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Summary Pharmaceutical Technology And Biopharmacy 1
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Summary Pharmaceutical Technologyand Biopharmacy 1
Lecture 1: Biopharmaceutics
The effect of a drug substance, an active pharmaceutical
ingredient (API), is not only determined by its properties
(both pharmacological and toxicological), but also by
the extend and rate of delivery of the substance to the
site of action, determined by the extend and rate of
drug release, the site of the release and the transport of
the drug substance from its site of absorption to the site
of action are important. These factors are for a big part
determined by the dosage form, administration route,
physicochemical structures and functional aspects of
the dosage form. Development of a dosage form is not easy.
Between administration and action
The drug in the dosage form must be dissolved, for example in the aqueous liquid in the GI tract. After this
it must pass the membrane to enter the blood circulation. After absorption the drug is distributed over the
body through the bloodstream and ECF. The site of action can be reached this way. During intravenous
injection, the drug is already
dissolved and directly injected into
the blood stream. Targeted drugs
specifically target one organ or
receptor in the human body. Other
exceptions are drugs that act local
(like dermally applied drugs or
inhaled drugs).
The fate of a drug is described with pharmacokinetics, or in other words, what the body does to the drug
after administration. There are 4 processes occurring (ADME): absorption, distribution, metabolism, and
excretion. Developments aim to change the pharmacokinetics like prolonging absorption or reducing
metabolism.
Intravenous injection (IV)
During IV, the complete dose of the
drug is injected in the systemic
circulation, leading to a
bioavailability of 100% and direct
action. The drug is dissolved in an
aqueous solution. In the
concentration versus time curve,
certain characteristics are seen.
After injection, there is first the distribution phase, where
the drug is distributed over the organs and fluids. The concentration rapidly decreases. After this there is
elimination (metabolism or excretion), leading to a straight line. By extrapolating this line to T0, the volume
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,of distribution (Vd) is calculated. This tells us about where the drug ends up and helps calculation of doses.
- Volume of distribution varies per drug: from a volume just smaller that our body volume to volume way
smaller. It is a virtual volume based on the concentrations measured in the plasma. If the drug is not widely
distributed but remains in the plasma, a small Vd is found. When the drug accumulates in organs and
compartments, large Vds are found.
Non-intravenous routes
In other routes, first absorption should occur before entering the circulation.
- Intramuscular or subcutaneous: drug must pass the
endothelial membrane.
- Oral route: drug must dissolve in GI tract and pass GI
membrane. Also, blood passes through the portal vein after it
comes from the GI tract. Via this way it goes to the liver, which
can inactivate the drug and reduce the free drug in the
circulation (first-pass effect).
- Rectal administration: drug must pass the colon membrane.
- Sublingual: passage over the membrane under the tongue.
- Pulmonary: most drugs act locally, but some pass the pulmonary membrane.
In the case of a non-intravenous administration, a different
concentration versus time curve is seen. There is no distribution
phase, but instead there is an absorption phase. The plasma
concentration increases and there is more absorption than
elimination. When the absorption becomes smaller, then the
elimination, a peak is seen where Tmax (time with maximum
concentration) and Cmax (maximum concentration) can be obtained.
After the peak, more elimination than absorption occurs (depends on
half-life how fast), and a new dose is necessary. The concentration is
kept below the toxicity level (maximum tolerable concentration) and
above the minimally effective concentration.
Pharmaceutical availability and bioavailability
Pharmaceutical availability is the fraction of total amount of the
drug present in the dosage form that will dissolve in the fluid of the
GI tract.
Bioavailability is the fraction of total amount of administered drug
that reaches the systemic circulation in an unchanged way.
- So: bioavailability = pharmaceutical availability – fraction unable to pass the membrane / metabolized in
the lumen, wall of GI or in the liver. Bioavailability is never higher than pharmaceutical availability.
In formulation of a drug, the mode of action (pharmacodynamics), site of action, side-effects,
pharmacokinetics (ADME), desired intensity and duration of action and the route of administration are
important.
Physicochemical properties
Dissolution and absorption are determined by physicochemical properties, like diffusion, solubility,
dissolution rate, particle size, crystalline habit, polymorphism, amorphous, hydrates, molecular structure
and charge, Log P (lipophilicity), and stability.
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,- Diffusion is spontaneous transport caused by differences in drug concentration. First
law of Fick: larger flux when there is a larger concentration gradient.
- Solubility is important for absorption: an equilibrium between the energetic state of the
drug in the liquid and the energetic state of the drug in solid form. Both the presence of
polar group and the ability to form a crystal are important. More polar and less able to
form a crystal leads to more soluble. Also important for solubility are the salt form, solvent, and particle
size. High solubility causes high concentration, being a driving force for diffusion and rate of dissolution.
- Dissolution rate is linked to solubility. Dissolution of a solid in a liquid occurs through transport of
dissolved molecules to the stagnant or boundary layer (thin layer surrounding the particle when it is
dissolving) by diffusion. The difference between the saturation
concentration and the bulk concentration is important.
