PARTICLE SCIENCE

THE SOLID STATE

[Type text] Page 1

 Particle science and powder technology

Objectives:

1. Define the solid state

2. Describe particle size, analysis, reduction and separation

The solid state

Solid particles are made of molecules that are held in close proximity to

each other by intermolecular forces. Particles are held together by

hydrogen bonds or by van der waals forces i. e dipole-dipole (keesom), dipole-

induced dipole (debye) and induced dipole- induced dipole (London) forces.

Positive pole is aligned to negative pole of the next molecule.

Crystallization
Materials in solid state can be crystalline or amorphous or a combination.

Crystalline particles have molecules packed in order. Crystals have a melting

point i.e. crystal lattices break down after gaining sufficient energy.

Crystals with weak forces holding molecules have low melting point.

Crystals are produced by inducing change from liquid state to solid state i.e

cooling a molten substance to below melting point e.g suppositories or have a

solution and change it into solid state by supersaturation and addition of

antisolvent. This process of crystal formation is called nucleation or growth.

Supersaturated solutions are not thermodynamically stable.

Dr. Kabara The solid state

 Polymorphism
The existence of a substance in more than one crystalline form is called

polymorphism. A change in packing arrangement of the same molecule to give

more than different crystal forms could lead to significant changes in the

properties of the solid e.g M.P, dissolution rate, resistance to compaction or

breaking.

Many drugs and excipients exhibit polymorphism. Monotropic polymorphism

is where one form of polymorph is stable (has highest M.P) while the rest

are unstable. The other forms (metastable forms) eventually turn to stable

form. Enantropic polymorphs (under different conditions of temperature

and pressure)can reversibly transform between stable forms.

There is a correlation between MP of different polymorphs and the rate of

dissolution. The polymorph with the lowest MP will most easily give up

molecules for dissolution. High MP polymorphs have strong lattice hence

molecules are hard to remove. They therefore have low dissolution rate.

Metastable forms can dissolve to give supersaturated solutions. The

supersaturated solution eventually turns to saturated form by settling of

stable form. The process is not instantaneous. The supersaturated form may

exist long enough to cause increased bioavailability of a drug.

Stable polymorphic forms of drugs will have the slowest rates of dissolution

(α-polymorph of chloramphenicol)there may be occasions when it may be

desirable to speed the dissolution by using metastable forms(β-polymorph of

Dr. Kabara The solid state

 chloramphenicol palmitate). The risk associated with using the metastable

form is that it reverts to stable form during product life and gives

sequential changes in properties. In manufacturing of drugs, the same

polymorphic form should be used. Polymorphism can be affected by

impurities, change in solvent and temperatures.

Hydrates and solvates

When solvent is trapped in the crystalline lattice of a solid, it forms a

hydrate if the solvent is water or a solvate if the solvent is different. If the

solvent is ethanol, it is called ethanolate. The hydrates can be of many

forms, i.e mono,di,tri e.t.c.it is undesirable to have solvates in

pharmaceuticals as they are unnecessary impurities.

Hydrates have different properties to anhydrous forms, these differences

are referred to as pseudopolymorphism. Anhydrous form could dissolve

easily than hydrated form due to water forming hydrogen bonds and hence

tying the lattice together (e.g.theophylline).in cases where the hydrated

forms dissolve faster, it could be explained as water forming a wedge

between the particles of the molecule, hindering the molecules from bonding

strongly.

Amorphous state

Amorphous substances have molecules not packed together in a long-range

repeated ordered manner. Amorphous solids do not have MP. For low

molecular weight materials, amorphous forms may be produced due to fast

rate of solidification. Crystals could also be broken by milling. Amorphous

Dr. Kabara The solid state

 forms have a characteristic temperature at which major changes in

properties (mobility) occur. This is called glass transition temperature

(Tg).if the amorphous form is stored below the Tg, it becomes brittle. If

stored above Tg, it becomes rubbery.

Tg can be lowered by adding a plasticizer e.g. water, which increases

mobility. Most amorphous forms can absorb large quantities of water vapour.

Most drugs can degrade in amorphous form by hydrolysis but remain stable

in crystalline form. It is possible that some drugs will degrade by hydrolysis

when amorphous but not degrade when crystalline. Processing of crystalline

drugs could lead to formation of partially amorphous materials. If the β-

polymorph of chloramphenicol palmitate is milled. It leads to formation of

partially amorphous form which leads to high plasma levels. Milling could also

lead to acquisition of high energy which leads to α-form with low plasma

concentration.

Crystal habit

The external shape of a crystal is known as the crystal habit. It is a result

of rate of growth of different faces. The largest face of the crystal is

always the slowest growing. The face where drug is deposited becomes the

smaller part of the crystal. The growth on different faces will depend on

the relative affinities of the solute for the the growing faces of the

crystal. Every molecule is made of different functional groups i.e. polar and

apolar. If crystal growth occurs in an aqueous media, deposition of solute will

occur on faces which make the particle more polar (non-polar faces grow).

