Micromeritics.ppt

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Dr. Mohammad Shariare

Assistant Professor

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• Micromeretics is the science and technology of small particles

• Micromeretics is thus the study of the fundamental and derived properties

of individual as well as collection of particles

Introduction

Importance in

pharmacy

The study of particle size and particle size distribution has a number of application

in the field of pharmacy including:

i.The physical properties of powders such as bulk density, porosity and compressibility are dependent on the particle size and size distribution. For example the bulk density of light and heavy magnesium carbonate differs because of the difference in their particle size.

ii.The flow properties of powders are dependent upon the particle size, size distribution and particle shape. Asymmetric particles have poor flow characteristics and hence granulation techniques are used to convert blends of drug and other additives into particles of uniform size having good flow properties iii.The rate of dissolution of poorly soluble drugs are directly related to the size of the drug particles. In general a decrease in particle size of drug increase the dissolution rate

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Smaller the particle size, more is the surface area for oxidation.

v. Properties of drugs such as rate of absorption and hence the pharmacological activity depend on the particle size

vi. Elegance of pharmaceutical preparations such as emulsions, suspensions, ointments often depend on the particle size of dispersed phase

vii. Release characteristics of drugs from ointments, creams and suppositories are depend on the particle size of the dispersed drug

viii. Particle size of the dispersed drug also influence the spredability and performance of some cosmetic preparations like dusting powders

ix. Particle size and size distribution has a profound influence on the uniform mixing of solids

x. The stability of systems such as colloid suspension and emulsions depend on the particle size. As the particle size increases, the stability of these systems decreases

xi. Even the feel, texture and colour of certain drugs depends upon the particle size. For example the difference in colour of yellow and red mercuric oxide is due to the deference in their particle size

xii. Process such as extraction and dying are accelerated following a reduction in the particle size of the material

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

_{Particle size and size distribution}



_{Particle shape}



_{Particle volume}



_{Particle number}



_{Particle surface area}

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Particle size

Disperse system

0.5 - 10.0 µm

Suspension, fine emulsion

10.0 - 50.0 µm

Coarse emulsion, flocculated

suspension

50.0 - 100.0 µm

Fine powder range

150.0 - 1000.0 µm

Coarse powder range

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 _{The size of a spherical particle can be easily expressed in terms of its diameter, d. For a}

perfect sphere the surface area is given by : S = πd2_{and the volume is given by V =}

πd3_/6

 _{A non-spherical particle has a definite surface area and volume but being asymmetric it}

is not possible to express its size in diameter. Its size is therefore expressed in terms of equivalent spherical diameter by using some measurable property such as surface area, volume etc.

 Surface diameter, d_sis the diameter of a sphere having the same surface area as that of

the asymmetric particle

 Volume diameter, d_v is the diameter of a sphere having the same volume as the

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Martin's diameter (M)

The length of the line which bisects the particle image. The lines may be drawn in any direction which must be maintained constant for all image measurements.

Feret's diameter (F)

is the distance between two tangents on opposite sides of the particle, parallel to some fixed direction.

• Stoke’s diameter, d_st refers to the diameter of a sphere with the same density as the

asymmetric particle which undergoes sedimentation at the same rate as the asymmetric particle in a given fluid within the range of Stoke’s law.

• Projected diameter, d_p is the diameter of a sphere having the same observed area as the

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 Average particle size (d_mean)can be calculated from the following formula:

d_mean= ∑nd / ∑n , where n is the number of particles and d is the diameter of particles

 Edmundson derived such a general equation for calculation of the average particle size, d_mean

=

[

]

 _{Where n is the number of particle in each size range , d is the diameter of particles in a given}

size range, p is an index related to the size of an individual particle and f is the frequency index. d raised to the power p = 1 gives the particle length; p = 2 gives the particle surface and p = 3 gives the particle volume

 _{The value of p also indicate the type of mean obtained. If the value of p is positive the mean}

is arithmetic, if p is zero the mean is geometric and if p is negative then the mean is harmonic

 _{For a collection of particles the frequency with which a particle in a certain size range occurs}

is expressed as ndf

Average particle size

∑ndp+f

∑ndf

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mean (d

_wm

)

∑nd ∑n √∑nd2

∑n

3√∑nd2

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 _{Powder is polydisperse that is consists of a mixture of particles of varying size and shape. It is}

therefore necessary to know not only the size of a certain particle in the sample but also the number of particles of the same size present in the sample. Thus we need to know the size range present and number or weight fraction for each range which is called particle size distribution.

