Download Done By: Haya Tabaza Advanced Technology Lecture #10

Done By: Haya Tabaza
Advanced Technology
Lecture #10
- From a pharmaceutical point of view we can see that solid solutions/dispersions have many
advantages in the drug delivery system ; they allow for a rapid dissolution rate resulting in the
increase of the rate and extent of the absorption of a drug so we expect that both AUC and
Cmax - after the administration of the drug in a solid solution/dispersion form that is properly
formulated - is going to be higher than the administration of the drug in the conventional dosage
form.
- Sometimes it’s possible that the increase in AUC and Cmax is resulted from some
mechanisms ; like reduction in the presystemic metabolism which happens by the saturation of
the metabolic machinery in the liver or in the brush border at the intestinal mucosa .
We know that the first pass metabolism is a saturable process which means that there is a limit
for its capacity ; for example if it can do a processing for 10 molecules/min and the drug was
given at a rate of 5 molecules/min >>> the metabolic machinery can eliminate this drug , so
basically you will get the very small fraction of the drug passing through this metabolism and
entering into systemic circulation which leads to a decrease in the bioavailability.
Now what happens if the rate of administration was increased to 20 or 30 or more - due to
enhancement of dissolution/solubility so that the rate of absorption was increased- ? it will lead
to the saturation of the metabolic machinery , hence the ratio of the drug being
eliminated/metabolized by the liver enzymes will be lower so that a higher percentage of the
drug administered will reach the systemic circulation.
So this could be one of the mechanisms that are used to enhance the bioavailability of the drugs
by the formulation of solid solutions/dispersions indirectly.
- Most of the drugs that have significant first pass metabolism are hydrophobic; which expected
to have problems in the solubility and dissolution ; so we can improve the solubility + dissolution
rate + bioavailability in that way (saturation of the metabolic enzymes).
- For example ; 17-bestradiol which its bioavailability was improved by increasing the rate and
extent of the absorption and the saturation of the carrier.
- Sometimes there might be a direct effect of the carrier itself on the enzymes that are
responsible for the metabolism , and this happens when the enzyme – that is responsible for the
metabolism- is a brush border enzymes that is found on the surface of the intestinal mucosa (at
the external surface of the cell membrane) , in this situation we might have some carriers that
works as inhibitors for the brush border enzymes and this happens when the carrier is a
surfactant ( surfactants have the property of being absorbed at the active site of the enzymes
and they inhibit the binding between the substrate and the enzyme) .
These 2 mechanisms might be responsible for the reduction in the presystemic metabolism.
- In some cases we might have an advantage related to the transformation of the liquid to a
solid form; So if there is a liquid drug , we can transform it to the solid form in order to improve
its processability , but how this happens ? for example if we have benzyl benzoate or valproic
acid or low melting point active ingredient like Orlistat ; in these cases when its formulated as a
solid solution or dispersion its actually distributed molecularly in a solid matrix of the drug , if
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Done By: Haya Tabaza
Advanced Technology
Lecture #10
they are not distributed molecularly in a solid matrix of the drug it will distribute as a very small
volume elements within the solid matrix of the drug , So the overall state of the system is Solid
and it can be processed as any solid material . So we can transform a liquid drug and
incorporate it into a solid form.
- Through the proper formation of the solid dispersion we also can avoid the polymorphic
changes that might happen during the storage. One of mechanisms to improve the solubility and
dissolution of the drugs is by changing its solid form by the transformation of the drug from the
crystalline form into an amorphous form. It’s not necessarily to have a carrier to get the
amorphous form , all what you need is a solution of the drug then do spray/freeze drying ,or
milling of the solid particles , or bring a solution then do rapid crystallization by any method you
want (like cooling/evaporation/solid addition etc..).
Now what is the advantages of the presence of a carrier ?
instead of having drug molecules close to each other and any energy investment in the
environment results in a change in its arrangement , its binds with the most stable crystalline
arrangement which means that the drug molecules are separated by the carrier so that the
process of the approach of the molecules toward each other will be limited and the potential for
recrystallization will be limited too.
This is an important issue to make solid solution/dispersion that is properly formulated which
can stabilize the metastable/amorphous form.
But at the same time if it’s not properly formulated we will have the same problems and risks for
changes in its solid form and crystallinity ; referring to slide 31 – 32 you can find that this point is
no 4 of advantages and no 1 in limitations.
Will all the carriers gives us a stabilization effect against solid - solid transformation ?
No , it’s must be a glassy carrier ; if it’s a rubbery carrier at room temperature ( Storage Temp.)
that have a high molecular mobility which means that the diffusional resistance will be low and
the molecules have the ability to approach each other and arrange itself in a stable crystalline
form .
- Even if we have amorphous particles, if the molecules were compressed inside the particle
there is no rearrangement and its difficult to transform from amorphous to crystalline or from
meta stable crystalline to stable crystalline , in these cases the carrier locks the molecules and
limits its movement .
- A carrier with low glass transition temp. >>> it’s rubbery at room temp >> no resistance.
- Glass transition temp.(GTT) changes in the presence of plasticizers ; for example the GTT of
PVP is high and might be lowered by the presence of the plasticizers like glycerol or water
(water is the most important plasticizer // the water content of the polymer films will affect the
GTT).
