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College aantekeningen Pharmaceutical Technology and Biopharmacy 1 (WBFA059-05)
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College aantekeningen colleges Pharmaceutical Technology and Biopharmacy 1 t/m 12.
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PHARMACEUTICAL TECHNOLOGY AND BIOPHARMACY 1LECTURE 1: BIOPHARMACEUTICAL ASPECTS OF DRUG A DMINISTRATION
The design of a dosage form starts with therapeutic developments and technological developments.
Therapeutic developments → Biopharmaceutical objectives, like release profile, route of
administration and targeting. Technological developments → Technological objectives, like process
control, stability and reproducibility. With a therapeutically active substance and excipients the
formulation of a dosage form is designed.
The therapeutic effect is determined by:
1. Intrinsic pharmalogical and toxicological properties of the substance (receptor interaction)
2. The extend and rate of delivery of the substance to the site of action:
I. The extend and rate of drug release from the dosage form
II. The site of release of the drug substance from the dosage form
III. The transport of the drug substance from its site of absorption to the site of action
i. The physico-chemical properties of the drug substance
ii. The physico-chemical properties of the dosage form
iii. The structure of the dosage form
iv. The site of drug release from the dosage form
v. The route of drug administration
The general route of a drug:
Drug in dosage form → Dissolution → Dissolved drug → (Membrane) transport into the systemic
circulation: ‘Absorption’ → Distribution, Metabolism and Elimination → Site of action
Exceptions: (1) intravenously injected drugs, (2) targeted drugs and (3) locally applied and locally
acting drugs (e.g. dermal or nasal drug)
Pharmacokinetics: 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 substances (metabolites)
Excretion: The removal of the drug or its metabolites from the body, via urine, bile, sweat or breath.
Administration of the drug via the intravenous injection: ‘most direct route’
- The complete dose of the drug is injected in the systemic blood circulation
- Bioavailability = 100%
- The drug should be dissolved and has to be in an aqueous solution
Pharmacokinetics after intravenous injection
- Distributions of drug over the body (fluids, tissues and organs may have different
concentrations)
o Volume of distribution: Vd; the apparent volume in which the drug is dissolved (L/kg)
after administration
o Metabolism and excretion eliminate (e) the drug from the body
, o Clearance: Cl; the blood or plasma volume which is cleared from all drug per unit of
time (ml/min)
- First order elimination process:
𝐷0
𝐶𝑝 = exp[−𝑘𝑒 𝑡]
𝑉𝑑
Cp: concentration in blood (or plasma)
D0: dose
𝐶𝑙
ke: elimination rate constant → 𝑘𝑒 =
𝑉𝑑
t; time
The volume of distribution
No concentration of the drug in organs, fluids or tissues: Vd < Vbody
Concentration of drug in organs, tissues or fluids (compartments): Vd > Vbody
Absorption
Only dissolved drug may be able to pass the absorption membranes. Drug have to enter the blood
flow: this is called the absorption process. Once the drug gets into the blood, the metabolism and
elimination processes start.
- Minimally effective concentration: when above → effect of the drug is measurable (MEC)
- Maximum tolerable concentration: toxicity level → side effects occur (MTC)
Pharmaceutical availability: amount of drug released from the dosage form.
Bioavailability: amount of drug absorbed in the systemic circulation (passed by the elimination in the
gut and liver). It depends on the dosage form and route of administration.
Relevant physico-chemical drug properties:
Diffusion, solubility, dissolution rate, particle size, cyrstalline habit, polymorphism, amorphism,
hydrates, molecular structure and charge (acid, base, salt), partition coefficient and stability.
There are two types of transport mechanisms: diffusion and convection.
Diffusion is spontaneous transport caused by differences in drug concentration. Mass transport per
surface unit per unit of time: flux.
Convection is the transfer of heat by the circulatory motion at a nonuniform temperature owing to the
variation of its density and the action of gravity.
Passive transport → para-cellular uptake in tight junctions (intercellular spaces, aqueous pores) or in
the villi and microvilli in the intestines. Charged molecules are less lipophilic than the charged versions
of acids and bases. The driving force for passive transport is generally the non-ionised fraction of the
dissolved drug. Protonated acids and deprotonated bases are the driving force for the absorption
process. The higher the non-ionised fraction (NIF) the faster and more complete the absorption will
be.
