Unit-3 MICROMERITICS.pdf physical pharmacy 1
- 2. ❖Introduction Knowledge of Size and surface area of a particle can be related to the physical, chemical and pharmacological properties of drug. Clinically particle size of the drug effect its release from dosage form that are administered in different routes. The successful formulation of suspension, emulsions, tablets should have both physical stability and pharmacological response. In the area of tablet and capsule manufacture control of particle size is essential in achieving the necessary flow properties and proper mixing of granules.
- 3. ❖ Particle size and Distribution Particles of one size are called mono disperse and sample is known as mono disperse sample Particles of more than one size are called poly disperse sample known as poly disperse sample In poly disperse sample two properties are important A. Shape and Surface area of individual particles B. Size range and number or weight of particles. The size of the sphere expressed in terms of its diameter. As the degree of assymetry of particles increases difficulty of expressing size in terms of diameter. There is no one unique diameter for a particle . Equivalent spherical diameter which relates the size of the particle to the diameter of a sphere having the same surface area, volume, or diameter.
- 4. Thus the surface diameter ds is the diameter of the sphere having same surface area. The diameter of the sphere having same volume as the particle is the volume diameter dv whereas projected diameter dp is the diameter of a sphere having same observed area as the particle when viewed normal to its most stable plane. The size can also expressed as stokes diameter dst which describes an equivalent sphere undergoing sedimentation at the same rate as the assymetric particle. Type of diameter used to reflects the method employed to obtain the diameter. Projected diameter is obtained by microscopic techniques where as stokes diameter is determined from sedimentation studies of suspended particles.
- 5. Any collection of particles is usually poly disperse. It is therefore necessary to know not only the size of a certain particle but also how many particles of the same size exists in the sample. Estimation of size range present and number and weight fraction of each particle size is important. Particle size distribution is use to estimate an average particle size for the sample. ❖Average Particle size Microscopic examination ofa sample of a powder conducted and recorded the number of particles lying in various size ranges. Data from such determination is used to calculate average or mean diameter.
- 6. N is the number of particles in a size range whose mid point d is the one of the equivalent diameter. P indicates size of individual particle because d raised to the power p=1,p=2,p=3 is an expression of the particle length, surface, or volume respectively. For a collection of particles the frequency with which a particle in a certain range occurs is expressed by ndf. When the frequency index f has values of ,1,2,or 3the size frequency distribution is expressed in terms of total number, length, surface or volume of particles.
- 7. ❖ Particle size distribution When the number or weight of particles lying within a certain size range is plotted against the size range or mean particle size so called frequency distribution curve is obtained. An alternative method of representating data is to plot either the cumulative percentage over or under a particle size.
- 8. PSD is usually defined by the method by which it is determined. The most easily understood method of determination is sieve analysis, where powder is separated on sieves of different sizes. Thus, the PSD is defined in terms of discrete size ranges when sieves of these sizes are used. The PSD is usually determined over a list of size ranges that covers nearly all the sizes present in the sample. Some methods of determination allow much narrower size ranges to be defined than can be obtained by use of sieves, and are applicable to particle sizes outside the range available in sieves. However, the idea of the notional "sieve", that "retains" particles above a certain size, and "passes" particles below that size, is universally used in presenting PSD data of all kinds. The PSD may be expressed as a "range" analysis, in which the amount in each size range is listed in order.
- 9. It may also be presented in "cumulative" form, in which the total of all sizes "retained" or "passed" by a single notional "sieve" is given for a range of sizes. Range analysis is suitable when a particular ideal mid-range particle size is being sought, while cumulative analysis is used where the amount of "under-size" or "over-size" must be controlled. The way in which "size" is expressed is open to a wide range of interpretations. A simple treatment assumes the particles are spheres that will just pass through a square hole in a "sieve". In practice, particles are irregular – often extremely so, for example in the case of fibrous materials – and the way in which such particles are characterized during analysis is very dependent on the method of measurement used.
- 10. ❖Measurement Techniques 1.Sieve analysis Sieve analysis is often used because of its simplicity, cheapness, and ease of interpretation. Methods may be simple shaking of the sample in sieves until the amount retained becomes more or less constant. Alternatively, the sample may be washed through with a non-reacting liquid (usually water) or blown through with an air current.
