Download Done By: Walaa Wahdan Advanced Technology Lecture #8 Last

Done By: Walaa Wahdan
Advanced Technology
Lecture #8
Last lecture we discussed the internal structure and arrangement that allow the solid solutions
and dispersions affect the physiochemical properties of drugs, and change its dissolution and
solubility.
 We may have different types of arrangements and configurations like:
1- Simple Eutectic mixtures:
Are simple physical mixtures, for example: the eutectic mixture between the two local
anesthetics procaine and lidocaine.
We can form these mixtures by co-grinding or co-milling (grinding the crystals to bring them
closer as much as possible).
During the preparation of solid solutions and dispersions, using solvent method or melting
method, rapid solidification of melt or evaporation of solvent may happen >>>>
crystallization of component A and crystallization of component B both happening separately
and individually resulting in crystal very close to each other.
There is some sort of affinity between A&B
>>> some sort of intermolecular inter action, bonds will
form between A&B, which will weaken the bonds within same crystals in the molecules >>> as
a result reduction in MP of both will happen (eutectic mixture: to melt together).
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Phase diagram :
Not necessary that the presence of
component A and B in eutectic mixture lead to
reduction of the melting point below room
temperature (as in lidocaine and procaine
MIX).
Melting point of the mixture will decrease
depending on composition.
E: common melting point of both.
Examples of this type include phenacetin phenobarbital, chloramphenicol-urea,
griseofulvin –succinic acid, paracetamol-urea,
and the dispersions of griseofulvin and
tolbutamide in polyethylene glycol (PEG-2000).
Here the carrier not necessary always a high molecular weight polymer (PEG-2000), mostly
it is a low molecular weight (like phenacetin –phenobarbital, succinic acid).
Eutectic mixtures are systems with crystals of both A&B, what this mean?
If we put a sample of this eutectic mixture in DSC (differential scanning calorimeter, a device
for studying thermal phenomena).
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Done By: Walaa Wahdan
Advanced Technology
Lecture #8
DSC: 2 electrical heaters (one for sample)
with 2 aluminum bands, controlled by a
computer processor.
It contains sensors for measuring TEMP
of the bands.
We can control the amount of energy of
both heaters.
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Now we ask the computer to increase the temperature of both sample and reference bands at a
rate of 10c/min (from 25c to 300c).
The sample heater will give higher energy to increase the temperature of the sample from 25c
to 35c after one minute (because it contains a mass), so the two bands will reach the same
temperature after one minute.
>>>> This will give as the following chart:
Heat flow is the difference of energy between the two heaters.
Heat flow > 0, will not stay as straight line; because of the
thermal transitions of the sample (exothermic like degradation,
breaking down the bonds and crystallization of a material or
endothermic like melting, de-solvation and solid-solid
transformation from one crystalline form to another or from
crystalline form to amorphous form).
In the melting process (endothermic), the amount of energy consumed for the elevation of
temperature and for the melting of the sample. So the sample heater will give higher energy
to maintain constant heating rate (heat flow will increase then decreases to the original state).
In the eutectic mixture there are two peaks one for each crystals (A&B), MP will be on Temp.
lower than the pure MP of the substances.
2- Solid solutions:
Are homogenous molecular dispersion, (Component A&B dissolved in common solvent,
sprayed by spray drier, which give droplet >>> losses solvent >>> 2 solutes concentrate and
increasing concentration>> super saturation>> crystallization process).
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Done By: Walaa Wahdan
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Advanced Technology
Lecture #8
If A&B have high affinity for each other, then it may form co-crystals (true molecular solution).
If solidification happens, then all the crystals will be the same as this. Each sample will
contain the same composition (but in the eutectic mixture previously, not
necessary each sample contains the composition, because it’s a physical
mixture of crystal).
If we pass the solid solution in DSC, it will give one peak because we have
single solid phase.
The ratio of 2 components in the crystal depends on: ratio of drug and carrier,
affinity of both and most stable arrangement between them (but mostly the carrier exist in
higher ratio to form the water soluble matrix which will increase the dissolution). Drug called
co-former (lower ratio).
There are two types of arrangement of solid solutions (for co-former and carrier or guest and
host molecules):
- These arrangements depend on: 1. Molecular size of drug compared to carrier.
2. Affinity of drug to the carrier (ability to form intermolecular interactions).
1. Substitutional (‫)احالل‬: both must have the same size and can make
intermolecular interactions to contribute to the formation of the crystals
(similarity in the intermolecular interactions of both).
Ex: lactose, saccharin sodium
2. Interstitial: carrier and co-former have different size (molecular size of drug
lower than size of carrier – most important requirement-) and mostly without
intermolecular interactions (in case of polymer –PVP- as a carrier or highly
hydrophobic drug with hydrophilic polymer); guest molecules will fill the voids
between host molecules. *more common*
3- Glass solutions and suspensions:
Amorphous (not crystalline solids).
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Here the droplets dryed gradually, the polymer concentration
increases and the solution become more viscuos >>>
molecules with lower ability to diffuse toward each other to
form supra molecular structure (crystals)>>> lower molecular
mobility to form the most stable arrangment.
Particles with amorphous carrier and drug as molecules
formed (glass solution, amorphous solid).
Glass: amorphous solid below glass transtion temperature.
Glass transition temperature: is the temperature above which an amorphous material exist in
ruppary state and below which it exist in glassy state.
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Done By: Walaa Wahdan
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Advanced Technology
Lecture #8
Glass suspension: means some molecules could meet to form supramolecular structure
(amorphous particles) dispersed within the amorphous carrier.
Amorphous Precipitations in a Crystalline Carrier:
The solidification of the amorphous drug particles in crystalline carrier, depending on the
proparties of the drug, carrier and the procees.
5- Complex formation:
The interactions between the drug and carrier lead to complex formation (new chemical entity).
With reversal property to give the free drug , it can lead to good or poor properties.
Ex: hydroxy propyl beta cyclodextrane, digoxin and hydroquinone, ibuprofen and caffeine
Good luck 
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