Dr. Kabara The solid state

 The external face can alter the external properties of a drug e.g dissolution

rate is altered by the changes in surface area. Crystal habit can also cause a

change in powder flow. It is possible to change crystal habit by manipulating

the rate of growth by adding impurities which preferentially interact with

one face of the crystal. The face where the impurity interacts stops

growing. The impurity may either be a similar molecule to the crystal hence

it attaches to one face and stops further growth or it could be a surfactant

that adsorbs at one face.

Dr. Kabara The solid state

 Particle size analysis

Dimensions

Solid particles are assumed to be approximately spherical and measured by

estimating the diameter. The approximation is referred to as equivalent diameter

of the particle.

Equivalent diameters

More than one sphere can be generated.

Projected area diameter

Is based on a circle of equivalent area to that of projected image of a solid

particle. Perimeter diameter is based on a circle having the same perimeter as the

particle. Feret’s diameter is determined from the mean distance between two

parallel tangents to the projected outline of the particle. Martin’s diameter is the

mean chord length of the projected particle perimeter, which can be considered as

the boundary separating equal particle areas. Other methods for measuring

particle size are sieve aperture, sedimentation characteristics, volume and surface.

In general, the method used to determine the particle size dictates the type of

equivalent diameter that is measured.

Particle size distribution

Most powders contain particles of different equivalent diameters. The size

distribution can be broken down into different size ranges which can be presented

in the form of a histogram. The histogram presents an interpretation of the

particle size distribution and enables the percentage of particles having a given

Dr. Kabara The solid state

equivalent diameter to be determined. The histogram allows different size

distributions to be compared. The normal curve has a symmetrical distribution

around a central peak frequency value (mode). A frequency curve with an elongated

tail towards higher size ranges is positively skewed: the reverse is negatively

skewed. These skewed curves can be normalized by using a logarithmic scale. They

are thus referred to as log normal distributions. In some curves, more than one

mode occurs; e.g. two modes will give bimodal frequency distribution, this may be

due to milling of powder. Some of the unbroken particles show a second mode

towards the higher size range.

An alternative to the histogram is the cumulative frequency distribution. If the

addition sequence starts with the coarsest particles, it produces cumulative

percent (frequency) undersize. The reverse is the cumulative percent oversize.

In order to quantify the degree of skewness of a particle distribution, the

interquartile coefficient of of skewness (IQCS) is determined by

IQCS= (c-a)-(a-b)

(c-a)+(a-b)

Where a- the median diameter

b and c are the lower upper quartile points.

The IQCS can be between -1 and +1. If IQCS is zero, there is symmetrical

distribution. Kurtosis is the measure of degree of symmetry. Thick tailed sharp

peaked curves are described as leptokurtic (+); thin tailed blunt peaked curves are

platykurtic (-), normal distribution is mesokurtic (0).

Dr. Kabara The solid state

Mean particle sizes

Particle sizes are represented by a mean, median and mode as measures of central

tendency. The mean can be of different types:

Arithmetic mean

It is achieved by summating a particular parameter for all individual particles in a

sample and dividing the value achieved by the total number of particles. Means can

be related to the diameter, surface volume or mass of a particle. These are

referred to as number mean. To measure mass, mass mean is used.

Geometric means

It is applied where we have log-normal distribution. Refer to equation on page 126.

Particle size analysis methods

Sieve methods

Equivalent diameter: sieve size diameter

The range of analysis is between 45ᶙM to 1000ᶙM according to ISO. Dry powders

are usually used. For particles in suspension, wet sieving can be used. Sieves are

woven, mesh-like stainless steel of known aperture diameters. Usually, a sieve

stack comprising of 6-8 sieves is used. Powder is loaded on the coarsest sieve and

the sieve is subjected to mechanical vibration. It is recommended that sieving

continues until less than 0.2% passes through the sieve in any 5 minute range. An

alternative method is use of air jet method where a vacuum is applied at the

bottom of the sieve.

Dr. Kabara The solid state

Microscope method

Equivalent diameters: projected area diameter, perimeter diameter, feret’s

diameter, and martin’s diameter.

Range of analysis: light microscope- 1 ᶙm to 1000ᶙm. Electron microscope 0.001 to

1000ᶙm.

Sample preparation and analysis: specimen prepared for light microscope must be

adequately dispersed on the slide to avoid analysis of agglomerated particles.

Principles of measurement

Size analysis on a light microscope is carried out on the two dimensional images of

particles. This assumption is valid for most solids but not for dendrites, fibres or

flakes. The latter should be viewed in their most stable orientation. Particle size

analysis is carried out using a projection screen with screen distances related to

particle dimensions by a predetermined calculation factor. Particles are compared

with the two sets of circles that correspond most closely to the equivalent particle

diameter being measured. The field of view is divided into segments to facilitate

measurement of different numbers of particles.

Alternative techniques include scanning electron microscope and transmission

electron microscope. These allow three dimensional measurements and can extend

lower size limit of measurement.