- 11. Advantages: This technique is well-adapted for bulk materials. A large amount of materials can be readily loaded into 8-inch- diameter (200 mm) sieve trays. Two common uses in the powder industry are wet-sieving of milled limestone and dry-sieving of milled coal. Disadvantages: Many PSDs are concerned with particles too small for separation by sieving to be practical. A very fine sieve, such as 37 μm sieve, is exceedingly fragile, and it is very difficult to get material to pass through it. The amount of energy used to sieve the sample is arbitrarily determined. Over-energetic sieving causes attrition of the particles and thus changes the PSD, while insufficient energy fails to break down loose agglomerates.
- 12. Although manual sieving procedures can be ineffective, automated sieving technologies using image fragmentation analysis software are available. These technologies can sieve material by capturing and analyzing a photo of material. 2.Sedimentation techniques These are based upon study of the terminal velocity acquired by particles suspended in a viscous liquid. Sedimentation time is longest for the finest particles, so this technique is useful for sizes below 10 μm, but sub-micrometer particles cannot be reliably measured due to the effects of Brownian motion. Typical apparatus disperses the sample in liquid, then measures the density of the column at timed intervals.
- 13. Advantages: This technique determines particle size as a function of settling velocity. Disadvantages: Sample must be dispersed in a liquid medium... some particles may (partially or fully) dissolve in the medium altering the size distribution, requiring careful selection of the dispersion media. Density is highly dependent upon fluid temperature remaining constant. X-Rays will not count carbon (organic) particles. Many of these instruments can require a bulk sample (e.g. two to five grams).
- 14. 3.Air elutriation analysis Material may be separated by means of air elutriation which employs an apparatus with a vertical tube through which fluid is passed at a controlled velocity. When the particles are introduced, often through a side tube, the smaller particles are carried over in the fluid stream while the large particles settle against the upward current. If we start with low flow rates small less dense particle attain terminal velocities, and flow with the stream, the particle from the stream is collected in overflow and hence will be separated from the feed. Flow rates can be increased to separate higher size ranges. Further size fractions may be collected if the overflow from the first tube is passed vertically upwards through a second tube of greater cross- section, and any number of such tubes can be arranged in series.
- 15. Advantages: A bulk sample is analyzed using centrifugal classification and the technique is non-destructive. Each cut-point can be recovered for future size-respective chemical analyses. This technique has been used for decades in the air pollution control industry (data used for design of control devices). This technique determines particle size as a function of settling velocity in an air stream (as opposed to water, or some other liquid). Disadvantages: A bulk sample (about ten grams) must be obtained. It is a fairly time-consuming analytical technique.
- 16. ❖ Number and weight distributions ❖The data for number distribution were collected by counting technique such as microscopy also determined by sedimentation or sieving analysis. ❖Two approaches are available. Provided the general shape and density of particles are independent of the size range present in the sample ❖An estimate of the weight distribution of the data can be obtained by calculating the percent weight nd3 and cumulative percent frequency under size weight.
- 18. Particle number A significant expression in particle technology is the number of particles per unit weight N which is expressed in terms of dvn The number of particles per unit weight is obtained as follows Assume that the particles are spheres the volume of a single particle = ∏ dvn 3 /6 and mass (volume ×density) = ∏ dvn 3 ρ/6g ∏ dvn 3 ρ/6g/ 1particle = 1g/N N=6/ ∏ dvn 3 ρ
- 19. ❖Methods of determining Particle size Many methods available for determining particle size such as optical microscopy, sieving, sedimentation and particle volume measurement. 1. Optical microscopy (range: 0.2-100 µm). 2. Sieving (range: 40-9500 µm). 3. Sedimentation (range: 0.08-300 µm). 4. Particle volume measurement (range: 0.5-300 µm).
- 20. Particle size Method 1 μm Electron microscope, ultracentrifuge, adsorption 1 – 100μm Optical microscope, sedimentation, coulter counter, air permeability >50 μm Sieving
- 21. 1. Optical Microscopy • According to the optical microscopic method, an emulsion or suspension is mounted on ruled slide on a mechanical stage. • The microscope eyepiece is fitted with a micrometer by which the size of the particles can be estimated. • The field can be projected on to a screen where the particles are measured more easily or a photograph can be taken from which a slide is prepared and projected on a screen for measurement. Disadvantage of microscopic method The diameter is obtained from dimensions of the particle. The number of particles that must be counted (300-500) to obtain a good estimation of the distribution makes the method somewhat slow and tedious
- 22. ❖Sieving (range: 40-9500 µm) Standard size sieves are available to cover a wide range of size. These sieves are designed to sit in a stack so that material falls through smaller and it reaches a mesh which is too fine for it to pass through the stack of sieves is mechanically shaken to promote the passage of the solids. The fraction of the material between pairs of sieve sizes is determined by weighing the residue on each sieve. The result achieved will depend on the duration of the agitation and the manner of the agitation.
