Relationship Between Formation of

Complexes & Prodrugs and

Absorption/Dissolution

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

Complexation
Complex (coordinated compound) is ...

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..!!!

It can be detrimental (decrease

Complex is also found within the
solubility)
plasma such as in heme B as

Tetracyclines & calcium

cofactor of hemoglobin.

Complex formed between betalactam antibiotics and metal ions,

such as Cu2+, will decrease duration

How Complex can Increase Drug

Solubility?
Cyclodextrins

How Complex can Increase Drug

Solubility?
Cyclodextrins

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

Highlight..!!!
Before being complexed with
cyclodextrin, ITRACONAZOLEs
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.

Highlight..!!!
Cholesterol
Vitamin A
Methane clathrate is associated
Linoleic and linolenic acid
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

Highlight..!!!
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

Ampicillin

Several drugs is formed into

prodrug to enhance the
affinity to carrier/transporter
so that it can increase the
absorption.

THANK YOU