Micromixing

Last updated April 24, 2019

In pharmaceutics, micromixing is a process in which ingredient particles rearrange to form a blend. Development of pharmaceutical formulations requires understanding how the ingredients blend with each other and how the blending progresses through different stages. It is also important to establish in a scientific manner when the blending is considered complete, establishing the margins of blending performance, so that in production the blending is complete before the blending process stops.

Pharmaceutics is the discipline of pharmacy that deals with the process of turning a new chemical entity (NCE) or old drugs into a medication to be used safely and effectively by patients. It is also called the science of dosage form design. There are many chemicals with pharmacological properties, but need special measures to help them achieve therapeutically relevant amounts at their sites of action. Pharmaceutics helps relate the formulation of drugs to their delivery and disposition in the body. Pharmaceutics deals with the formulation of a pure drug substance into a dosage form. Branches of pharmaceutics include:

In chemistry, a mixture is a material made up of two or more different substances which are mixed. A mixture refers to the physical combination of two or more substances in which the identities are retained and are mixed in the form of solutions, suspensions and colloids.

Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.

Optimal blending

In order to achieve optimal blending, the micromixing process must be studied to determine mixing parameters such as blending time, blending speed, type and size of blender. When blending is performed too long, overblending may occur, with particles re-aggregating, resulting in segregation of the previously ideal blend.^[1]

In industrial process engineering, mixing is a unit operation that involves manipulation of a heterogeneous physical system with the intent to make it more homogeneous. Familiar examples include pumping of the water in a swimming pool to homogenize the water temperature, and the stirring of pancake batter to eliminate lumps (deagglomeration). Mixing is performed to allow heat and/or mass transfer to occur between one or more streams, components or phases. Modern industrial processing almost always involves some form of mixing. Some classes of chemical reactors are also mixers. With the right equipment, it is possible to mix a solid, liquid or gas into another solid, liquid or gas. A biofuel fermenter may require the mixing of microbes, gases and liquid medium for optimal yield; organic nitration requires concentrated (liquid) nitric and sulfuric acids to be mixed with a hydrophobic organic phase; production of pharmaceutical tablets requires blending of solid powders. The opposite of mixing is segregation. A classical example of segregation is the brazil nut effect.

Tools

Formulation scientists and technologists need tools to select ingredients for new formulations. Tablets contain multiple ingredients beyond the active pharmaceutical ingredients (API) such as fillers, tableting agents, disintegrants, and absorption enhancers or agents that slow down and control absorption. Choice of materials is important to assure the flow characteristics, potency, and absorption of specific formulations. In addition, proper particle size grades of the ingredients must be selected to produce an optimum blend for capsule filling.

A scientist is someone who conducts scientific research to advance knowledge in an area of interest.

Chemical technologists and technicians are workers who provide technical support or services in chemical-related fields. They may work under direct supervision or may work independently, depending on their specific position and duties. Their work environments differ widely and include, but are not limited to, laboratories and industrial settings. As such, it is nearly impossible to generalize the duties of chem techs as their individual jobs vary greatly. Biochemical techs often do similar work in biochemistry.

Tablet (pharmacy) solid form for doses of drugs or medication to be taken orally

A tablet is a pharmaceutical dosage form. Tablets may be defined as the solid unit dosage form of medicament or medicaments with or without suitable excipients and prepared either by molding or by compression. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include diluents, binders or granulating agents, glidants and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment, or to enhance the tablet's appearance.

Methods

In order to study the rate and uniformity of blending, destructive analytical methods, such as dissolution followed by chromatographic separation and detection are often used. These methods require samples to be pulled from the blend, followed by time consuming laboratory analysis. In production, such analysis delays may lengthen time required for production formulation development.

Chromatography is a laboratory technique for the separation of a mixture. The mixture is dissolved in a fluid called the mobile phase, which carries it through a structure holding another material called the stationary phase. The various constituents of the mixture travel at different speeds, causing them to separate. The separation is based on differential partitioning between the mobile and stationary phases. Subtle differences in a compound's partition coefficient result in differential retention on the stationary phase and thus affect the separation.

