Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

Salas-Zúñiga, Reynaldo; Rodríguez-Ruiz, Christian; Höpfl, Herbert; Morales-Rojas, Hugo; Sánchez-Guadarrama, Obdulia; Rodríguez-Cuamatzi, Patricia; Herrera-Ruiz, Dea

In the research project presented herein, two cellulosic polymers were chosen to evaluate their effect on maintaining the supersaturated state achieved during the dissolution of cocrystalline solid phases of nitazoxanide, a poorly soluble drug. Subsequently, polymer-cocrystal powder formulations were developed. To select adequate candidates from the series of widely used polymers in the pharmaceutical industry that delay the nucleation and/or crystallization of NTZ in supersaturated conditions, the solvent-shift approach was used [24] , see Figure S1 . Figure 1 demonstrates the results with the polymers tested for NTZ in pH 7.5 PBS at room temperature, finding that non-cellulosic polymers (Kollisolv ® and Kolliphor ® P407) do not significantly help in delaying NTZ precipitation, while polyvinylpyrrolidone (PVP-Kollidon ® 25) and cellulosic polymers (HPC 80,000, HPC 370,000, HPMC, Methocel ® MC and Methocel ® 60 HG) enable the increase of the concentration of NTZ in aqueous solution up to at least 1.0 mg/mL. Considering the hydrogen bonding capacity, NTZ has one H-bond donor group (NH) and four H-bond acceptor sites [8] . As can be observed in Scheme 1, the cellulosic polymers HPMC and Methocel ® 60 HG contain a large number of O-H donor groups, which are complementary for the formation of hydrogen bonds with hydrogen bond acceptors, explaining the good precipitation inhibitor properties for NTZ. The remaining polymers tested herein lack strong H-bond donor functions that could interact through hydrogen bonds with NTZ. These findings are supported by previous reports in the literature, e.g., in 2010, Warren et al. described the effectiveness of cellulosic polymers as crystallization inhibitors for danazol [52] . Other reports showed that HPMC reduces efficiently the nucleation and crystal growth of felodipine [53] and celecoxib [54] under non-sink conditions. Moreover, it is reasonable to assume that cellulose derivatives do inhibit, not only nucleation but also crystal growth and agglomeration into larger sized particles (see SEM results) that otherwise may form from during NTZ precipitation. In other words, the precipitation delay of NTZ can also be attributed to surface interactions between the NTZ particles and the polymer, forming drug-polymer complexes, which is derived in the modification of the NTZ solubilization properties.