Part 1: Dissolution

1. Definition & Key Concepts

 Dissolution: The process where a solid drug forms a homogeneous mixture at the
molecular level in a solvent (usually GI fluids).

 Key Concepts:

o Solute-Solvent Interaction: Drug molecules break from the solid surface to

interact with solvent.

o Diffusion Layer: A stagnant boundary layer forms around the particle; drug must
diffuse through this to reach the bulk solution.

o Rate-Determining Step: For poorly soluble drugs, dissolution limits absorption

and bioavailability.

o Sink Conditions: Maintained when dissolved drug is kept below 10–30% of

saturation solubility (via rapid absorption or dilution).

2. Types of Dissolution Models

 Noyes–Whitney (Diffusion Layer): Based on a stagnant boundary layer.

 Hixon–Crowell (Cube Root): Used when surface area decreases uniformly.

 First-order: Rate depends on concentration gradient.

 Zero-order: Constant rate (controlled release).

3. The Noyes–Whitney Equation

This describes the dissolution rate10.

dC/dt = DA/h (Cs-C)

 Interpretation:

o dC/dt: Dissolution rate.

o D: Diffusion coefficient (increases with Temp).

o A: Surface area (Larger A = Faster rate).

o h: Thickness of diffusion layer (Smaller h = Faster rate; agitation reduces h).

o Cs: Saturation solubility.

o C: Concentration in bulk solution.

Part 2: Factors Affecting Dissolution

A. Physicochemical Factors

 Solubility: Higher solubility → Faster dissolution.

 Particle Size: Smaller particles → Larger surface area → Faster dissolution.

 Polymorphism:

o Amorphous: Random structure, highest energy, fastest dissolution.

o Metastable: Intermediate energy/packing, faster than stable form.

o Stable: Tightly packed, lowest energy, slowest dissolution.

 Wettability: Improved by surfactants.

 pH: Weak acids dissolve faster in high pH; Weak bases dissolve faster in low pH.

 Temperature: Higher temp increases dissolution.

B. Formulation Factors

 Excipients:

o Binders: Increase hardness/decrease porosity → Slower dissolution.

o Lubricants (Hydrophobic): Form water-repellent layer (e.g., Mg Stearate) →

Slower dissolution.

o Surfactants: Improve wetting/reduce surface tension → Increase dissolution.

o Disintegrants: Break tablets into smaller particles → Increase dissolution.

 Compression Force:

o High Force: Harder, less porous tablets → Slower dissolution.

o Low Force: More porous → Faster water penetration → Faster dissolution.

 Coating:

o Enteric: Dissolves only in alkaline pH (intestine).

o Controlled Release: Polymers greatly slow dissolution.

 Crystal Shape: Spherical flows better than needles (needles pack tightly, reducing
surface area).
  Solid Dispersions: Hydrophilic carriers (PEG, PVP) keep drug amorphous/molecular →
Significantly increase rate.

C. Physiological Factors

 GIT pH:

o Stomach (pH 1-3): Good for weak bases.

o Intestine (pH 6-7.5): Good for weak acids.

 Gastric Emptying:

o Slow: Good for weak bases (dissolve in acid), bad for weak acids.

o Fast: Moves drug to intestine (large surface area/fluid) → Generally increases

dissolution.

 Food Effect:

o High fat → increases bile → helps lipophilic drugs.

o Heavy meals → slow emptying → delayed dissolution.

o Food generally increases viscosity (slows diffusion) but increases fluid volume.

 Bile Salts: Act as natural surfactants/form micelles → Increase dissolution of poorly

soluble drugs.

 Fluid Volume: More fluid = better dissolution (prevents saturation).

Apparatus Name Used For

Capsules, floating tablets, slow disintegrating

I Basket
tablets.

II Paddle Most common. Tablets, film-coated, suspensions.

Reciprocating Modified release, enteric coated (simulates GI

III
Cylinder transit).

IV Flow-Through Cell Poorly soluble drugs, implants, powders.

V Paddle Over Disk Transdermal patches.

 Apparatus Name Used For

VI Cylinder Transdermal patches (alternative to V).

VII Reciprocating Holder Implants, suppositories, devices.

Part 4: Permeation

1. Definition & Concepts

 Permeation: Movement of dissolved drug across membranes (e.g., intestinal wall) into
circulation.

 Fick’s Law: Rate is proportional to concentration gradient.

 Log P: Measures lipophilicity; determines ability to cross lipid membranes.

2. Types of Permeation

 Passive Diffusion (Most Common): High → Low conc. No energy.

o Transcellular: Through lipid bilayer (Lipophilic/Unionized drugs).

o Paracellular: Between cells (Small/Hydrophilic drugs).

 Facilitated Diffusion: High → Low conc. Uses carrier. No energy. (e.g., Glucose).

 Active Transport: Low → High conc. Uses Energy (ATP) & carriers. (e.g., Levodopa).

 Endocytosis: Membrane engulfs drug (Pinocytosis/Phagocytosis). Used for large

molecules (proteins).

 Pore Transport: Through aqueous channels (very small ions).

Part 5: Factors Affecting Permeation

A. Drug-Related Factors

 Lipophilicity: Higher Log P (1–3) = Better permeation.

 Molecular Weight: Small molecules (< 500 Da) permeate better.

 Ionization: Unionized = Lipophilic = High Permeation.

 o Weak acids absorb in stomach (acidic pH).

o Weak bases absorb in intestine (alkaline pH).

 Hydrogen Bonding: More H-bonds = More polar = Lower permeation.

B. Biological Factors

 Surface Area: Intestine has villi (huge area) → High permeation.

 Blood Flow: High flow maintains concentration gradient → Faster permeation.

 Membrane Thickness: Thinner membrane (intestine) = Faster permeation.

 Transporters:

o Uptake: Increase permeation (e.g., PepT1).

o Efflux (P-gp): Pump drug out → Decrease permeation.

 Metabolism: Enzymes (CYP3A4) destroy drug before absorption → Decrease

permeation.

C. Formulation Factors

 Permeation Enhancers: Loosen tight junctions or increase fluidity (e.g., Ethanol, Oleic
acid).

 pH Modifiers: Adjust local pH to keep drug unionized (e.g., Citric acid).

 Surfactants: Improve wetting and inhibit P-gp (e.g., Tween 80).

 Lipid-Based (SNEDDS/SMEDDS):

o Increase solubility.

o Enhance lymphatic transport (bypass liver).

o Inhibit efflux pumps.