Particle Size Reduction PDF

# Particle size reduction ## Milling - The terms comminution, pulverization, milling and grinding are used synonymously for describing the process of size reduction. - The function of size reduction is to aid effectively in further processing. - Facilitate the powder mixing - Increase the...

# Particle size reduction ## Milling - The terms comminution, pulverization, milling and grinding are used synonymously for describing the process of size reduction. - The function of size reduction is to aid effectively in further processing. - Facilitate the powder mixing - Increase the dissolution rate of soluble ingredients - During the production of suspension to reduce the sedimentation rate - Reduce the bulk volume of the material to facilitate transportation. ## Applications of Size Reduction in Pharmaceutical Industry | Application | | :---: | | Dissolution and therapeutic efficacy | | Extraction | | Drying | | Flowability | | Mixing | | Formulation | ## Size Reduction Process - An example This image depicts a milling device reducing particle size of a material. The material enters the mill from the top, it then falls onto a metal plate with a rotating shaft that has impellers or blades, this breaks down the material into smaller particles. The material then travels through a wire mesh sieve to remove any very fine material, with the remaining larger material being recirculated by another blade and a shaft. ## Surface area to mass ratio The table below illustrates how particle surface area changes with decreased particle size, keeping the total mass constant. | | 10 µm (Coarse) | 2.5 µm (Fine) | 0.1 µm (Ultrafine) | | :---: | :---: | :---: | :---: | | Total mass | 1 | 1 | 1 | | Particle number | 1 | 64 | 1,000,000 | | Surface area per particle | 1 | 0.0625 | 0.0001 | | Total surface area per mass | 1 | 4 | 100 | - **10 µm (Coarse)** - Filtered in proximal airway, may irritate skin and mucosa - **2.5 µm (Fine)** - Reaches peripheral airway, cannot enter systemic circulation - **0.1 µm (Ultrafine)** - Higher adsorbed toxic material on surface, may enter systemic circulation ## 1 - Dissolution and Therapeutic Efficiency - The surface area per unit weight *increases* by size reduction. - This increased surface area effects the *therapeutic efficiency* of drugs possessing low solubility in body fluids by *increasing the area of contact* between the solid and the dissolving surfaces. - Thus, a given weight of finely powdered drug *dissolves in a shorter time* than does a coarser powder. Example: - The control of fineness of Griseofulvin has led to an oral dosage regimen half that was originally required. - The duration of an intramuscular injection of procaine penicillin can be controlled by the size of the suspended particles. - Parenteral suspensions should be easily drawn into a syringe (*syringeability*) and readily ejected from the syringe (*injectability*). - Syringeability and injectability are related to viscosity and particle size. - The size of particles used in *inhalation aerosols* determines position and retention time of the particles in the bronchopulmonary system. - The time required for the dissolution of solid chemicals in the preparation of solutions is shortened by the use of smaller particle size. ## 2 - Extraction - Smaller particles have a larger total surface area, which allows the solvent to come into contact with more of the material at once. This facilitates a more thorough extraction. - With smaller particles, the solvent does not need to penetrate as deeply into the material to reach the compounds of interest. This significantly reduces the time required for extraction. - After extraction, the remaining solid material needs to be separated from the liquid extract. Proper control of particle size helps achieve a faster and more efficient filtration process, preventing clogging and allowing for clearer filtrates. ## 3 - Drying - Milling increases surface area and *reduces the distance* moisture must travel, *speeding up* the drying process. - In wet granulation (during tablet production), sieving the wet mass ensures faster and more consistent drying. - **Micronization** and subsequent drying remove trapped solvents, enhancing the stability of the product. ## 4 - Flowability - Particle size and size distribution significantly influence the flow behavior of powders and granules. - Freely flowing powders and granules ensure consistent product quality in high-speed filling equipment and tablet presses. - Reducing particle size in suspensions with a high dispersed phase concentration increases viscosity. ## 5 - Mixing - The mixing or blending of several solid ingredients is *easier and more uniform* if the ingredients are approximately of the same size, *leading to uniformity of dose*. - Solid pharmaceuticals that are artificially colored are often milled to distribute the coloring agent to ensure that the mixture is not mottled as is uniform from batch to batch. ## 6 - Formulation - **Lubricants**, used in compressed tablets and capsules function by virtue of their ability to coat the surface of the granulation or powder. A fine particle size is essential if the lubricant is to function properly. - The milling of ***semi-solids*** (ointments and cream and pastes) provides a smooth texture and a better appearance in addition to improving physical stability. ## Mechanisms of Size Reduction - Each type of milling