|last3=Esmaeilzadeh|first3=Feridun|date=2010-11-01|title=Micronization of creatine monohydrate via Rapid Expansion of Supercritical Solution (RESS)|journal=The Journal of Supercritical Fluids|volume=55|issue=1|pages=316–324|doi=10.1016/j.supflu.2010.05.009}}</ref>

=== 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.<ref name=":0" /> There are various submethods to SAS which differ in the method of introduction of the supercritical fluid into the organic solution.<ref name=":1">{{Cite journal|last1=De Marco|first1=I.|last2=Rossmann|first2=M.|last3=Prosapio|first3=V.|last4=Reverchon|first4=E.|last5=Braeuer|first5=A.|date=2015-08-01|title=Control of particle size, at micrometric and nanometric range, using supercritical antisolvent precipitation from solvent mixtures: Application to PVP|journal=Chemical Engineering Journal|volume=273|pages=344–352|doi=10.1016/j.cej.2015.03.100|bibcode=2015ChEnJ.273..344D }}</ref>

=== PGSS ===
In the PGSS method (Particles from Gas Saturated Solutions) the solid material is melted and the supercritical fluid is dissolved in it.<ref>{{Cite journal|last1=Tanbirul Haque|first1=A. S. M.|last2=Chun|first2=Byung-Soo|date=2016-01-01|title=Particle formation and characterization of mackerel reaction oil by gas saturated solution process|journal=Journal of Food Science and Technology|volume=53|issue=1|pages=293–303|doi=10.1007/s13197-015-2000-3|issn=0022-1155|pmc=4711435|pmid=26787949}}</ref> However, in this case the solution is forced to expand through a nozzle, and in this way [[nanoparticle]]s 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.