Fluconazole–excipient compatibility studies as the first step in the development of a formulation candidate for biowaiver

Abstract

The biowaiver of bioequivalence studies on class I drugs of the biopharmaceutics classification system (BCS) is aimed mainly at reducing the costs and the exposure of health volunteers to a new pharmaceutical formulation. Fluconazole is an important antifungal agent but in the literature it is not clear whether it belongs to BCS class I or III. Compatibility studies are considered to be the first step in product development and on considering a biowaiver candidate these gain even greater importance since the final product will not be submitted to in vivo tests. The aim of this study was to qualitatively determine the composition of a commercially available fluconazole formulation in the form of capsules with regard to the presence of critical excipients and to carry out compatibility studies by differential scanning calorimetry (DSC). One formulation did not contain sodium lauryl sulfate and contained mannitol, in contrast to the reference formulation, which could hinder the acceptance of the biowaiver. The interaction of fluconazole with microcrystalline cellulose and calcium hydrogen phosphate dihydrate was observed; however, no indication of incompatibility was found in the DSC analysis of the commercial pharmaceutical formulations. These interactions were also studied by Fourier transform infrared spectroscopy, where small changes in the bands were observed, and by X-ray Powder diffraction and scanning electron microscopy that did not evidence any modification in the solid state characteristics.

Thermal analysis studies on the compatibility of furosemide with solid state and liquid crystalline excipients

“…According to the literature, the DSC curve of magnesium stearate shows endothermic events: the first at 84.3 -97.4 °C corresponding to dehydration; second at 112.6 -121.9 °C and a third at 150.6 -158.7 °C, indicating melting of palmitic and stearic acid compounds [9]. The obtained peaks are attributed to successive loss events of adsorbed structural water molecules (the yellow peak probably refers to the melting of magnesium stearate), and are in line with the literature findings [10][11][12][13][14]. With the increase in the temperature, an endothermic peak is observed, probably due to the low amount of magnesium palmitate that may coexist [15].…”

“…The DSC diagram shows an endothermic peak at 147 o C, which represents the loss of crystalline water [16,17]. At 209.8 o C an acute endothermic peak appears, which is consistent with literature data [10,11,13,15,[18][19][20] suggesting that at approximately 200-225 °C, the β-lactose portion in the molecule melts. After this endothermic phenomenon, thermal decomposition of -lactose follows, which is characterized as caramelization.…”

“…Two more degradation processes occur in the regions of 100 -130 o C and 130 -180 o C, probably due to alginate backbone destruction and hydroxyl groups loss (chemical degradation process). These thermotropic parameters are consistent with those recorded in the literature, according to which, upon heating of sodium alginate under a N2 atmosphere, an endothermic peak (dehydration) appears at about 100 o C, followed by an exothermic peak (decay) which, depending on the heating rate, appears between 240 -260 o C [10][11][12][13][14]. In the present study, the enthalpy, ΔH, of the dehydration was found to be equal to -383.6 J mol -1 .…”

“…2c). The ΔΗ values of glass transition increase as the molecular weight of PVP increases [10,13,15,21]. Namely, ΔH= -141.5 J mol -1 for MW: 10,000, -171.7 J mol -1 for MW:29,000 and -237.0 J mol -1 for MW:55,000.…”

Comparator product issues for biowaiver implementation: the case of Fluconazole

“…However, the other products did not includ this information in the product leaflet. If fluconazole is considered as BCS Class III the influence of excipients is a major concern since, besides the dissolution difference, they may modify negatively the permeability of the drug (Kubbinga, Moghani, Langguth, 2014;Ono and Sugano, 2014;Parr et al, 2016;Teleginski et al, 2015).…”