A powder is an assembly of dry particles dispersed in air. If two different powders are mixed perfectly, theoretically, three types of powder mixtures can be obtained: the random mixture, the ordered mixture or the interactive mixture.
A powder is called free-flowing if the particles do not stick together. If particles are cohesive, they cling to one another to form aggregates. The significance of cohesion increases with decreasing size of the powder particles; particles smaller than 100 μm are generally cohesive. [1] [2]
A random mixture can be obtained if two different free-flowing powders of approximately the same particle size, density and shape are mixed (see figure A). [3] Only primary particles are present in this type of mixture, i.e., the particles are not cohesive and do not cling to one another. The mixing time will determine the quality of the random mixture. However, if powders with particles of different size, density or shape are mixed, segregation can occur. [4] Segregation will cause separation of the powders as, for example, lighter particles will be prone to travel to the top of the mixture whereas heavier particles are kept at the bottom.
The term ordered mixture was first introduced to describe a completely homogeneous mixture where the two components adhere to each other to form ordered units. [5] However, a completely homogeneous mixture is only achievable in theory and other denotations were introduced later such as adhesive mixture or interactive mixture.
If a free-flowing powder is mixed with a cohesive powder an interactive mixture can be obtained. The cohesive particles adhere to the free-flowing particles (now called carrier particles) to form interactive units as shown in figure B. [3] An interactive mixture may not contain free aggregates of the cohesive powder, which means that all small particles must be adhered to the larger ones. The difference from an ordered mixture is instead that all carrier particles do not need to be of the same size and a different number of small particles attached to each one. A narrow size range of the carrier particles is preferred to avoid segregation of the interactive units. [6] In practice a combination of a random mixture and an interactive mixture may be obtained which consists of carrier particles, aggregates of the small particles and interactive units. [7]
The formation of interactive mixtures cannot automatically be assumed, especially if smaller carrier particles [8] or a greater proportion of fine particles [9] [10] are used. If an interactive mixture is to be formed, it is necessary that enough force is exerted by the carrier particles during dry mixing to break up the aggregates formed by the fine particles. Adhesion can then be achieved if the adhesive forces exceed the gravitational forces that otherwise lead to separation of the constituents. [3]
Interactive mixtures for example can be used in the manufacturing of tablets [11] enhancing the dissolution of poorly soluble drugs [12] or for nasal administration. [3] One common application is for inhalation therapy, where the concept has been used in the development of alternatives to pressurised metered dose inhalers. [13]
The quality by design initiative (QbD) of the U.S. Food and Drug Administration requires a process to be controllable and predictable. Theories and methods to characterize powder mixture have facilitated the implementation of QbD approaches to predict flow properties of powder mixture. For example, QbD approach is shown to be useful for predicting flow performance and finding design space during formulation development. [14]
The schematic formation of a random mixture (A) and an interactive mixture (B) by dry mixing two powder materials.
A discrete element method (DEM), also called a distinct element method, is any of a family of numerical methods for computing the motion and effect of a large number of small particles. Though DEM is very closely related to molecular dynamics, the method is generally distinguished by its inclusion of rotational degrees-of-freedom as well as stateful contact, particle deformation and often complicated geometries. With advances in computing power and numerical algorithms for nearest neighbor sorting, it has become possible to numerically simulate millions of particles on a single processor. Today DEM is becoming widely accepted as an effective method of addressing engineering problems in granular and discontinuous materials, especially in granular flows, powder mechanics, ice and rock mechanics. DEM has been extended into the Extended Discrete Element Method taking heat transfer, chemical reaction and coupling to CFD and FEM into account.
A tablet is a pharmaceutical oral dosage form or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume.
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).
Selective laser sintering (SLS) is an additive manufacturing (AM) technique that uses a laser as the power and heat source to sinter powdered material, aiming the laser automatically at points in space defined by a 3D model, binding the material together to create a solid structure. It is similar to selective laser melting; the two are instantiations of the same concept but differ in technical details. SLS is a relatively new technology that so far has mainly been used for rapid prototyping and for low-volume production of component parts. Production roles are expanding as the commercialization of AM technology improves.
Excipient is a substance formulated alongside the active ingredient of a medication. Excipients serve various purposes, including long-term stabilization, bulking up solid formulations containing potent active ingredients in small amounts, or enhancing the therapeutic properties of the active ingredient in the final dosage form. They can facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients can also aid in the manufacturing process by improving the handling of active substances, facilitating powder flowability, or preventing denaturation and aggregation during the expected shelf life. The selection of excipients depends on factors such as the route of administration, dosage form, and active ingredient.
