Experimental and theoretical studies over the stability in co-amorphous samples

Abstract

The solubility, bioavailability and processability of crystalline drugs can be improved converting theminto an amorphous state. However, a particular issue related to amorphous solids is that they are highenergystates and therefore metastable. In this work, the stability of the amorphous binary system formedby the H2 receptor antagonist (famotidine, FMT) and a NSAID (ibuprofen, IBU) in 1:1 molar ratio wasstudied. The sample was prepared by cryo-milling process; its amorphous nature was confirmed by thelack of the diffraction peaks and the observation of the Tg (transition glass) signal. This sample wasphysically stable when stored for 60 days at different temperatures. The high stability, confirmed by FTIRanalysis, is due to a solid state interaction between the guanidine group of FMT and carboxylic acid ofIBU forming a heterodimer trough the heterosynthon N-H?O. Two conformers were proposed for theheterodimer and the lowest energy conformer was analyzed to determine the presence of bond criticalpoint in order to deeper understand this interaction. Besides, molecular dynamics simulations wereconducted. Physical consequences of these results are discussed for the co-amorphous phase in terms ofthermal properties (Tg), hydrogen bonding distributions and molecular diffusion, since these propertiesare important to justify the stability of this metastable material. The estimated Tg is in good agreementwith the experimental value. In addition, the radial distribution functions suggest that the heterosynthon N-HO is found in this amorphous model. Taking all together, our results suggest that, the high stabilityobserved in this amorphous sample is due to a strong interaction (N-H?O) between both drugs as wasconfirmed by FTIR and DFT calculations. Moreover, molecular simulations could be employed to predictphysical properties and justify the stability of this amorphous phase.