 _{The particle size distribution in a powder may be quantified by one of the following way:}

1. By determining the number of particles present in each size range (usually determined by

microscopic technique)

2. By determining the weight of particles present in each size range (usually determined by sedimentation and sieving methods)

 _{When the number of particles is plotted against the mean particle size, the curve obtained is}

known as the number frequency distribution curve and when the weight of particles is plotted against the mean particle size, the curve obtained is known as the weight distribution frequency curve

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A polydisperse powder is said to have a normal distribution if a typically bell shaped frequency distribution curve is obtained, in such case one half of the curve is super imposable on the other half

Negatively skew indicates that the tail on the left side longer than the right side of the mass distribution and the bulk of the values lie to the right of the mean

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 _{Particle number, N is defined as the number of particles per unit weight of a powder}

and can be obtained in the following manner. If the particles of the powder are spherical, the volume of single particle is πd_vn3_{/6 and the mass is πd}

vn3ρ/6 g per

particle where d_vnis the mean diameter based on volume and number and ρ is density of the particle.

 _{The number of particles per gram can then obtained from the expression:}

N =

Or N =

Particle number

Mass of one particle 1 gm of the powder

1 πd_vn3_ρ/6

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

_{The following methods are generally used for the determination of particle}

size and particle size distribution:

1.

Microscopic technique

2.

Sieving technique

3.

Sedimentation technique

4.

Optical and electrical sensing zone method

5.

Laser light scattering techniques

Selection of particle size analysis method

Particle size analysis method selection depends mainly on the properties of the powder particles and the type of size information required.

• Solubility • Density • Cohesivity

• Ease of handling

•Toxicity

• Cost effectiveness

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Optical microscopy is generally used for particle size measurement in the range of 0.2 µm to about 100.0 µm. At least 300 to 500 particles must be counted in order to obtain a good size distribution analysis of data.

1. Microscopic technique:

For submicron particles it is necessary to use electron microscopy either

 _{TEM (Transmission Electron Microscopy) or}

 _{SEM (Scanning Electron Microscopy).}

 _{TEM and SEM (0.001 – 5.0 µm)} Advantages

• Relatively inexpensive

• Each particle individually examined - detect aggregates, 2D shape, colour, • Permanent record - photograph

• Small sample sizes required

Disadvantages

• Time consuming - few particles examined • Very low throughput

• No information on 3D shape

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Advantages

Particles are individually examined

Visual means to see sub-micron specimens

Particle shape can be measured

Disadvantages

Very expensive

Time consuming sample preparation

Materials such as emulsions difficult/impossible to prepare

Low throughput - Not for routine use

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2. Sieving technique:

Sieving technique is generally useful for coarse particles since the technique is limited by the smallest size and hence measurement of sizes smaller than 50.0 µm is difficult

 _{Sieve analysis is performed using a nest or stack of sieves where each lower sieve}

has a smaller aperture size than that of the sieve above it.

 _{Sieves can be referred to either by their aperture size or by their mesh size (or sieve}

number).

 _{The mesh size is the number of wires per linear inch.}  _{Approx. size range : 5µm - ~3mm}

 _{Standard woven wire sieves}

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• Particles may aggregate during sieving due to generation of electrostatic charge

• Moisture can also lead to aggregation of powders and the actual particle size may not be obtained

• Attrition of particles during sieving may lead to size reduction

• Sieve loading and duration of mechanical shaking can influence the results

Disadvantages:

• This method is very simple, not expensive and easy to prepare

Advantages:

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British Pharmacopoeia Volume IV

Appendix XVII A. Particle Size of PowdersParticle size classification of powders (Ph. Eur. method 2.9.12, Sieve test)

The degree of fineness of a powder may be expressed by reference to sieves that comply with the specifications for non-analytical sieves (2.1.4).

