1. PHC 222 Part(I) Dr. Huda Al Salem
Lecture (10)

2. How to improve water solubility?
1- Salt formation

3. 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

4. 1- Salt formation Example 1
Many GIT disturbances can be treated by ingestion of water-soluble compounds.
Example 1
Tartaric acid >>>>Na K tartrate is used as mild laxative

5. 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

6. How to improve water solubility?
2- Incorporation of water-solubilizing groups

7. 2- Incorporation of water-solubilizing groups
a- Type of group introduced
b- Degree of permanency
c- The biological effect of the group
d- Methods of introduction

8. 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.

9. 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.

10. b- Degree of permanency
1- 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.

11. 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).

12. 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

13. 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.

14. d- Methods of introduction
e.g.:
Acetal protection of a ketone during Reduction of an Ester.

15. d- Methods of introduction
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

16. d- Methods of introduction
2- Sulphonic acid groups (-SO3H)

17. d- Methods of introduction
3- Basic groups
-By alkylation or acylation
-Amide derivatives are usually more stable than esters in aqueous solutions

18. d- Methods of introduction
4- Polyhydroxy groups

19. d- Methods of introduction
5- Ether groups

20. Solubility
3- Formulation Methods

21. Cosolvents Colloidal Solutions
3- Formulation Methods
Cosolvents
Colloidal Solutions

22. 3- Formulation Methods A-Cosolvents
a second solvent added to the original solvent, in small concentrations, to form a mixture that dissolve the solute.
Requirements
1- Minimal toxic effect
2- Should not affect stability of the drug
Example
Paracetamol elixir in an aqueous solution
is dissolved by the use of mixture of
ethanol & 1,2-dihydroxypropane,

23. B-Colloidal Solutions
3- Formulation Methods
B-Colloidal Solutions
Prepared 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)