Automatic methods

These use a form of pre-calibrated variable distance to split particles into

different size ranges. An example is a comparator which uses a variable diameter

Dr. Kabara The solid state

light spot on a photomicrograph of a particle under analysis. The variable iris

controlling the light spot is linked electronically to a series of counter memories,

each corresponding to a different size range.

A second technique uses a double prism mounted on a light microscope eye piece.

The image from the prism is displayed on the video monitor. The double prism

allows the light to pass through the monitor unaltered where the usual single

particle image is produced. When the prisms are sheared against one another,

double images are obtained. The prism shearing mechanism is linked to a pre-

calibrated micrometer scale.

Fully automatic size analysis has the advantage of being more objective, faster and

allows a wider variety of range of particle shapes to be measured.

Electron stream sensing zone method (coulter counter)

Equivalent diameter: volume diameter

Range of analysis: 0.1ᶙm to 1000ᶙm

Sample preparation and analysis conditions

Particles are dispersed in an electrolyte and agitated to remove any agglomerate. A

dispersant could be used to maintain particles apart.

Principles and measurement

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

Dr. Kabara The solid state

changes in electrical signal that 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 mercury

thread rebalancing on a U-tube. The volume of electrolyte displaced by the particle

at the orifice causes changes in electrical resistance between the electrodes that

is proportional to the volume of the particle. The change in resistance is converted

into a voltage pulse which is amplified and processed electrically. Pulses falling

within pre-calibrated limits or thresholds are used to split the particle size

distribution into many different size ranges. In order to accommodate various size

ranges, different orifice sizes can be used.

Laser light-scattering methods

Equivalent diameter: projected area diameter, volume diameter.

Sample preparation and analysis

Depending on the type of measurement, particles can be presented either in liquid

or in air suspension.

Principles of measurement

Measurement is based on interaction of laser light with particles.

Fraunhofer diffraction

For particles larger than the wavelength of light, any interaction with particles

causes light to be scattered in a forward direction with only a small change in

angle. The Fraunhofer diffraction produces light intensity patterns that occur at

regular angular intervals and are proportional to particle diameter producing the

Dr. Kabara The solid state

scatter. The composite diffraction pattern produced by different diameter

particles may be considered to be the sum of all individual patterns produced by

each particle in the size distribution. Light emitted by helium-neon laser is incident

on the sample of particles and diffraction occurs. The light is focused directly

onto a photo-detector, which converts the signals into an equivalent area diameter.

Alternatively, light is directed by a lens onto a rotating filter, which is used to

convert equivalent area diameters into volume diameters which are quantified by

final focusing on to a photo-detector using a second lens. The light influx signals

occurring on the photodetector are converted into an electrical current, which is

digitalized and processed into size distribution data using a microprocessor.

Fraunhofer diffraction is useful for particles larger than the wavelength of laser

light.

Sedimentation method

Equivalent diameters: dd (frictional) drag diameter and dst stroke diameter

Range of analysis: by centrifugal sedimentation, 0.4 to 50ᶙ m. Gravitational, 8 to

120ᶙ m.

Sample preparation and analysis conditions

Size distribution can be determined by examining the powder as it sediments out.

Where the powder is not uniformly dispersed in a fluid, it can be introduced as a

thin layer on the surface of the liquid. If the powder is hydrophobic, it may be

necessary to introduce a dispersing agent to aid in wetting. In case the powder is

soluble in water, a non aqueous medium can be used.

Dr. Kabara The solid state

Principle of measurement

Two categories can be used, i.e. measurement of particles in a retention zone and

use of non-retention zone measurement e.g. use of a pipette (e.g. Andreasen

pipette). This pipette consists of a 200mm tall graduated cylinder which can hold

about 500mL 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 a centrifuge tube. The amount of powder can

then be determined by weight following drying or centrifuging. Alternatively,

chemical analysis can be done.

The largest size present in each sample is then calculated from stokes’ law. The

Stokes’ law is an expression of the drag factor in a fluid and is linked to the flow

conditions characterized by a Raynauds Number. Drag is one of the three forces

acting on a particle sedimenting by gravitational field.

Stokes’ Equation:

Stokes’ equation for determining particle diameter is based on the following

assumptions:

 Near-spherical particles

 Motion equivalent to that in a liquid of infinite length

Dr. Kabara The solid state

  Terminal velocity conditions

 Low settling velocity so that inertia is negligible

 Large particle size relative to fluid molecular size, so that diffusion is

negligible.

 No particle aggregation

 Laminar flow conditions, characterized by particle Raynolds Numbers of less

than apprx. 0.2

Sedimentation size analysis using retention zone method, also uses Stokes’ law

to quantify particle size. One of the limitations of gravitational sedimentation is

that particle size below 5ᶙm takes too long to settle due to convection,

diffusion and Brownian motion. These effects can be decreased by using

centrifugal force instead of gravitational force. Stokes equation needs to be

altered to suit this new force. To minimize the effects of distance, a two layer

fluid system can be used.

Selection of particle size analysis methods

The limitation on the choice of method should be governed by:

 Properties of the powder particles

 Type of size information required

Dr. Kabara The solid state