6.1 Dosage Forms, Drug Delivery, and Dissolution

Dosage Form Classification

A dosage form is the physical form in which a drug is administered. Classification by physical state organizes every product a pharmacist dispenses:

• Solid — tablets, capsules, granules, powders, lozenges. Solids are stable, dose-accurate, and convenient. Tablets dominate because of low cost, precision, and patient acceptance.
• Liquid — solutions, suspensions, emulsions, syrups, elixirs, tinctures. Liquids are easier to swallow and faster to absorb (no disintegration step) but less stable, bulkier, and harder to dose precisely.
• Semisolid — ointments, creams, gels, pastes, suppositories. Used topically, rectally, vaginally, or transdermally for local or systemic effect.
• Gaseous/aerosol — metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), nebulized solutions. Deliver drug directly to the respiratory tree for asthma, COPD, and some infections.
• Injectable — solutions, suspensions, or emulsions given by IV, IM, SC, intrathecal, or intradermal routes. Bypass absorption barriers; require sterility, pyrogen control, and isotonicity.

Drug Delivery Systems and Release Profiles

Release kinetics define when and how fast drug appears in solution at the absorption site:

• Immediate release (IR) — disintegrates and dissolves promptly; onset is rapid but duration is short (e.g., immediate-release metoprolol).
• Sustained release (SR) and Controlled release (CR) — slow the release to maintain plasma levels within the therapeutic window over a prolonged period, reducing dosing frequency and peak-related side effects.
• Extended release (ER/XR) — a regulatory term encompassing SR and CR products; FDA labels use ER.
• Delayed release (DR) — release occurs at a time or site distinct from administration; enteric-coated aspirin and delayed-release proton-pump inhibitors bypass the stomach to protect the drug or the gastric mucosa.

Disintegration and Dissolution

A solid oral dosage form must disintegrate into primary particles before drug can dissolve. For poorly soluble drugs, dissolution is the rate-limiting step in absorption.

The Noyes-Whitney equation describes dissolution kinetics:

dC/dt = (D · S / h) · (Cs − C)

where D is the diffusion coefficient, S the effective surface area, h the stagnant boundary-layer thickness, Cs the saturation solubility, and C the bulk concentration. Formulators raise dissolution rate by micronization (increasing S), salt formation (raising Cs), amorphous solid dispersions (raising apparent Cs), and surfactants (wetting particles and lowering h). Polymer polymorphism also matters: the metastable polymorph dissolves faster but may convert to the stable form on storage.

USP dissolution apparatus: Apparatus 1 (basket, 50-120 rpm) suits capsules and floating dosage forms; Apparatus 2 (paddle, 50-200 rpm) is the most common for tablets. Media are typically 500-900 mL of simulated gastric or intestinal fluid at 37 °C, with sampling at defined intervals to plot a dissolution profile. Sink conditions — keeping C below about 20% of Cs — prevent backward driving of dissolution and let the data reflect intrinsic drug release.

Physicochemical Properties of Drugs and Excipients

A tablet is not drug alone; excipients make it manufacturable, stable, and bioavailable:

• Fillers (diluents) — lactose, microcrystalline cellulose; provide bulk.
• Binders — povidone, starch paste; hold granules together.
• Disintegrants — croscarmellose, sodium starch glycolate, crospovidone; swell or wick water to break the tablet apart.
• Lububricants — magnesium stearate, stearic acid; reduce friction and sticking but, in excess, hydrophobic coatings can slow dissolution.
• Glidants — colloidal silicon dioxide; improve powder flow.
• Preservatives — benzalkonium chloride, parabens, sodium benzoate; protect multi-dose liquids from microbial growth.
• Surfactants — polysorbates, sodium lauryl sulfate; wet particles and, above the critical micelle concentration, solubilize lipophilic drugs.
• Buffers and tonicity agents — citrate, phosphate, sodium chloride; maintain pH and osmolality in parenterals and ophthalmics.

Biopharmaceutics Classification System (BCS)

The BCS predicts oral absorption from two properties: solubility (drug dissolves completely in 250 mL across the physiological pH range) and permeability (>90% absorbed across the intestine). FDA BCS-based biowaivers allow certain Class I and Class III generics to skip in vivo bioequivalence studies.

Class II drugs benefit most from formulation strategies (micronization, amorphous dispersions, lipid systems) that boost apparent solubility. Class IV drugs often require enabling formulations or alternative routes.

Advanced Drug Delivery Technologies

• Transdermal patches — drug embedded in a polymer matrix or reservoir with a rate-controlling membrane; bypasses gut and liver first-pass, but only small lipophilic molecules (estradiol, fentanyl, nicotine, scopolamine) permeate intact skin.
• Implants and depots — subcutaneous or intramuscular depots (depot medroxyprogesterone, haloperidol decanoate) and nondegradable implants (etonogestrel rod, leuprolide polymeric implant) deliver drug over weeks to years.
• Liposomes — phospholipid vesicles entrap drug, reduce toxicity (liposomal doxorubicin, amphotericin B liposome), and exploit leaky tumor vasculature via the enhanced permeability and retention (EPR) effect.
• Nanoparticles — polymeric or lipid nanoparticles improve solubility (paclitaxel albumin nanoparticles) and enable targeted delivery.
• Prodrugs and antibody-drug conjugates — chemical linkage masks a poorly permeable or unstable drug; enzymatic or linker cleavage releases active species at the target.