Micromeritics

Amit M. GuptaLecturer

Agnihotri Collage of pharmacy, Wardha

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

Importance of Study of 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

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. 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 solution depends on the several factors. One factor is the particle size. Thus particles having small dimensions will tend to increase the rate

of solution.

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

fanto meter………………..10-15 meter

Particle Dimension in Pharmaceutical Disperse system

Particle size Micrometer (µ m) Millimeter (mm) Disperse systems0.5-10 0.0005 - 0.010 Suspension, fine

emulsion

10-50 0.010- 0.050 Coarse emulsion, flocculated suspension

50- 100 0.50- 0.100 Lower range of sieve range,

fine powder range

150-1000 0.150-1.000 Coarse powder range

1000- 3360 1.000- 3.360 Average granule size

Particle size and analysisStokes’ law/relation

ηη

v18

gddD

9

gdd2r 212

212

2

1

21

18

gdd

vD

v: velocity of the sedimentation in cm/secr: particle radius in cm D: particle diameter in cm

d1: density of the particle in g/ml d2: density of the liquid in g/mlg = gravitational constant=980.7 cm·sec-2

Η = the viscosity of the medium in poises, i.e., g·cm-1·sec-1

(poise) in cgs unitsIncidentally, the water at 20o has a viscosity of approximately one centipoises (0.01 poise).1 g·cm-1·sec-1 = 1 p = 100 cp =0.1Pa·s 1 cp =1 mPa·s

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.

Particle sizeDetermined by microscopic method

size group of counted

particles/μm

Middle value μm

“d”

Number of particles per

group “n”

“nd”

40-60 50 15 750

60-80 70 25 1750

80-100 90 95 8550

100-120 110 140 15400

120-140 130 80 10400

∑n=355 ∑nd=36850

8.103355

36850

n

nddav

Particle sizeDetermined by sieving method

Sieve number

Arithmetic mean opening

(mm)

Weight retained (G)

%

Retained

%Retained×

Mean opening

20/40 0.630 15.5 14.3 9.009

40/60 0.335 25.8 23.7 7.939

60/80 0.214 48.3 44.4 9.502

80/100 0.163 15.6 14.3 2.330

100/120 0.137 3.5 3.3 0.452

108.7 100.0 29.232

mm 2923.0

100

232.29

100

size ave%retaineddav

Methods of determining particle size

Optical Microscopy Sieving Methods Sedimentation Methods

Particle volume measurement: Coulter Counter Method (Electrical stream

sensing method) Laser light scattering methods.

Methods of determining surface area: Adsorption method Air permeability method

Microscopy 0.2 to 100 μm provide information of shape also

Principe of operation•Optic or electronic measures

•Two dimensional projection

•Projection screen or

circles

•Image analysing programs

•Measures

•Feret diameters

•Equal circles

•Size range- 0.001-1000 m

•Gives number average,or area

average

Benefits– “Simple” and intuitive– Give shape information– Reasonable amount of sample

Drawbacks– Statistic relevance “tedious” if

image analyse can not be used– Risk for bias interpretation– Difficult for high concentrations– Sample preparation might be

difficult

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.

In practice sieves can be obtained for size analysis over a range from 5 to 125 000 µm.

0.001 0.01 0.1 1 10 100 1000

ISO RangeParticle diameter (µm)

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.

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 or nest (layer) of sieves which have the smallest mesh above a collector tray followed by meshes which get progressively coarser towards the top of the series.

A sieve stack usually comprises 6-8 sieves with a progression based on a √2 or 2√2 change in diameter between adjacent aperture.

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 arbitrary and BS 1796 recommends sieving to be continued until less than 0.2% material passes a given sieve aperture in any 5 minutes interval

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.

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)

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.

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.

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.

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.

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,

The largest particle diameter in each sample is then calculated from Strokes’ Law.

The particle size may be obtained by gravity sedimentation as expressed in Strokes’ law.

V = =

or dst = √Where ,v = rate of settling

h = Distance of the fall in time , t

dst = the mean diameter of the particles based on the velocity of sedimentation

ρs= density of the particles

ρo = density of the dispersion medium

g = Acceleration due to gravity

ηo = Viscosity of the medium

Note: The question holds spheres falling freely without hindrance and at a constant rate.

h dst2 (ρs- ρo) g

t 18ηo

18ηo h (ρs- ρo) gt

Coulter Counter Method (Electrical stream sensing zone method)

Coulter Counter Method (Electrical stream sensing zone method) is a sophisticated method. It is a precise and accurate method.

