1. Micromeritics

2. What is Micromeritics? The Science and Technology of small particles is known as Micromeritics. Micromeritics deals with- Particle size and Size Distribution Methods of Determining particles size Particle shape and surface area Pore size

3. Importance of Studying Micromeritics Knowledge and control of the size and the size range of particle is of profound importance in pharmacy. Size and surface area can be related to the physical, chemical and pharmacological properties of a drug. 1.Particle size affect its release from dosage forms that are administered orally, parenterally, rectally and topically.

4. 2. Physical stability and pharmacologic response of suspensions, emulsion and tablets depends on particle size. 3. It is also important in flow properties and proper mixing of granules and powders in tableting. 4. Both Tablets and capsules are produced using equipment which controls the mass of drug and other particles by volumetric filling. Therefore any interference with the uniformity of fill volumes may alter the mass of drug incorporated into the tablet or capsules. Thus reduce the uniformity of the medicine.

5. 5. Powders with different particle sizes have different flow and packing properties which alter the volumes of powder during each encapsulation or tablet compression. 6.The rate of dissolution depends on the several factors. One factor is the particle size. Thus particles having small dimensions will tend to increase the rate of solution.

6. Different means of expressing particle size There are different means of expressing particle size: Millimeter (mm)……. …10 -3 meter Micro meter (µ m) ……...10 -6 meter nano meter (nm)…….. 10 -9 meter pico meter ……………. 10 -12 meter famto meter………………..10 -15 meter

7. Particle Dimension in Pharmaceutical Disperse system Particle size Micrometer (µ m) Millimeter (mm) Disperse systems 0.5-10 0.0005 - 0.010 Suspension, fine emulsion 10-50 0.010- 0.050 Coarse emulsion,flocculated suspension 50- 100 0.50- 0.100 fine powder range 150-1000 0.150-1.000 Coarse powder range 1000- 3360 1.000- 3.360Average granule size

8. Particle size and analysis Stokes’ law/relation v: velocity of the sedimentation r: particle radius D: particle diameter in cm d 1 : density of the particle d 2 : density of the liquid g = gravitational constant=980.7 cm·sec -2

9. ɳ = the viscosity of the medium in poises, i.e., g·cm-1·sec-1 (poise) in cgs units Incidentally, the water at 20 degree centigrade has a viscosity of approximately one centipoises (0.01 poise). 1 g·cm-1·sec-1 = 1 p = 100 cp

10. On micromeritics Micromeritics is the science of small particles; a particle is any unit of matter having defined physical dimensions. Micromeritics includes a number of characteristics including particle size, particle size distribution, particle shape, angle of repose, porosity, true volume, bulk volume, apparent density and bulkiness. A reduction in a powder’s particle size increases the number of particles and the powder’s total surface area.

11. The size of a sphere is usually expressed in terms of diameter. As the degree of asymmetry of particles increases, it is difficult to express size in terms of a meaningful diameter. Equivalent spherical diameter is used in this cases where the size of a particle is compared to the diameter of a sphere having the same surface area, volume, weight or rate of sedimentation. Equivalent surface diameter (ds) is the diameter of a sphere having the same surface area as the particle in question. Define equivalent volume diamtre (dv), equivalent weight diameter (dw), equivalent stokes diameter (dst) in the same way.

12. Methods of determining particle size Optical Microscopy Sieving Methods Sedimentation Particle volume measurement Methods of determining surface area Adsorption method Air permeability method

13. Optical Microscopy Ordinary microscope can be used to determine particle size having a range of 0.2 to 100 μm. Procedure An emulsion/suspension of the substance under examination is prepared first. The emulsion/suspension should be sufficiently dilute. The emulsion or suspension is then mounted on a mechanical stage of the microscope.

14. The microscope eyepiece is fitted with a micrometer by which the size of the particles or droplets can be measured. The field can be projected onto a screen where the particles are measured more easily A photograph can also be taken from which a slide is prepared and projected on a screen for measurement.