equipment will produce an approximate size reduction range. - The extent of size reduction is always related to milling time. ## Mechanisms of Milling Mills are designed to apply energy for size reduction using different mechanisms: - Cutting - Compression - Impact - Attrition - **Impact** - Occurs when a moving particle strikes a stationary surface - **Attrition** - Occurs when two surfaces move relative to each other - **Shear** - Occurs when a material is subjected to compression followed by shear forces to break down the material. - **Compression** - Occurs when a material is crushed between two surfaces by applying pressure. ## 1 - Cutting - **Mechanism:** Force is applied over a narrow area using a sharp edge, slicing the material into smaller pieces - **Example:** Knife mills or cutters used for fibrous materials. ## 2 - Compression - **Mechanism:** Material is crushed between two surfaces by applying pressure. - **Example:** Roller mills or jaw crushers used for brittle materials. ## 3 - Impact - **Mechanism:** Material comes into contact with a fast-moving part, transferring kinetic energy that creates internal stress and breaks the particles. - **Impact** occurs when the material is more or less stationary and is hit by an object moving at high speed or when the moving particle strikes a stationary surface. - **Example:** Hammer mills or ball mills used for both brittle and soft materials. ## 4 - Attrition - **Mechanism:** Material subjected to shear forces due to the relative motion of two surfaces, leading to particle breakage. - **In attrition:** the material is subjected to pressure as in compression, but the surfaces are moving relative to each other resulting in shear forces. - **Example:** Fluid energy mills or pin mills used for fine grinding. ## Milling Equipment | Methods | Example | Approx. particle size (μm) | | :---: | :---: | :---: | | Cutting | Scissors, Shears, Cutter Mill | 100-80,000 | | Compression | Roller Mill, Pestle-Mortar | 50-10,000 | | Impact | Hammer Mill, Disintegrator| 50-8000 | | Attrition | Colloidal Mill, Roller Mill | 1-50 | | Combined Impact and Attrition | Ball Mill, Fluid Energy Mill | 1-2000 | - Cutting and compression have limited uses in the pharmaceutical industry. - Impact and attrition are used more widely, both separately or in combination. - The term *mill* is normally used for machines for size reduction. ## Equipment - **Cutting methods:** Cutter mills - **Compression methods:** End runner mill & edge runner mill - **Compression & Attrition:** Roller mill - **Impact mill:** Hammer mill & Vibration mill - **Impact & Attrition:** Ball mill, Pin mill & Fluid energy mill ## Cutter Mills - On the small scale, size reduction by cutting can be carried out by a knife or a root cutter. - On a large scale, *cutter mills* are used like: - **Rotary Knife Cutters** are ideal for reducing tough, fibrous materials through cutting and shearing, achieving a maximum of 80-mesh size. - **Disc Mills** provide finer size reduction with adjustable settings and are suitable for pre-milled or suspended materials, offering versatility in pharmaceutical and industrial processes. ## Runner Mills - Can be carried out on a small scale using a mortar and pestle. - End-runner and edge runner mills are mechanized forms of mortar and pestle type compression milling. - Alternative efficient equipment (roller mill) - for mixing. This image depicts an end runner mill. It consists of a pestle and a mortar, the mortar is a steel bowl, and a pestle, that crushes and mixes the material with blades that scrape the material against the mortar as well. The grinding of material occurs because the pestle rotates in the mortar. This image depicts an edge runner mill. It consists of a large bowl or pan, with steel rollers on the outside, the rollers rotate and grind the material against the bowl as the material falls under the rollers. ## Three-Roller Mill - Roller mills consist of two to five smooth rollers, with the most common having three, that operate at different speeds. This results in a combination of compression and attrition. - The material travels from a *hopper* through two rollers, where it's crushed and sheared. This process happens again through a second set of rollers, with a narrower gap, which provides finer crushing. - A scraper removes the processed material from the final roller. - Used for size reduction in semi-solid preparation. ## Hammer Mills - Hammer mills consist of a series of four or more hammers, connected to a central shaft enclosed in a rigid material case. - During milling, the hammers *swing out radially* at high speed from the rotating central shaft, this creates a high impact with the material. - The velocity of the hammer produces high strain rates, so high that most particles undergo *brittle fracture*. - Any particles retained in the mill by a screen are further milled. ### Applications of Hammer Mills - Produce intermediate grade powders from almost any substance apart from sticky materials that clog or choke the screen. - Used for powdering barks, leaves, roots, and filter cakes. - Hammers with cutting edges can be used for granulation (the damp masses being cut to granules by the hammer). This produces granules with high uniformity. ### Advantages of Hammer Mills - Rapid in action. - Can be used for different types of materials. - The product size is controlled via - Speed of the rotor - Type and shape of the