Micronization is the

process A process is a series or set of activities that interact to produce a result; it may occur once-only or be recurrent or periodic. Things called a process include: Business and management * Business process, activities that produce a specific s ...

of reducing the

average In colloquial, ordinary language, an average is a single number or value that best represents a set of data. The type of average taken as most typically representative of a list of numbers is the arithmetic mean the sum of the numbers divided by ...

diameter In geometry, a diameter of a circle is any straight line segment that passes through the centre of the circle and whose endpoints lie on the circle. It can also be defined as the longest Chord (geometry), chord of the circle. Both definitions a ...

of a

solid Solid is a state of matter where molecules are closely packed and can not slide past each other. Solids resist compression, expansion, or external forces that would alter its shape, with the degree to which they are resisted dependent upon the ...

material's particles. Traditional techniques for micronization focus on mechanical means, such as

milling Milling may refer to: * Milling (minting), forming narrow ridges around the edge of a coin * Milling (grinding), breaking solid materials into smaller pieces by grinding, crushing, or cutting in a mill * Milling (machining), a process of using ro ...

and grinding. Modern techniques make use of the properties of supercritical fluids and manipulate the principles of

solubility In chemistry, solubility is the ability of a chemical substance, substance, the solute, to form a solution (chemistry), solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form su ...

. The term micronization usually refers to the reduction of average particle diameters to the

micrometer Micrometer can mean: * Micrometer (device), used for accurate measurements by means of a calibrated screw * Micrometre The micrometre (English in the Commonwealth of Nations, Commonwealth English as used by the International Bureau of Weights ...

range, but can also describe further reduction to the

nanometer 330px, Different lengths as in respect to the Molecule">molecular scale. The nanometre (international spelling as used by the International Bureau of Weights and Measures; SI symbol: nm), or nanometer (American spelling Despite the va ...

scale. Common applications include the production of active chemical ingredients, foodstuff ingredients, and

pharmaceuticals Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

. These chemicals need to be micronized to increase efficacy.

Traditional techniques

Traditional micronization techniques are based on

friction Friction is the force resisting the relative motion of solid surfaces, fluid layers, and material elements sliding against each other. Types of friction include dry, fluid, lubricated, skin, and internal -- an incomplete list. The study of t ...

to reduce particle size. Such methods include

, 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 Cutting is the separation or opening of a physical object, into two or more portions, through the application of an acutely directed force. Implements commonly used for wikt:cut, cutting are the knife and saw, or in medicine and science the sca ...

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 A supercritical fluid (SCF) is a 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 soli ...

in the micronization process. These methods use supercritical fluids to induce a state of

supersaturation In physical chemistry, supersaturation occurs with a solution (chemistry), solution when the concentration of a solute exceeds the concentration specified by the value of solubility at Solubility equilibrium, equilibrium. Most commonly the term ...

, which leads to

precipitation In meteorology, precipitation is any product of the condensation of atmospheric water vapor that falls from clouds due to gravitational pull. The main forms of precipitation include drizzle, rain, rain and snow mixed ("sleet" in Commonwe ...

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. 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. 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. The supercritical fluid methods result in finer control over particle diameters, distribution of particle size and consistency of morphology. Because of the relatively low pressure involved, many supercritical fluid methods can incorporate thermolabile materials. Modern techniques involve renewable, nonflammable and nontoxic chemicals.

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 Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...

supercritical

phase Phase or phases may refer to: Science *State of matter, or phase, one of the distinct forms in which matter can exist *Phase (matter), a region of space throughout which all physical properties are essentially uniform *Phase space, a mathematica ...

. Thereafter, the

mixture In chemistry, a mixture is a material made up of two or more different chemical substances which can be separated by physical method. It is an impure substance made up of 2 or more elements or compounds mechanically mixed together in any proporti ...

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 Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...

- to return to the

gas Gas is a state of matter that has neither a fixed volume nor a fixed shape and is a compressible fluid. A ''pure gas'' is made up of individual atoms (e.g. a noble gas like neon) or molecules of either a single type of atom ( elements such as ...

state. This phase change severely decreases the solubility of the mixture and results in precipitation of particles. 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.

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

of the system. As a result, particles of small diameter are formed. There are various submethods to SAS which differ in the method of introduction of the supercritical fluid into the organic solution.

PGSS

In the PGSS method (Particles from Gas Saturated Solutions) the solid material is melted and the supercritical fluid is dissolved in it. However, in this case the solution is forced to expand through a nozzle, and in this way

nanoparticle A nanoparticle or ultrafine particle is a particle of matter 1 to 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 100 nm in only two directions. At ...

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.

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.

Progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

, for example, can be micronized by making very tiny crystals of the progesterone. 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 Vaginal bleeding is any expulsion of blood from the vagina. This bleeding may originate from the uterus, vaginal wall, or cervix. Generally, it is either part of a normal menstrual cycle or is caused by hormonal or other problems of the reproductiv ...

in premenopausal women. Compounding pharmacies can supply micronized progesterone in sublingual tablets, oil caps, or transdermal creams.project-aware > Managing Menopause > HRT > About Progesterone
Page uploaded September 2002

Creatine Creatine ( or ) is an organic compound with the nominal formula . It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates, where it facilitates recycling of ...

is among the other drugs that are micronized.

References

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External links

Example of a Micronizing Mill
McCrone Micronizing Mill Materials science Unit operations