Fluidization is a process similar to liquefaction whereby a granular material is converted from a static solid-like state to a dynamic fluid-like state. This process occurs when a fluid is passed up through the granular material.
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.
A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for treating asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as cromoglicate or nedocromil.
Magnesium stearate is the chemical compound with the formula Mg(C
18H
35O
2)
2. It is a soap, consisting of salt containing two equivalents of stearate (the anion of stearic acid) and one magnesium cation (Mg2+). Magnesium stearate is a white, water-insoluble powder. Its applications exploit its softness, insolubility in many solvents, and low toxicity. It is used as a release agent and as a component or lubricant in the production of pharmaceuticals and cosmetics.
The CFD-DEM model, or Computational Fluid Dynamics / Discrete Element Method model, is a process used to model or simulate systems combining fluids with solids or particles. In CFD-DEM, the motion of discrete solids or particles phase is obtained by the Discrete Element Method (DEM) which applies Newton's laws of motion to every particle, while the flow of continuum fluid is described by the local averaged Navier–Stokes equations that can be solved using the traditional Computational Fluid Dynamics (CFD) approach. The interactions between the fluid phase and solids phase is modeled by use of Newton's third law.
In particle segregation, particulate solids, and also quasi-solids such as foams, tend to segregate by virtue of differences in the size, and also physical properties such as volume, density, shape and other properties of particles of which they are composed. Segregation occurs mainly during the powder handling and it is pronounced in free-flowing powders. One of the effective methods to control granular segregation is to make mixture's constituents sticky using a coating agent. This is especially useful when a highly active ingredient, like an enzyme, is present in the mixture. Powders that are inherently not free flowing and exhibit high levels of cohesion/adhesion between the compositions are sometimes difficult to mix as they tend to form agglomerates. The clumps of particles can be broken down in such cases by the use of mixtures that generate high shear forces or that subject the powder to impact. When these powders have been mixed, however, they are less susceptible to segregation because of the relatively high inter-particulate forces that resist inter-particulate motion, leading to unmixing.
Ciclosporin is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant. It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis, rheumatoid arthritis, dry eye and other auto-immune related conditions. A variety of pre-clinical and clinical studies have been and are investigating its use to treat lung-related disorders via inhalation.
A self-microemulsifying drug delivery system (SMEDDS) is a drug delivery system that uses a microemulsion achieved by chemical rather than mechanical means. That is, by an intrinsic property of the drug formulation, rather than by special mixing and handling. It employs the familiar ouzo effect displayed by anethole in many anise-flavored liquors. Microemulsions have significant potential for use in drug delivery, and SMEDDS are the best of these systems identified to date. SMEDDS are of particular value in increasing the absorption of lipophilic drugs taken by mouth.
Pharmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as part of the pharmaceutical industry. 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 grains or granules from a powdery or solid substance, producing a granular material. It is applied in several technological processes in the chemical and pharmaceutical industries. 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.
Tableting is a method of pressing medicine or candy into tablets. Confectionery manufacture shares many similarities with pharmaceutical production.
The extended discrete element method (XDEM) is a numerical technique that extends the dynamics of granular material or particles as described through the classical discrete element method (DEM) by additional properties such as the thermodynamic state, stress/strain or electro-magnetic field for each particle. Contrary to a continuum mechanics concept, the XDEM aims at resolving the particulate phase with its various processes attached to the particles. While the discrete element method predicts position and orientation in space and time for each particle, the extended discrete element method additionally estimates properties such as internal temperature and/or species distribution or mechanical impact with structures.
A powder is a dry, bulk solid composed of many very fine particles that may flow freely when shaken or tilted. Powders are a special sub-class of granular materials, although the terms powder and granular are sometimes used to distinguish separate classes of material. In particular, powders refer to those granular materials that have the finer grain sizes, and that therefore have a greater tendency to form clumps when flowing. Granulars refer to the coarser granular materials that do not tend to form clumps except when wet.
The Cohesion number (Coh) is a useful dimensionless number in particle technology by which the cohesivity of different powders can be compared. This is especially useful in DEM simulations of granular materials where scaling of the size and stiffness of the particles are inevitable due to the computationally demanding nature of the DEM modelling.
Pulmonary drug delivery is a route of administration in which patients use an inhaler to inhale their medications and drugs are absorbed into the bloodstream via the lung mucous membrane. This technique is most commonly used in the treatment of lung diseases, for example, asthma and chronic obstructive pulmonary disease (COPD). Different types of inhalers include metered-dose inhalers (MDI), dry powder inhalers (DPI), soft mist inhalers (SMI) and nebulizers. The rate and efficacy of pulmonary drug delivery are affected by drug particle properties, breathing patterns and respiratory tract geometry.