Properties of particulate Solids
Prepared by:
Mohammad Mahareeq
Solid state properties
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Three states of matter; solid, liquid and gas
In sealed container:
Vapours diffuse to occupy the total space
Liquids flow to fill part of the container
Solids retain their original shape unless a compressive force is
applied to them
The physical form of solids(packing of molecules, size and
shape of particles) has an influence on the material behaviour
Solid particles are made of molecules closed to each other by
intermolecular forces:
Hydrogen bonds
Van derWaals forces
crystallization
• Crystals are produced by inducing a change from the liquid to
the solid state by:
 Cooling a molten sample to below the melting point
 Making a solution from the material and cooling the solution to
form solid state material
• In order to make a solid precipitate out of solution:
 Remove the liquid by evaporation (e.g. sea salt is produced)
 Cool the solution, as most materials become less soluble as temp.
is decreased
 Add another liquid which will mix with the solution, but in
which the solute has a low solubility.(Antisolvent)
• Example: if a drug is insoluble in water and freely
soluble in alcohol; water is added to a near saturated
solution of the drug in ethanol
• Crystals are formed through the process called
nucleation and growth:
• Nucleation is the formation of a small mass onto
which a crystal can grow
• Growth is the addition of more solute molecules onto
the nucleation site
Crystallinity
• Crystal habit & internal structure can affect bulk &
physicochemical property of molecule.
• Crystal habit is description of outer appearance of
crystal.
• Internal structure is molecular arrangement within the
solid.
• Change with internal structure usually alters crystal
habit.
Eg. Conversion of sodium salt to its free acid form
produce both change in internal structure & crystal
habit.
Different shapes of crystals
• Cubic or isometric - not
always cube shaped. Also
find as octahedrons (eight
faces) and dodecahedrons
(10 faces).
• Tetragonal- similar to cubic
crystals, but longer along
one axis than the other,
forming double pyramids
and prisms.
• Orthorhombic - like
tetragonal crystals except
not square in cross section
(when viewing the crystal
on end), forming rhombic
prisms or dipyramids (two
pyramids stuck together).
• Hexagonal - six-sided
prisms. When you look at
the crystal on-end, the cross
section is a hexagon.
• Trigonal - possess a single
3-fold axis of rotation
instead of the 6-fold axis of
the hexagonal division.
• Triclinic - usually not
symmetrical from one side
to the other, which can lead
to some fairly strange
shapes.
• Monoclinic - like skewed
tetragonal crystals, often
forming prisms and double
pyramids.
Different shapes of crystals
Different shapes of crystals
• Depending on internal structure; compounds are
classified as
1. Crystalline
2. Amorphous
• Crystalline compounds are characterized by
repetitious spacing of constituent atom or molecule in
three dimensional array.
• In amorphous form atoms or molecules are randomly
placed.
• Solubility & dissolution rate are greater for
amorphous form than crystalline, as amorphous form
has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed
whereas crystalline form results in poor absorption.
Polymorphism
• It is the ability of the compound to crystallize as more than one
distinct crystalline species with different internal lattice.
• Any change in the crystallization conditions; crystals will form
with different pattern
• The change could be due to different solvent, different stirring or
different impurities being present
• Polymorphic forms are Crystals with different packing
arrangements
• Different crystalline forms are called polymorphs.
• Polymorphs are of 2 types
1. Enatiotropic
2. Monotropic
• The polymorph which can be changed from one form into another
by varying temp. or pressure is called as Enantiotropic
polymorph.
Eg. Sulfur.
• One polymorph which is unstable at all temp. & pressure is called
as Monotropic polymorph.
Eg. Glyceryl stearate.
Polymorphism
• Polymorphs differ from each other with respect to their
physical property such as
Solubility
Melting point
Density
Hardness
Compression characteristic
• During preformulation it is important to identify the
polymorph that is stable at room temp.
Eg. 1)Chloromphenicol exist in A,B & C forms,
of these B form is more stable & most
preferable.
2)Riboflavin has I,II & III forms, the III form
shows 20 times more water solubility than
form I.
Amorphous State
• Amorphous solids have very different properties from the crystal
form:
 Crystals have a melting point, whereas the amorphous from does
not.