Where the degree of fineness of powders is determined by sieving, it is defined in relation to the sieve number(s) used either by means of the following terms or, where such terms cannot be used, by expressing the fineness of the powder as a percentage m/m passing the sieve(s) used.

The following terms are used in the description of powders:

Coarse powder: Not less than 95% by mass passes through a number 1400 sieve and not more than 40 % by mass passes through a number 355 sieve.

Moderately fine powder: Not less than 95% by mass passes through a number 355 sieve and not more than 40% by mass passes through a number 180 sieve.

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United States Pharmacopeia

General Chapters: <811> POWDER FINENESS

Classification of Powders by Fineness

Classification of Powder d50 Sieve Opening (µm) Very Coarse > 1000

Coarse 355–1000

Moderately Fine 180–355

Fine 125–180

Very Fine 90–125

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3. Sedimentation technique:

Andreason pipette is generally used for the determination of particle size distribution by the sedimentation technique. The residue of dried sample obtained at a particle time is the weight fraction having particles of sizes less than the size obtained by the Stoke’s law calculation for that time period of settling.

 _{Size distribution is determined by allowing a homogeneous suspension to settle in a}

cylinder and taking samples from the settling suspension at a fixed horizontal level at intervals of time.

 _{Each sample will contain a representative sample of the suspension, with the exception}

of particles greater than a critical size, all of which will have settled below the level of the sampling point.

 _{The concentration of solid in a sample taken at time t is determined by centrifugation of}

the sample followed by drying and weighing or simply by drying and weighing.

 _{This concentration expressed as a percentage of the initial concentration gives the}

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Advantages:

• The apparatus is inexpensive and the technique is simple

• The results is obtained are precise provided the technique is adequately standardised

Disadvantages:

• The method is laborious since separate analyses are required for each experiment

photosensitive detector consisting

of a series of concentric rings.



_{Distribution of scattered intensity is}

analysed by computer to yield the

particle size distribution.

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Advantages:



_{Non-intrusive : uses a low power laser beam}



_{Fast : typically <3minutes to take a measurement and analyse.}



_{Precise and wide range - up to 64 size bands can be displayed covering a}

_{The relationship of the auto-correlation function obtained to time intervals is}

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 _{Particle shape affects the packing properties and flow of a powder and it also has some}

influence on the surface area

 _{Surface area per unit weight or volume is an important characteristics which determine surface}

adsorption and dissolution rate of particle

 _{A sphere has a minimum surface area per unit volume. The more asymmetric the particle}

becomes, the greater is the surface area per unit volume

 _{A sphere is characterised by its diameter, while an asymmetric particle is difficult to characterise}

in terms of surface diameter

 _{Hence the asymmetric particle’s surface diameter is measured in terms of some equivalent}

spherical diameter

 The specific surface area of a powder is defined as the surface area per unit volume (S_v) or per

unit weight (S_w)

 _{The specific surface area per unit volume is given by:}

S_v ₌

S_w ₌S_v/ρ

Where ρ is the density of particles

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

_{Particle volume measurement}

1. Coulter counter method (Electrical stream sensing method)



_{Methods of determining surface area}

1. Adsorption method

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Advantages

• It is precise and accurate method • Analysis range is wide

Disadvantages

• It is a sophisticated method • It is expensive method

• The number and size of particles suspended in an electrolyte is determined

by causing them to pass through an orifice an either side of which is

immersed an electrode.

• The changes in electric impedance

(resistance) as particles pass through

the orifice generate voltage pulses

whose amplitude are proportional to the

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 _{Methods of determining surface area}

1. Adsorption method 2. Air permeability method

1. Adsorption method:

Particles with large specific surface area (small particle size) are good adsorbents for the adsorption of gases and solutes from solution. The amount of gas or solute adsorbed on the sample of powder to form a monolayer is found out and from this data, the surface area of the powder is determined.

