Dissolution looks simple: put tablets in a medium and watch drug release. In practice, many tablets fail. The reason is almost always the same and easy to miss. If you understand this one concept—how much wetted drug surface area your tablet creates and maintains during the test—you can predict, troubleshoot, and design for success. This idea sits behind every viva question on dissolution and every failure investigation you will ever face.
The one concept: wetted surface area controls dissolution
The dissolution rate of a solid drug is described by the Noyes–Whitney/Nernst–Brunner idea: dC/dt = k × A × (Cs − C). Each term matters:
- A is the wetted surface area of drug exposed to the medium.
- Cs is the saturation solubility at the surface (depends on pH, surfactant, temperature, solid form).
- C is the bulk concentration (rises with time; lowers the driving force).
- k groups diffusion and hydrodynamics (boundary layer thickness, viscosity, rotation speed).
Almost every failure is “A went down,” “Cs was too low,” or “k was poor.” The test method can also inflate C so high you lose driving force (no sink conditions). Map your problem to these terms and your path forward becomes obvious.
How tablets lose wetted surface area
Tablets do not fail because of a single “bad excipient.” They fail because the system produces too little wetted API surface. Common ways this happens:
- Poor or delayed disintegration. If the tablet stays intact or only cracks, the drug surface area is tiny. Low-disintegration microstructure often comes from too strong a binder, too much compression, or under-dosed disintegrant.
- Over-lubrication with magnesium stearate. Mg stearate coats particles with a hydrophobic film. Long lubrication time or high shear reduces wetting (higher contact angle), slows water ingress, and blocks disintegrant wicking. This shrinks wetted area even if the tablet breaks apart.
- Hydrophobic API or excipients. Waxy drugs, high talc, or hydrophobic glidants trap air at the surface. Bubbles decrease the true wetted area. Deaeration and small amounts of surfactant can help.
- Over-compression and low porosity. High hardness is not the enemy; porosity is. Tight compacts slow water penetration, delaying deaggregation. Less deaggregation means fewer fine particles and lower surface area.
- Granule densification and particle growth. Wet granulation or drying near solubility can dissolve and reprecipitate API into larger crystals. Larger particles have much less surface area per unit mass.
- Coating that does not rupture fast enough. A too-strong or too-thick film coat delays exposure of the core. Plasticizers and curing time matter; insufficient mechanical stress during swelling slows rupture.
- Excipients that gel. Some binders or starches can form a surface gel layer at the tablet edge. That gel acts as a diffusion barrier and reduces effective area.
- Aging and moisture. Storage can cause lubricant migration (“blooming”), stronger solid bridges, or polymorphic transitions. All can reduce wetting or slow disintegration.
When the driving force is too small: solubility and sink conditions
Even with good surface area, poor Cs or high C kills the driving force.
- pH-dependent solubility. Weak acids dissolve faster in higher pH; weak bases in lower pH. If the method uses the wrong buffer, Cs is low and release lags. Matching medium pH to the drug’s pKa can restore the driving force at the surface.
- Sink conditions. A rule of thumb: the medium volume should dissolve at least three times the dose at Cs. If dose/solubility is high, C approaches Cs quickly and the term (Cs − C) collapses. Solutions: raise volume, add surfactant, or change pH.
- Surfactants. Small amounts (e.g., sodium lauryl sulfate) lower interfacial tension and improve wetting (bigger A) and apparent solubility (higher Cs). Too little does nothing; too much can change mechanism or create micellar solubilization that does not reflect in vivo behavior.
- Deaeration. Air lowers wetting and reduces the true area. Deaerate media or use vacuum/sonication to minimize bubbles on tablet and particles.
Hydrodynamics and method artifacts
The apparatus controls k (mass transfer) and sometimes distorts results.
- Apparatus 2 (paddle) coning. Powder can form a cone under low speeds. The lower turbulence means thicker boundary layers (lower k). Mitigate by increasing RPM, using proper vessel geometry, or switching to basket if justified.
- Basket clogging. Fibrous disintegrants or sticky mass can plug mesh, strangling surface renewal. Choose mesh size carefully and verify visually.
- Sampling and filters. Filters can adsorb drug or retain fine particles that would pass the compendial definition of dissolved. Validate filter recovery and sampling location to avoid dead zones.
- Temperature control. A few degrees matter. Lower temperature decreases Cs and increases viscosity (lower k). Confirm 37 ± 0.5 °C at the sampling point.
- Medium prep. Incomplete buffer, wrong ionic strength, or CO2 ingress alters pH and Cs. Standardize preparation and document pH at 37 °C.
Process parameters that quietly kill dissolution
Formulation is only half the story. Process history sets microstructure and wetting.
- Lube time and energy. Mg stearate needs the minimum required. Extra minutes in a high-shear blender markedly reduce wetting. Track energy, not just time.
- Compression force and dwell. Higher force lowers porosity and can melt or smear lubricants across surfaces. Longer dwell (slow turret, large punches) intensifies the effect.