15. Popular measurements in microscopic method are- 1.Martin diameter 2.Feret diameter

16. Martin Diameter This is not an diameter in its actual sense but the common basis of a group of diameters. The Martin diameter, xM, is that chord dividing the projection area of the particle into two equal halves.

17. orientation of measurement

18. Martin Diameter, Maximal (MARTIN_MAX), or Minimal (MARTIN_MIN) This is the maximal or minimal Martin diameter after consideration of all possible orientations (0°...180°). The Martin diameters for a sufficient number of orientations are calculated, and their maximum or minimum, respectively, is selected. Martin Diameter, Mean Value (MARTIN_MEAN) This is the mean value of the Martin diameters of all possible orientations according to the principle described above.

19. Feret Diameter It is defined as the distance between two parallel tangents of the particle at an arbitrary angle. Feret Diameter, Maximum (FERET_MAX) or Minimum (FERET_MIN) Maximal or minimal Feret diameter after consideration of all possible orientations (0°...180°). The Feret diameters for a sufficient number of angles are calculated, and their maximum or minimum is selected. If a particle has an irregular shape, the Feret diameter usually varies much more than with regularly shaped particles. The maximum can therefore be significantly larger, the minimum significantly smaller than the diameter of the equivalent circle.

20. Feret Diameter, Mean Value (FERET_MEAN) Mean value of the Feret diameters over all orientations according to the principle described above.

22. Advantages of microscopic method Simple and intuitive Give shape information Reasonable amount of sample

23. Disadvantages of microscopic method Diameter of particle is obtained only from two dimensions of the particle :length and breadth. No estimation of depth (thickness) of the particle is ordinarily available The number of particles that must be counted (300-500) to obtain a good estimation of the distribution makes the method slow and tedious. So, microscopic examination of a sample should be undertaken even the when other methods of particle analysis are being used, because the presence of agglomerates and particles of more than one component may often be detected.

24. Particle size Determined by microscopic method size group of counted particles/μm Middle value μm “d” Number of particles per group “n” “nd” 40-605015750 60-8070251750 80-10090958550 100-12011014015400 120-1401308010400 ∑n=355∑nd=36850

25. Sieving Method Sieving method is an ordinary and simple method. It is widely used as a method for the particle size analysis. Range of analysis: The International Standards organization (ISO) sets a lowest sieve diameter of 45 µm and since powders are usually defined as having a maximum diameter of 1000 µm, this could be considered to be the upper limit.

26. Sample preparation and analysis condition 1. Sieve analysis is usually carried out using dry powders. 2. Although, for powders in liquid suspension or which agglomerate during dry sieving, a process of wet sieving can be used.

27. Principle of Measurement: Sieve analysis utilizes a woven, punched or electroformed mesh often in brass, bronze or stainless steel with known aperture (hole) diameters which form a physical barrier to particles. Most sieve analyses utilize a series, stack ( Load /Mountain ) of sieves which have the smallest mesh above a collector tray followed by meshes which get progressively coarser towards the top of the series.

28. A sieve stack usually comprises 6-8 sieves. Powder is loaded on to the coarsest sieve of the assembled stack and the nest is subjected to mechanical vibration for, say 20 minutes. After this time, the particles are considered to be retained on the sieve mesh with an aperture corresponding to the minimum or sieve diameter. A sieving time of 20 minutes is usually performed.

29. ADVANTAGES AND DISADVANTAGES OF SEIVING METHOD Advantages: 1. This method is very simple. 2. Not expensive 3. Easy to operate Disadvantages: 1. Not too much precise method. 2. Not applicable for all disperse systems.

30. Particle size Determined by sieving method Sieve number Arithmetic mean opening (mm) Weight retained (G) % Retained %Retained × Mean opening 20/400.63015.514.39.009 40/600.33525.823.77.939 60/800.21448.344.49.502 80/1000.16315.614.32.330 100/1200.1373.53.30.452 108.7100.029.232

31. Sedimentation Methods Sedimentation Method is also an ordinary and simple method. It is widely used as a method for the particle size analysis. Range of analysis: 0.001 0.01 0.1 1 10 100 1000 Centrifugal sedimentation Gravitational Particle diameter (µm)

32. Sedimentation method is based on the principle of stoke's law The equation is applicable only for particles having spherical shape, falling freely without hindrance and at a constant rate. The law can be applied to irregularly shaped particles as long as one realizes that the diameter obtained is a relative particle size equivalent to that sphere falling at the same velocity as that of the particles under consideration.

