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)