- 24. ❖ Sedimentation (range: 0.08-300 µm) By measuring the terminal settling velocity of particles through a liquid medium in a gravitational centrifugal environment using andreason apparatus. The particle size in the sub sieve can be obtained by gravity sedimentation as expressed in stokes law V =h/t = dst 2(ρs- ρo)g / 18ƞ0 Dst = √ 18ƞ0 / (ρs - ρo)gt V is the rate of settling h is the distance of fall in time t, dst is the mean diameter of the particles based on velocity of sedimentation , ρs is density of the particles
- 25. For stokes law to apply a further requirement is that the flow of dispersion medium around the particle as its sediments is laminar or stream line. The rate of sedimentation of a particle must not be so rapid that turbulence is setup because this in turn will affect the sedimentation of the particle. Whether the flow is turbulent or laminar is indicated by dimension less Reynolds number Re Re =v d ρ0 /ƞ0 Reaaranging this equation V= Re ƞ / d ρ0 = d2 (ρs- ρo)g /18ƞ
- 26. Anderson apparatus usually consists of a 55ml vessel containing 10 ml pipette sealed in to a ground glass stopper. When the pipette is in place in the cylinder its lower tip is 20cm below the surface of the suspension. Procedure A 1%or 2% suspension of particles in a medium containing suitable deflocculating agent is introduced in to the vessel and brought to550ml mark The stoppered vessel is shaken to distribute the particles uniformly through out the suspension and the apparatus with pipette in place its clamped securely in constant temperature bath. At various time intervals 10ml of samples are withdrawn and discharged by means of two way stopcock.
- 27. The samples are evaporated and weighed or analyzed by appropriate means correcting for the deflocculating agent that has been added. The particle diameter corresponds to the various time periods is calculated by stokes law with ‘h’ in the equation being the height of the liquid above the lower end of the pipette at the time each sample is removed. The residue or dried sample obtained at particular time is the weight fraction having particles of size less than the size obtained by stokes law calculation for that time period of settling. The weight of each sample residue is therefore called weight undersize and sum of the successive weights are called cumulative weight under size
- 28. ❖ Particle volume measurement Instrument used to measure the volume of particles is coulter current The instrument separates on the principle that when a particle suspended in a conducting liquid passes through a small orifice on either sides of which are electrodes, a change in electric resistance occurs. A known volume of a dilute suspension is pumped the orifice, the particles pass through one at a time. A constant voltage is applied across the electrodes to produce a current. As the particle travels through the orifice it displaces its own volume of electrolyte.
- 29. Results in an increased resistance between two electrodes. The change in resistance which is related to particle volume causes a voltage pulse that is amplified and fed to a pulse height analyzer calibrated in terms of particle size. The instrument records electronically all those particles producing pulses that are within the two threshold values of the analyzer. By systematically varying the threshold settings and counting the no of particles in a constant sample size it is possible to obtain a particle size distribution. The instrument is capable of counting particles at the rate approximately 4000 per second. The data can readily converted to volume and weight distributions.
- 30. Advantages Used in pharmaceutical sciences to study particle growth and dissolution and the effect of anti bacterial agents on growth of microorganisms.
- 31. ❖ PARTICLE SHAPE AND SURFACE AREA Shape and surface area of the particle is very desirable. The shape affects the flow and packaging properties of a powder as well as having influence on the surface area. The surface area per unit weight or volume is an important characteristic of a powder when one is surface adsorption and dissolution studies. Particle shape A sphere has minimum surface area per unit volume. The more assymetric the particle the greater the surface area per unit volume. A spherical particle is characterized completely by its diameter. As the particle becomes more asymmetric it becomes more difficult to assign a diameter to a particle.