Range of analysis:

0.001 0.01 0.1 1 10 100 1000

Coulter counter

Particle diameter (µm)

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 conditionsSample preparation and analysis conditions

Wallace Coulter - Coulter orifice - 1948-1956

Cell counter

vacuum

orifice

©J.Paul Robinson©J.Paul Robinson

1.The particle suspension is drawn through an aperture accurately drilled through a sapphire crystal set into the wall of a hollow glass tube.

2. Electrodes, situated on either side of the aperture and surrounded by an electrolyte solution.

3. Monitor the change in electrical signal which occurs when a particle momentarily occupies the orifice and displaces its own volume of electrolyte..

4. The volume of suspension drawn through the orifice is determined by the suction potential created by a mercury thread rebalancing in a convoluted U tube.

5.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.

Principle of Measurement

6.The change in resistance is converted between into a voltage pulse which is amplified and processed electronically .

7. Pulses falling within pre-calibrated limits or thresholds are used to split the particle size distribution into many different size

ranges.

In order to carry out size analysis over a wide diameter range itwill be necessary to change orifice diameter used, to preventCoarse 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 sophisticated method. 2. It is a expensive method.

The first Coulter Counter

Other Methods to Determine Particle SizeLaser Light Scattering

X-ray Sedimentation

Electrical Sensing Zone

Particle Size by Surface Area

Light energy diffraction or light scattering

Laser Holography 1.4 to 100 μm provide information on shape

Cascade impaction

Air is drawn through a series of orifices of decreasing size; the air flow is normal to collecting surfaces on which aerosols are collected by inertial impaction.

The particles, separated stepwise by their momentum differences into a number of size ranges,are collected simultaneously

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 & hence optimal flow; particle flakes have high surface to volume

ratio & poor flow

Packing geometry– Characterization by porosity & bulk density Bulk density is always less than true density- due to

interparticle pores/voids Particle can have single true density but different bulk

densities

Derived properties of powders : Apart from fundamental properties, there are

derived properties. These are based on fundamental properties. These are :

1. Porosity, 2. Packing arrangements, 3. Densities of particles: Bulk density, Tap

density, Granule density. Dense particles are less cohesive than less dense particles of the same size & shape.

4. Particle volume: Bulk volume, Tap volume, Void volume. Instrument used for measurement is coulter counter. Dilute suspension is passed through a small orifice and change in electric resistance is measured.

coulter counter

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

A. Adsorption method: 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.

Principe of operation – Measures the adsorption of

gas molecules • Remove adsorbed

molecules• Introduce gas• Measure pressure

differences

Range – 0.01 to over 2000 m2/g.

Benefits– Well established– High precision– Gives inner pores

Drawbacks– Over estimation of available area– Experimental difficulties

Air permeability method

Measures: – Specific area

Principe of operation – Measures the pressure drop in a

particle bed

– Conditions• Laminar flow• Know Kozenys constant • Homogenous particle bed

Benefits– Simple equipment– Relevant for many applications

Drawbacks– Has to know

• Porosity• Kozenys constant

– Needs uniform density of particles

B. Air permeability method: Here the principle is “resistance to the flow of a fluid through a plug of powder is the surface area of powder.

“Greater the surface area, the greater will be the resistance to flow.”

The instrument used is Fisher subsieve sizer.

B. Air permeability method: Here the principle is “resistance to the flow of a fluid through a plug of powder is the surface area of powder.

“Greater the surface area, the greater will be the resistance to flow.”

The instrument used is Fisher subsieve sizer.

6. Bulkiness- Reciprocal of bulk density,

7. 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.

Flow rate is expressed by Pressibility Index (I)=[1-v/vo]100

8. Compaction

9. Angle of repose

10. Carr’s Index: (Tapped density - Poured density) x 100

Tapped density

11. Hausner’s ratio: Tapped density x 100

Poured density

Other characteristics of micromeritics

100VoidPorosity

bulk

bulk

V

VVVoid

bulka V

sample theofweight )density(ρapparent

aρ

1B)bulkiness(

100V

VVPorosity

bulk

bulk

V

sample theofweight )density(ρ true t

POWDER FLOW

Factors affecting packing geometry:Particle size & size distribution- void spaces in

between can be filled with fine particles

Particle shape & texture-open structure vs. tight packing

Surface properties-electrostatic forces

Handling & processing conditions-prior to flow

FLOW through orifice Factors: 1. ORIFICE DIAMETER: Powder flows proportional to orifice diameter

provided that powder head remains considerably greater than orifice diameter.

2. HOPPER WIDTH: Make adjustments so that minimum hopper widths

are large enough to produce arch stresses greater than arch strength.