A separation process is a method that converts a mixture or solution of chemical substances into two or more distinct product mixtures. At least one of results of the separation is enriched in one or more of the source mixture's constituents. In some cases, a separation may fully divide the mixture into pure constituents. Separations exploit differences in chemical properties or physical properties between the constituents of a mixture.

Hyperspectral imaging

Near-infrared hyperspectral imaging can show the distribution of ingredients in pharmaceutical tablets. In addition to laboratory analysis, imaging of near line pull-samples has been used to indicate whether the mixing endpoint has been achieved. However, such measurements were performed once blending was completed, and therefore, did not yield information about the progression of micromixing during the blending process.^[2]

Infrared radiation (IR), sometimes called infrared light, is electromagnetic radiation (EMR) with longer wavelengths than those of visible light, and is therefore generally invisible to the human eye, although IR at wavelengths up to 1050 nanometers (nm)s from specially pulsed lasers can be seen by humans under certain conditions. IR wavelengths extend from the nominal red edge of the visible spectrum at 700 nanometers, to 1 millimeter (300 GHz). Most of the thermal radiation emitted by objects near room temperature is infrared. As with all EMR, IR carries radiant energy and behaves both like a wave and like its quantum particle, the photon.

Hyperspectral imaging, like other spectral imaging, collects and processes information from across the electromagnetic spectrum. The goal of hyperspectral imaging is to obtain the spectrum for each pixel in the image of a scene, with the purpose of finding objects, identifying materials, or detecting processes. There are two general branches of spectral imagers. There are push broom scanners and the related whisk broom scanners, which read images over time, and snapshot hyperspectral imaging, which uses a staring array to generate an image in an instant.

A medical laboratory or clinical laboratory is a laboratory where clinical pathology tests are carried out on clinical specimens to obtain information about the health of a patient to aid in diagnosis, treatment, and prevention of disease. Clinical Medical laboratories are an example of applied science, as opposed to research laboratories that focus on basic science, such as found in some academic institutions. Bio Consulted resource contains a list of all clinical and research laboratories present in Biosciences in Europe.

Related Research Articles

In chemistry, spectrophotometry is the quantitative measurement of the reflection or transmission properties of a material as a function of wavelength. It is more specific than the general term electromagnetic spectroscopy in that spectrophotometry deals with visible light, near-ultraviolet, and near-infrared, but does not cover time-resolved spectroscopic techniques.

An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts, or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance concerned such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The selection of appropriate excipients also depends upon the route of administration and the dosage form, as well as the active ingredient and other factors. A comprehensive classification system based on structure-property-application relationships has been proposed for excipients used in parenteral medications.

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.

Elemental analysis is a process where a sample of some material is analyzed for its elemental and sometimes isotopic composition. Elemental analysis can be qualitative, and it can be quantitative. Elemental analysis falls within the ambit of analytical chemistry, the set of instruments involved in deciphering the chemical nature of our world.

A multispectral image is one that captures image data within specific wavelength ranges across the electromagnetic spectrum. The wavelengths may be separated by filters or by the use of instruments that are sensitive to particular wavelengths, including light from frequencies beyond the visible light range, i.e. infrared and ultra-violet. Spectral imaging can allow extraction of additional information the human eye fails to capture with its receptors for red, green and blue. It was originally developed for space-based imaging, and has also found use in document and painting analysis.

In the manufacture of pharmaceuticals, encapsulation refers to a range of dosage forms—techniques used to enclose medicines—in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are:

An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole. The ODT serves as an alternative dosage form for patients who experience dysphagia or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population and 18-22% of all patients in long-term care facilities ODTs also have a faster onset of effects than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription.

Chemical imaging is the analytical capability to create a visual image of components distribution from simultaneous measurement of spectra and spatial, time information. Hyperspectral imaging measures contiguous spectral bands, as opposed to multispectral imaging which measures spaced spectral bands.

The term micromeritics was given to the science and technology of small particles by J. M. DallaValle. It is thus the study of the fundamental and derived properties of individual as well as a collection of particles. The knowledge and control of the size of particles is of importance in pharmacy and materials science. The size, and hence the surface area of a particle, can be related to the physical, chemical and pharmacologic properties of drugs. Clinically, the particle size of a drug can affect its release from dosage forms that are administered orally, parenterally, rectally and topically. The successful formulation of suspensions, emulsions and tablets; both physical stability and pharmacologic response also depends on the particle size achieved in the product.