Dissolution rate is measured by placing a tablet into a holder,
which is placed in liquid. Measuring
the concentration leads to measuring of how much of the drug has dissolved and over which
surface. Dissolution rate can be increased by increasing the surface of dissolution and increasing the
concentration gradient. More small cubes leads to increased surface and dissolution rate. Also by
increasing the solubility the dissolution rate is increased.
- Specific surface area is related to the size of a particle, the density, and its mass. Sg = 6 / (diameter *
density) * m.
- Disintegration is the individual release of drug particles to make the full surface available. When
disintegration does not occur correctly, dissolution occurs a lot slower.
- Charge is important for solubility. Ionized forms of acids and bases dissolve better in aqueous solvents,
and acids dissolve better in alkaline solvent, while bases dissolve better in acidic solvent.
- Salt forms have higher dissolution rate than the free acid or base. The environment of the stagnant layer
is changed, leading to increased solubility of the drug in the stagnant layer. However, absorption occurs
faster with a non-charged molecule. Basic drugs however can form salts with HCl, leading to coating of the
particles and causing low bioavailability.
- Polymorphism is important when changing a crystal to an amorphous particle, leading to increased
energy state and solubility. An amorphous material leads to higher dissolution and absorption. Amorphous
materials are unstable and will crystallize again. Tricks are applied to keep a drug
amorphous.
Bioavailability determination
To determine bioavailability, the concentrations versus time curves of the oral
administered drug and the intravenously administered drug should be
compared. AUCo/AUCi gives the bioavailability (because the bioavailability of an
intravenous injection is always 100%). If necessary, a dose correction can be
done. The drugs lost during absorption are measured (no membrane passage, or metabolism).
Membrane passage
There are different ways that a compound can pass the membrane:
- Para-cellular: passive transport through tight junctions, by small and highly water-
soluble drugs
- Lipophilic drugs enter the membrane bilayer and can be transported there as well
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, - Active transport: occurs through transporters. Transporters can also pump
drugs out of the body, leading to a low bioavailability (like the PGP)
Absorption and charge and log P
Uncharged molecules easily pass the membrane. Charge depends on the pH of
the environment. In the GI tract, there are a lot of different pH values:
stomach has a low pH, small intestine gets higher and colon again a little more
acid. Henderson Hasselbalch calculates the non-ionized fraction.
Weak acid: Ionized / non-ionized = 10^ pH-pKa, and NIF [1 + 10pH – pKa]-1
Weak base: Ionized / non-ionized = 10^ pKa-pH, and NIF [1 + 10 pKa – pH]-1
- A weak acid is transported over the membrane in places with low pH, but does not pass the membrane
when there is a higher pH. They can be absorbed in the stomach (although only small surface and thick
mucosa) or the upper part of the duodenum.
- A weak base does not pass the membrane in low pH but passes it in a
high pH. Therefore basic drugs are absorbed in the duodenum and the
beginning of the jejunum.
This effect is described by the pH partition hypothesis.
Log P is another important factor for absorption. High log P means quick
transport from the aqueous lumen to the lipophilic membrane, even with
a low non-ionized fraction. Because this way, new non-ionized fractions are formed, causing a
compensation mechanism for the low non-ionized fraction.
So, estimation of driving force for absorption process: look at the non-ionized
fraction and the log P. If the log P is high, a low amount of non-ionized drug
might still lead to a big enough absorption rate. One charged group is not
prohibitive for passive absorption, but more groups are.
Biopharmaceutical classification system (BCS)
- Class I: high permeability and high solubility
- Class II: high permeability and low solubility
- Class III: low permeability and high solubility
- Class IV: low permeability and low solubility (generally not used, but sometimes by using a dispersion
tablet and ritonavir, which is a GPG inhibitor)
A drug has high solubility when the highest dose dissolves in 250 ml of aqueous buffer with a pH between 2
and 7.5. When solubility is not high enough, different things can be changed: reduce particle size, add
surfactants, add buffers, salts, amorphous drug, use different crystalline habits, complexes, eutectic
mixtures, derivatives of the drug.
A drug is highly permeable when the extend of absorption after administration is over 90%. This can be
measured by caco2 analysis or Ussing chamber. Low permeability can be because of a too large molecule, a
too hydrophilic molecule, a charged molecule, certain enzymes in the lumen, metabolism by intestinal wall
or liver, or efflux transporters. Improving permeability is harder than improving solubility.
Dose number (DN) is the total dose of the drug, divided by the maximum amount of drug that can dissolve
in the volume availabile for dissolution. DN = d / (V * Cs)
- DN < 0.1: no effect of solubility on absorption rate
- DN > 10: solubility affects absorption rate and bioavailability
- DN 0.1 – 10: solubility may affect absorption rate and bioavailability
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