Investigation of physicochemical properties and in-vitro in-vivo evaluation of agomelatine polymorphs

Abstract

In the present study, Form I, Form II and Form III of agomelatine were prepared to investigate the variability of polymorphs, then the stability relationship between the different forms and the in-vitro in-vivo correlation were established. The presence of three polymorphs of agomelatine was corroborated through studies by XRPD, TGA and DSC. All the forms obtained were then subjected to the powder and intrinsic dissolution tests. The results showed that Form II melted at 109.29 °C and possessed the highest heat of fusion was thermodynamically more stable, which was monotropically related to the two other. The IDR ranked in the order of Form III > Form II. Form I and Form III both underwent solvent-mediated phase transformation (SMPT) to Form II during dissolution and the transition points were 62 and 45 min, respectively. Pharmacokinetic profiles were acquired after oral administration of tablets, showing that the ka and AUC0–12 h of Form I, Form II, Form III were 0.58 ± 0.11, 0.34 ± 0.05, 0.74 ± 0.07 h−1 and 296.25 ± 49.39, 186.05 ± 45.93, 331.16 ± 54.74 ng*h/ml, respectively. Good linearities between IDR and ka, IDR and AUC were established, suggesting that the agomelatine polymorphic forms with faster dissolution rates in-vitro would increase the rate and extent of oral absorption in-vivo. These results demonstrated that IDR was predictive in estimating the relative bioavailability of agomelatine polymorphic forms.