Particle size analysis, particle size measurement, or simply particle sizing is the collective name of the technical procedures, or laboratory techniques which determines the size range, and/or the average, or mean size of the particles in a powder or liquid sample.

Transmission Raman spectroscopy (TRS) is a variant of Raman spectroscopy beneficial in probing bulk content of diffusely scattering samples. Although it was demonstrated in the early days of Raman spectroscopy it was never exploited in practical settings, probably due to limitations of technology at the time. It was rediscovered in 2006, where the authors showed it was capable of allowing Raman spectroscopy through many millimetres of tabletted or powdered samples. In addition, this research has also identified several highly beneficial analytical properties of this approach, including the ability to probe bulk content of powders and tissue in the absence of subsampling and to reject Raman and fluorescence components originating from the surface of the sample.

Acoustic resonance spectroscopy (ARS) is a method of spectroscopy in the acoustic region, primarily the sonic and ultrasonic regions. ARS is typically much more rapid than HPLC and NIR. It is non destructive and requires no sample preparation as the sampling waveguide can simply be pushed into a sample powder/liquid or in contact with a solid sample. To date, the AR spectrometer has successfully differentiated and quantified sample analytes in various forms;. It has been used to measure and monitor the progression of chemical reactions, such as the setting and hardening of concrete from cement paste to solid. Acoustic spectrometry has also been used to measure the volume fraction of colloids in a dispersion medium, as well as for the investigation of physical properties of colloidal dispersions, such as aggregation and particle size distribution. Typically, these experiments are carried out with sinusoidal excitation signals and the experimental observation of signal attenuation. From a comparison of theoretical attenuation to experimental observation, the particle size distribution and aggregation phenomena are inferred.

Drug manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs by pharmaceutical companies. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, granulation, coating, tablet pressing, and others.

Granulation is the process of forming of grains or granules from a powdery or solid substance, producing a granular material. It is applied in several technological processes in chemical and pharmaceutical industry. Typically, granulation involves agglomeration of fine particles into larger granules, typically of size range between 0.2 and 4.0 mm depending on their subsequent use. Less commonly, it involves shredding or grinding solid material into finer granules or pellets.

Malvern Instruments is a Spectris plc company. Founded in the late 1960s, the company is a manufacturer and supplier of laboratory analytical instruments, was influential in the development of the Malvern Correlator, and remains notable for its work in the advancement of particle sizing technology. The company produces technology for materials analysis; principally instruments designed to measure the size, shape and charge of particles. Additional areas of development now include equipment for rheology measurements, chemical imaging and chromatography.

Tableting is a method of pressing medicine or candy into tablets. Confectionery manufacture shares many similarities with pharmaceutical production.

Micro-compounding refers to the mixing or processing of polymer formulations in the melt on a very small scale, typically several ml. The advantage of the use of a micro-compounder for R&D are significant: it gives faster, yet reliable results with much smaller samples and at much less investment costs, thus speeding up the innovation process in R&D of polymer materials, pharmaceutical, biomedical and nutritional applications.

AFM-IR is one of a family of techniques that are derived from a combination of two parent instrumental techniques; infrared spectroscopy and scanning probe microscopy (SPM). The term was first used to denote a method that combined a tuneable free electron laser with an atomic force microscope equipped with a sharp probe that measured the local absorption of infrared light by a sample; it required that the sample be coupled to an infrared-transparent prism and be less than 1μm thick. It improved the spatial resolution of photothermal AFM-based techniques from microns to circa 100 nm.

References

↑ Osorio, Juan G.; Stuessy, Gina; Kemeny, Gabor J.; Muzzio, Fernando J. (April 2014). "Characterization of pharmaceutical powder blends using in situ near-infrared chemical imaging". Chemical Engineering Science. 108: 244–257. doi:10.1016/j.ces.2013.12.027.
↑ Micromixing Analysis for Formulation Developers, Gabor J Kemeny, Gina Stuessy, Natalie Crothers; American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, October 2011, Washington, DC (poster Archived 2015-04-16 at the Wayback Machine )