MEDICINAL CHEMISTRY
Unit I
Prepared By:
Neetu Sabarwal
Department of Pharmaceutical
Chemistry
SOS Pharmaceutical Sciences
Jiwaji University. Gwalior
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DEFINITION:
The ability of a chemical compound
to elicit a pharmacological/
therapeutic effect is related to the influence of various
physical and chemical (physicochemical) properties of
the chemical substance on the bio molecule that it
interacts with.
1)Physical Properties
Physical property of drug is responsible for its action
2)Chemical Properties
The drug react extracellularly according to simple
chemical reactions like neutralization, chelation, oxidation etc
Physico-chemical properties in relation to
biological action
Drug action results from the interaction of drug molecules with either
normal or abnormal physiological processes.
Drugs normally interact with targets (which they are proteins, enzymes,
cell lipids, or pieces of DNA or RNA).
The ability of a chemical compound to elicit a pharmacologic
/therapeutic effect is related to the influence of its various physical and
chemical (physicochemical) properties
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Various Physico-Chemical Properties are,
Ionization of Drug
Solubility
Partition Coefficient
Hydrogen Bonding
Protein binding
Chelation
Bioisosterism
Geometrical and optical isomerism
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Ionization of drug
Most of the drugs are either weak acids or base
and can exist in either ionised or unionised state.
Ionization = Protonation or deprotonation
resulting in charged molecules.
The ionization of the drug depends on its pKa &
pH.
The rate of drug absorption is directly
proportional to the concentration of the drug at
absorbable form but not the concentration of the
drug at the absorption site.
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Ionization form imparts good water solubility
to the drug which is required of binding of
drug and receptor interaction
Unionized form helps the drug to cross the cell
membrane.
Eg; Barbituric acid is inactive because it is
strong acid. while, 5,5 disubstituted
Barbituric acid has CNS depressant action
because it is weak acid.
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SOLUBILITY OF ORGANIC MEDICINAL
AGENTS
Importance of solubility:
(1) Formulation of the drug in an appropriate dosage
form and
(2) Bio- disposition: Disposition of drugs in the living
system after administration ( absorption, distribution,
metabolism, and excretion).
The solubility expression: in terms of its affinity/philicity or
repulsion/phobicity for either an aqueous (hydro) or lipid (lipo)
solvent.
♣hydrophilic.................... water loving
♣lipophobic..................... lipid hating
♣lipophilic....................... lipid loving
♣hydrophobic.................. water hating 7
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SOLUBILITY OF ORGANIC MEDICINAL AGENTS
In order for a chemical compound to dissolve in a particular
solvent/medium the compound must establish attractive forces
between itself and molecules of the solvent.
It is possible to estimate the solubility properties of an OMA
(hydrophilic vs. lipophilic) by examining the structure of the
drugs and noting whether its structural features promote
affinity for aqueous or lipid media.
The most important intermolecular attractive forces (bonds)
that are involved in the solubilization process are:
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The most important intermolecular attractive forces (bonds)
:that are involved in the solubilization process are
1. Van der Waals Attraction
■ weakest intermolecular force (0.5-1.0 kcal/mole)
■ electrostatic
■ occurs between nonpolar groups (e.g. hydrocarbons)
■ highly distance and temperature dependent
2. Dipole- Dipole Bonding
■ stronger (1.0 to 10 kcal/mole)
■ occurs electrostatically between electron deficient and electron
excessive /rich atoms (dipoles)
■ hydrogen bonding is a specific example of this bonding and serves as a
prime contributor to hydrophilicity
+
+ O H
N: H O C + O
H
H O H
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3. Ionic Bonding
■ electrostatic attraction between cations and anions
■ common in inorganic compounds and salts of organic
molecules O
■ relatively strong (5 kcal/mole)
+
+ - C Na
N H Cl -
O
4. Ion-Dipole Bonding
■ electrostatic between a cation/anion and a dipole
■ relatively strong (1-5 kcal/mole)
■ low temperature and distance dependence
■ important attraction between OMAs and H2O
H
O
O H
C
N
+
H
H
- O
O H
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Solubility Prediction
The relative solubility of a drug is a function of
the presence of both lipophilic and hydrophilic
features within its structure, which serve to
determine the extent of interaction of the OMA with
lipid and/or aqueous phases.
The relative solubility of a drug can be
determined in the laboratory, i.e. the partition
coefficient [P; the ratio of the solubility of the
compound in an organic solvent to the solubility of
the same compound in an aqueous environment
(i.e., P=[Drug]lipid/ [Drug]aqueous). P is often
expressed as a log value.
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Solubility Prediction
A mathematical procedures also have been
developed to estimate the relative solubility of an
organic molecule based upon differential
contributions of various structural features to overall
solubility.
For example, the relative solubility of a drug is the
sum of the contributions of each group and
substituent to overall solubility.
Example:
Examination of the structure of chloramphenicol
(indicates the presence of both lipophilic (nonpolar)
and hydrophilic (polar) groups and substituents. 14
Solubility Prediction
Lipophilic
Hydrophilic
Hydrophilic Lipophilic
OH O
O2N CH CH NH C CHCl2
CH2OH
Chloramphenicol
Hydrophilic
The presence of oxygen and nitrogen containing functional groups
usually enhances water solubility. While lipid solubility is enhanced by
nonionizable hydrocarbon chains and ring systems.
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Solubility Prediction
1.Laboratory Estimation of Relative Solubility
The relative solubility of an organic compound is measured by determining the
extent of its distribution into an aqueous solvent (usually pH 7.4 buffer) and a
lipid solvent (usually n-octanol). These experiments generate a value, P, the
partition coefficient for that particular compound.
Conc. of compunds in C8H16OH
Partition coefficient =
Conc. of compunds in H2O
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NEXT 4 PHYSICOCHEMICAL PROPERTIES
WILL BE DISCUSSED TOMORROW IN NEXT
PPT
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