Table of Contents
1. Organic Chemistry Fundamentals
Bonding and Structure
- • Carbon hybridization: sp³ (tetrahedral, 109.5°), sp² (trigonal planar, 120°), sp (linear, 180°)
- • Electronegativity trend: F > O > N > Cl > C > H
- • Bond polarity: Determines solubility, reactivity, and drug-receptor interactions
- • Resonance: Electron delocalization affects stability and reactivity
Acid-Base Chemistry
pKa and Drug Ionization
- • Henderson-Hasselbalch equation
- • Weak acids: pKa = pH + log([HA]/[A⁻])
- • Weak bases: pKa = pH + log([BH⁺]/[B])
- • 50% ionized when pH = pKa
Ion Trapping
- • Weak acids: Ionized in basic pH (trapped)
- • Weak bases: Ionized in acidic pH (trapped)
- • Non-ionized form crosses membranes better
- • Clinical application: Overdose treatment
Reaction Types
| Reaction | Description | Drug Examples |
|---|---|---|
| Oxidation | Addition of O, removal of H | CYP450 metabolism (hydroxylation) |
| Reduction | Addition of H, removal of O | Azo reduction, ketone reduction |
| Hydrolysis | Cleavage by water | Ester/amide prodrug activation |
| Conjugation | Attachment of polar groups | Glucuronidation, sulfation |
2. Functional Groups in Drugs
| Functional Group | Structure | Properties | Drug Examples |
|---|---|---|---|
| Hydroxyl (-OH) | R-OH | H-bonding, ↑water solubility | Morphine, Propranolol |
| Amino (-NH₂) | R-NH₂ | Basic, salt formation | Amphetamine, Amines |
| Carboxyl (-COOH) | R-COOH | Acidic, ionized at body pH | Aspirin, NSAIDs |
| Ester (-COO-) | R-COO-R' | Prodrug linkage, hydrolyzable | Enalapril, Aspirin |
| Amide (-CONH-) | R-CONH-R' | Stable, peptide bonds | Lidocaine, Acetaminophen |
| Ether (-O-) | R-O-R' | Anesthetic properties | Diethyl ether, Metoprolol |
| Halogen | R-X (F, Cl, Br) | ↑Lipophilicity, ↓metabolism | Halothane, Fluoroquinolones |
| Sulfonamide | R-SO₂NH-R' | Antibacterial activity | Sulfamethoxazole |
Heterocyclic Rings in Drugs
5-Membered Rings
- • Imidazole: Antifungals (ketoconazole)
- • Thiazole: Penicillins, Thiazide diuretics
- • Pyrrole: Porphyrins
- • Furan: Nitrofurantoin
6-Membered Rings
- • Pyridine: Niacin, Isoniazid
- • Pyrimidine: Barbiturates, DNA bases
- • Piperidine: Fentanyl, Meperidine
- • Morpholine: Some antibiotics
Fused Rings
- • Indole: Serotonin, Tryptophan
- • Purine: Caffeine, Theophylline
- • Quinoline: Chloroquine, Fluoroquinolones
- • Benzodiazepine: Diazepam
3. Stereochemistry & Drug Activity
Types of Isomers
- • Constitutional isomers: Different connectivity (structural isomers)
- • Stereoisomers: Same connectivity, different spatial arrangement
- - Enantiomers: Non-superimposable mirror images (chiral)
- - Diastereomers: Not mirror images (cis/trans, different chiral centers)
Chirality in Drugs
R/S Nomenclature
- • Based on Cahn-Ingold-Prelog priority rules
- • Assign priorities by atomic number
- • R = clockwise; S = counterclockwise
- • (Lowest priority pointing away)
Pharmacological Significance
- • Enantiomers may have different potencies
- • One may be active, other inactive
- • One may cause side effects
- • Racemic mixtures vs. single enantiomers
Clinical Examples of Chirality
| Drug | Active Enantiomer | Clinical Note |
|---|---|---|
| Ibuprofen | S-(+)-ibuprofen | R-form is inactive but converts to S in vivo |
| Omeprazole/Esomeprazole | S-omeprazole (esomeprazole) | Single enantiomer marketed separately |
| Propranolol | S-(-)-propranolol | 100x more potent β-blocker |
| Warfarin | S-warfarin | 3-5x more potent; metabolized by CYP2C9 |
| Thalidomide | R-form sedative; S-form teratogenic | Historic tragedy; racemizes in vivo |
4. Analytical Methods
Titrimetric Analysis
Acid-Base Titration
- • Strong acid/base titrants
- • Indicators: Phenolphthalein, Methyl orange
- • Non-aqueous titration for weak acids/bases
- • Applications: Alkaloid assays
Redox Titration
- • Iodometry: Indirect iodine determination
- • Iodimetry: Direct iodine titration
- • Permanganometry: KMnO₄ titrant
- • Cerimetry: Cerium titrant
Complexometric Titration
- • EDTA as complexing agent
- • Metal ion determination
- • Eriochrome Black T indicator
- • Applications: Ca²⁺, Mg²⁺, hardness
Precipitation Titration
- • Argentometry: AgNO₃ titrant
- • Mohr method (chromate indicator)
- • Volhard method (back-titration)
- • Fajans method (adsorption)
Chromatography
| Technique | Separation Principle | Applications |
|---|---|---|
| HPLC | Partition, adsorption, ion exchange | Drug assay, purity, degradation products |
| GC | Volatility differences | Volatile compounds, residual solvents |
| TLC | Adsorption on silica | Identity, purity screening (Rf values) |
| Ion Exchange | Ionic interactions | Amino acids, proteins, ions |
| Size Exclusion | Molecular size | Proteins, polymers, MW determination |
