Elusive Seed Formation via Electrical Confinement: Control of a Novel Cocrystal in Cooling Crystallization

Abstract

Pharmaceutical cocrystals are multicomponent materials formed to enhance the properties of active pharmaceutical ingredients (APIs) and are commercially used to increase the number of drug candidates that successfully make it through the drug discovery pipeline. Nevertheless, the industrial production of cocrystals and other elusive solid forms remains a challenge. The main limitations are due to challenges related to the scale-up, solid-form control, and undesirable parameters needed for the preparation method. This study leverages the features of electrospray crystallization to generate elusive cocrystal forms that contain the API acetaminophen (paracetamol) and its regioisomer metacetamol. We report the formation of a new cocrystal, which is held together by van der Waals interactions, and the use of the newly electrosprayed cocrystals as seeds to tune the performance of cooling crystallization, allowing this commonly used crystallization method to produce the elusive cocrystal. The electrosprayed cocrystal displays a previously unseen sponge-like surface topology and a fourfold solubility enhancement over those found for single-component APIs. This new technology expands the accessibility to new solid forms that were previously inaccessible by other crystallization methods.

Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

“…117 Al-Ani et al also applied electrospraying to generate an elusive drug–drug cocrystal containing hydrogen-bonded paracetamol (PCM) and its regioisomer metacetamol (MCM) held together by van der Waals interactions, that were previously inaccessible by conventional crystallization methods. 128 The electrosprayed cocrystal exhibited an unprecedented sponge-like surface topology, with a 4-fold solubility enhancement over the parent components in an isopropanol/water mixture. It was delineated that the electric charge involved in electrospraying effectively suppressed the electronegative features of proton acceptors, enabling other forces such as van der Waals interactions to be the predominant drivers for structure formation (PCM–MCM), while hydrogen bonding was solely present between the coformer molecules (PCM–PCM, MCM–MCM).…”

Advances and Opportunities Concerning Nucleation Measurement and Control Technology in Crystallization

“…It seems to be a good method to use the new electrospray-produced cocrystal as a seed crystal to adjust the performance of cooling crystallization. 188 This new technology separates crystal nucleation and crystal growth, allowing better control of each individual event and expanding the possibility to new solid forms. In the heterogeneous nucleation process, a generalizable method is called nanoAC for active in situ control of the growth of newly formed phases around a single precursor and the synthesis of crystals for practical applications.…”

“…Developing simpler and more economical devices and methods can lower the entry barrier for NCTs. It seems to be a good method to use the new electrospray-produced cocrystal as a seed crystal to adjust the performance of cooling crystallization . This new technology separates crystal nucleation and crystal growth, allowing better control of each individual event and expanding the possibility to new solid forms.…”

Separation and nucleation kinetics of l-menthol polymorph through a swift cooling crystallization process

“…14 With the cooling crystallization process, pharmaceutical cocrystals that are multi-component substances formulated to enhance the properties of active pharmaceutical ingredients (APIs) and are commercially used to enhance several drug additives successfully through the drug discovery pipeline, this new technology expands to access new solid forms. 15 An important idea for the development of new food products, based on further control and application of cocrystallization techniques is useful in the food industry with unique properties. 16 Yuasa et al reported l -menthol in coexistence with various excipients and noticed that whisker growth is an important problem during medicinal preparation in pharmaceutical indutries.…”