Quantitative analysis and evaluation of stability of solid-state of mebendazole Forms A and C in suspensions by powder X-ray diffraction using the Rietveld method.

TICONA, JULIAN; PRADO, LIVIA DERIS; FERREIRA DE CARVALHO PATRICIO, BEATRIZ; ANTUNES ROCHA, HELVÉCIO; FANDARUFF, CINIRA; KUZNETSOV, ALEXEI; BIANCO, ISMAEL D.; CEBALLOS, MARCELO R.; CUFFINI, SILVIA L.

San José

Congreso; V Reunión de la Asociación Latinoamericana de Cristalografía (LACA); 2022

Asociación Latinoamericana de Cristalografía (LACA)

Abstract. Controllingthe different solid forms in active pharmaceutical ingredients (APIs)is a challenge for the pharmaceutical industry. Mebendazole (MBZ) isa broad-spectrum API, indicated for the treatment of parasitosis[1], [2], and has three solid-stateForms A, B and C[3].These forms exhibit significantly differences in dissolutionproperties [4], [5], which cause considerable changes intherapeutic effect, Form A being similar to placebo terapeutic whenat least 30% is present in the formulation[6], [7]. Theproblem is aggravated because the pharmacopoeias presentdiscrepancies in the control of the MBZ Forms. It was proven that theInternational, European and British pharmacopoeias indicate Form Cfor use as a raw material [8]–[10],however, the United States and Brazilian pharmacopoeias do notmention it [11], [12].Furthermore, there are no reports on solid forms stability studies insuspensions, particularly under the temperature and humidityconditions recommended by the pharmaceutical industry. The objectiveof this work was to evaluate the solid-state stability of MBZ insuspensions and the transformation kinetics from the quantificationof Forms A and C, in order to improve the control of raw materialsand formulations. Samples for the study were prepared with differentstarting reference concentrations of Form A (1%, 5%, 10%, 20% and 30%w/w). These samples were stored from 1 to 24 months under prolongedstability conditions (PS−30°C/75%RH) and from 1 to 6 months underaccelerated stability conditions (AS−40°C/75%RH). A method wasdeveloped and validated to carry out the drying process andquantification of Forms A and C in suspension samples. A datacollection was performed by powder X-ray diffraction (PXRD), and forthe quantification of phases the Rietveld method and the Topasprogram (RM-Topas) [13]were used. The requirements of the pharmaceutical industry werefulfilled to carry out these measures. Avrami's equation was used todetermine the kinetic parameters. The presence of Form A was verifiedin all commercially available MBZ products, in differentpharmaceutical formulations, both for human and veterinary use. It isevident, therefore, that this is a current problem for thepharmaceutical industry. In suspensions, in PS and AS condition, acalculated initial value of 10±1% and 4±1 of Form A respectively,is sufficient to cause a phase transformation greater than 30% in thefirst month, with a complete transformation in nine and six monthscorrespondingly. Considering this one, it was described that at least30% of Form A in the formulation is sufficient to suppress thedesirable pharmacological activity. In the AS condition, and forhigher initial reference concentrations of Form A (20 and 30%) fromPS condition, increase in the transformation rate was observed, asexpected. These results demonstrate that in suspensions, formulationsfor paediatric use, the solid-state fase transformation takes placeat considerably lower times than those established by thepharmaceutical industry as the product's shelf life (2 years). Thiswork presents, in an unprecedented way, the kinetic study of thesolid-state transformation of MBZ in suspensions, as well as avalidated method of quantification by RM-XRD of Forms A and C of MBZ.Therefore, it is up to regulatory agencies and Pharmacopoeias inBrazil and other countries to review and implement changes in thecurrent specifications for this drug.p { margin-bottom: 0.08in; direction: ltr; color: #000000; line-height: 0.17in; text-align: justify; orphans: 2; widows: 2 }p.western { font-family: "Times New Roman", serif; font-size: 10pt; so-language: en-GB }p.cjk { font-family: "Times New Roman"; font-size: 10pt; so-language: de-DE }p.ctl { font-family: "Times New Roman"; font-size: 10pt; so-language: ar-SA }a:link { color: #0000ff }a.sdfootnotesym-western { so-language: es-ES-u-co-trad }