33. The particles must not be aggregated or clumped together in the suspension because such clumps would fall more rapidly than the individual particles and erroneous result may occur. The proper deflocculating agent must be found for each sample that will keep the particles free and separate as they fall through the medium.

34. Sample preparation and analysis conditions In this method particle size can be determined by examining the powder as it sediments out. (a) In cases where the powder is not uniformly dispersed in a fluid it can be introduced as a thin layer on the surface of the liquid. (b) If the powder is lyophobic, e.g. hydrophobic in water, it may be necessary to add dispersing agent to aid wetting of the powder. (c) In case where the powder is soluble in water it will be necessary to use non- aqueous liquids or carry out the analysis in a gas.

35. Principle of Measurement Particle size analysis by sedimentation method can be divided into two main categories according to the method of measurement used. 1. One of the type is based on measurement of particle in a retention zone. 2. Another type uses a non-retention measurement zone.

36. An example of a non-retention zone measurement is known as the pipette method. In this method, known volumes of suspension are drawn off and the concentration differences are measured with respect to time. One of the most popular of the pipette methods was that developed by Andreasen and Lundberg and commonly called the Andreasen pipette.

38. The Andreasen fixed-position pipette consists of a 200 mm graduate cylinder which can hold about 500 ml of suspension fluid. A pipette is located centrally in the cylinder and is held in position by a ground glass stopper so that its tip coincides with the zero level. A three way tap allows fluid to be drawn into a 10 ml reservoir which can then be emptied into a beaker or centrifuge tube.

39. The amount of powder can be determined by weight following drying or centrifuging. The weight of each sample residue is therefore called the weight of undersize and the sum of the successive weight is known as the cumulative weight of undersize. It can be expressed directly in weight units or percent of the total weight of the final sediment. The data of cumulative weight of undersize is used for the determination of particle weight distribution, number distribution.

40. The particle diameter in each sample is then calculated from Stokes’ Law. Note: The method is applicable for spheres falling freely without hindrance and at a constant rate.

41. Coulter Counter Method Coulter Counter Method is a sophisticated method. It is a precise and accurate method. The method is based on determination of particle size by measuring particle volume. Range of analysis: 0.001 0.01 0.1 1 10 100 1000 Coulter counter Particle diameter (µm)

42. 1. Powder samples are dispersed in an electrolyte to form a very dilute suspension. 2.The suspension is usually subjected to ultrasonic agitation for a period to break up any particle agglomerates. 3. A dispersant may also be added to aid particle deagglomeration. Sample preparation and analysis conditions

43. Wallace Coulter - Coulter orifice - 1948-1956 Cell counter vacuum orifice ©J.Paul Robinson

44. The particle suspension is drawn through an aperture accurately drilled through a sapphire crystal set into the wall of a hollow glass tube. Electrodes, situated on either side of the aperture and surrounded by an electrolyte solution. Monitor the change in electrical signal which occurs when a particle momentarily occupies the orifice and displaces its own volume of electrolyte. The volume of suspension drawn through the orifice is determined by the suction potential created by a mercury thread. Principle of Measurement

45. The volume of electrolyte fluid which is displaced in the orifice by the presence of a particle causes a change in electrical resistance between the electrodes which is proportional to the volume of the particle. The change in resistance is converted between into a voltage pulse which is amplified and processed electronically.

46. In order to carry out size analysis over a wide diameter range it will be necessary to change orifice diameter used, to prevent coarse particles blocking a small diameter orifice. Conversely, finer particles in a large diameter orifice will cause too small a relative in volume to be accurately quantified. Advantages: 1. It is one of the precise and accurate method. 2. Analysis range is wide. Disadvantages:1. It is a expensive method.

