Not Every Solubility Problem Needs a Complex Solution
When a development team encounters a BCS Class II molecule with poor aqueous solubility, the instinct is often to reach for the most technically sophisticated tool available: an amorphous solid dispersion by hot melt extrusion or spray drying, or a lipid-based formulation system. These technologies are powerful, but they are also complex, expensive, and demanding in terms of development time and manufacturing infrastructure.
A nanosuspension, a stabilised colloidal dispersion of drug nanocrystals in an aqueous medium, offers a different proposition. It keeps the API in its crystalline form, which means no stability concerns around amorphous recrystallisation. It improves dissolution rate through surface area enhancement, without requiring a polymer matrix, a solvent system, or a high-shear processing step. For the right molecule, it is genuinely the simplest route to adequate oral bioavailability.
The Science of Dissolution Enhancement by Nanosuspension
The Noyes-Whitney equation tells us that dissolution rate is proportional to surface area. Reducing a drug particle from a D90 of 100 micrometres to a D90 of 200 nanometres increases the specific surface area by approximately a factor of 500, producing a proportional increase in intrinsic dissolution rate. For BCS Class II molecules where dissolution is the rate-limiting step in absorption, this translates into a meaningful increase in Cmax and AUC relative to a conventional micronised formulation.
Nanosuspensions can also achieve a modest increase in apparent solubility relative to the bulk crystalline form through the Ostwald-Freundlich effect, which predicts an increase in solubility for very small particles due to the increased surface free energy. This effect is generally modest for particles above 100 nanometres, and the primary driver of bioavailability improvement in pharmaceutical nanosuspensions is dissolution rate enhancement rather than solubility enhancement.
Nanosuspension vs. ASD: Choosing the Right Approach
| Factor | Nanosuspension | Amorphous Solid Dispersion (ASD) |
| API solid state | Crystalline throughout | Amorphous; stability risk |
| Solubility enhancement mechanism | Dissolution rate (surface area); modest Ostwald-Freundlich effect | Supersaturation; higher apparent solubility; requires precipitation inhibitor |
| Magnitude of enhancement | Moderate; typically 2-10 fold improvement in AUC vs micronised | Can be substantial; 10-100 fold for low-solubility molecules |
| Development complexity | Lower; no polymer excipient system required | Higher; polymer selection, drug-polymer miscibility, downstream processing |
| Manufacturing equipment | Wet milling or media milling; established technology | Spray drying or HME; specialist equipment |
| Physical stability | High; crystalline API is thermodynamically stable | Lower; amorphous conversion risk requires careful packaging and storage |
| Best suited for | Moderate solubility gap; stable crystalline API; simple downstream processing | Severe solubility gap; molecule responds well to supersaturation strategy |
Critical Formulation Considerations for Nanosuspensions
Stabiliser Selection
Nanosuspensions are thermodynamically unstable systems that will aggregate if not adequately stabilised. Stabilisers adsorb to the particle surface and prevent particle-particle contact by steric or electrostatic mechanisms. Common pharmaceutical stabilisers for nanosuspensions include HPMC, HPMC-AS, poloxamer 188, poloxamer 407, and polysorbate 80. The selection of stabiliser type and concentration is empirical and depends on the surface chemistry of the specific API.
Milling Parameters
For wet-milled nanosuspensions, the target particle size and size distribution are controlled by milling time, bead size and loading, mill speed, and temperature. Milling at elevated temperature can lead to polymorphic conversion in sensitive molecules, making temperature monitoring and control during milling important. The milling process must be developed and characterised to define the process parameters that reproducibly achieve the target particle size specification.
Downstream Conversion to Solid Dosage Form
Most clinical and commercial nanosuspension products are converted from the liquid nanosuspension intermediate into a solid dosage form, typically a tablet or capsule, by spray drying, fluid bed granulation, or lyophilisation. The conversion process must maintain the nanoparticle size distribution: if particles aggregate during drying or granulation, the bioavailability advantage is lost. Redispersibility testing of the final solid dosage form in simulated gastrointestinal fluids is an important part of the characterisation package.
Ardena’s Nanosuspension Development Capabilities
Ardena’s nanomedicine team at Oss has wet milling and media milling capability for nanosuspension development at both screening and scale-up. Particle size characterisation by DLS and laser diffraction, stabiliser screening, and downstream conversion studies are conducted as part of integrated nanosuspension development programmes.