hammer - Size and shape of the mesh in the screen - The operation is continuous. - No friction between moving particles, leading to little metal abrasion and little contamination. ### Disadvantages of Hammer Mills - The high speed of the operation leads to heat generation, which affects thermolabile materials and drugs containing gums, fats and resins. Water cooling can be used to overcome the heat generated. - The rate of feed must be controlled, otherwise clogging or damaging the machine may take place. - The high speed of the operation may lead to hammer damage in presence of foreign objects, such as metals or stones in the feed (therefore, careful screening of the feed is essential). ## Vibration Mill - A cylindrical tank is filled (80% maximally) with porcelain or stainless-steel balls. - During milling, the whole body of the mill is vibrated by the motion of springs, and size reduction occurs by repeated impact with the vibrating balls. - It is a highly efficient mill. ## Ball Mills - In the ball mill, the particles receive *impacts* from the falling balls and are subjected to *attrition* as the balls slide over each other. - It consists of a cylinder rotating on a horizontal axis. - The cylinder may be made of metal, porcelain or rubber to reduce the abrasion and noise. - The cylinder contains 30-50% of it's capacity in balls. - Balls of different sizes are used to improve milling efficiency, the larger balls crush the feed, while smaller one form the fine product. ### Ball Mill Operations This image depicts a ball mill in operation (in a cross-section). The cylinder rotates with the balls inside, the balls are impacted by the cylinder and the balls themselves impact the material. ### Correct Cascade Operation of a Ball Mill This image depicts a cross-section of a ball mill in operation, demonstrating the best practice for the operation of a ball mill. The correct operation is to have a **cascade** of balls, to have balls flowing freely over each other to ensure consistent and effective milling. ### Ball Mill - Amount of Feed The amount of feed is critical. - Overfeeding exerts a *cushioning effect* on the other hand. - A small amount of feed increases the possibility of metal abrasion and contamination. ### Ball Mill - Speed of Rotation Speed of rotation is also critical. - Low speed leads to sliding of balls over one another, this will result in a loss of impact forces. - High speed leads to centrifugal force, which pushes the balls towards the wall. This will result in a loss of grinding. - The *optimum speed* is "about 2/3 the centrifugal speed", this allows both *impact and attrition*. ### Advantages of Ball Mills - **Versatile:** suitable for wet and dry grinding. - **Wide variety of materials**. - **Fine and uniform particle size**. - **Available in different sizes:** Can be used in R&D and for large production, compared to vibration mills which are mainly used on a small scale. - **Moderate energy consumption**. - **Homogenous mixture of the product.** - **Size reduction takes place in a closed container**: can be used for toxic materials. ### Disadvantages of Ball Mills - **Contamination** due to abrasion of the ball material. - **Soft and sticky materials**: can form a cake on the side of the mill or on the ball surfaces, which is reduced if a rubber tank was used. - **Very noisy:** compared to vibration mills. - **Slow:** compared to vibration mills, it is much slower (10 times the needed time). - **Wide size range** compared to vibration mills. ## Fluid Energy Mills - Called a *jet mill* or *micronizer*. - The *impacts and attrition* occur between rapidly moving particles. - A fluid (usually compressed air) is injected at high pressure through nozzles at the bottom of the loop, this creates a high velocity circulation in a very turbulent condition. - The high velocity of the air gives rise to zones of turbulence into which solid particles are fed. - Used mainly to grind sensitive materials (inert gas can be used with very sensitive materials) to fine powder. - Pretreatment with another mill may be needed to increase the efficiency of grinding. This image depicts the cross-section of a fluid energy mill. The material is fed into the center of the machine. The mill uses compressed air jets to propel the material through a turbulent zone, in the turbulent zone, particles collide and break down into smaller particles. The fines are then separated from the larger particles in a classifier. ### Advantages of Fluid Energy Mills - Very small particle size of the product (smallest possible). - Cooling effect of the gases counteracts the heat produced during attrition, which protects the heat-sensitive materials. - No source of abrasion and contamination. ### Disadvantages of Fluid Energy Mills - Energy consumption. - The fed device may be clogged with a clump of materials. - Compressed air may produce static electricity. ## Pin Mill (Kek Mill) - Works by impact and attrition. - Consists of two discs with closely spaced pins, one disc is fixed, and the other is rotating at high speed. - Impact and attrition occurs between the particles and the pins. This image depicts a pin mill cross-section. The material is fed into the mill, the material then falls between two metal plates, one is fixed, and one is rotating at high speed. The rotating plate has pins protruding, and as the material falls between the two plates, it is impacted by the rotating