Relationship Between Formation of Complexes & Prodrugs and

Absorption/Dissolution

Sukamto S M

Various Methods to Enhance Drug Solubility

Physical modifications

• Particle size reduction• Modification of the crystal habits• Drugs dispersion in carriers• Solubilization by surfactants

Chemical modifications

Complexations Soluble pro-drugs Salt formations

Other techniques

Co-crystallization Co-solvency Solubilizing agents Nanotechnology approach

COMPLEXATION

Complexation

Complex (coordinated compound) is ...

Complexation

• 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

– It can be detrimental (decrease solubility)• Tetracyclines & calcium

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• Complex is also found within the plasma such as in heme B as cofactor of hemoglobin.• Complex formed between beta-lactam antibiotics and metal ions, such as Cu2+, will decrease duration of the antibiotics.

How Complex can Increase Drug Solubility?

Cyclodextrins

How Complex can Increase Drug Solubility?

Cyclodextrins

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Of those three types of cyclodextrin, the most used is β-cyclodextrins. However, it is contraindicated for parenteral dosage form. In this case, the formulators use the derivates of β-cyclodextrins.

How Complex can Increase Drug Solubility?

Cyclodextrins

How Complex can Increase Drug Solubility?

Cyclodextrins

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

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Before being complexed with cyclodextrin, ITRACONAZOLE’s solubility is about 1 ng/mL. After being complexed with cyclodextrin, 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.– Gallic acid– Urea– Thiourea– Zeolith

• The guest molecules which can be trapped in the “cage” formed by the compounds above.– Cholesterol– Vitamin A– Linoleic and linolenic acid

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Methane clathrate is associated with the source of energy and

can cause tsunami.

PRODRUG APPROACH

Prodrugs• An ideal prodrug is a chemical entity that has no pharmacological

activity against a designated physiological target, 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

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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

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Salting-In Addition of salt will INCREASE solubility of the compound. Salting-Out Addition of salt will DECREASE solubility of the compound

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.– Bacampicillin– Pivampicillin– Talampicillin

• Several drugs is formed into prodrug to enhance the affinity to carrier/transporter so that it can increase the absorption.– ACE Inhibitors, except Captopril

and Lisinopril

Ampicillin

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