Polymorphism of Sildenafil: A New Metastable Desolvate

Abstract

A new anhydrous polymorph of the free base of sildenafil and two solvates (acetonitrile and propanenitrile) have been discovered and fully characterized. The new polymorph can be considered a desolvate of the acetonitrile solvate and is related to the most stable form I by morphotropism. The new polymorph can only be obtained by desolvation of the acetonitrile solvate. Thus, this study is a new example of the importance of this multicomponent family of solid forms in the discovery of new polymorphs of active pharmaceutical ingredients.

Identifying conformational isomers of organic molecules in solution via unsupervised clustering

“…The flexibility of τ E reveals a moderate degree of conformational rearrangement available to the conformer, despite the restrictive environment traditionally associated with a crystal. This observation has been addressed by Barbas et al 29 who have recorded the presence of a dynamic disorder in the propyl groups at room temperature in form I, which disappears at temperatures lower than 100K. The authors justify this observation with the fact that these functional groups do not establish strong intermolecular interactions with the surrounding atoms within the crystal, resulting in a moderate degree of flexibility in the chain.…”

“…7 Sildenafil is the main component of Viagra, 7 which is known to have two polymorphic forms. 29,30 Sildenafil is a relatively large molecule consisting of 63 atoms and a number of ring structures. The two forms of sildenafil (denoted form 1 and form 2) are morphotropically related to one another as a noncrystallographic rearrangement can transform one to the other, 30 with form I being the thermodynamically stable form.…”

“…Both forms have two molecules in the asymmetric unit adopting different conformations. 29,30 With the use of a data clustering approach we demonstrate how characteristic conformational configurations can be identified a priori for a molecule in the gas phase in order to then extract quantitative information on conformational states from enhanced sampling molecular dynamics simulations performed in solution under experimentally relevant conditions. Our methodology also enables the breakdown of the free energy of a conformational state into enthalpic and entropic contributions, providing a valuable insight into the effect of the solvent on conformational isomerism.…”

Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era

“…Moreover, sildenafil faces polymorphic transition and has been produced as salt, co-crystal or solvate Table 1 . The most common crystal forms of sildenafil are the monoclinic Form I and the orthorhombic Form II [ 15 ], while the most common salts are sildenafil citrate monohydrate and sildenafil saccharinate [ 16 ].…”

Sildenafil–Resorcinol Cocrystal: XRPD Structure and DFT Calculations

“…Moreover, we have previously discovered and analyzed, through a combined virtual/experimental cocrystal screen, new hybrid salt-cocrystal forms of Sildenafil [9]. Significant research has also been performed to synthesize and analyze a variety of Sildenafil solvates [5,[10][11][12]. From a pharmaceutical point of view, these studies are very relevant because the presence of solvent molecules in the solid state may modify the solubility and the bioavailability of the drug [13][14][15][16][17].…”