- Granulation solvent and endpoint. Too much liquid causes over-granulation and big, dense granules with low final surface area. Drying near the API’s solubility can cause Ostwald ripening (crystal growth).
- Milling. Excessive fines from hard milling can paradoxically over-lubricate (more surface to coat) and increase blend segregation, causing lot-to-lot variability in A.
- Roller compaction settings. High specific compaction force yields hard ribbons that are hard to deaggregate, reducing surface renewal during dissolution.
Quick diagnostic flow: what to change first
- 1) Verify the method. Check pH, surfactant level, medium volume, deaeration, temperature, apparatus alignment, RPM, and filters. Confirm sink conditions for your dose and solubility.
- 2) Watch the tablet. Run a transparent vessel, record the first 10 minutes. Do you see coning, sticking, gelling, or late rupture of coat?
- 3) Compare hardness/porosity. Test low vs high compression force. If low-force tablets pass and high-force fail, porosity and wetting are the issues.
- 4) Lube challenge. Cut Mg stearate by 25–50% and halve lubrication time. If dissolution improves, you have a wetting problem.
- 5) Medium sensitivity. Add 0.05–0.5% surfactant or adjust pH one unit. A large jump indicates low Cs or poor wetting is limiting.
- 6) Particle size check. Compare API d90 fresh vs after processing and stability. Growth signals lower A.
- 7) Filter recovery. Spike dissolved drug into medium and pass through your filter. If recovery is low, the method under-reports.
Case snapshots
- Over-lubrication: Immediate-release tablet passed at R&D, failed at scale. Investigation found 12-minute lubrication instead of 3. Contact angle rose by 15°, disintegration slowed, Q at 30 min dropped from 85% to 62%. Fix: cap lube time, reduce Mg stearate by 30%, add 0.1% SLS. Result: robust pass across hardness range.
- pH mismatch: Weakly basic API failed in pH 6.8. In pH 4.5 with 0.05% SLS, it passed easily. Root cause: low ionization at 6.8 led to low Cs. Final method: 250 mL pH 4.5 + SLS, justified by biorelevance for proximal gut exposure.
- Coat too strong: Film-coated tablets showed a 15-minute lag. Coat tensile strength exceeded rupture threshold at swelling. Adjusted plasticizer and reduced cure temperature. Lag vanished; overall profile met target without changing the core.
Viva essentials: how to explain and defend your decisions
- State the mechanism first. “Dissolution rate depends on wetted surface area, driving force (Cs − C), and mass transfer. Our failure indicates loss of wetted area due to over-lubrication and reduced porosity.”
- Tie tests to the model. “We reduced lubricant to increase A, added mild surfactant to raise Cs and improve wetting, and increased RPM to increase k.”
- Discuss sink conditions. “At 900 mL, the dose/solubility ratio was 2.5, not sink. We increased volume and verified linearity of release with volume.”
- Show control strategy. “We set in-process limits on lube time and specific compaction force, and monitor tablet porosity and disintegration as surrogates for wetted area.”
- Acknowledge trade-offs. “We kept surfactant low to avoid non-biorelevant micellar solubilization and verified with a two-media test.”
Designing a robust tablet for dissolution
- Formulate for wetting. Use hydrophilic fillers (lactose, MCC) and consider a small anionic surfactant. Avoid excessive talc. Choose disintegrants that both wick and swell.
- Control microstructure. Target a porosity that supports fast water ingress. Tune binder amount to avoid gel layers. Avoid over-granulation.
- Minimize lubricant impact. Use the lowest effective Mg stearate, validate alternate lubricants (sodium stearyl fumarate), and cap lube time/shear.
- Protect API surface area. Limit thermal exposure and solvent that can promote crystal growth. If needed, stabilize with polymers (e.g., PVP) to reduce recrystallization.
- Coating only as strong as needed. Optimize solids, plasticizer, and cure to ensure rapid aqueous access for IR products.
- Choose a realistic method. Set pH, volume, and apparatus to reflect likely in vivo conditions, while keeping sensitivity to manufacturing drift.
Stability and lifecycle: monitoring and controls
- Trend dissolution vs porosity and disintegration over time. Include stressed conditions to detect wetting loss due to humidity or lubricant migration.
- Watch API solid form. Polymorph changes and particle growth reduce Cs and A. Use XRPD/DSC and particle sizing before and after stability.
- Control limits that matter. Set actionable ranges for lube time, specific compaction force, coat weight gain, and moisture. These are the levers that protect wetted area and driving force.
Takeaway
Most dissolution failures are not mysteries. They are expressions of one principle: the test measures how much wetted drug surface area you create and how strong the driving force is to move drug into solution under the method’s hydrodynamics. Anything that blocks wetting, lowers solubility at the surface, or weakens mixing will slow release. Build your diagnosis and your design around A, Cs, C, and k. If you do, you will have solid viva answers and fewer late-night investigations—and tablets that pass for the right reasons.
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
Mail- Sachin@pharmacyfreak.com