Unexpected performance of physical mixtures over solid dispersions on the dissolution behaviour of benznidazole from tablets.

LEONARDI D.; SALOMON C.J.

Rosario

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

Chagas?f disease is an endemic parasitic disease caused by Trypanosoma cruzi and discovered in 1909.(1)  Even though the disease was discovered more than 100 years ago, there is still a lack of suitable formulations for the treatment of Chagas disease, as mentioned by the World Health Organization (WHO).(2) Benznidazole (BZL) is the primary drug of choice in the treatment of Chagas disease. According to the Biopharmaceutics Classification System (BCS), BZL belongs to Class III. Although BZL is widely prescribed to treat Chagas disease, the problem of its solubility is still an important challenge for the formulation scientists. One of the most widely applied strategies to increase the solubility/dissolution of poorly water-soluble drugs are the solid dispersions (SDs) (3) This work investigated the feasibility of developing benznidazole (BZL) tablets, allowing fast, reproducible, and complete drug dissolution, by compresing BZL:PEG 6000 physical mixtures (PMs) and solid dispersions.  Materials and Methods Solid dispersions (SDs) were prepared by the solvent evaporation method at different drug:polymer ratios (w/w). These formulations were characterized in the liquid state by dissolution studies and in the solid state by X-ray diffraction and scanning electron microscopy. The preparation of solid dispersion-based BZL tablets by the wet granulation method was carried out and the influence of pregelatinized starch (PS) and starch (S) on the disintegration time and drug dissolution rate was analyzed.  Results SDs showed significant improvement in the release profile of BZL as compared to the pure drug. As demonstrated by XRD, the crystalline character of BZL remained almost unaltered in both PMs and SDs. BZL release from the PEG 6000 tablets increased by the presence of PS instead S. Unexpectedly, BZL release from tablets containing PMs was almost equal as compared to the BZL release from tablets containing SDs.  Conclusion SDs of BZL-PEG 6000 prepared by the solvent evaporation method resulted in greater increases in drug dissolution, in comparison with the pure drug. As demonstrated by XRD, the crystalline character of BZL remained almost unaltered in both PMs and SDs. Then, the modification of the surface morphology and shape of the particles offered an explanation of better dissolution rate from the BZL-PEG 6000 systems. Flow properties of the granules, as well as, disintegration analysis and technological parameters of the tablets indicated that PEG 6000 and PS are suitable excipients for the development of BZL tablets with improved dissolution rate. Unexpectedly, it was found that tablets containing PMs exhibited the same release patterns of BZL as compared to the corresponding SDs systems. As a consequence, it is concluded that BZL tablets with enhanced dissolution behaviour was successfully formulated through the preparation of ordinary PMs, avoiding the disadvantages associated with the laborious SDs.  Acknowledgments The National University of Rosario (UNR), the National Council Research (CONICET, Argentina), are gratefully acknowledged for financial support.    References 1) Salomon CJ. 2012. First century of chagas' disease: An overview on novel approaches to nifurtimox and benznidazole delivery systems. J Pharm Sci 3:888-894.  2) WHO. Chagas disease: control and elimination. Report of the Secretariat to the Executive Board, 124th :http://apps.who.int/gb/ebwha/pdf_files/EB124/B124_17- en.pdf. 2009.  3) Tajarobi F, Abrahmsén-Alami S, Larsson A. 2011. Dissolution rate enhancement of parabens in PEG solid dispersions and its influence on the release from hydrophilic matrix tablets. J Pharm Sci 100:275-283.