Enhancing the Pharmaceutical Properties of Pirfenidone by Mechanochemical Cocrystallization

Abstract

Pirfenidone is an important drug molecule used in the treatment of idiopathic lung fibrosis. Although approved by the USFDA in 2014, pirfenidone's aqueous solubility is too high and must be mitigated by additives. In this work, the cocrystallization of pirfenidone is explored as an alternative approach to reducing its solubility. Herein, an anhydrous form of pirfenidone is reported, alongside its first two reported cocrystals. The new crystalline solids are thoroughly characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction analysis (PXRD), Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Equilibrium solubility and intrinsic dissolution rates (IDR) are studied for the cocrystals and compared to that of the parent drug. Both cocrystal forms exhibit drastically lower aqueous solubility (by up to 90%) and dissolution rates, rationalized based on both lattice energy calculations and consideration of intermolecular interactions in the solid state. Furthermore, we compare the physicochemical properties of solution-based material with that of material produced mechanochemically. Importantly, no differences are observed between the two production methods. This work demonstrates the strength of crystal engineering strategies to beneficially modify important pharmaceutical properties and highlights the potential of mechanochemistry to facilitate this in an environmentally benign way.

Local Delivery of Pirfenidone by PLA Implants Modifies Foreign Body Reaction and Prevents Fibrosis

“…was achieved by co-foaming of the dry PLA and PF powders in supercritical CO 2 by the methodology proposed by us earlier [61], that allowed to bypass a problem of poor compatibility of a hydrophobic carrier material (PLA) [58] and a highly hydrophilic drug (PF) [54]. The layer-by-layer laser sintering [62,63] was applied to form the solid and mechanically stable implants.…”

“…The temperature load on the bulk of the polymer did not exceed 63.2 °C. Since the melting point of PF was evaluated at 102–111 °C, the chemical structure of the drug impregnated into the implant was preserved [ 54 ].…”

“…The temperature control of sintering was carried out using a FLIR T530/24 • infrared camera (FLIR Systems, Wilsonville, OR, USA). The temperature load on the bulk of the polymer did not exceed 63.2 • C. Since the melting point of PF was evaluated at 102-111 • C, the chemical structure of the drug impregnated into the implant was preserved [54].…”

“…Phototoxicity of PF is an additional problem associated with its systemic application [34]. These conditions, plus frequency of oral dosing and the cost of the treatment, indicate that the local delivery and sustained/prolonged release of PF may help to significantly improve the efficiency and safety profile of PF [36,[51][52][53][54].…”

“…We think that the application of polymer IDDS for PF delivery may be among the most feasible and flexible approaches because of the high controllability of the composition and the material properties of medical polymers, availability of the clinically approved slowly-biodegradable materials such as polylactic acid (PLA) and its co-polymers (reviewed in details in [ 57 ] and [ 58 ]), and the technologies for manufacturing of implants from these compounds [ 1 , 17 ]. A challenge in the polymer IDDS approach is the hydrophobicity of the PLA-based polymers [ 58 ], that limits the loading capacity of such implants for highly hydrophilic drugs (like PF [ 54 ]).…”