- 32. Surface area = ∏d3 Volume= ∏d3 / 6 Where d is the diameter of the particle. The surface area and volume of spherical particle are therefore proportional to the square and cube respectively of the diameter. To obtain an estimate of the surface or volume of a particle whose shape is not spherical one must choose a diameter that is characteristic of the particle and relate this to the surface area or volume through a correction factor. Suppose the particles are viewed microscopically it is desired to compute surface area and volume from the projected diameter dp of the particles.
- 33. The square and cube of the chosen dimension are proportional to surface are and volume respectively. Surface area = αs dp2 = ∏ds 2 Volume = αv dp3 = ∏dv 2/6 Where αv is the volume factor and dv is the equivalent volume diameter. Specific surface area The specific surface is the surface area per unit volume Sv,or per unit weight Sw.
- 34. Sv= surface area of particles / volume of particles = n αs d2 / n αv d3 = αs / αv d Where n is the number of particles. The surface area per unit weight Sw=Sv/ρ Ρ is the true density of the particles Sw = αs / ρ dvs αv Where the dimension is now defined as dvs the volume surface diameter characteristic of specific surface.
- 35. ❖ Methods for determining surface area 1.Adsorption method 2.Air permeability method. 1.Adsorption method ▪ Surface area is most commonly determined based on Brunauer-Emmett-Teller (BET) theory of adsorption. ▪ Most substances adsorb a monomolecular layer of gas under certain conditions of partial pressure of gas and temperature. ▪ The adsorption process is carried out at liquid nitrogen temperatures -196˚C.
- 36. ▪ Once surface adsorption has reached equilibrium, the sample is heated at RT and Nitrogen gas is desorbed. ▪ Its volume is measured. As each N2 mol. occupies fixed area, one can compute surface area of pre-weighed sample. 2. Air Permeability method: Powder is packed in sample holder Packing appears as series of capillaries Air is allowed to pass through the capillaries at constant pressure Resistance is created as air passes through capillaries thus causing pressure drop. Greater the surface area greater the resistance Air permeability is inversely proportional to the surface area
- 38. DERIVED PROPERTIES OF POWDER Size or diameter is a fundamental property of a particle. Volume, density, porosity etc. are the properties derived from fundamental properties. e.g.Volume can be calculated from the diameter of the particle (4/3 πr3). However, derived properties can also be calculated without the use of fun5 damental properties.
- 39. + DENSITY ▪ Apparent bulk density- is determined by pouring presieved (40#) bulk drug into a graduated cylinder via a funnel and note the volume as is (g/ml) without subjecting to any external force. ▪ Tapped density: The cylinder is subjected to fixed no. of taps on a mechanical tapper apparatus (approx. 100) until the powder bed has reached minimum. (useful for determining the appropriate size for capsule formulation)
- 40. Bulk density = Mass of the powder Bulk volume Tapped bulk density = Mass of the powder Tapped Bulk volume
- 41. Applications Decides the size of the capsule based on bulk and tapped volume of a given sample. Higher the bulk volume, lower the bulk density and bigger the size of the capsule Helps to decide proper size of a container or packing material. Light powders When particles packed loosely. Lots of gaps between particles. Bulk volume increases Light powders have high bulk volume hence low density
- 42. DENSITY True density ✓Volume occupied by voids (inter-particle spaces) and intraparticle pores are not included in this measurement. ✓Calculated by suspending drug in solvents of various densities & in which the compound is insoluble. ✓After vigorous agitation, samples are centrifuged briefly, and then left to stand undisturbed till settling/ flotation has reached equilibrium.
- 43. ✓The sample that remains suspended corresponds to the true density of the material. Calculated with a pycnometer. True Density Determination 1. Helium displacement method (for porous powders) 2. Liquid displacement method (for non porous powders)
- 44. Liquid displacement method ▪ Select the solvent in which powder is insoluble ▪ Pycnometer or sp. gravity bottle is used. ▪ Wt. of pycnometer: w1 ▪ Wt. of pycnometer + sample: w2 ▪ Sample wt.: w3=w2-w1 ▪ Wt. of pycnometer + sample + solvent: w4 ▪ Wt. of liquid displaced by sample: w5 = w4-w2 ▪ Thus, true density = w3/ w5
- 45. Helium displacement Method Helium gas is selected as it does not adsorb on solid sample. It enters the pores. very useful for estimating the true density of porous solids. Helium Pycnometer ❑ Sample holder (A) ❑ Valve(B) ❑ Pressure detector (C) ❑ Piston (D)
- 46. Sample holder Sealed after placing the sample. Valve Connected to sample holder Has provisions for removing air from the sample holder and introducing helium gas Pressure detector Maintains preset constant pressure Piston Reads the corresponding pressure It is also related to the volume of the powder.
