Development of orally disintegrating tablets (ODTs) of frovatriptan by use of Quality by Design strategies

Over last years, Orally Disintegrating Tablets (ODTs) have gained increasing attention due to their advantages compared to conventional oral dosage forms, mainly represented by the possibility of disintegrating in the saliva in a very short period of time without the need to water intake. Frovatriptan (FRO) is one of the safest triptans, administered as a rescue treatment for immediate pain relief of acute migraine headache attacks. In this study an ODT formulation of FRO was developed with the aim of achieving an easier oral administration together with a faster dissolution and absorption of the drug and, consequently, a more rapid onset of action. The development of ODTs was carried out following innovative Quality by Design principles for the pharmaceutical industry, aimed at making the regulatory approval process more flexible without compromising patient safety. Nemrod and Modde 9.1 packages were used for the Design of Experiments (DoE). ODTs were prepared by direct compression mixing the powders in the proportions defined by the plan of the experimental design. The disintegration time was determined by evaluating the time it took a tablet to reach full dispersion after its addition to 5 ml of artificial saliva maintained at 37 °C. To evaluated the amount of drug dissolved, an aliquot of simulated saliva was withdrawn after disintegration of the tablet and assayed for drug concentration by capillary electrophoresis. Differential scanning calorimetry (DSC) was used for evaluating the drug-excipient compatibility. Individual samples of the drug and excipients as well as 1:1 (w/w) physical mixtures of the drug and selected excipients were scanned in pierced Al pans at 10 °C min-1 between 30 and 300 °C under static air. After careful selection, by compatibility studies, of the suitable excipients, a screening matrix was applied to investigate the effects of four different critical process parameters (CPPs), i.e. the type and the amount of both superdisintegrant and ODT special excipient, on two critical quality attributes (CQAs), namely the tablet disintegration time and % of drug released at the disintegration time. The levels considered for each CPP are shown in Table 1. All the other excipients necessary for the formulation (diluent, lubricant, sweetening and flavouring agents) were kept constant. The combination Pharmaburst-sodium alginate was selected for the following optimization phase, because it showed a positive effect on both the considered responses, allowing for obtaining simultaneously a rapid disintegration time (3 sec) and a good percentage of drug released (26%) at the mouth level. A Central Composite Design (CCD) was then applied and the response surface methodology led to draw contour plots and sweet spot plots. The definition of the Design Space (DS) was accomplished by using Monte-Carlo simulations, as the zone of input variables, where it is assured that CQAs reach the desired values with a given probability corresponding to 95% (α<0.05). A Plackett-Burman design was employed to validate the DS: four additional verification points were tested demonstrating that all the measured CQAs fulfilled the requirements and a good agreement between the predicted and measured results was found. Inside the DS, the following combination of CPPs was selected as working point, because it enabled for obtaining ODTs with the lowest disintegration time: FRO 2.5%, Pharmaburst 60%, sodium alginate 15%, lemon flower 0.5% aspartame, 0.5%, sodium stearyl fumarate 1%, lactose 20.5%. The optimized ODT formulation showed a disintegration time less than two seconds, sufficient hardness and low friability. Application of the Quality by Design principles led to the definition, with a limited number of experiments, of a DS, where every combination of the CPPs fulfilled the values of CQAs required and could be chosen as potential working points to obtain ODTs with a disintegration time less than 5 sec and with suitable mechanical properties.