Crystallization of undercooled liquid fenofibrate

Abstract

Formulation of hydrophobic drugs as amorphous materials is highly advantageous as this increases their solubility in water and therefore their bioavailability. However, many drugs have a high propensity to crystallize during production and storage, limiting the usefulness of amorphous drugs. We study the crystallization of undercooled liquid fenofibrate, a model hydrophobic drug. Nucleation is the ratelimiting step; once seeded with a fenofibrate crystal, the crystal rapidly grows by consuming the undercooled liquid fenofibrate. Crystal growth is limited by the incorporation of molecules into its surface. As nucleation and growth both entail incorporation of molecules into the surface, this process likely also limits the formation of nuclei and thus the crystallization of undercooled liquid fenofibrate, contributing to the good stability of undercooled liquid fenofibrate against crystallization.

Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

“…5b, the crystal growth rates were 1.05, 5.37, 7.58, 5.83 and 2.4 mm s À1 at room temperature (22 C), 40, 50, 60 and 70 C, respectively. The maximum crystal growth rate of the FEN was observed at 50 C. This agrees with Amstad's study that the maximum crystal growth rate of FEN is at 50 C. 12 ATR-FTIR results conrm that the B-FEN crystallisation at 40 and 50 C resulted in predominately FEN form IIa (Fig. 6d).…”

“…9 The high molecular mobility can possibly be attributed to weak intermolecular interactions, 10,11 which results in the low probability of FEN molecules forming stable nuclei and heterogeneous nucleation is the main route to initiate the crystallisation. 12 Heterogeneous nucleation triggers, including scratching the surface or placing an FEN seed on the surface of amorphous FEN, resulted in an immediate initiation of crystallisation. 12 Three FEN polymorphs have been documented in the Cambridge Structural Database (CSD).…”

“…12 Heterogeneous nucleation triggers, including scratching the surface or placing an FEN seed on the surface of amorphous FEN, resulted in an immediate initiation of crystallisation. 12 Three FEN polymorphs have been documented in the Cambridge Structural Database (CSD). The stable form I (with a melting point at 80 C) is the standard polymorph used as API in commercial tablets and capsules.…”

“…26 Therefore this study further investigated the combined effect of growth temperature and availability of free surface on the crystallisation behaviour of amorphous FEN. As the homogeneous nucleation of amorphous FEN is a slow process, 12,27 the heterogeneous nucleation and crystallisation of FEN was initiated by scratching the surface of amorphous FEN using a metal spatula.…”

NMR Relaxometry to Characterize the Drug Structural Phase in a Porous Construct

“…The Gaussian line shape confirms that the drug has solidified, but the remaining Lorentzian line shape indicates the presence of a highly amorphous state of the solidified drug or supercooled liquid. 23,24 When the bulk drug solidifies, a highly ordered bulk crystal structure forms. In a confined environment of 15 nm pores, as used here, fenofibrate has been shown to produce nanocrystals by 13 C MAS ssNMR and XRPD.…”