(523f) Microwave-Assisted Evaporative Crystallization for Enhancing Physicochemical Properties of Pharmaceuticals By Size Reduction

Solving bioavailability problems of new active pharmaceutical ingredients is a major challenge for the pharmaceutical industry, since nearly 50% of the new active substances in the pipeline are poorly soluble in water [1-3]. One approach to address this problem is to increase the dissolution rate and achieve a higher bioavailability of drugs by reducing particle size through the selection of proper crystallization conditions [4-7].

Solvent evaporation can be significantly enhanced by microwave irradiation during the crystallization processes, resulting in reduced particle size due to the rapid crystallization induced by the high prevailing supersaturations. In this study the effect of microwave heating on the evaporative crystallization of niflumic acid (NIF) is investigated and compared to conventional heating. NIF is an important active pharmaceutical ingredient, with anti-inflammatory activity accompanied by an analgesic effect[8]. According to the Biopharmaceutics Classification System (BCS), NIF belongs to class II, having a low solubility in water (26 μg mL^-1 at 25 °C).

Microwave heating is fundamentally different from conventional (conductive) heating. In particular, microwaves offer rapid and volumetric heating, without the need of heat transfer surfaces or heat transfer fluids. In addition, as microwaves couple directly with the (polar) molecules of the solution, heat transfer stops immediately when the microwave heating is turned off thus minimizing thermal inertia. In principle, microwave irradiation can significantly speed up solvent evaporation in crystallization processes, resulting in rapid crystallization and reduced particle size [9]. The effect of microwaves on the solvent evaporation rate and its effects on crystal size and crystallinity were studied.

A single-mode microwave setup was used for evaporative crystallization of NIF, with and without the polymer excipient, polyvinylpirrolidone (PVP). Clear undersaturated solutions of NIF in ethanol were prepared. When microwave heating is used for solvent evaporation, the 5 mL solution started boling within 4 seconds with maximum microwave power (300 W). The solvent was completely evaporated within 21 seconds at 300 W applied microwave power. Significantly larger times were needed for complete solvent evaporation when conventional heating was used.

Particle sizes decreased to submicron-size range when microwave-assisted evaporative crystallization was applied. Further, in the events of microwave-assisted evaporative crystallization of NIF in the presence of PVP, the drug morphology changed from rectangular to spherical shape and nanoparticles (around 200 nm) were produced. According to the structural analysis, the drug was in crystalline form without the PVP excipient and an amorphous solid dispersion was formed with PVP.

A 2.5-fold increase in the dissolution rate of the produced niflumic acid crystals was observed compared to the dissolution rate of the original drug. When niflumic acid was produced together with the excipient PVP in the microwave system, an amorphous solid dispersion was created with particles in the nano-size range, which showed a 5-fold increase in dissolution rate compared to that of the crystalline niflumic acid samples created by the microwave irradiation in the absence of PVP [10].

Microwave irradiation offers a novel way for drug formulation, and by reducing the particle size the dissolution rate and bioavailability of the active pharmaceutical ingredient can be enhanced.

References

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