19.2 Dissolution & Excipients
Key Takeaways
- The Noyes-Whitney equation dC/dt = (D·S/h)·(Cs − C) shows that dissolution rate rises with larger particle surface area (S), higher saturation solubility (Cs), greater diffusion coefficient (D), and thinner diffusion layer (h); under sink conditions C is negligible so the driving force approximates Cs.
- Dissolution rate can be increased by micronisation (e.g. griseofulvin), salt formation, amorphous forms, and increased agitation; each lever maps to a specific term in the Noyes-Whitney equation.
- Common tablet excipients include fillers/diluents (lactose, microcrystalline cellulose), binders (povidone, starch paste), disintegrants (croscarmellose, sodium starch glycolate, crospovidone), lubricants (magnesium stearate), glidants (colloidal silicon dioxide), preservatives (parabens, benzyl alcohol), and antioxidants (ascorbic acid, sodium metabisulfite).
- Excessive magnesium stearate (a hydrophobic lubricant) slows disintegration and dissolution by forming a water-repellent film around particles — a classic exam trap linking excipient choice to bioavailability.
- Dissolution testing uses USP Apparatus I (basket) and II (paddle); for BCS Class I and III drugs (highly soluble), dissolution profiles serve as a bioequivalence surrogate supporting biowaivers.
The Noyes-Whitney Equation
When a solid drug particle is placed in an aqueous medium, it dissolves through a diffusion layer at the particle surface. The Noyes-Whitney equation quantifies the dissolution rate:
dC/dt = (D · S / h) · (Cs − C)
| Symbol | Meaning | How to increase it |
|---|---|---|
| D | Diffusion coefficient of the drug in the medium | Higher temperature, lower viscosity |
| S | Surface area of the solid exposed to the medium | Smaller particles, micronisation |
| h | Thickness of the stagnant diffusion layer | Increased agitation/stirring |
| Cs | Saturation solubility of the drug at the particle surface | Salt forms, amorphous forms, pH adjustment |
| C | Bulk concentration of drug in the surrounding fluid | Maintained low by sink conditions |
The driving force for dissolution is the concentration gradient (Cs − C). Under sink conditions, C is kept negligible (typically C < 0.1·Cs), so the gradient approximates Cs and the equation simplifies to dC/dt ≈ (D·S/h)·Cs. Dissolution testing apparatus maintain sink conditions by using a large volume of medium.
Levers to increase dissolution — and the drug each illustrates
| Strategy | Noyes-Whitney term changed | Classic example |
|---|---|---|
| Micronisation (particle size reduction) | ↑ S (surface area) | Griseofulvin — micronised griseofulvin has markedly higher bioavailability than the non-micronised form |
| Salt formation (e.g. sodium or hydrochloride salt) | ↑ Cs (solubility) | Sodium diclofenac dissolves faster than the free acid |
| Amorphous form (no crystal lattice energy to overcome) | ↑ Cs | Amorphous solid dispersions used for some BCS Class II drugs |
| Increased agitation | ↓ h (diffusion layer) | Paddle/basket rotation in dissolution testing |
Exam trap: Do not confuse solubility (Cs, an equilibrium property of the molecule) with dissolution rate (dC/dt, a kinetic property of the formulation). A salt form raises Cs; micronisation raises S. Both increase dC/dt but through different terms in the equation.
Excipients: Functions and Clinical Pitfalls
Excipients are the inactive ingredients formulated alongside the active drug to produce a stable, manufacturable, and patient-acceptable dosage form. Although described as 'inert', excipients can influence dissolution, bioavailability, and tolerability.
| Functional class | Examples | Function |
|---|---|---|
| Fillers / diluents | Lactose, microcrystalline cellulose (MCC) | Add bulk so the tablet is large enough to compress |
| Binders | Povidone (PVP), starch paste | Hold granules together after compression |
| Disintegrants | Croscarmellose sodium, sodium starch glycolate, crospovidone | Swell on contact with water, causing the tablet to break apart |
| Lubricants | Magnesium stearate, stearic acid | Reduce friction between granule and die wall during compression |
| Glidants | Colloidal silicon dioxide | Improve powder flow into the die |
| Preservatives | Parabens (methyl/propyl hydroxybenzoate), benzyl alcohol | Prevent microbial growth in multi-dose liquids |
| Antioxidants | Ascorbic acid, sodium metabisulfite | Prevent oxidative degradation of the drug |
| Sweeteners, flavours, colours | Sucrose, aspartame; vanillin; titanium dioxide, FD&C colours | Improve palatability and aid identification |
How excipients affect bioavailability and safety
- Hydrophobic lubricants slow dissolution. Magnesium stearate is the classic culprit: at high concentrations or long blending times it coats drug particles with a water-repellent film, reducing wetting (effectively lowering S) and slowing disintegration. This is a favourite exam link between an excipient and reduced bioavailability. Using water-soluble lubricants (e.g. sodium stearyl fumarate) or limiting stearate concentration mitigates this.
- Disintegrants are essential for rapid tablet breakdown. Without an effective disintegrant, disintegration (step 1 of oral absorption) is delayed and the entire absorption cascade slows.
- Excipient allergies and intolerances. Lactose as a filler is problematic for lactose-intolerant patients; gelatin (capsule shells) is an animal-derived concern for some dietary and religious groups; gluten in starch-derived excipients matters in coeliac disease; parabens can cause contact dermatitis and rare hypersensitivity. A pharmacist must read the excipient list when a patient reports a reaction to a 'non-allergic' drug.
Dissolution Testing: Apparatus and Regulatory Role
Dissolution testing measures the amount of drug released from a dosage form into a defined medium over time, producing a dissolution profile that is both a quality control (QC) tool and a bioequivalence surrogate.
| USP Apparatus | Name | Typical use |
|---|---|---|
| USP I | Basket | Capsules and dosage forms that tend to float |
| USP II | Paddle | Immediate-release tablets (most common) |
| USP III | Reciprocating cylinder | Extended-release products |
| USP IV | Flow-through cell | Poorly soluble drugs, microparticles |
For BCS Class I and III drugs (highly soluble), where rapid dissolution means absorption is not dissolution-limited, dissolution profile comparison (f2 similarity factor) can serve as a bioequivalence surrogate in lieu of an in-vivo pharmacokinetic study — the basis of the biowaiver. For Class II and IV drugs, in-vivo bioequivalence studies are generally still required because dissolution is rate-limiting and formulation-dependent.
According to the Noyes-Whitney equation dC/dt = (D·S/h)·(Cs − C), which change will increase the dissolution rate of a poorly soluble solid drug?
Which of the following is a disintegrant used in tablet formulations to promote rapid breakup on contact with water?
A pharmaceutical manufacturer receives complaints that a batch of tablets shows slower-than-expected drug release. Investigation reveals no change in the active ingredient or particle size. Which excipient-related cause is most likely?