- 47. Working: Air in the sample holder removed by vacuum Helium gas introduced through valve Pressure adjusted and set at particular value with the help of piston At this position, the reading on the scale denotes U1 U1= volume of empty sample holder Place standard known true volume Vstd of stainless steel spheres Air removed and helium gas introduced through valve.
- 48. Pressure adjusted to preset value with the help of piston At this position, the reading on the scale denotes U2 The difference between U1 and U2 gives the volume occupied by the standard. The last step involves determination of volume of sample. The standard is replaced with sample and the reading is noted, Us. The difference between U and Us gives the
- 49. Vstd = True volume of std.sample Vtest = true volume of the test sample U1 - U2 = Volume occupied by the std. sample U1 - Us = Volume occupied by the test sample Vtest = Vstd . (U1- Us ) U1 - U2
- 50. Powder flow properties • Powders may be free-flowing or cohesive (Sticky). • Many common manufacturing problems are attributes to powder flow. 1. Powder transfer through large equipment such as hopper. 2. Uneven powder flow excess entrapped air within powders capping or lamination. 3. Uneven powder flow increase particle’s friction with die wall causing lubrication problems and increase dust contamination risks during powder
- 51. 4. Powder storage, which for example result in caking tendencies within a vial or bag after shipping or storage time. 5. Separation of small quantity of the powder from the bulk-specifically just before the creation of individual doses such as during tableting, encapsulation and vial filling which affect the weight uniformity of the dose (under or over dosage).
- 53. Powder flow properties ▪ Pharmaceutical powders may be broadly classified as free-flowing or cohesive. ▪ Most flow properties are significantly affected by changes in particle size, density, electrostatic charges, adsorbed moisture. ▪ Good flow property is required for easy and uniform flow from hopper to die cavity ensuring accurate weight and dose. ▪ Angle of repose is calculated for estimating flow properties. ▪ It is defined as the maximum angle possible between the surface of a pile of the powder and the horizontal plane
- 55. ▪ Simple flow rate apparatus consisting of a metal tube from which drug flows through an orifice onto an electronic balance, which is connected to a recorder. ▪ Angle of repose determination using reposograph
- 56. ❖Fixed funnel method The material is poured through a funnel to form a cone. The tip of the funnel should be held close to the growing cone and slowly raised as the pile grows, to minimize the impact of falling particles. Stop pouring the material when the pile reaches a predetermined height or the base a predetermined width. Rather than attempt to measure the angle of the resulting cone directly, divide the height by half the width of the base of the cone. The inverse tangent of this ratio is the angle of repose. Tan θ = h/r where h is the height of the heap r is the radius
- 57. Another method is % compressibility (Carr’s index) bulk volume - tapped volume ×100 bulk volume Hausner ratio = tapped density/ Bulk density Or = Bulk volume/ tapped volume Hausner ratio was related to interparticle friction • Value less than 1.25 indicates good flow (=20% Carr).
- 58. • More cohesive, less free-flowing powders such as flakes. • Between 1.25 and 1.5 added glidant improves flow. • >1.5 added glidant doesn’t improve flow.
- 59. Packing properties (Porosity) Porosity definition: It is the ratio of the volume of voids between particles, plus the volume of pores, to the total volume occupied by the powder, including voids and pores. A set of particles can be filled into a volume of space in different ways.
- 60. This is because by slight vibration, particles can be mobilized and can occupy a different spatial volume than before. This changes the bulk volume because of rearrangement of the packing geometry of the particles. In general, such geometric re arrangements result in a Example: A set of monosized spherical particles can be arranged in many different geometric configurations. In Fig.a, when the spheres form a cubic arrangement, the particles are most loosely packed and have a porosity of 48%
- 61. In Fig.b, when the spheres form a rhombohedral arrangement, they are most densely packed and have a porosity of only 26% The porosity used to characterize packing geometry is linked to the bulk density of the powder.
- 62. Thus bulk density, is a characteristic of a powder rather than individual particles and can be variable. The bulk density of a powder is always less than the true density of its component particles because the powder contains inter particle voids. Thus, powder can possess a single true density but can have many different bulk densities, depending on the way in which the particles are packed and the bed porosity.