pins and is broken down into smaller pieces. ## Factors Affecting Size Reduction - **Nature of the material** - Material hardness - Material brittleness and plasticity - Material stickiness - Fibrous materials - **Moisture content** - **Temperature** - **Particle shape** ## 1.a - Surface Hardness - **Surface hardness**: the hardness of material is measured by a scratch criterion, this scale was devised by German mineralogist called **Mohs**. - Harder materials are more difficult to *comminute* (reduce to small particles) and lead to abrasive wear of metal mill parts, which causes product contamination. - Conversely, materials with large elastic components, such as rubber, are extremely soft, yet difficult to achieve size reduction. ### Mohs' Scale - Mohs' scale is a table of materials, at the top of which is *diamond*; it has a Mohs hardness of more than 7. It has a surface so hard that it can scratch anything below it. - At the bottom of the table with Mohs hardness less than 3 is *talc*. It is soft enough to be scratched by anything above it. This image depicts the Mohs' scale. The scale ranges from 1 - 10, with *talc* being the softest substance at 1, and *diamond* being the hardest substance at 10. ## 1.b - Material Brittleness and Plasticity - **Brittleness** refers to a material's tendency to fracture rather than deform plastically when subject to stress. - **Materials with plastic behavior**: include **rubber** (soft under ambient conditions), **waxy substances** such as stearic acid (soften when heated), and "sticky" materials such as **gums**. - These materials are capable of consuming large amounts of energy through elastic and plastic deformation without size reduction or fragmentation. ## Glass Transition point (Tg) - The *glass transition point* (Tg) refers to the temperature at which an amorphous (non-crystalline) material transitions from a hard, brittle "glassy" state to a soft, rubbery, or viscous state. - Below this temperature, the material behaves like a brittle solid, above it, the material exhibits more plastic or elastic behavior. ## 1.b - Material Brittleness and Plasticity - Continued - **Polymeric materials:** which resist comminution at ambient or elevated temperatures, can be more easily size reduced by decreasing the temperature below the glass transition point of the material. - When this is carried out, the material undergoes a transition from plastic to brittle behavior, and *crack propagation* is facilitated. ## 1.d - Fibrous Material - **Fibrous materials** cannot be crushed by pressure or impact and must be cut. ## 2 - Moisture content - Dry powders containing less than 5% water are more brittle and easily comminuted. - The presence of more than 5% water hinders comminution and produces a sticky mass upon milling. The sticky material clogs the milling equipment, which leads to reduced efficiency and frequent interruptions. - Water concentration more than 50% transforms the mass into a slurry or fluid suspension; in this case wet milling should be used. ### How to overcome moisture issues - Pre-drying - Use moisture absorbent (desicant) - Use cryomilling - Use wet milling ## 3 - Temperature - The heat evolved during milling *softens and melts materials* with a low melting point, such as synthetic gums (polyethylene glycol & polyvinylalcohol), waxes (paraffin wax) and resins. - *Heat sensitive drugs*, such as Aspirin and vitamin C, can be degraded or even charred. - *Pigments*, such as ocher and sienna, may change their shade of color if the milling temperature is excessive. - *Unstable compounds*, such as organic nitrates and peroxides, may explode if the temperature is high. ## 4 - Particle Shape - An impact mill produces sharp, irregular particles, which may not flow readily. When specifications demand a milled product that will flow freely, it may be better to use an attrition mill, which produces free-flowing spherioidal particles. | Property | Impact Mill | Attrition Mill | | :---: | :---: | :---: | | Particle Shape | Irregular, sharp-edged | Spheroidal, rounded | | Flowability | Poor (particles interlock) | Good (free-flowing particles) | | Surface Texture| Rough | Smooth | | Preferred Applications | Tablets, where flow is less critical | Capsule filling, powders requiring good flow | ## Wet and Dry Grinding | Aspect | Dry Milling | Wet Milling | | :---: | :---: | :---: | | Particle Size Limit | ~100 µm (without aids) | ~10 µm (limited by flocculation) | | Dust Hazards | Present | Eliminated | | Power Consumption | Generally higher | Lower (in low-speed mills) | | Need for Drying | No-Needed | Needed | | Application | Moisture-sensitive products | Non-sensitive or water-compatible products | ## Factors Influencing Mill Choice Factors affecting mill choice for any given application: - **Product specifications** - Desired particle size and distribution - Particle shape - Moisture content - Physical and chemical properties - **Mill Capacity and Production Rate** - Matching production needs with equipment capacity. - **Dust Control** - Minimising drug loss - Reducing health hazards and contamination risks. - **Sanitation** - Ease of cleaning and sterilisation. - **Auxiliary Equipment Compatibility** - Integration with cooling systems, dust collectors, and feeders. - **Operation Mode** - Suitability for batch or continuous processes. - **Economic Considerations** - Equipment cost - Power and space requirements - Labor costs.