Solubility of a substance (Cs) is equilibrium and is determined by: crystalline habit, salt form, solvent
(pH, surfactants, etc.) and particle size (only matters when < 1 μm). Solubility is important because the
dissolved amount of drug is the driving force for diffusion or partition driven transport. Solubility is
one of the parameters that determines dissolution rate.
,Dissolution rate is a measure of the actual release rate of the compound at the given particle size. It
depends on the concentration difference, distance difference and the surface.
How to increase the dissolution rate:
- Surface: the size of the surface area of a certain mass of powder is related to the particle size
of that powder. Sg = 6 / (d∙ρ) ∙ m
- Charge (ionisation of acids and bases)
- Salt form
- Crystalline habit or amorphous material (polymorphism)
Charge: degree of ionisation; weak acids or bases. The ionised form of an acid or base dissolve much
better in aqueous solvents than the non-ionized form:
- An acid dissolves good in alkaline solvents
- A base dissolve good in acidic solvents
Weak acids: absorption from the stomach is possible, but due to the small surface area and thick
mucosal layers and wall of the stomach more absorption from the upper part of the duodenum.
Weak bases: best absorption from the intestines, because of their good dissolution in the stomach
absorption mainly from upper parts of the small intestines.
In general, one charged group is not prohibitive for passive absorption, but more groups are!
Lipophilicity: Driving force = NIF ∙ 10log(P) = NIF ∙ P
Log P: of the non-ionized molecule
P: partition coefficient
NIF: non-ionized fraction
Salt form: salts have a higher dissolution rate than the free acid or base. The ions in the salt change
the environment (pH) of the stagnant layer surrounding the dissolving particle, which increases the
solubility of the drug in the stagnant layer.
Polymorphism: crystalline materials dissolve in general slower than amorphous material. In the latter
case the dissolving molecule does not need to be released from the crystalline lattice. However most
amorphous materials are not stable and will be transformed in time to the crystalline state again. So
only applicable for drugs that crystallize very slowly. Different crystal habits may have different
dissolution rates.
Bioavailability is important: efficacy and toxicity are often related to blood or plasma concentrations.
Exposure is determined by area under the concentration versus time curve (AUC). Because the
intravenous administration bioavailability is 100%, the bioavailability is calculated as followed:
𝐴𝑈𝐶𝑜𝑟
𝑓=
𝐴𝑈𝐶𝑖𝑛𝑡𝑟𝑎𝑣𝑒𝑛𝑜𝑢𝑠
The gastro-intestinal tract as organ for drug absorption:
- Stomach: pH 1.5 – 5.0
- Small intestine: Duodenum: pH 2.0 – 6.8
Jejunum: pH 6.8
Ileum: pH 6.8 – 7.4
- Colon: pH 7.4 – 6.0
, The Biopharmaceutical Classification System (BCS)
BCS class I: high permeability, high solubility (heaven)
BCS class II: high permeability, low solubility
BCS class III: low permeability, high solubility
BCS class IV: low permeability, low solubility (hell)
Technologies for poorly soluble drugs:
Particle size reduction, surfactants, buffers in formulation, salts, amorphous drug, different crystalline
habits, complexes, eutectic mixtures, derivatives of the drug substance.
Permeability is high when the bioavailability is >90% or the drug passes the membrane easily.
Reasons for a low permeability is that the molecule is too large, is too hydrophilic, is charged or
enzymes or conditions in intestinal lumen, intestinal wall or liver break down the drug or there are
efflux transporters.
Dose number (DN) is a dimensionless parameter that links solubility (Cs) to dose (d) and volume
available for dissolution (V) →
𝑑
𝐷𝑁 =
𝑉 ∙ 𝐶𝑠
DN < 0.1; no effect of solubility on absorption rate
DN > 10; solubility will affect absorption rate and bioavailability
0.1 < DN < 10; solubility may affect absorption rate and bioavailability
Often the structure of a product determines its functionality and it is brought into the dosage form
during the production process. An adequate execution of the production process is essential to get a
drug product with the appropriate quality and performance attributes.
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