ABSTRACT
Orotic acid (OA), a heterocyclic compound also known as vitamin B13, has shown potent antimalarial and cardiac protection activities; however, its limited water solubility has posed a barrier to its use in therapeutic approaches. Aiming to overcome this drawback, OA freeze-dried nanocrystal formulations (FA, FB, and FC) were developed by using the high-energy milling method. Polysorbate 80 (FA) and povacoat® (FC) were used alone and combined (FB) as stabilizers. Nanocrystals were fully characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, thermal analysis (thermogravimetry and derivative thermogravimetry, and differential scanning calorimetry), and X-ray powder diffraction revealing an acceptable polydispersity index, changes in the crystalline state with hydrate formation and z-average of 100-200 nm, a remarkable 200-time reduction compared to the OA raw material (44.3 µm). Furthermore, saturation solubility study showed an improvement of 13 times higher than the micronized powder. In addition, cytotoxicity assay revealed mild toxicity for the FB and FC formulations prepared with povacoat®. OA nanocrystal platform can deliver innovative products allowing untapped the versatile potential of this drug substance candidate.
Subject(s)
Nanoparticles/chemistry , Orotic Acid/chemistry , Solubility/drug effects , Water/chemistry , Animals , Calorimetry, Differential Scanning/methods , Cell Line , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Freeze Drying/methods , Mice , Particle SizeABSTRACT
Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231 nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.
Subject(s)
Furosemide/chemistry , Nanoparticles/chemistry , Calorimetry, Differential Scanning/methods , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Microscopy, Electron, Scanning/methods , Particle Size , Rotation , Solubility , Spectroscopy, Fourier Transform Infrared/methods , Water/chemistry , X-Ray Diffraction/methodsABSTRACT
In this study, nanoparticles of various poorly water soluble compounds were prepared by wet milling that was carried out using a rotation/revolution mixer and zirconia balls. To be compared with Beads mill, rotation/revolution mixer has superior in very quick process (5 min) and needs very few amounts of zirconia balls (2.4 g) for pulverizing drugs to nanometer range. Phenytoin, indomethacin, nifedipine, danazol, and naproxen were selected as the standard poorly water soluble compounds. Various parameters of the rotation/revolution mixer were studied to decide the optimal pulverization conditions for the production of nanoparticles of the abovementioned compounds. The rotation/revolution speed, shape of the mixing vessel, amount of zirconia balls, and volume of the vehicle (methylcellulose solution) mainly affected the pulverization of the compounds. Using the mixer, phenytoin could be pulverized to nanoparticles within a few minutes. The particle size was confirmed by using a scanning electron microscope and a particle size analyzer. The crystallinity of the pulverized phenytoin particles was confirmed by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). It was observed that the pulverized phenytoin particles retained their crystallinity, and amorphous phenytoin was not detected. Particles of other poorly water soluble compounds were also reduced to the nanometer range by using this method.
