Investigating the Role of the Reduced Solubility of the Pirfenidone–Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers

Abstract

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower C max and T max in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Study on Sulfamethoxazole–Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties

“…The comparative diffusion studies of SMX and SMX–PIP were carried out using the modified Franz diffusion apparatus by a dialysis membrane-70 ( M w : 14,000 Da, Himedia) . The dialysis membrane separated the donor and acceptor compartments with a diffusion area of 1.13 cm 2 .…”

“…The comparative diffusion studies of SMX and SMX−PIP were carried out using the modified Franz diffusion apparatus by a dialysis membrane-70 (M w : 14,000 Da, Himedia). 35 The dialysis membrane separated the donor and acceptor compartments with a diffusion area of 1.13 cm 2 . To obtain preliminary in vitro comparative data of the materials, the studies were conducted in buffer media (pH 6.8), which mimics the intestinal pH.…”

Molecular Docking of Pharmaceutical Cocrystal As a Ligand: Do We Need to Rethink?

“…Also, it is to be noted that some cocrystals do not undergo complete dissociation or solution-mediated phase transformation in solubility/dissolution studies . However, it was observed that these cocrystals transform into individual components upon going into systemic circulation from the oral route of administration . Thus, using a cocrystal as a ligand to be docked in the binding pocket as a substrate/inhibitor of any receptor defeats the underlying purpose, as these cocrystals are not supposed to manifest any pharmacological action different from the API itself.…”

Pirfenidone–flavonoid cocrystals with reduced solubility and dissolution rate

“…16 The recommended daily dosage of PFD is also high (2403 mg), which will cause severe side effects. 16,17 A sustained-release formulation is believed to be able to maintain plasma concentration over a longer duration of time, thereby increasing bioavailability and reducing dosage (or dosing frequency) and dose related side effects. [16][17][18][19] Recently, two cocrystals of PFD with fumaric acid and trimesic acid were reported by A. Ghosh.…”

“…16,17 A sustained-release formulation is believed to be able to maintain plasma concentration over a longer duration of time, thereby increasing bioavailability and reducing dosage (or dosing frequency) and dose related side effects. [16][17][18][19] Recently, two cocrystals of PFD with fumaric acid and trimesic acid were reported by A. Ghosh. 18 These forms exhibit drastically reduced solubility and dissolution rates, and have the potential to be developed as sustained release formulations.…”