Complexation in pharmaceuticals involves forming complexes between drug molecules and ligands or excipients to enhance drug properties such as solubility, stability, taste masking, controlled release, and targeted delivery. Different types of complexation include coordination complexes, molecular complexes, metal ion coordinate complexes, and inclusion complexes, each utilizing various interactions to improve drug formulations. This technique is crucial for enhancing bioavailability, reducing toxicity, and advancing therapeutic strategies in fields like cancer treatment.

2. COMPLEXATION
Dr. Seemab Zafar

3. COMPLEXATION
Complexation in pharmaceutical systems refers to the formation of complex structures or
compounds involving a drug molecule and another molecule, typically a ligand or an
excipient.
This interaction can have various purposes in pharmaceuticals;
• Improved Solubility: Complexation can enhance the solubility of poorly soluble drugs,
making them more bioavailable for absorption in the body.
• Stability: Complexation can increase the stability of drugs, protecting them from
degradation due to factors like light, heat, or moisture.
• Taste Masking: Some drugs have unpleasant tastes, and complexation can be used to
mask these tastes, making the medicine more palatable.
• Controlled Release: Complexation can be part of controlled-release drug formulations,
where the drug is slowly released from the complex over time.
• Targeted Delivery: In some cases, complexation can be used to target drug delivery to
specific sites in the body, improving therapeutic outcomes.

4. Types of Complexation
1. Coordination Complexes
A coordination complex consists of an ionic substrate, usually a
transition metal ion, and one or more attached ligands which may
be either cations or anions.
It is a product of Lewis acid base reactions; Lewis acids can accept
a pair of a nonbonding valence electrons, thus forming a Lewis
acid base complex. (Gilbert Newton Lewis, a physical
chemist at California Univ.)
The metal ions in chemical reactions act as an acid (i.e., accept an
electron pair) and the ligand acts as a base (i.e., donate an
electron pair) and thereby a coordinate covalent bond forms
between a metal ion and attached Ligands.

5. Types of Complexation contd.
2. Molecular Complexes
Molecular complexes form between ligand and substrate using
noncovalent bonds such as van der Waals forces, electrostatic forces,
hydrogen bonding, or hydrophobic effects, charge transfer, etc.
• Based on the involved substrate and ligand, molecular complexes
can be further subdivided into;
• A).Small molecule small molecule complex and
• B).Small molecule large molecule complex.

6. Types of Complexation, Molecular Complexation
contd.
A). Small molecule small molecule complex
An interaction between small ligand and a small substrate can be
borne because of opposite polarity.
For example, interaction between benzocaine and caffeine takes
place due to the dipole dipole interaction between the electrophilic
nitrogen atom of caffeine and nucleophilic oxygen of benzocaine.
It also includes molecular dimers, trimers, etc., pharmaceutical
cocrystal, including other self-association to form aggregates (e.g.,
surfactant micelles).

7. Types of Complexation , Molecular Complexation
contd.
B). Small molecule large molecule complex
Interactions between small substrates and large ligand also form
molecular complexes via drug protein binding, enzyme substrate interaction, and
inclusion complexes.
 Therefore, a reversible molecular interaction exists between;
drug-protein (albumin),
intramolecular interactions (e.g., base base interactions in the DNA helix),
attachment of small molecules into the small pockets of large molecules (Ras
gene), and
inclusion complexes (e.g., CD complexes), etc. Drug-CD complexes are one of
the examples of molecular complexes of relatively small substrates and large
ligands

8. RAS gene –-----”Sarcoma” and Carcinoma
RAS genes are viral genes transduce from the rodent genome and responsible for
the highly oncogenic properties of RNA tumor viruses.
• Sarcomas form in the mesenchymal cells. Sarcoma is the general term for a
broad group of cancers that begin in the bones and in the soft (also called
connective) tissues. including fat, blood vessels, nerves, bones, muscles and
cartilage.
• Carcinomas develop in the epithelial cells that line the body's internal
organs and outer surfaces.

9. Cyclodextrins (CD) Drug
Complex

10. Types of Complexation contd.
3. Metal Ion Coordinate Complexes
Metal ion coordinate complexes, (metal complexes), in which the ligands or
counter ions (a base), donate a pair of electrons to the central metal ion (an
acid) to form the coordinate covalent bond.
The number of bonds between the ligand or ligands and central metal ion is
represented as coordination number of the complex.
For example, the silver ammonia coordinate complex has two as the
coordination number as two ammonia molecules (ligand) bind to the central
metal ion Ag

11. Metal Ion Coordinate Complexes---- contd.
• When a single metal atom binds with more than one site of multidentate ligand, a
chelate is formed and the ligand is called the chelating agent.
Examples are: ethylenediaminetetraacetic acid, tartaric acid,
citric acid, etc.
drugs like tetracycline can bind with different
metal ions such as calcium, iron , magnesium , and
form hydrophilic chelates which are less bioavailable
• Various metal-containing complexes are widely used as therapeutics and
diagnostics.
Platinum complexes such as cisplatin and carboplatin are widely used as
anticancer drugs.
• Magnetic nanoparticles (MNPs) i.e., magnetite Fe3O4 positively impacts Theranostic
applications in Nano medicine).
• Re(I) tricarbonyl complexes (Rhenium tricarbonyl) used as a bimodal contrast agent for MRI and
optical imaging of nanoparticles.

12. Types of Complexation ------ contd.
4. Inclusion complex
• Inclusion complex is the molecular complexes where interaction takes
place between a substrate (guest) and a cage (host) containing one or
more ligand molecules.
• The binding ability of hosts and guests is mainly attributed to
hydrophobic interactions and the corresponding character of size and
shape between their structures.
• CD is one of the most important molecular complexes where a single
ligand molecule interacts with one or more substrate molecules

13. Some Advantages of Inclusion Complexes
• Inclusion complex of drugs has shown several advantages including;
enhancement of stability,
aqueous solubility,
systemic availability, and
 safety of drugs.
 Stability of prostaglandin E2 (evacuation of uterine contents and labor
induction) and prostaglandin A2 (has a role as a human metabolite) has been
evaluated with different inclusion complexes formed with different derivatives
of β-CDs.
 The submaximal concentration of curcumin bioavailability has been shown to
be improved via adopting this encapsulation technique.
 Drug-induced toxicity has been shown to be reduced through such
entrapment.
 Ulceration potential of indomethacin or piroxicam (NSAID) has shown to be
reduced via inclusion in β-CD or hydroxypropyl β-CD.

14. FUNDAMENTAL METHODS OF FORMATION
OF DRUG COMPLEXES
• Physical Blending Method
• Kneading Method
• Coprecipitation Technique
• Solution/Solvent Evaporation Method
• Neutralization Precipitation Method
• Milling/Co grinding Technique
• Atomization/Spray Drying Technique
• Lyophilization/Freeze Drying Technique
• Microwave Irradiation Method
• Supercritical Antisolvent Technique
• Extrusion

15. Complexation ----------- Conclusion:
Complexation is an extensively used technique to improve;
Solubility of several pharmaceutical ingredients, and
subsequently
The Bioavailability of poorly water-soluble drugs.
Cancer therapy and other therapeutic fields
Another advantage using complexation in drug delivery
application included improved bioavailability with reduced TOXICITY