 Polymeric materials(or other large molecules)have large
molecules and flexible that they do not align perfectly to form
crystals. They are described as semi crystalline. It is not possible
to produce pure crystals from them.
• For low molecular weight materials:
 Amorphous form may be produced if the solidification process is
too fast to have a chance to align to form crystals(this could
happen when a solution is spray dried). Crystals may be formed
and then may be broken.(happen if milled).
• Amorphous forms change characteristics at Tg(the
glass transition temp.)
 Store below Tg, the amorphous will be brittle.
 Store above Tg, it becomes rubbery and the increase in
mobility allows rapid conversion to the crystalline
form.
• Tg of an amorphous material can be lowered by the
addition of plasticizer(water vapor can work as a
plasticizer)
• Materials can be changed to partially amorphous by
milling and extensively when micronized, depending
on the amount of the energy used in milling.
Polymorphism and Bioavailability
• Many drugs are hydrophobic(i.e. very limited solubility and
slow dissolution)
• Drugs which are freely soluble in water, bioavailability is not
limited by the dissolution
• Polymorphic form has to be controlled throughout the
production process and the shelf life of drug
• Drugs shall be made with the most stable polymorphic form
• For dissolution and bioavailability problems it is sometimes
desirable to use the metastable form. The risk is that it will
convert back to the stable form during the product life
 Try to find the most appropriate polymorphic form
• Products are checked with Raman spectroscopy and X-Ray
diffraction
Techniques for studies of crystals
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Microscopy
Hot stage microscopy
Thermal analysis
X-ray diffraction
Microscopy
• Material with more than one refractive index are
anisotropic & appear bright with brilliant colors against
black polarized background.
• The color intensity depends upon crystal thickness.
• Isotropic materials have single refractive index and this
substance do not transmit light with crossed polarizing
filter and appears black.
• Advantage :
By this method, we can study crystal morphology &
difference between polymorphic form.
• Disadvantage :
This require a well trained optical crystallographer, as
there are many possible crystal habit & their appearance
at different orientation.
Hot stage microscopy
• The polarizing microscope fitted with hot stage is
useful for investigating polymorphism, melting point
& transition temp.
• Disadvantage :
In this technique, the molecules can degrade during
the melting process.
Hot stage microscopy
• Diagrammatic
representation
• Results of hot stage
microscopy
Thermal analysis
• Differential scanning calorimetry (DSC) & Differential
thermal analysis (DTA) are particularly useful in the
investigation of polymorphism.
• It measures the heat loss or gain resulting from physical or
chemical changes within a sample as a function of temp.
• For characterizing crystal forms , the heat of fusion can be
obtained from the area under DSC- curve for melting
endotherms.
• Similarly, heat of transition from one polymorph to another
may be calculated.
• A sharp symmetric melting endotherm can indicate relative
purity of molecule.
• A broad asymmetric curve indicates presence of impurities.
• Disadvantage :
Degradation during thermal analysis may provide
misleading results.
Thermal analysis
Deferential Scanning Calorimetry (DSC):
• Differential scanning calorimetry is a technique we use to study what
happens to polymers when they're heated.
• We use it to study what we call the thermal transitions of a polymer.
• Thermal transitions are the changes that take place in a polymer when
they are heated.
• The melting of a crystalline polymer is one example. The glass
transition is also a thermal transition.
• how do we study what happens to a polymer when we heat it?
 We heat our polymer in a device that looks something like this:
 We make a plot as the temperature increases. On the x-axis we
plot the temperature. On the y-axis we plot the difference in
heat output of the two heaters at a given temperature.
Heat Capacity
• When we start heating the two pans, the computer will plot the
difference in heat output of the two heaters against
temperature. That is to say, we're plotting the heat absorbed by
the polymer against temperature. The plot will look something
like this at first.
• The amount of heat it takes to get
a certain temperature increase
is called the heat capacity, or Cp.
• The heat flow is in units of heat, q supplied per unit time, t.
• The heating rate is temperature increase T per unit time, t.
• Let's now divide the heat flow q/t by the heating rate T/t. We
end up with heat supplied, divided by the temperature increase.
The Glass Transition Temperature:
• When we heat the polymer a little more, after a certain
temperature, our plot will shift upward suddenly, like this:
• This means we're now getting more
heat flow.
