Engineering a New Access Route to Metastable Polymorphs with Electrical Confinement

Abstract

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.

Influence of Volume on the Nucleation of Model Organic Molecular Crystals through an Induction Time Approach

“…Confinement is also believed to lead to a higher control in the polymorphism and stabilization of metastable polymorphs through regulation of the nucleation process by the porous confinement size, affecting the critical nucleus size of the working compound. ,, A control in polymorphism is specifically crucial for pharmaceutical compounds since polymorphism can lead to increased bioavailability and stability, with some metastable forms reportedly observed to have better dissolution and micromeritic properties, making them more ideal for drug formulations . This improvement in properties is mostly due to a change in the nature of the solid crystal’s packingas observed on how the layered structure of the elusive acetaminophen form III leads to increased compressibility and dissolution. − Thus, it is essential to understand better how confinement, small volumes, and pore size affect nucleation kinetics.…”

Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization

“…Al-Ani et al used an electrospray technique to confine ACT into nanodroplets, which resulted in the formation of the metastable polymorph II. They showed that using confinement, 98% of the nucleated crystals were ACT-II and 2% was ACT-I [ 102 ]. These studies show that confinement is promising for directing pharmaceutical polymorphism.…”

Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes

“…The use of a heterogeneous particle or a foreign substrate may direct the crystallization of PCA to a certain polymorph, but an extra purification step was necessary to isolate it from the desired polymorphic product. Other special technologies, such as the combination of metal-assisted and microwave-accelerated evaporation [ 49 ], inkjet printing [ 50 ], plasmonic trapping-induced crystallization [ 51 ], electrical confinement [ 52 ], and laser irradiation [ 53 ] have been reported, however, all of them are seldom employed in manufacturing.…”