- Plasticizers works as lubricants so that they make the movements easier , they are small
molecules that prevent the polymeric strands from binding to each other by intermolecular
interactions ; instead they position them self to bind with the polymeric strands and reduce the
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Done By: Haya Tabaza
Advanced Technology
Lecture #10
intermolecular interactions between the polymeric strands so that they can move relative to
each other which is the rubbery character.
- When you have molecules that can move relative to each other and you apply a force or give
them a thermal energy, the diffusional resistance that they offer against the movement of the
drug molecules in between will be lowered.
- An advantage for PVP is high GTT but if the dosage form have PVP we should be aware of
the moisture effect on its GTT ( reduction ) thus its can’t prevent the recrystallization of the drug
anymore.
- We expect that the polymers - that are used as carriers- are hygroscopic (loves water)
because they are hydrophilic (ex: PVP , PEG, Methyl cellulose ,… )
- We try to use a polymers that have high GTT, but if we used polymers with low GTT we have
to ensure that the packaging is designed to have low moisture content. Other than that the drug
will be changed so that its dissolution , solubility and bioavailability will be affected.
- If the polymer have low GTT or we have high temperatures in the process conditions we will
have a problem in processing and production of our dosage form , so the material will be sticky
resulting in many problems in tableting , easy of handling and the processability of the dosage
form - due to the problems in tackiness and stickiness- .
- The polymer is chosen according to its effects on the dosage form; sometimes PEG might be
better to a certain case and Methyl cellulose will be better for another one.
- In the formulations when we have many carriers and drugs we don’t have a universal solution
for all the cases.
- The controlled release gastro-retentive system for Gabapentin have higher bioavailability than
immediate release formulation ; Gabapentin is relatively water soluble and there is no problems
in its solubility , but its absorbed through active absorption pumps , so if we have immediate
release formulation only a limited amount will pass due to the saturation of these pumps , but if
we use a controlled release form that will gradually release the drug we will have a better
bioavailability by releasing a small amounts . The same concept applies for Liver enzymes .
Sustained-release Solid Solutions / Dispersions:
when we have a hydrophobic –water insoluble- carrier , the rate limiting step is water
penetration and its limited by the hydrophobicity of the carrier (carnauba wax/beeswax /paraffin
wax or water insoluble polymer like methacrylic acid ester copolymers/methyl cellulose /
polyvinyl acetate ).
Characterization of Solid Solutions / Dispersions:
By logic we have to study the bioavailability but it’s very expensive so it’s considered to be a
very late step.
Characterization can be done using dissolution testing(paddle – basket – flow through systems)
to study drug release properties from solid solutions/dispersions.
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Done By: Haya Tabaza
Advanced Technology
Lecture #10
- We can study the solubility hence some carriers have solubilizing effect , others like
surfactants and complexing agents also affects solubility .
- Meta stable crystals or amorphous forms have higher solubility than the stable crystal forms so
we can study the equilibrium solubility in addition to the dissolution.
- We can study the internal structure of the particles, whether they are in solid solution/solid
dispersion/crystalline form /amorphous form by using thermoanalytical methods; Differential
thermoanalysis and hot stage microscopy.
- X-Ray diffraction also can be used.
- We can evaluate the samples through IR spectroscopy, it’s a vibrational spectroscopy , thus
each function group have an absorption band at a certain wave number, This vibration depends
on the environment its found in ;the functional groups of the amorphous form interacts with a
different bonds from the crystalline form so that it have a different IR spectrum when compared
to the crystalline form.
- If we have a drug that do intermolecular interaction with the carrier we will have a spectrum
that is different from the drug free or carrier free spectrums or physical mixing of the carrier and
drug (without processing by spray congealing or spray drying).
- Also you can use the scanning electron microscopy; which will show you the surface of the
particles having the drug crystals on it so we conclude that not all the drug molecules are in the
solid solution/dispersion form and there is a crystals on the surface which usually happens when
we have high drug loading ( high amounts of the drug compared to the carrier ).
- Polarized light microscope ; the light wave moves in a single direction by a certain filter , the
crystalline material will diffract the light and change its direction , so the crystalline materials
have an anisotropic property which means when we have a sample mixed of amorphous and
crystalline we can only see the crystalline forms.
- Another example ; if we have an amorphous carrier and a crystalline drug we can only see the
drug crystals.
- Also if we have a Glass solution studied after its preparation directly >> Darkness and nothing
can be seen , but if it is exposed to elevated temp/humidity >>> Recrystallization might happens
so that you can detect the growth of the crystals after a certain time.
- All these techniques doesn't eliminate the need for bioavailability and bioequivalence testing;
these tests and techniques are intended to direct the formulation studies; so we can study the
dissolution/solubility/internal structure/…. to choose a formula that have the best enhancement
of dissolution and solubility , or to choose a formula that gives us the best aging resistance
properties ( resistant to recrystallization or solid form transformation).
- Solid form transformation can be easily detected by DSC , X-Ray diffraction , Polarized light
microscope.
Good Luck ^_^
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