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Relationship Between Formation of

Complexes & Prodrugs and

Sukamto S M

Various Methods to Enhance Drug Solubility Physical modifications Chemical modifications • Particle size reduction • Modification of the crystal Complexations habits  • Drugs dispersion in carriers Soluble pro-drugs  • Solubilization by surfactants Salt formations Other techniques  Co-crystallization  Co-solvency  Solubilizing agents  Nanotechnology approach .


..Complexation Complex (coordinated compound) is ..

such as Cu2+.Complexatio n • Complexation of a drug may occur: – Within the dosage form – In the gastrointestinal fluid • Complexation has two effects on absorption: – It can be beneficial (increase solubility) • Cyclodextrin & itraconazole Highlight. will decrease duration .. • Complex formed between betalactam antibiotics and metal ions.!!! – It can be detrimental (decrease • Complex is also found within the solubility) plasma such as in heme B as • Tetracyclines & calcium cofactor of hemoglobin.

How Complex can Increase Drug Solubility? Cyclodextrins .

the most used is βcyclodextrins. In this case.. However. . it is contraindicated for parenteral dosage form. the formulators use the derivates of β-cyclodextrins.How Complex can Increase Drug Solubility? Cyclodextrins Highlight.!!! Of those three types of cyclodextrin.

How Complex can Increase Drug Solubility? Cyclodextrins .

How Complex can Increase Drug Solubility? Cyclodextrins .

!!! Before being complexed with cyclodextrin. .Cyclodextrins-Complexed Drugs • Miconazole – It has poor solubility – After being complexed with cyclodextrin. the solubility increases up to 55-fold and dissolution rate goes up to 255-fold. • • • • • • PGE2 (Prostarmon®) Piroxicam (Brexin®) Itraconazole (Sporanox®) Aripiprazole Omeprazole Dexamethasone Highlight. After being complexed with cyclodextrin. ITRACONAZOLE’s solubility is about 1 ng/mL.. the solubility increases to 10 mg/mL.

Clathrates It is a cage-like lattice of one type of molecules entraps a second type of molecules. .

.Clathrates • Several compounds can form clathrates.. Highlight.!!! – Cholesterol – Vitamin A Methane clathrate is associated – Linoleic and linolenic acid with the source of energy and can cause tsunami. – – – – Gallic acid Urea Thiourea Zeolith • The guest molecules which can be trapped in the “cage” formed by the compounds above.


but is metabolically transformed into a compound with the desired activity • Prodrugs can be used: – To improve drug delivery or pharmacokinetics (solubilicity & lipophilicity) – To change properties of the drugs – To decrease toxicity – To target the drug to specific cells or tissues Highlight.Prodrugs • An ideal prodrug is a chemical entity that has no pharmacological activity against a designated physiological target..!!! Codeine  Morphine .

Lipophilicity Vs Solubility An increase in lipophilicity is usually accompanied by a decrease in water solubility .

Prodrugs to Increase Solubility • Introduction of an ionizable functional group allowing various salts of such prodrugs to be formed. – Phosphate esters  Prednisolone phosphate – Amino acid esters  Valacyclovir – Hemiesters of dicarboxylic acids.  Chloramphenicol sodium succinate • Disruption of the crystal lattice  Vidarabine Highlight.!!!  Salting-In  Addition of salt will INCREASE solubility of the compound..  Salting-Out  Addition of salt will DECREASE solubility of the compound .

. – Bacampicillin – Pivampicillin – Talampicillin Ampicillin • Several drugs is formed into prodrug to enhance the affinity to carrier/transporter so that it can increase the absorption.Prodrugs to Increase Lipophilicity • Many prodrugs feature the addition of a hydrophobic group in order to increase their lipid solubility to improve their gastrointestinal absorption.