Micronization

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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.

Contents

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]

Related Research Articles

In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent called the mobile phase, which carries it through a system on which a material called the stationary phase is fixed. Because the different constituents of the mixture tend to have different affinities for the stationary phase and are retained for different lengths of time depending on their interactions with its surface sites, the constituents travel at different apparent velocities in the mobile fluid, causing them to separate. The separation is based on the differential partitioning between the mobile and the stationary phases. Subtle differences in a compound's partition coefficient result in differential retention on the stationary phase and thus affect the separation.

<span class="mw-page-title-main">Filtration</span> Process that separates solids from fluids


Filtration is a physical separation process that separates solid matter and fluid from a mixture using a filter medium that has a complex structure through which only the fluid can pass. Solid particles that cannot pass through the filter medium are described as oversize and the fluid that passes through is called the filtrate. Oversize particles may form a filter cake on top of the filter and may also block the filter lattice, preventing the fluid phase from crossing the filter, known as blinding. The size of the largest particles that can successfully pass through a filter is called the effective pore size of that filter. The separation of solid and fluid is imperfect; solids will be contaminated with some fluid and filtrate will contain fine particles. Filtration occurs both in nature and in engineered systems; there are biological, geological, and industrial forms.

In physical chemistry, supersaturation occurs with a solution when the concentration of a solute exceeds the concentration specified by the value of solubility at equilibrium. Most commonly the term is applied to a solution of a solid in a liquid, but it can also be applied to liquids and gases dissolved in a liquid. A supersaturated solution is in a metastable state; it may return to equilibrium by separation of the excess of solute from the solution, by dilution of the solution by adding solvent, or by increasing the solubility of the solute in the solvent.

<span class="mw-page-title-main">Spray drying</span> Method of converting liquid or slurry to powder

Spray drying is a method of forming a dry powder from a liquid or slurry by rapidly drying with a hot gas. This is the preferred method of drying of many thermally-sensitive materials such as foods and pharmaceuticals, or materials which may require extremely consistent, fine particle size. Air is the heated drying medium; however, if the liquid is a flammable solvent such as ethanol or the product is oxygen-sensitive then nitrogen is used.

<span class="mw-page-title-main">High-performance liquid chromatography</span> Technique in analytical chemistry

High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify specific components in mixtures. The mixtures can originate from food, chemicals, pharmaceuticals, biological, environmental and agriculture, etc, which have been dissolved into liquid solutions.

A supercritical fluid (SCF) is any substance at a temperature and pressure above its critical point, where distinct liquid and gas phases do not exist, but below the pressure required to compress it into a solid. It can effuse through porous solids like a gas, overcoming the mass transfer limitations that slow liquid transport through such materials. SCF are superior to gases in their ability to dissolve materials like liquids or solids. Also, near the critical point, small changes in pressure or temperature result in large changes in density, allowing many properties of a supercritical fluid to be "fine-tuned".

<span class="mw-page-title-main">Electrospinning</span> Fiber production method

Electrospinning is a fiber production method that uses electric force to draw charged threads of polymer solutions or polymer melts up to fiber diameters in the order of some hundred nanometers. Electrospinning shares characteristics of both electrospraying and conventional solution dry spinning of fibers. The process does not require the use of coagulation chemistry or high temperatures to produce solid threads from solution. This makes the process particularly suited to the production of fibers using large and complex molecules. Electrospinning from molten precursors is also practiced; this method ensures that no solvent can be carried over into the final product.

Supercritical fluid extraction (SFE) is the process of separating one component (the extractant) from another (the matrix) using supercritical fluids as the extracting solvent. Extraction is usually from a solid matrix, but can also be from liquids. SFE can be used as a sample preparation step for analytical purposes, or on a larger scale to either strip unwanted material from a product (e.g. decaffeination) or collect a desired product (e.g. essential oils). These essential oils can include limonene and other straight solvents. Carbon dioxide (CO2) is the most used supercritical fluid, sometimes modified by co-solvents such as ethanol or methanol. Extraction conditions for supercritical carbon dioxide are above the critical temperature of 31 °C and critical pressure of 74 bar. Addition of modifiers may slightly alter this. The discussion below will mainly refer to extraction with CO2, except where specified.

<span class="mw-page-title-main">Fluidized bed</span>

A fluidized bed is a physical phenomenon that occurs when a solid particulate substance is under the right conditions so that it behaves like a fluid. The usual way to achieve a fluidized bed is to pump pressurized fluid into the particles. The resulting medium then has many properties and characteristics of normal fluids, such as the ability to free-flow under gravity, or to be pumped using fluid technologies.