2. Air permeability method

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

_{Porosity of powders}



_{Packing arrangement in powder beds}



_{Density of powders}



_Bulkiness



_{Flow properties of powders}

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- _{Bulk volume is equal to the true volume for a non porous material. Most}

pharmaceutical solids are porous, they have internal pores or capillary space and hence the bulk volume is greater than the true volume. The volume of the spaces known as the void volume is given by

v = V_b - V_p

Where V_bis the bulk volume and V_p is the true volume of the particles

 _{The porosity or voids ε is defined as the ratio of the void volume to the bulk volume of}

the powder packing

Thus, ε =

 _{Porosity is expressed as percentage i.e., ε x 100}

Porosity of powders

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 _{A bed or heap of powder consists of a number of particles each in contact with its}

neighbours

 _{Theoretically two types of packing's are possible. These include the closest or}

rhombohedral packing and the most open or loosest or cubical packing

 _{The fraction of the total volume occupied by the free space between the particles is}

porosity. If the powder bed consists of spherical particles a theoretical porosity of 26% is possible in the closest packing and 48% in the loosest packing.

 _{When the particles of varying sizes are present porosity lower than the theoretical}

minimum of 26% is possible. On the other hand if the powder contains floccules or aggregates the porosity may go beyond the theoretical maximum of 48% due to large void space with entrapped air.

Packing arrangement in powder beds

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Density of Powder

• Density is universally defined as the mass per unit volume

• However difficulty in determining the true volume of powders arises because these contain microscopic cracks, internal pores and capillary spaces. Based on the method of determination, three types of densities can be

found-1.True density – density of materials exclusive of pores

True density =

2.Granule density - is the ratio of the mass of the granular powder and the volume occupied by the granular material together with its intraparticular spaces.

Granule density =

Mass of the powder True volume

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3. Bulk density – bulk density of a powder is defined as the ratio of the mass of the powder and its bulk volume.

Bulk Density =

Mass of the powder Bulk volume

Bulkiness -

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Flow properties of powders

• The flow properties of powders is an important parameter to be considered in the production of pharmaceutical dosage forms since most of the processes such as uniform filling of dies during tabletting.

• Powders may be free flowing or may have poor flow. The poor flow of powders are generally attributed to one or more of the following reasons –

1. Cohesiveness or stickiness between particles due to presence of Van der Waals, surface free energy and electrostatic force

2.Adhesion between the particles and the container walls due to the above forces 3.Friction between particles due to surface roughness or morphology

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• The cohesiveness of particles has been found to depend upon a number of factors including particle size, shape, density or porosity of the powders and the presence of absorbed moisture layer on the powder surface.

• Thus very fine particles less than < 10.0 µm in size tend to be more cohesive due to their larger surface area and densed materials tend to be less cohesive than lighter ones

• Poor flow some times result from presence of moisture which increase the cohesiveness, drying of granules can easily remove this problem.

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Assessment of flow properties of powders

Flow properties of powders is generally assessed by determining the angle of repose of the powders. It is defined as the maximum angle possible between the surface of a pile of powder and the horizontal plane. The angle which the heap forms with the horizontal surface is the angle of repose and is determined by the formula :

Tan θ = h/r

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tapped bulk density – initial bulk density

Carr′s Index (%)

= ˣ 100

tapped bulk density



_{Hausner′s ratio}

₌



_{Hausner′s ratio of less than 1.1 indicates excellent flow, between 1.2 fair flow}

and 1.5 indicates very poor flow

tapped bulk density

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Improvement of powder flow properties

Flow properties of powders can be improved by the following methods :

1.Altering the particle size – increasing the average particle size of particles improve the flow properties due to the reduction in the cohesive forces.

2.Removal or addition of fines – small amount of fines may improve flow, while large amount of fines may reduce the flow property

3.Altering the particle shape and texture – Spherical and smooth surface particles

4.Altering the surface forces – reduction in electrostatic force by reduction in friction during processing

5.Removing extra moisture – drying of powders can remove the moisture which decreases cohesiveness and improve powder flow