Properties of particulate Solids

Prepared by:Mohammad Mahareeq

Solid state properties

• 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

• 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.

Different shapes of crystals

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.

• 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.

Polymorphism

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

• 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

• Results of hot stage microscopy

• Diagrammatic representation

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.

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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.

X-ray diffraction

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