<span class="mw-page-title-main">Supercritical carbon dioxide</span> Carbon dioxide above its critical point

Supercritical carbon dioxide is a fluid state of carbon dioxide where it is held at or above its critical temperature and critical pressure.

<span class="mw-page-title-main">Fragrance extraction</span> Separation process of aromatic compounds from raw materials

Fragrance extraction refers to the separation process of aromatic compounds from raw materials, using methods such as distillation, solvent extraction, expression, sieving, or enfleurage. The results of the extracts are either essential oils, absolutes, concretes, or butters, depending on the amount of waxes in the extracted product.

A molecularly imprinted polymer (MIP) is a polymer that has been processed using the molecular imprinting technique which leaves cavities in the polymer matrix with an affinity for a chosen "template" molecule. The process usually involves initiating the polymerization of monomers in the presence of a template molecule that is extracted afterwards, leaving behind complementary cavities. These polymers have affinity for the original molecule and have been used in applications such as chemical separations, catalysis, or molecular sensors. Published works on the topic date to the 1930s.

Supercritical fluid chromatography (SFC) is a form of normal phase chromatography that uses a supercritical fluid such as carbon dioxide as the mobile phase. It is used for the analysis and purification of low to moderate molecular weight, thermally labile molecules and can also be used for the separation of chiral compounds. Principles are similar to those of high performance liquid chromatography (HPLC); however, SFC typically utilizes carbon dioxide as the mobile phase. Therefore, the entire chromatographic flow path must be pressurized. Because the supercritical phase represents a state whereby bulk liquid and gas properties converge, supercritical fluid chromatography is sometimes called convergence chromatography. The idea of liquid and gas properties convergence was first envisioned by Giddings.

Polymer nanocomposites (PNC) consist of a polymer or copolymer having nanoparticles or nanofillers dispersed in the polymer matrix. These may be of different shape, but at least one dimension must be in the range of 1–50 nm. These PNC's belong to the category of multi-phase systems that consume nearly 95% of plastics production. These systems require controlled mixing/compounding, stabilization of the achieved dispersion, orientation of the dispersed phase, and the compounding strategies for all MPS, including PNC, are similar. Alternatively, polymer can be infiltrated into 1D, 2D, 3D preform creating high content polymer nanocomposites.

<span class="mw-page-title-main">Ultrasonic nozzle</span> Type of spray nozzle

Ultrasonic nozzles are a type of spray nozzle that use high frequency vibrations produced by piezoelectric transducers acting upon the nozzle tip that create capillary waves in a liquid film. Once the amplitude of the capillary waves reaches a critical height, they become too tall to support themselves and tiny droplets fall off the tip of each wave resulting in atomization.

In materials science, cocrystals are "solids that are crystalline, single-phase materials composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts." A broader definition is that cocrystals "consist of two or more components that form a unique crystalline structure having unique properties." Several subclassifications of cocrystals exist.

<span class="mw-page-title-main">Ceramic nanoparticle</span>

Ceramic nanoparticle is a type of nanoparticle that is composed of ceramics, which are generally classified as inorganic, heat-resistant, nonmetallic solids that can be made of both metallic and nonmetallic compounds. The material offers unique properties. Macroscale ceramics are brittle and rigid and break upon impact. However, Ceramic nanoparticles take on a larger variety of functions, including dielectric, ferroelectric, piezoelectric, pyroelectric, ferromagnetic, magnetoresistive, superconductive and electro-optical.

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<span class="mw-page-title-main">Carbon dioxide cleaning</span> Family of methods for parts cleaning and sterilization

Carbon dioxide cleaning (CO2 cleaning) comprises a family of methods for parts cleaning and sterilization, using carbon dioxide in its various phases. Due to being non-destructive, non-abrasive, and residue-free, it is often preferred for use on delicate surfaces. CO2 cleaning has found application in the aerospace, automotive, electronics, medical, and other industries. Carbon dioxide snow cleaning has been used to remove particles and organic residues from metals, polymers, ceramics, glasses, and other materials, and from surfaces including hard drives and optical surfaces.

<span class="mw-page-title-main">Non ideal compressible fluid dynamics</span>

Non ideal compressible fluid dynamics (NICFD), or non ideal gas dynamics, is a branch of fluid mechanics studying the dynamic behavior of fluids not obeying ideal-gas thermodynamics. It is for example the case of dense vapors, supercritical flows and compressible two-phase flows. With the term dense vapors, we indicate all fluids in the gaseous state characterized by thermodynamic conditions close to saturation and the critical point. Supercritical fluids feature instead values of pressure and temperature larger than their critical values, whereas two-phase flows are characterized by the simultaneous presence of both liquid and gas phases.

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. 1 2 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. 1 2 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. 1 2 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. 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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