1. Milling 26-2-2014

2. Is the reduction in the size mass by conversion of the large solid unit mass into smaller one by mechanical process. This needs energy to break down the mass into smaller one and this process depends on the size of the starting material (the feed), the orientation of the material in the crushing machine, the time of milling to which these materials are subjected, the type of mill and the particle size required. The large particles need large energy than the small one. Different types of mill give different types of orientation and power.

3. The process of size reduction is conducted by applying force which results from different sources (compression, shearing or tension). Compression is a crushing force, shearing is a cutting force and tension is the force that tend to elongate a particle or pull it apart. Each particle will have initial defect of different degrees and possible internal stress as a result of prior manufacturing operations. Cracks started inside the mass and when the force applied exceeds the force of attraction between particles, the cracks will be bigger and a reduction in the particle size proceeds as the force is continued.

4. Various terms (crushing, disintegration, dispersion, grinding, and pulverization) have been used synonymously with comminution depending on the product, the equipment, and the process. Milling equipment is usually classified as coarse, intermediate or fine according to the size of the milled product. Coarse milling produces particles larger than 20-mesh, intermediate milling produces particles from 200 to 20 mesh (74 to 840 microns), and fine milling produces particles smaller than 200- mesh.

5. Advantages of Milling: Increase surface area which increases the solubility, and dissolution rate of material so enhance its bioavailability. Increase in the area of contact between the solid and the dissolving fluid. Improve color and/or active ingredient dispersion in tablet excipient. Improve mixing of materials together so give fewer problems in uniformity of weight and contents of tablets. Higher surface area means better drying. Improve mixing of materials together so give fewer problems in uniformity of weight

6. Disadvantages of Milling: A possible change in polymorphic form of the active ingredient rendering it less or totally inactive or unstable. i.e. will affect the therapeutic activity of drug. Possible degradation of the drug as a result of heat buildup during milling by oxidation or adsorption of unwanted moisture due to the increased surface area. A decrease in bulk density may cause problems in the flowability of material. A decrease in particle size may create static charge problems causing the small drug particles to agglomerate therefore effectively decreasing surface area. This may decrease the dissolution rate.

7. Pharmaceutical Application The surface area per unit weight, which is known as the specific surface, is increased by size reduction. This increased specific surface affects the therapeutic efficiency of medicinal compounds that possess a low solubility in body fluids by increasing the area of contact between the solid and the dissolving fluid. Thus, a given weight of a finely powdered medicinal compound dissolves in a shorter time than does the same weight of a coarser powder.

8. The control of fineness of griseofulvin led to an oral dosage regimen half that of the originally marketed product. The rectal absorption of aspirin from a theobroma oil suppository is related to particle size. Increased antiseptic action has been demonstrated for calomel ointment when the particle size of calomel has been reduced. The size of particles used in inhalation aerosols determines the position and retention of the particles in the bronchopulmonary system

9. Size may affect texture, taste, and rheology of oral suspensions in addition to absorption. Extraction from animal glands (liver & pancreas), and from crude vegetable drugs, is facilitated by comminution. The time required for extraction is shortened by the increased area of contact between the solvent and the solid and the reduced distance the solvent has to penetrate into the material. Similarly, the time required for dissolution of solid chemicals in the preparation of solutions is shortened by the use of smaller particles. The drying of wet masses may be facilitated by milling, which increases the surface area and reduces the distance the moisture must travel within the particle to reach the outer surface.

10. In the manufacturer of compressed tablets, the granulation of the wet mass results in more rapid and uniform drying. The dried tablet granulation is then milled to a particle size and distribution that will flow freely and produce tablets of uniform weight. The flowability of powders and granules in high-speed filling equipment and in tablet presses affects product uniformity. The mixing or blending of several solid ingredients of a pharmaceutical is easier and more uniform if the ingredients are approximately the same size. This provides a greater uniformity of dose.

11. Solid pharmaceuticals that are artificially colored are often milled to distribute the coloring agent to ensure that the mixture is not mottled and is uniform from batch to batch. 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 ointments, creams, and pastes provides a smooth texture and better appearance in addition to improved physical stability.

12. Size Distribution and Measurement In naturally occurring particulate solids and milled solids, the shape of particles is irregular, and the size of the particles varies within the range of the largest and smallest particles. For convenience of mathematical treatment, an irregular particle is considered in terms of an equivalent sphere. The size of the particle can then be expressed by a single parameter that is the diameter (d). It is only required that the surface area is proportional to the square of the diameter and the volume is proportional to the cube of the diameter. The volume of a particle may be determined by displacement in a liquid and equated to the volume of a hypothetic sphere possessing an equivalent diameter. As the volume of a sphere is πd 3 /6, the equivalent diameter of an irregular particle with a volume V is:

13. The effective diameter of particles based on their rate of sedimentation is commonly used in pharmacy. The rate of sedimentation is the time required for the particle to settle between two fixed points in a suitable liquid. The effective or Stokes' diameter is the diameter of a sphere that requires the same time to settle between two fixed points in the liquid as does the irregular particle. The arithmetic average diameter is the sum of the diameters of the separate particles divided by the number of particles and it is equal to:

14. Using the logarithmic form of this equation, the geometric mean diameter of a number of particles is calculated by using the following equation: Size distributions that follow the probability law are referred to as normal or Gaussian distribution as shown in the figure below:

15. Methods for Size Distribution Measurement: 1- Microscopy: It is the most direct method for size distribution measurement. In an ordinary microscope is used to measure particles from 0.4-150 microns. With special lenses and ultraviolet light, the lower limit may be extended to 0.1 micron.