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Physico-Chemical Properties of Drugs
Physico-Chemical Properties of Drugs
Physico-Chemical Properties of Drugs
drugs important?
Approximately 30-40% of potential
drugs are
later rejected for their inappropriate
pharmacokinetic (ADME) parameters
ADME
Absorption
Distribution
Metabolism
Elimination
Drugs are weak organic acids (acetylsalicylic acid ) or weak organic bases
(procaine), or their salts (ephedrine hydrochloride).
The degree of ionized drugs are in solution is highly dependent on the pH.
Ionization of a drug has an important effect on its absorption,
distribution and elimination.
There are many examples of the alteration of pH to change these
properties.
ionized drug
pKa pH
Both acidic and basic drugs are exactly 50% ionized at the pH of
their pKa values.
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potentiometry
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SPARC
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Drug lipophilicity
Is an important physico-chemical parameter that influences the distribution and destiny of drugs in the
body.
Lipophilicity is the measure of the partitioning of a compound between a lipidic and an aqueous phase.
Lipophilicity is one of the most informative physicochemical properties in medicinal chemistry and
since long successfully used in quantitative structure activity relationship (QSAR) studies.
Its important role in governing pharmacokinetic and pharmacodynamic events has been extensively
documented.
Lipophilicity is also a highly important descriptor of blood brain barrier (BBB) permeability.
Last, but not least, lipophilicity plays a dominant role in toxicity prediction .
partition coefficient P , is defined as the ratio of the concentrations of a neutral compound in organic
and aqueous phases of a two - compartment system under equilibrium conditions. It is commonly used
in its logarithmic form, log P . Whereas 1 - octanol serves as the standard organic phase for
experimental determination, other solvents are applied to better mimic special permeation conditions
such as the cyclohexane water system for BBB permeation.
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P = corg / caq
P
- is the partition coefficient of the system
n-octanol - water
- informs about the ratio of drug solubility
in an aprotic environment (lipids)
and protic environment (in water)
- it informs about the amphiphilic nature of the substance in vitro
- parameter P (log P) is considered the most important
lipophilic
parameter, which is fairly good correlation to the overall biological
effects in many groups of drugs
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The ionization of acids and bases in the first degree of distribution coefficient
can be calculated from the equation:
+ A-
BH + = H
+B
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Experimental determination
partition coefficient
(The method usually involves the following: solubilization of the compound in a mixture of mutually
presaturated buffered water and octanol, separation of octanol and aqueous phases, and direct
measurement of the solute concentration in both phases. )
Potentiometric Method
(The potentiometric method for log P determination has been correlated with the shake - flask
method .
Therefore, the method is appropriate only for ionizable compounds with accurately determined
aqueous pKa values. )
Chromatographic Methods
(lipophilicity can be determinated by liquid chromatography, including reversed phase, thin - layer,
micellar, reversed - phase (RP) HPLC, RP - ion - pair and countercurrent chromatography.
from TLC RF values, respectively. RM of HPLC and GC P calculated from the retention times tM)
Electrophoretic Methods
Theoretical calculations of
lipophilicity
most used methods are:
Substructure - based Methods
Fragmental Methods (1.)
Atom - based Methods (2.)
Property - based Methods (3.)
Methods based on 3D structure representation
Methods based on topological descriptors
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Fragmental Methods
Fragmental methods cut molecules down into fragments and
apply correction factors in order to compensate for
intramolecular interactions.
Defining fragments larger than single atoms guarantees, that
significant electronic interactions are comprised within one
fragment; this is a prime advantage of using fragments. On the
other hand, fragmentation can be arbitrary and missing
fragments may prevent calculation. These are the main
disadvantages.
reductionistic approaches:
KLOGP and KOWWIN
AB/LogP
combines the advantages of both reductionistic and constructionistic
approaches by using hierarchical cluster analysis.
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For two relatively immiscible solvents log P can be considered proportional to the molar
Gibbs free energy of transfer between octanol and water:
Eq. (1)
Empirical Approaches
SPARC
MLP Methods
Hydrophobic Interactions (HINT)
Calculated Lipophilicity Potential (CLIP)
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MLOGP
MLOGP uses the sum of lipophilic (carbons and halogens) and hydrophilic
atoms (nitrogens and oxygens) as two basic descriptors.
TLOGP
VLOGP
ALOGPS
CSlogP
A_S+logP
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Drug solubility
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Drug salts
The selection of an appropriate
salt form for a potential drug
candidate is an opportunity to
modulate its characteristics to
improve bioavailability, stability,
manufacturability, and patient
compliance.
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Drug salts
Most used drug salts
Anions
Hydrochloride
Citrate
Chloride
Bromide
Acetate
Maleate
Mesylate
Phosphate
Sulphate
Tartrate
Nitrate
Aminoacids
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Prediction of the
solubility
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Prediction of the
solubility
Log S an intrinsic solubility in neutral state is indicative of a
compounds solubility (S).
When experimental solubilities of compound is not known, the log S
values can be calculated using ALOGPS a predictor.
This method uses E-state indices as descriptors and a neural
network [2] as the modeling engine.
Another methods for prediction of solubility:
AC logS
AB/logS
[2] I.V. Tetko, V.Y. Tanchuk, T.N. Kasheva, A.E.P. Villa, J. Chem. Inf. Comput. Sci. 41
(2001) 1488.
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