5. Spectroscopic Techniques
UV-Visible Spectroscopy
Beer-Lambert Law: A = εbc
- • A: Absorbance (log I₀/I)
- • ε: Molar absorptivity (L/mol·cm)
- • b: Path length (cm)
- • c: Concentration (mol/L)
- • Chromophores: Groups absorbing UV-Vis (C=C, C=O, aromatics)
- • Applications: Quantitation, purity, dissolution testing
Infrared Spectroscopy
Functional Group Identification
- • O-H stretch: 3200-3600 cm⁻¹ (broad)
- • N-H stretch: 3300-3500 cm⁻¹
- • C-H stretch: 2850-3000 cm⁻¹
- • C=O stretch: 1650-1750 cm⁻¹ (strong)
- • C=C stretch: 1600-1680 cm⁻¹
- • C-O stretch: 1000-1300 cm⁻¹
- • Fingerprint region: 600-1400 cm⁻¹
- • Applications: Identity, polymorphism
Mass Spectrometry
- • Principle: Ion formation, separation by m/z ratio
- • Molecular ion (M⁺): Gives molecular weight
- • Fragmentation: Provides structural information
- • Ionization methods: EI, ESI, MALDI
- • LC-MS/MS: Highly specific, quantitative drug analysis
- • Applications: Structure elucidation, metabolite identification, forensics
NMR Spectroscopy
- • ¹H NMR: Hydrogen environments, integration, splitting
- • ¹³C NMR: Carbon skeleton, chemical shifts
- • Chemical shift (δ): Position relative to TMS reference
- • Coupling (J): Spin-spin interaction, structural information
- • Applications: Structure determination, stereochemistry
6. Medicinal Chemistry Principles
Lipinski's Rule of Five
Criteria for Oral Bioavailability
- • Molecular weight: ≤500 daltons
- • LogP: ≤5 (lipophilicity)
- • H-bond donors: ≤5 (NH, OH)
- • H-bond acceptors: ≤10 (N, O)
- Note: Most orally active drugs satisfy 3+ of these criteria
Structure-Activity Relationships (SAR)
Key Concepts
- • Pharmacophore: Essential features for activity
- • Auxophore: Groups modifying activity
- • Toxicophore: Groups causing toxicity
- • Systematic modification to optimize
Common Modifications
- • Chain length variation
- • Ring substitution
- • Bioisosteric replacement
- • Stereochemistry changes
Bioisosteres
| Original Group | Bioisosteric Replacement | Benefit |
|---|---|---|
| -COOH | Tetrazole, sulfonamide | Similar acidity, different stability |
| -OH | -NH₂, -SH | H-bonding capacity |
| -H | -F | Block metabolism, similar size |
| Benzene ring | Thiophene, pyridine | Modified electronic properties |
Prodrugs
- • Definition: Inactive form that converts to active drug in vivo
- • Purposes: Improve absorption, reduce side effects, target delivery
- • Examples:
- - Enalapril → Enalaprilat (ACE inhibitor)
- - Omeprazole → Sulfenamide (PPI activation)
- - Levodopa → Dopamine (CNS delivery)
- - Valacyclovir → Acyclovir (better absorption)
7. Chemistry of Drug Classes
Beta-Lactam Antibiotics
- • Core structure: 4-membered β-lactam ring
- • Mechanism: Inhibit transpeptidase (cell wall synthesis)
- • Penicillins: Thiazolidine ring fused to β-lactam
- • Cephalosporins: Dihydrothiazine ring fused to β-lactam
- • Resistance: β-lactamase cleaves the ring
- • β-lactamase inhibitors: Clavulanic acid, sulbactam, tazobactam
Opioid Structure
- • Natural: Morphine, Codeine (phenanthrene skeleton)
- • Semi-synthetic: Oxycodone, Hydromorphone
- • Synthetic: Fentanyl (piperidine), Methadone
- • Key features: Phenolic -OH (3-position), basic nitrogen
- • SAR: Modifications affect potency and receptor selectivity
Steroid Hormones
- • Core: Cyclopentanoperhydrophenanthrene (4 fused rings)
- • Glucocorticoids: 11-OH, 17-OH, 21-OH (cortisol)
- • Mineralocorticoids: Aldosterone (18-aldehyde)
- • Androgens: 17β-OH, no C19 methyl
- • Estrogens: Aromatic A-ring, phenolic 3-OH
- • Progestins: 3-keto, Δ⁴ double bond
8. Quality Control & Stability
Drug Stability
Degradation Pathways
- • Hydrolysis: Esters, amides, lactams
- • Oxidation: Aldehydes, phenols, thiols
- • Photodegradation: Light-sensitive drugs
- • Racemization: Chiral compounds
Stability Enhancement
- • pH adjustment (buffer systems)
- • Antioxidants (BHT, sodium metabisulfite)
- • Light protection (amber containers)
- • Temperature control
Compendial Standards
- • USP (United States Pharmacopeia): Official standards for US
- • BP (British Pharmacopoeia): UK standards
- • Ph.Eur. (European Pharmacopoeia): European standards
- • Monographs include: Identity, purity, assay, storage conditions
- • Impurity limits: Specified for safety
Key Takeaways
- ✓Henderson-Hasselbalch determines ionization state
- ✓Enantiomers can have drastically different activities
- ✓Beer-Lambert Law: A = εbc for UV-Vis quantitation
- ✓IR fingerprint region unique to each compound
- ✓Lipinski's Rule of 5 predicts oral absorption
- ✓β-Lactam ring essential for penicillin activity
- ✓Prodrugs are inactive until metabolized
- ✓Hydrolysis is most common degradation pathway