Entacapone Polymorphs: Crystal Structures, Dissolution, Permeability, and Stability

Abstract

Entacapone (ETP) is a catechol-O-methyltransferase (COMT) drug used to treat Parkinson’s disease. ETP is available in the marketplace under the brand name Comtan since 2010, and ETP form-I was first reported in a patent published in 2001. However, analysis of its X-ray crystal structures and stability relationship of ETP polymorphs and their dissolution and permeability profile have not yet been reported. We crystallized two new conformational polymorphs of ETP from a water and acetone mixture and studied the structural origin of polymorphism and their phase transformations, stability, equilibrium solubility, dissolution, and permeability properties. The ETP molecule adopts different conformations in the polymorphic structures with slight changes in carbonyl and nitrile group orientations. Thermal analysis suggests that form-III and form-IV are enantiotropically related to form-I, which is the thermodynamically stable form at ambient conditions. In contrast, form-II is monotropically related to form-I. Equilibrium solubility, dissolution, and permeability studies show that form-II persists in the slurry medium and dissolves faster with a high flux rate compared to the stable form-I in phosphate buffer solution at 37 ± 0.5 °C.

Polymorphs with Remarkably Distinct Physical and/or Chemical Properties

“…Bommaka et al [157] . discovered two new polymorphic forms of entacapone (Scheme 11), a catechol‐O‐methyltransferase (COMT) drug used to treat Parkinson's disease.…”

Professor Roger Davey: Master ofAllCrystal Trades

“…With an emphasis on molecular conformation, Gui and Yu et al 21 studied the crystal energy landscape of the polymorphs of nifedipine highlighting its value for the understanding of its extensive polymorphism. Conformational polymorphs of the Parkinson's drug Entacapone are reported and studied by Nangia et al, 15 while Rietveld et al 19 present an extensive exploration of the phase diagram of the anesthetic drug Butamben. Steed et al 24 studied the complex solid form landscape of mexiletine hydrochloride salts.…”

“…More than 20 crystallization scientists trained by Roger have gone on to work in the pharmaceutical industry for at least six different companies. This virtual special issue in Celebration of the Career of Roger Davey contains papers that deal with pharmaceutical materials − or arise from the collaboration between academia and the pharmaceutical industry − or come directly from the pharmaceutical industry. , …”

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

“…However, the application of these methods remains limited due to several issues such as drug loading efficiency and stability concerns. Further, developing an SR formulation of a highly water-soluble drug without a polymer is a challenging task because of the naturally fast-dissolving nature of the drug. − Pharmaceutical cocrystals have gained substantial importance and popularity in recent years for improving the poor physicochemical properties of active pharmaceutical ingredients (API) such as solubility, − dissolution rate, − permeability, − stability, − and processability − by incorporating a second molecule (coformer) in the same lattice without compromising their structural integrity and therapeutic benefits . Along with this, we also note that there are minimal studies on the role of cocrystals in achieving SR of highly water-soluble drugs without using any rate-controlling membrane (polymers). − Therefore, in this context, it is of great significance to explore a new solid form of PFD to be developed as an SR formulation that can potentially address the aforementioned problems of PFD by delaying its release rate.…”