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Objectives:
Solid particles are made of molecules that are held in close proximity to
induced dipole (debye) and induced dipole- induced dipole (London) forces.
Crystallization
Materials in solid state can be crystalline or amorphous or a combination.
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
more than different crystal forms could lead to significant changes in the
breaking.
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
dissolution. The polymorph with the lowest MP will most easily give up
molecules are hard to remove. They therefore have low dissolution rate.
stable form. The process is not instantaneous. The supersaturated form may
Stable polymorphic forms of drugs will have the slowest rates of dissolution
form is that it reverts to stable form during product life and gives
easily than hydrated form due to water forming hydrogen bonds and hence
between the particles of the molecule, hindering the molecules from bonding
strongly.
Amorphous state
repeated ordered manner. Amorphous solids do not have MP. For low
(Tg).if the amorphous form is stored below the Tg, it becomes brittle. If
mobility. Most amorphous forms can absorb large quantities of water vapour.
Most drugs can degrade in amorphous form by hydrolysis but remain stable
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
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
occur on faces which make the particle more polar (non-polar faces grow).
rate is altered by the changes in surface area. Crystal habit can also cause a
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
Dimensions
of the particle.
Equivalent diameters
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
distribution can be broken down into different size ranges which can be presented
particle size distribution and enables the percentage of particles having a given
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
IQCS= (c-a)-(a-b)
(c-a)+(a-b)
The IQCS can be between -1 and +1. If IQCS is zero, there is symmetrical
peaked curves are described as leptokurtic (+); thin tailed blunt peaked curves are
Particle sizes are represented by a mean, median and mode as measures of central
Arithmetic mean
sample and dividing the value achieved by the total number of particles. Means can
Geometric means
Sieve methods
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
stack comprising of 6-8 sieves is used. Powder is loaded on the coarsest sieve and
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
1000ᶙm.
Sample preparation and analysis: specimen prepared for light microscope must be
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
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
electron microscope. These allow three dimensional measurements and can extend
Automatic methods
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-
Fully automatic size analysis has the advantage of being more objective, faster and
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
orifice and displaces its own volume of electrolyte. The volume of suspension drawn
at the orifice causes changes in electrical resistance between the electrodes that
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
or in air suspension.
Principles of measurement
Fraunhofer diffraction
For particles larger than the wavelength of light, any interaction with particles
angle. The Fraunhofer diffraction produces light intensity patterns that occur at
regular angular intervals and are proportional to particle diameter producing the
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.
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
Fraunhofer diffraction is useful for particles larger than the wavelength of laser
light.
Sedimentation method
120ᶙ m.
thin layer on the surface of the liquid. If the powder is hydrophobic, it may be
Two categories can be used, i.e. measurement of particles in a retention zone and
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
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
Stokes’ Equation:
assumptions:
Near-spherical particles
negligible.
No particle aggregation
Sedimentation size analysis using retention zone method, also uses Stokes’ law
that particle size below 5ᶙm takes too long to settle due to convection,
altered to suit this new force. To minimize the effects of distance, a two layer