Download Done By: Sanaa Otoom Advanced Technology Lecture# 2 Last

Done By: Sanaa Otoom
Advanced Technology
Lecture# 2
Last lecture we discussed the problems that affect bioavailability, which are
solubility, stability and permeability, and how we can solve them. The solutions for
solubility problem was the simplest since we can change the physiochemical
properties of drug or provide our drug in a form that is available for absorption by
drug design system “in molecular solution state”.
In comparison with solubility, solutions for stability and permeability are harder, some
solutions for stability can be straight forward like: - enteric coated tablets of drug that
has hydrolytic instability in stomach.
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Gastro-retentive system in which all release process occurs before absorption
window to improve bioavailability of drugs that have narrow absorption
window “through active transport process in proximal small intestine” such as
gabapentin.
For alendronate sodium, solubility very high but bioavailability low (0.1% 0.001%)  we need to change its permeability by either change its chemical
structure “pro-drug” or change the diffusional barrier by permeation enhancers
such as simple surfactants that make disruption of cellular barrier function or
efflux inhibitors “P-gb inhibitors”, the problem when we use permeation
enhancers is that we interfere with the normal function of our GI system,
remember example cyclosporine (its formula contains micro surfactants as
emulsifying agents to emulsify the drug but they affect both permeability and
efflux system which leads to chronic inflammation and histo-pathological
changes of intestinal mucosa).
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We discussed the intrinsic solubility, it describes the worst case of
solubility of the drug “weak acid or weak base” , the intrinsic solubility is
the basic for our classification of drugs “BCS classification system” :
We depend on BCS classification on Dose number = (Maximum dose of drug/250
ml)/ Aq. Solubility (mg/ml)
Which aq. Solubility we use? We take the least or worst solubility at different media
with different PHs  will be close to intrinsic solubility.
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Done By: Sanaa Otoom
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Advanced Technology
Lecture# 2
Now if the Dose/250 ml > Aq. Solubility ((Dose Number > 1 )) : poorly
soluble
Sometimes we use another term for classification which is the intrinsic
dissolution:
Intrinsic dissolution rate: dissolution rate of material in Aq. Media from
constant area of solid surface ( (mg/min)/cm² )
Dissolution rate depends on surface area.
 When we use this term?
1- It’s used when we need to compare the interaction between the solid and
solvent when other variables are constant.
2- When we compare the solubility or dissolution properties of different solid
forms “like different crystal forms of drug” or comparing pro-drug with its
parent compound, or comparing different salts of compound “sodium,
potassium, procaine salt, benzathine salt” and their parent acids  when
we talk about salts we know that the solubility of sodium and potassium
salts higher than parent drug, in benzathine or procaine salts like
benzathine penicillin its solubility less than parent compound. Another
Example: protamine insulin is poorly soluble salt (polyelectrolyte complex)
because when we add protamine to insulin they form precipitate.
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The procedure of measuring dissolution rate:
Prepare disks of drug and salts or pro-drug with its parent compound and
compress the disk in which only one surface available then put it in
dissolution tester, take samples with time and the relationship between M
“amount of dissolved material” and T will be as follow:
M
Time
Slope = intrinsic dissolution rate
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Done By: Sanaa Otoom
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Advanced Technology
Lecture# 2
 The primary problems for class 2 and class 4 compounds are solubility and
dissolution. Change the dissolution rate of compound might affect the
dissolution rate only but not solubility or might change the dissolution rate
by its change on solubility, how?
Milling techniques we change the dissolution rate by changing surface area
but solubility doesn’t change.
Same applies upon using Wetting agents hydrophilic polymers.
But when we change the solid state of the compound “convert it from
crystalline form A to crystalline form B or amorphous form” in this case we
change the solubility and dissolution accordingly. The same for salts and cocrystals.
From slide 15: Pro-drug (?)  why question mark? Because prodrug may
either increase or decrease the solubility by this approach. Example:
phenytoin is antiepileptic drug poorly soluble compound class 2 drug,
fosphenytoin is phosphate ester prodrug of phenytoine used for IV
administration of phenytoin in status epilepticus. Another cause for question
mark is high cost of this process, if we have justification of preparation of
prodrug to solve the problem of poor solubility poor dissolution rate poor
bioavailability we can use it.
Solid solutions and solid dispersions: they enhance the dissolution rate of
compounds and provide the drug in solution state but this molecular solution
is not liquid in its overall it will be in solid state “drug in carrier will give solid
solution, if this carrier is water soluble the molecules of drug that are
suspended inside carrier will be exposed suddenly to Aq. Environment, so we
don’t have dissolution for drug we have dissolution for the carrier itself. In
case of dispersions we can have solid particles dispersed in carrier. For a
conclusion solid dispersions and solutions can work through two mechanisms
increase dissolution rate of the compound or presentation the compound in
solution to the absorptive process.
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Done By: Sanaa Otoom
Advanced Technology
Lecture# 2
1- For class two compounds, formulation design can change the problem of
solubility.
2- Class three or class 4 compounds “low permeability” we need lead
optimization: change the structure of the compound to change the
permeability problems, we can use formulation approaches but they are
limited in their efficacy here.
3- Class 4 drugs the low permeability might be due to the narrow absorption
window, here we can use gastro-retentive forms to optimize bioavailability.
 Now how we can pick the right technique to be used?
o Low cost: most important one.
o Simple manufacturing procedures: this insures that manufacturing
procedure contain least number of variables to insure robustness of our
procedure.
o Robust: lower variables, resemble precision in analytical methods. We can
reduce variables by reducing number of excipients, reducing
manufacturing steps.
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o Simple and favorable regulatory position: if we need to use a lot of
excipients, a lot of manufacturing processes, organic solvents have certain
Toxicity , the regulatory agencies put restrictions on accepting our product.
Also the formulation technology must provide easy release rate profile:
carvidelol
% released
T
An ideal technology will allow me to produce different products for different
therapeutic agents with different release rate that is suitable to product’s
requirments.
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Patent protection: technology to be used must not under patent
protection, do not use the same technology of the patented product,
you need to develop your own technology.
Good Luck ^_^
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