47. The first Coulter Counter

49. Other Methods to Determine Particle Size Laser Light Scattering X-ray Sedimentation Electrical Sensing Zone Particle Size by Surface Area

50. Light energy diffraction or light scattering

51. Laser Holography 1.4 to 100 μm provide information on shape

52. PARTICLE PROPERTIES & FLOW Particle size - Larger than 250µ are free flowing but as size falls below 100µ it is cohesive; collection of powder will be either- A. Monodisperse ( having particles of same size ) or B. Polydisperse (having particles of more than one size). Particle shape - Spheres have minimum contact/surface area & hence optimal flow; particle flakes have irregular shape & high surface to volume ratio & poor flow.

53. Other properties of powders : Apart from fundamental properties, there are some other properties. These are based on fundamental properties. These are : 1. Porosity 2. Packing arrangements 3. Densities of particles: Bulk density, Tapped density. Dense particles are less cohesive than less dense particles of the same size & shape. 4. Particle volume: Bulk volume, Tap volume.

54. 5. Particle surface area: Surface area is important characteristic for understanding surface adsorption and dissolution rate studies. Methods for determining surface area: A. Adsorption method B. Air permeability method

55. Bulk density :The weight per volume of a powder. It is defined as the mass of many particles of the material divided by the total volume they occupy. The total volume includes particle volume, inter-particle void volume and internal pore volume. Tapped density: Tapped density is the term used to describe the bulk density of a powder (or granular solid) after consolidation/compression prescribed in terms of "tapping" the container of powder a measured number of times, usually from a predetermined height. The method of "tapping" is best described as "lifting and dropping".

56. Bulk volume: The bulk volume of a powder is the weight of the powder divided by the density. Tapped volume: The tapped volume of a powder is the weight of the powder (after tapping a certain period of time) divided by the density.

57. Adsorption method for measurement of surface area: An instrument used to obtain data for calculation of surface area is Quantasorb. The absorption and desorption is measured with thermal conductivity detector, when a mixture of helium and nitrogen is passed through the cell, containing powder. Here nitrogen is absorbate gas and helium is inert and is not adsorbed on surface. With the help of mathematical calculations and graph studies, nitrogen adsorbed and area are calculated.

58. Flow properties: Powders may be free-flowing or cohesive. Factors those affect flow properties are- a) particle size b) shape c) porosity d) density e) texture. Compaction Angle of repose Carr’s Index: (Tapped density - Poured density) x 100 Tapped density Hausner’s ratio: Tapped density x 100 Poured density

59. Angle of repose (measurement of flow property) The angle of repose is a parameter used to estimate the flowability of a powder. h r θ Powders with low angles of repose will flow freely and powders with high angles of repose will flow poorly. A number of factors, including shape and size, determine the flowability of powders. Shape: Spherical particles flow better than needles. Size: Very fine particles do not flow as freely as large particles. a) 250-2000 μm: flow freely if the shape is amenable b) 75-250 μm: may flow freely or cause problems, depending on shape and other factors c) less than 100 μm: Flow is problem with most substances.

61. Carr index The Carr index is an indication of the compressibility of a powder. It is calculated by the formula, VB - VT C = 100 × -------------- VB where VB is the freely settled volume of a given mass of powder, and VT is the tapped volume of the same mass of powder. It can also be expressed as, ρ B C = 100 × ( 1- ------------ ) ρ t where ρ B is the freely settled bulk density of the powder, and ρ t is the tapped bulk density of the powder.

62. The Carr index is frequently used in pharmaceutics as an indication of the flowability of a powder. A Carr index greater than 25% is considered to be an indication of poor flowability, and below 15%, of good flowability. The Carr index is related to the Hausner ratio, another indication of flowability, by the formula 1 C = 100 × ( 1 - ------- ) H

63. The Hausner ratio is a number that is correlated to the of a powder or granular material. It is calculated by the formula ρT H= -------------- ρB where ρB is the freely settled bulk density of the powder, and ρT is the tapped bulk density of the powder. The Hausner ratio is not an absolute property of a material; its value can vary depending on the methodology used to determine it. Hausner ratio