Experimental design model applied to the preformulation of Praziquantel solutions.

ORLANDI S.; LEONARDI D.; SALOMON C.J.

Rosario

Congreso; II Reunión Internacional de Ciencias Farmacéuticas (RICIFA); 2012

Introduction Praziquantel (PZQ) is an effective drug prescribed for the treatment of infections caused by endoparasites such as schistosomas, staves and taenias. PZQ shows a low solubility (about 0,4 mg/mL) and therefore an erratic bioavailability. (1) One of the methodologies widely used to increase the solubility of poorly water soluble drugs is its incorporation into cosolvent systems. (2) Propylene glycol (PPG), ethanol, glycerin and polyethylene glycol (PEG) 400 are solvents commonly used in this type of systems due to their biocompatibility. Often, the cosolvents systems are combined with surfactants in order to further increase the solubility of hydrophobic molecules. (3) Therefore, the aim of this work was the development of PZQ liquid systems based on cosolvents, surfactants and its combination mixtures through the application of experimental design models.  Materials and methods Experimental design model with simple center was employed to optimize the development of the cosolvents systems. Solvents water, PPG and PEG 400 were the factors in the design. (Table 1) PZQ was added to the mixture of solvent systems and then subjected to orbital shaking for 48 hours at a speed of 220 rpm at room temperature and finally filtered. The response to optimize was the concentration of PZC (determined by UV spectrophotometry at 264 nm). The assays were performed in duplicate. Then, the design was combined with a second experimental design model (Table 2) based on surfactants as factors [sodium lauryl sulfate (SLS), polysorbate 80 (Tween 80 ®) and poloxamer 237 (Pluronic F87 ®)] obtaining a ?mixtures by mixtures" experimental design. The procedure was similar to the above: in vials containing the mixture of solvents and surfactants was added the PZQ. The systems were shaken at room temperature for 48 hours. The response (maximum concentration of solubilised PZQ) was determinate. The assays were performed in duplicate.  Results PZQ solubility increased as the ratio of water in solvent media decreased. The PPG (100%) was able to solubilize 97% of PZQ. However, since the aim of this work was the formulation of PZQ solutions, water was required into the solution, at least in low amount. Thus, it was found that a mixture of solvents with a water/PEG 400/PPG of 15.8/15.8/63.4 % showed an increase of solubility 18 times respect to PZQ in aqueous solution. In adition, the system made up of water/PEG 400/PPG (33.4; 33.3; 33.3%) improved the drug solubility 15 times respect to PZQ. On the other hand, cosolvents/surfactants combinations showed minor impact on the solubility of the drug in comparison with PZQ cosolvents system, in contrast to other works dealing with different biomolecules, in which, the synergy of cosolvents/surfactants were clearly observed.(4)  Conclusions The cosolvents systems have been proved to be an effective technique to increase the solubility of PZQ. In contrast, the combination of surfactants and cosolvents did not exhibit further increase of PZQ solubilized over the cosolvents systems. It could be due to the fact that those cosolvents may alter the micelle structure characteristics and/or the polarity of micelle core and, therefore, its solubilization capacity. (4) References. 1)      Suleiman M, Karim E. Photothermal stability of Praziquantel. Saudi Pharmaceutical Journal (2004) vol 12 Nº4. 2)      Miyako Y, Khalef N, Matsuzaki  K, Pinal R. Solubility enhacement of hydrophobic compounds by cosolvents: Role of solute hydrophobicity on the solubilization effect. Int. J. Pharm. 393 (2010) 48-54. 3)      Ali W, Williams A, Rawlinson C. Stochiometrically governed molecular interactions in drug: Poloxamer solid dispersions. Int. J. Pharm. 391 (2010) 162-168.