• This means we've also got an
increase in the heat capacity.
• This happens because the polymer
has just gone through the glass transition
• Polymers have a higher heat capacity
above the glass transition temperature than they do below
it.
Crystallization
• Above the glass transition, the polymers have a lot of mobility.
• They wiggle and squirm, and never stay in one position for very long.
• When they reach the right temperature, they will have gained enough
energy to move into very ordered arrangements, which we call
crystals, of course.
• When polymers fall into these crystalline arrangements, they give off
heat.
• The temperature at the lowest point of
the dip is usually the polymer's crystallization temperature, or Tc.
• Also, we can measure the area of the dip,
and that will tell us the latent energy of
crystallization for the polymer.
 Crystallization is exothermic
 Amorphous do not crystallize
Melting
• If we keep heating our polymer past its Tc, eventually we'll
reach another thermal transition, one called melting.
• When we reach the polymer's melting temperature, or Tm, those
polymer crystals begin to fall apart, that is they melt.
• The chains come out of their ordered arrangements, and begin
to move around freely.
• Melting is a first order transition. This means that when you
reach the melting temperature, the polymer's temperature won't
rise until all the crystals have melted.
• We can measure the latent heat of
melting by measuring the area of this
peak.
• Because we have to add energy to make
it melt, we call melting an endothermic transition.
Putting It All Together:
• The crystallization dip and the melting peak
will only show up for polymers that can form
crystals.
• Completely amorphous polymers won't show
any crystallization, or any melting either.
• Because there is a change in heat capacity,
but there is no latent heat involved with the
glass transition, we call the glass transition a
second order transition.
• Transitions like melting and crystallization,
which do have latent heats, are called first
order transitions.
How much crystallinity?
• DSC can also tell us how much of a polymer is crystalline and how
much is amorphous.
• Many polymers contain both amorphous and crystalline material. But
how much of each? DSC can tell us.
• If we know the latent heat of melting, ΔHm, we can figure out the
answer.
• The first thing we have to do is measure the area of that big peak we
have for the melting of the polymer. The area of the peak is given is
units of heat x temperature x time-1 x mass-1. We usually would put this
in units such as joules x kelvins x (seconds)-1 x (grams)-1:
• When the same calculation for dip is done we can get the
total heat absorbed during the crystallization.
• We'll call the heat total heat given off during melting Hm,
total, and we'll call the heat of the crystallization Hc, total.
Now we're going to subtract the two:
•H' is the heat given off by that part of the polymer sample
which was already in the crystalline state before we heated
the polymer above the Tc.
•Devide by the specific heat of melting
• This is the total amount of grams of polymer that
were crystalline below the Tc.
• Now if we divide this number by the weight of our
sample, mtotal, we get the fraction of the sample that
was crystalline, and then of course, the percent
crystallinity:And that's how we use DSC to get
percent crystallinity.
X-ray diffraction
• Working :
When beam of non homogenous X-ray is allowed
to pass through the crystal, X-ray beam is
diffracted & it is recorded by means of
photographic plate.
• Diffraction is due to crystal which acts as 3
dimensional diffraction grating toward X-ray.
X-ray diffraction
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X-ray diffraction
• Random orientation of crystal lattice in the powder
causes the X-ray to scatter in a reproducible pattern of
peak intensities.
• The diffraction pattern is characteristic of a specific
crystalline lattice for a given compound.
• An amorphous form does not produce a pattern
mixture of different crystalline forms.
• Single – Crystal x-ray provide the most complete
information about the solid state.
Hydrates and Solvates
• Hydrates are crystallized materials in which water is trapped within
the lattice during the crystallization process
• Monohydrate = one molecule of water
• Where water is replaced by other solvents it is called solvate. (e.g.
ethanolate). It is undesirable to use solvates for pharmaceuticals
• The most usual situation is to have faster dissolution rate for
anhydrous form. (e.g. theophylline)
 Water could form hydrogen bonds between drug molecules and tie the
lattice together; this would give a much stronger, more stable lattice
• In some cases hydrates are more rapidly soluble (e.g. erythromycin)
 Water work as a wedge pushing tow molecules apart and prevent the
interaction between them, which will weaken the lattice and results in
a more rapid dissolution rate