Pharmaceutical development of micro and nanocrystals of a poorly water-soluble drug: Dissolution rate enhancement of praziquantel

Introduction: Different strategies have been applied to address the low aqueous solubility of drugs, since this property affects their oral absorption. In this context, particle size reduction approach can increase solubility and dissolution rate of drugs, so enhancing their bioavailability. Praziquantel (PZQ) is still the drug of choice for schistosomiasis control, however, the drug formulation is challenging considering its low aqueous solubility, which is a limiting step for its oral absorption.Objective: To prepare microcrystals (MCs) and nanocrystals (NCs) applying wet milling methods, to increase the dissolution profile of racemate praziquantel. Methods: PZQ suspensions were prepared in a colloid mill for obtaining MCs and in a pearl mill for obtaining NCs. The suspensions were characterized by multiple light scattering, laser diffraction and dynamic light scattering. Then, the suspensions were spray dried.The characterization of dry powders was carried out by different techniques such as Fourier transform infrared spectroscopy, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, laser diffraction and powder dissolution. To evaluate the effectiveness of the preparations, the infected mice were treated with 400 mg/kg of the compounds and analyzed.Results: After process optimization, the most promising samples had a d50 value of 6.84 mu m and an average diameter of 346.2 nm, respectively. After drying, the d50 values obtained for MC5 and NC5 were similar (11.77 mu m and 8.76 mu m, respectively). All powder samples presented enhanced dissolution compared to PZQ raw material, and there was a 13-fold increase in dissolution profiles by MC5. All the tested compounds provided a significant reduction in the parasitic load (above 70%) and changes in the oogram profile. The in vivo results suggest the ability of the MC and NC formulations to maintain the effectiveness of the PZQ compounds on the adult worms of S. mansoni, exerting even better activity on the eggs adhered to the tissue of the mammalian host.Conclusion: A scalable process was used to obtain MC and NC of PZQ with significantly improved dissolution in comparison to the pure drug. Moreover, the produced formulations were able to increase the ability of the PZQ to act on the parasite eggs trapped in the tissue and could potentially induce an early improvement of granulomatous lesions. The developed systems show promising aspects as candidate to be incorporated in a solid dosage form, with lower API concentration and even better drug activity.