3. HEAD SIZE: Pressure changes with powder head size. 4. HOPPER WALL ANGLE: Powders with low wall friction angles will empty freely 5. MASS FLOW: First in first out 6. FUNNEL FLOW: “Rat hole”

CHARACTERIZATION OF POWDER FLOW

Indirect Methods:1. Angle of repose2. Shear cell determinations which gives

relationship between flow factors & powder flowability

3. Bulk density measurements-% compressibility & flow, Carr method

4. Critical orifice diameter-direct measure of powder cohesion & arch strength

POWDER FLOW Direct Methods:1. Hopper flow rate2. Recording with flowmeter

HOW TO IMPROVE FLOW1. Alter particle size & size distribution2. Alter particle shape or texture3. Alter surface forces4. Formulation additives5. Vibration assisted hoppers6. Force feeders

Angle of reposeThe angle of repose is a parameter used to estimate the

flowability of a powder.

r

htangentθ

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.

Bulk density

The particle density or true density of a particulate solid or powder, is the density of the particles that make up the powder, in contrast to the bulk density, which measures the average density of a large volume of the powder in a specific medium (usually air).

Measurement OF Bulk density

The measurement of particle density can be done in a number of ways:

Archimedes' principle The powder is placed inside a pycnometer of known

volume, and weighed. The pycnometer is then filled with a fluid of known density, in which the powder is not soluble. The volume of the powder is determined by the difference between the volume as shown by the pycnometer, and the volume of liquid added (i.e. the volume of air displaced). A similar method, which does not include pore volume, is to suspend a known mass of particles in molten wax of known density, allow any bubbles to escape, allow the wax to solidify, and then measure the volume and mass of the wax/particulate brick.

A slurry of the powder in a liquid of known density can also be used with a hydrometer to measure particle density by buoyancy.

Another method based on buoyancy is to measure the weight of the sample in air, and also in a liquid of known density.

A column of liquid with a density gradient can also be prepared: The column should contain a liquid of continuously varying composition, so that the maximum density (at the bottom) is higher than that of the solid, and the minimum density is lower. If a small sample of powder is allowed to settle in this column, it will come to rest at the point where the liquid density is equal to the particle density.

Volumetric measurement A gas pycnometer can be used to measure the volume of a powder sample. A

sample of known mass is loaded into a chamber of known volume that is connected by a closed valve to a gas reservoir, also of known volume, at a higher pressure than the chamber. After the valve is opened, the final pressure in the system allows the total gas volume to be determined by application of Boyle's law.

A mercury is an instrument that allows the total volume of a powder to be determined, as well as the volume of pores of different sizes: A known mass of powder is submerged in mercury. At ambient pressure, the mercury does not invade the interparticle spaces or the pores of the sample. At increasing pressure, the mercury invades smaller and smaller pores, with the relationship between pore diameter and pressure being known. A continuous trace of pressure versus volume can then be generated, which allows for a complete characterization of the sample's porosity.

True densityThe density of the particles that make

up a powder or particulate solid, in contrast to bulk density, which measures the average density of a large volume of the powder in a specific medium (usually air).

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 ,

ρB

C = 100 × ( 1- ------------) ρT

where ρB is the freely settled bulk density of the powder, and ρT is the tapped bulk density of the powder.

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

1C = 100 × ( 1 - ------- )

H Both the Hausner ratio and the Carr index are sometimes criticized, despite

their relationships to flowability being established empirically, as not having a strong theoretical basis. Use of these measures persists, however, because the equipment required to perform the analysis is relatively cheap and the technique is easy to learn.

The Hausner ratio is a number that is correlated to the of a powder or granular material. It is calculated by the formula

ρTH= --------------

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.

The Hausner ratio is used in a wide variety of industries] as an indication of the flowability of a powder. A Hausner ratio greater than 1.25 is considered to be an indication of poor flowability. The Hausner ratio (H) is related to the Carr index (C), another indication of flowability, by the formula H = 100 / (100 − C). Both the Hausner ratio and the Carr index are sometimes criticized, despite their relationships to flowability being established empirically, as not having a strong theoretical basis. Use of these measures persists, however, because the equipment required to perform the analysis is relatively cheap and the technique is easy to learn

Hausner ratio

Porosity is a measure of the void spaces in a material, and is measured as a fraction, between 0–1, or as a percentage between 0–100%. The term is used in multiple fields including pharmaceutics, ceramics, metallurgy, materials, manufacturing, earth sciences and construction.

It is defined by the ratio:Vv

φ= ---------VT

where VV is the volume of void-space (such as fluids) and VT is the total or bulk volume of material, including the solid and void components. Both the mathematical symbols φ and n are used to denote porosity.