phc 222 part(i) dr. huda al salem
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PHC 222Part(I)
Dr. Huda Al Salem
Lecture (10)
How to improve water solubility?
1 -Salt formation
1 -Salt formation
-Salt formation usually improves the water solubility of acidic and basic drugs as the salts of these drugs dissociate in water.
-The degree of water solubility depends on the structure of the acid or base used to form the salt
1 -Salt formation
Many GIT disturbances can be treated by ingestion of water-soluble compounds.
Example 1Tartaric acid >>>>Na K tartrate is used as mild laxative
1 -Solubility -Salt formation is also used to change the taste of drugs to make them
more palatable to the patient
Example 2:Chlorpromazine HCl is water soluble but it has a very bitter taste. However, the water insoluble embonate salt is tasteless.. So it can be administered orally in the form of a suspension
How to improve water solubility?
2 -Incorporation of water-solubilizing groups
2 -Incorporation of water-solubilizing groups
a- Type of group introducedb- Degree of permanency
c- The biological effect of the groupd- Methods of introduction
a- Type of group introduced
1 -Incorporation of strongly polar alcohol, amine, amide, carboxylic acid, sulphonic acid and phosphorus oxyacid groups give analogues with water solubility higher than those formed by introduction of ether, aldehyde & ketonic functional groups.
2 -Introduction of acidic and basic groups give a wide range for dosage forms that increase water solubility.
a- Type of group introduced
3 -Zwitterions reduces water solubility.
4 -Incorporation of weakly polar groups such as carboxylic acid esters, aryl halides & alkyl halides
increases lipid solubility .
b- Degree of permanency1 -Groups that are bound directly to the carbon
skeleton of the lead compound by C-C, C-O & C-N bonds are attached to by irreversible bonds.
2 -Groups that are linked to the lead compound by ester, amide, phosphate & glycosidic links are more likely to be metabolized to reform the
parent lead compound .
C- The position of the group
In order to preserve the type of activity exhibited by the lead, the introduced group should be attached to a part of the structure that is not involved in the drug-receptor interaction (Pharmacophore).
C- The biological effect of the group
Some groups have certain biological activity..1 -acidic groups exhibit haemolytic properties.
2 -aromatic acid groups exhibit anti-inflammatory activity
3 -carboxylic acids with an alpha functional group exhibit chelation property.
4 -Basic groups have a tendency to change the mode of action
d- Methods of introduction
1-Water-solubilising groups may be introduced at any stage in the synthesis of a drug.
2-Many methods involve the use of protecting groups.
3 -Groups protected are either the water- solubilizing group or groups already present in the lead structure.
d- Methods of introductione.g:.
Acetal protection of a ketone during Reduction of an Ester.
d- Methods of introduction
O2N
CH2OH
NHCOCHCl2
OH
O2N
CH2OCOCH2CH2COONa
NHCOCHCl2
OH
NaOH
CO
O
OC
i)
ii)
Chloramphenicol (antibacterial) Chloramphenicol sodium succinate(antibacterial)
1 -COO- by acylation
Chloramphenicol sodium succinate is supplied as a lyophilized powder which is dissolved only in water when needed & not more than 48 hours
d- Methods of introduction
2 -Sulphonic acid groups (-SO3H)
N
OH
N
OH
SO3H
H2SO4
8-Hydroxyquinoline 8-Hydroxy-5-quinoline sulphonic acid(topical antiseptic)
Sulphonic acid groups can be incorporated into the structure by direct sulphonation with conc. H2SO4
d- Methods of introduction
3 -Basic groups-By alkylation or acylation
-Amide derivatives are usually more stable than esters in aqueous solutions
N NH
S
N N
S
NCH3
CH31-Azaphenothiazine Prothipendyl(neuroleptic & psychosedative)
NaNH2
Cl(CH2)3N(CH3)2
i)
ii)
d- Methods of introduction
4 -Polyhydroxy groups
CH3
OH
CH3
O-Na+
CH3
O
OH
OHC2H5ONa OHClOH
2-Methylphenol Mephenesin(muscle relaxant)
d- Methods of introduction
5 -Ether groups
N
N
HN
N
O
O
H3C
CH3
N
N
N
N
O
O
H3C
CH3
OH
O
Theophylline(bronchodilator)
Etofylline(bronchodilator)
Solubility
3 -Formulation Methods
3 -Formulation Methods
CosolventsColloidal Solutions
3 -Formulation Methods
A-Cosolventsa second solvent added to the original solvent, in small concentrations, to form a mixture that dissolve the solute.
Requirements1 -Minimal toxic effect
2 -Should not affect stability of the drugExampleParacetamol elixir in an aqueous solutionis dissolved by the use of mixture of ethanol & 1,2-dihydroxypropane,
3 -Formulation Methods
B-Colloidal SolutionsPrepared by dissolving a high concentration of the drug in an organic solvent that is miscible with water. Then, the concentrated solution is rapidly mixed with an aqueous solution containing a suitable stabilizer which adsorbed on
the surface of the colloidal particles .Ex: Shaving Cream (Foam) (g in L)
Mayonnaise (L in L) Blood (S in L)
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