Engineering a New Access Route to Metastable Polymorphs with Electrical Confinement

Polymorphism is the ability of solid materials, including active pharmaceutical ingredients (APIs), to exist in structurally distinctive arrangements. The existence of polymorphism and the difference in molecular packing can cause crystals to have a variety of different physical properties. Therefore, the ability to experimentally control and predict polymorph formation is vital to gain consistent access to desired properties of APIs. In this study, polymorphic control of the metastable form II of acetaminophen (paracetamol; PCM) was achieved, coupling the use of electrospraying (a method that uses electricity to atomize the precursor and create a charge on the surface of small droplets) and a template component, metacetamol (MCM). Previously, polymorphic control of APIs has been limited by the lack of ability to switch between polymorphic forms with the change of a single variable (such as voltage in electrospray experiments). Also, a single crystallization method that is transferable between a wide range of APIs to gain polymorphic control is not generally available. The electrospray technique as a crystallization method offers a potentially powerful, mechanistically distinct, and highly solvent-efficient alternative approach that promise to overcome these limitations. This work shows that polymorph formation is directly influenced by the thermodynamic conditions that induce crystallization and that they can be affected by electrospraying, guiding the crystal’s molecular arrangement via electric field orientation and confinement. Electrospray has the potential for broad applications in pharmaceutical crystallization and it can provide an alternative starting point to transfer polymorphic systems into continuous manufacturing platforms at an industrial scale.