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Fig. 1: (a) Schematic illustration of the microfluidic nebulator. Fluids are injected through the blue inlets, air is injected through the white inlets. (b) Scanning electron micrograph of spray dried NaCl nanoparticles. Inset: High resolution transmission electron micrograph of an amorphous NaCl nanoparticle¹

Many active ingredients, such as hydrophobic drugs, are poorly soluble in water. This limits their bioavailability and therefore their effectiveness as medication. The bioavailability of these materials significantly increases if they are formulated as amorphous nanoparticles. However, this is difficult to achieve as these materials often have a high propensity to crystallise such that crystal nuclei easily form and rapidly grow into large crystals.

Active ingredients are often formulated from solution for example through spray drying. Spray driers break solutions into drops that are subsequently dried by a stream of air. The drops contain solutes that solidify during the drying process and upon complete removal of the liquid, dry powders result. The size of these spray dried particles scales with the drop size, whereas their structure depends on the composition of the solution and the time it takes to dry a drop. During the drying process, molecules have a high mobility as they are in solution. Indeed, they move so quickly that they arrange into the energetically most favourable crystalline structure before the drop is dried. Hence, the resulting particles are crystalline. In special cases, crystallisation can be suppressed through the addition of crystallisation inhibiting additives. However, this requires careful tuning of the composition and concentration of the additive for each active ingredient.

Formulation of sub-100nm sized nanoparticles

The effectiveness of many hydrophobic drugs increases with increasing dissolution rate. The dissolution rate scales with the surface to volume ratio of these drugs. Hence, it is highly beneficial to formulate them as nanoparticles as these small particles have a very high surface to volume ratio. The size of spray dried particles scales with the drop size. Hence, to reduce the size of spray dried particles, smaller drops must be formed. The size of drops produced in commercial spray driers is similar to the size of the spray dry nozzle. Unfortunately, the fabrication and operation of nozzles with very small sizes is difficult, limiting the smallest size of drops that can be formed. Hence, particles produced in commercially available spray driers are large; their diameter typically exceeds 1µm. Even spray driers designed to produce small particles cannot make particles with diameters below 400nm.

We recently developed a microfluidic spray drier that enables formulation of much smaller drops. The nebulator contains two inlets for liquids and several inlets for gases, as schematically shown in Fig. 1a. This device produces drops with diameters more than 100 times smaller than the smallest dimension of its nozzle. Hence, the nebulator enables formulation of nanoparticles with diameters as small as 15nm.

A key feature of the nebulator is its ability to form very small drops. The formation of such small drops is enabled by a drop break-up mechanism that is distinctly different from the one observed in commercially available instruments: The nebulator exposes fluids to such high shear stresses that very small drops form. The very high shear stresses are achieved by a strong acceleration of the air inside a narrow microfluidic channel: The nebulator accelerates the air so strongly that it exceeds the speed of sound, 340m/s, in the final parts of the main channel. This high air velocity results in very high shear stresses that break fluid into drops much smaller than the smallest dimension of the nozzle. Remarkably, these drops are sufficiently small to enable the formulation of nanoparticles more than ten times smaller than nanoparticles produced with commercially available instruments.

Formulation of amorphous nanoparticles

The effectiveness of hydrophobic drugs can be increased even more if they are formulated as amorphous materials as the amorphous phase has a much higher solubility than the crystal. Remarkably, the nebulator can produce amorphous nanoparticles from almost any material. Even table salt, NaCl, a material with one of the highest propensities to crystallise, can be processed into amorphous nanoparticles, as shown in Fig. 1b.

Nanoparticles are amorphous if drops dry so fast that molecules do not have time to arrange into a crystal. However, even the smallest drops we made with the nebulator, which has a diameter of 300nm, would dry too slowly to kinetically inhibit crystallisation of materials with a high propensity to crystallise, if drops were dried with slowly flowing air. The amorphous nanoparticles produced in the nebulator indicate that the evaporation of the solvent in the nebulator must be accelerated. The origin of this fast evaporation lies again in the very fast speed of the airflow: The evaporation rate of a fluid is much higher if the surrounding air flows at high speeds. Remarkably, the airflow in the final parts of the nebulator is so fast that drops dry so quickly that solute molecules contained in the drop do not have time to arrange into a crystal structure. Hence, an amorphous nanoparticle results.

Conclusions

The solubility of active ingredients significantly increases if they are formulated as amorphous materials. The small size of the nanoparticles increases their dissolution rate as this parameter scales with the surface to volume ratio of the drug. Moreover, the amorphous structure of these nanoparticles increases their solubility and therefore the maximum amount of drug that can be dissolved in a unit volume. Hence, formulation of hydrophobic drugs as amorphous nanoparticles significantly increases their effectiveness as medication. The microfluidic nebulator enables formulation of almost any type of material, including materials with a very high propensity to crystallise, such as table salt, as amorphous nanoparticles. Thus, this device has the potential to significantly increase the effectiveness of many active ingredients. This would for example allow decreasing the administered dose of active ingredients, thereby minimising the risk for patients to suffer from undesired side effects.

References

¹Amstad, E.; Gopinadhan, M.; Holtze, C.; Osuji, C. O.; Brenner, M. P.; Spaepen, F.; Weitz, D. A. Science 2015, 349 (6251), 956-960.