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Summary pharmaceutical technology and biopharmaceutics 1
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pharmaceutical technology and biopharmaceutics 1 (pharmacie)
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1 - Biopharmaceutical aspects of drug administrationDissolution is the process in which a substance forms a solution (solid → solution).
The dissolution of a drug is important for its bioavailability and therapeutic
effectiveness. Drugs need to be dissolved in the aqueous liquids of the body, so they
can pass the absorptive membrane and enter the systemic blood circulation. Only
dissolved drugs can interact with the receptors of the membrane, so only a drug that
is dissolved, can pass the membrane.
Drugs are distributed over the body via the
blood circulation, but also through diffusion
through extracellular fluids. In this way, the site
of action is reached (e.g. an organ).
A solution is stable. It is a molecular dispersion of the drug (or any other molecule) in
a continuous matrix consisting of a fluid.
Exceptions to this scheme:
- Intravenously injected drugs (drug release, dissolution and absorption don’t
have to occur, because the dissolved drug is immediately injected in the blood
circulation)
- Targeted drugs (these are not distributed by blood circulation or diffusion
through extracellular fluids, but drugs that are specifically targeted to an organ
or a receptor in the human body)
- Locally applied and locally acting drugs (e.g. dermal, nasal or inhaled drugs)
What happens with a drug in the body? → ADME
- Absorption (uptake of the drug in the systemic blood circulation)
- Distribution (the distribution of the drug to the different compartments in the
body)
- Metabolism (the chemical conversion of drug substance by the body, often by
enzymes, to different active or inactive metabolites)
- Excretion (the removal of the drug or its metabolites from the body via urine,
bile/gal, sweat or breath)
Metabolites = an intermediate or end product of metabolism
Intravenous injection is the most direct and fastest route. The
complete dose of the dissolved drug is injected in the systemic
blood circulation. Since its immediately injected in the veins, its
bioavailability is 100%.
In the graph can you see 2 phases:
1. Distribution phase (the drug is distributed over different
organs and fluids of the body and the concentration
decreases rapidly)
2. Elimination phase (metabolism and excretion cause a
decrease in the concentration)
Vd: volume of distribution Intravenous injection
1
,When there is no concentration of the drug in organs, fluids or tissues, then will all
the concentration stay in the plasma/blood → small volume of distribution (Vd < body
volume
Concentration of the drug in organs, fluids or tissues → large volume of distribution
(Vd > body volume). This is characteristic for highly lipophilic drugs.
Portal vein system: the part of the blood that flows first to the liver. The liver has a lot
of enzymes that can break down, and thereby inactivates, drugs. This reduces the
amount of drug that can exert action. The consequence is a reduced therapeutic
effect. The first pass effect is a phenomenon in which a drug gets metabolized at a
specific location in the body that results in a reduced concentration of the active drug
upon reaching its site of action or the systemic circulation. So a high concentration
before the first pass effect is necessary to maintain a certain therapeutic effect.
In a non-intravenous route there is an absorption phase, during which
plasma drug concentration increases.
Absorption phase: absorption > elimination
Cmax / tmax: absorption = elimination
Elimination phase: absorption < elimination
Cmax is the maximum concentration of drug in the blood and tmax is the Non-intravenous route
point in time where the concentration of drug in the blood is maximum.
Plasma concentration above the toxicity level → the toxic side
effects take over the therapeutic effect of the drug
Plasma concentration below the minimally effectiveness level
→ no therapeutic effect
The range between the toxicity level and the minimally effectiveness level is called
the therapeutic window. Drug concentrations must be between these.
Pharmaceutical availability (PA) = total amount of drug that is present in the dosage
form that will dissolve in the fluids
Bioavailability (BA) = total amount of administered drug that reaches the systemic
circulation in an unchanged way, so after metabolism and passing the membrane
BA = PA – fraction that was unable to pass the absorptive membrane and fraction
that was metabolized
- Increase dissolution rate → increase plasma level → stronger therapeutic
effect + inducing side effects
- Releasing drug closer to side of action → increase therapeutic effect → less
side-effects
2
,A side effect is a therapeutic effect that occurs when treatment goes beyond the
desired effect, or a problem occurs in addition to the desired therapeutic effect.
Dissolution and absorption are determined by physicochemical properties:
- Diffusion
- Solubility (most important)
- Dissolution rate
- Particle size
- Crystalline habit
- Molecular structure and charge
- Partition coefficient (Log P)
- Stability
Partition coefficient (Log P) – distribution between an aqueous phase and an oily
phase of the drug. This determines if the drug will remain in the aqueous environment
of the lumen of the gastrointestinal tract or immediately will be transported into the
more lipophilic environment of the membrane of the gastrointestinal tract.
Diffusion is spontaneous transport caused by differences in drug concentration:
Flux: mass transport per surface unit per unit of time
D: diffusion coefficient is depending on solubility, viscosity and polarity.
It is a characteristic of a particular substance
∆c: difference in concentration
∆x: difference in distance
Solubility is defined as the maximum amount of a substance that will
dissolve in a given amount of solvent at a specified temperature. Solubility can also
be defined by the equilibrium between the energetic state of the drug molecule in the
liquid and the energetic state of the drug in the solid state. Solubility is determined by
- Crystalline habit
- Salt form
- Solvent (pH, surfactants/oppervlakte)
- Particle size (the smaller the particle, the higher the solubility)
A stable crystal doesn’t fall apart rapidly and thus has a low solubility
(1).
An unstable crystal falls rapidly apart and thus has a high solubility (352).
Salt formation approaches have widely been utilized to increase solubility, and
therefore, the dissolution rate of a drug. It is one of the most common methods to
increase the solubility of weakly acidic and basic drugs. So drugs often have a salt
form. Salts are formed when a compound that is ionized in solution forms a strong
ionic interaction with an oppositely charged counterion, leading to crystallization of
the salt form.
-Higher solubility → higher concentration → larger diffusion flux
-Poor solubility → low concentration → slow and incomplete absorption
3
, Dissolution is the transfer of molecules or ions from solid state into solution.
The dissolution rate is the rate at which solid dissolves in a solvent. So, the
dissolution rate is described by the Noyes-Whitney equation. You see the
saturation concentration (maximum solubility of the compound in the specific
liquid: Cs) and the bulk concentration Cb. The difference in concentration is a
consequence of the stagnant layer. A stagnant layer is a small film of liquid
surrounding the solid drug particle that is dissolving. In the
stagnant/boundary layer there is no convectional flow and drug molecules
are only transported by diffusion through this layer. Diffusion occurs because
the concentration of the drug in the bulk is lower
than the saturation concentration.
The Noyes-white equation can be made from the
Fick’s 1st law, when A (surface) is added:
∆x: thickness of the stagnant layer
How to determine intrinsic dissolution rate →
The diffusion coefficient D and the thickness of the boundary layer ∆x are difficult to
change, so they are considered constant. However, the concentration gradient and
the surface can be changed. So if you want to increase the dissolution rate, you have
to increase the concentration gradient by lowering Cb or raising the Cs. You can also
increase the area by decreasing the particle size.
Surface area of powder consisting of cubes or spheres:
6
Sm = 𝑑 𝑥 𝑝 x m
Sm: the surface of a certain powder
D: diameter
P: density
M: mass that is dissolved
The smaller the particle size, the larger the surface area (d in denominator).
4
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