🚀 Medicinal & Pharmaceutical Chemistry – Lecture 3 Physicochemical Properties of Drugs & Their Role in Drug Action

Physicochemical Properties of Drugs & Their Role in Drug Action

⭐ Why This Topic Matters

Before a drug shows any action in the body, it must reach the site, bind to the receptor, and stay stable.

All this depends on…

👉 Physicochemical Properties

This lecture will make these concepts super easy so you can score high in exams AND understand drug design better.

🔥 What You Will Learn in This Lecture

• ✔ What pKa tells about drug absorption

• ✔ Why LogP is the “passport” to cell membranes

• ✔ Why some drugs dissolve easily and some don’t

• ✔ How hydrogen bonding changes drug behaviour

• ✔ What makes a drug cross BBB

• ✔ What are isosteres and bioisosterism (exam favourite!)

• ✔ How stereochemistry can change a drug from medicine to poison

🧠 1. Ionization & pKa: The Real Reason Why Drugs Work

pKa = the pH at which 50% drug is ionized and 50% unionized.

Why is this important?

Forms	Properties
Ionized form	More soluble, less permeable
Unionized form	Less soluble, more permeable (crosses membranes easily)

💡 Rule of Absorption

• Weak acids absorb better in acidic pH
  Example: Aspirin in stomach

• Weak bases absorb better in alkaline pH
  Example: Morphine in intestine

🌊 2. Partition Coefficient (LogP): The Balance Between Water & Fat

LogP = measures lipid solubility (oil/water partition)

$$P = \frac{\text{Concentration in oil}}{\text{Concentration in water}}$$

👉 High LogP = High Lipid Solubility

• Easily crosses membranes

• More CNS penetration

• Example: Diazepam

👉 Low LogP = High Water Solubility

• Easily excreted

• Difficult to cross membranes

• Example: Penicillin G

Ideal LogP for a drug = 1 – 3

💧 3. Solubility of Drugs: Functional Groups Matter

How soluble a drug is depends on what groups it contains.

Functional Group	Effect
OH	↑ Solubility
COOH	↑ Solubility
NH2 (amine)	↑ Solubility
Aromatic ring	↓ Solubility (↑ lipophilicity)

💡 Example

Paracetamol = highly soluble

Ibuprofen = less soluble → more lipophilic → better membrane penetration

🤝 4. Hydrogen Bonding

Hydrogen bonding = improves water solubility.

BUT…

Too many H-bond donors/acceptors = poor permeability.

📝 Balanced H-bonding = balanced absorption.

🧬 5. Lipophilicity & Drug Absorption

A drug must have the perfect mix of water solubility and fat solubility.

Too hydrophilic →

❌ Cannot cross membranes → poor absorption

Too lipophilic →

❌ Gets trapped in fat/membranes → toxicity risk

Ideal drugs = moderately lipophilic (LogP 1–3)

🔄 6. Isosteres & Bioisosterism (Exam-Favourite!!)

Isosteres

Atoms/groups having similar:

• Size

• Shape

• Electronic configuration

Example: –CH3 and –Cl can act as isosteres

Bioisosterism

Replacing a functional group with another to:

• Improve potency

• Reduce toxicity

• Increase duration of action

• Improve stability

Examples:

• H → F (fluorine increases stability)

• –COOH → –SO2NH (reduces metabolism)

🔃 7. Stereochemistry: The 3D Shape That Changes Everything

Two molecules may look same on paper…

But different in 3D → completely different effects!

Examples:

Thalidomide

• One form = sedative

• Other = teratogenic (caused birth defects)

L-DOPA = active

D-DOPA = inactive

🥼 Why this matters?

Because receptors are 3D proteins → shape matters!

EXAM SHORT NOTES (Must-Memorize!)

✔ Define pKa

→ pKa is the pH at which 50% drug is ionized.

✔ Define LogP

→ LogP is the oil/water partition measure that tells drug’s lipophilicity.

✔ Bioisosterism

→ Replacing groups to improve pharmacological activity and reduce toxicity.

✔ Importance of stereochemistry

→ Determines drug binding, metabolism, and safety.

Viva Questions (High Probability)

1. What is the significance of pKa in drug absorption?

2. Define LogP with an example.

3. What are isosteres?

4. Give two examples of bioisosteres.

5. Why stereochemistry is important in drug design?