Cocrystal Formation via Resorcinol–Urea Interactions: Naringenin and Carbamazepine

Abstract

Improving the stability, bioavailability, and processability of active pharmaceutical ingredients (APIs) has been the key research goal in the field of pharmaceutical crystallization. Cocrystallization has been considered as an effective route to achieve this goal, and intense research over decades has revealed cocrystals of many APIs. However, most cocrystal formers have been designed based primarily on their molecular interactions not their health benefits. Herein, we choose naringenin (N), a natural flavonoid, as a novel cocrystal former as it has many health efficacies and the ability to form specific interactions. At a 1:1 stoichiometric ratio, N successfully forms a cocrystal with carbamazepine (CBZ), whose plasma concentration is known to be improved by natural flavonoids such as N. The resorcinol functional group of N and the urea functional group of CBZ are connected through hydrogen bonds, and the improved stability of the cocrystal seems to originate from this structure. The melting temperature of the cocrystal is 262 °C, which is higher than those of CBZ and N, and the better stability of the cocrystal is further confirmed by the observation of enhanced hydration stability (up to 30 days at 93% RH). This novel strategy of cocrystallization using natural flavonoids could improve the commercialization potential of API cocrystals.

Theoretical Molecular Docking Study of the Structural Disruption of the Viral 3CL-Protease of COVID19 Induced by Binding of Capsaicin, Piperine and Curcumin Part 1: A Comparative Study with Chloroquine and Hydrochloroquine Two Antimalaric Drugs

“…Based on a literature survey, we tested eighteen phytochemical compounds with reported antiviral properties including, Allicin (Xie et al,2020), Bornyl acetate , Capsaicin (Tang et al, 2020), Carvacrol (Bansal et al, 2020), Catechol (Mishra et al, 2020), Cinnamic acid (Silva et al, 2020), Curcumin (Bonfim et al, 2020), Eucalyptol (Patra et al, 2020), Gallic acid (Arsianti et al, 2020), Geraniol (Wei et al, 2020), Linalool (Del Bosco et al, 2020, Nicotinic acid (Corona et al, 2020), Phytic acid (Narayanaswamy and Esa 2018), Piperine (Chandani et al, 2019), Quercetin (Nile et al, 2020;Lopes et al, 2020;Aggarwa et al, 2020), Resorcinol (Lee et al, 2019), Terpinen-4-ol (Patra et al, 2020) and Viridiflorene (Shayeganmehr et al, 2018). Additionally, we have used as molecular docking controls, two FDA-approved old antimalarial drug, Chloroquine and Hydroxychloroquine (an analogue of chloroquine) recommended for treating COVID-19 patients (Gautret et al, 2020).…”

Apigenin Cocrystals: From Computational Prescreening to Physicochemical Property Characterization

“…28 All of them have been discovered to be popular coformers to form cocrystals with other flavonoids. 29,30 Additionally, the crystallographic data of the APG crystalline structure were also reported for the first time in this work.…”

Crystalline Multicomponent Solids: An Alternative for Addressing the Hygroscopicity Issue in Pharmaceutical Materials

“…96 In a very recent report, Lee and co-workers synthesized a new cocrystal with a natural flavonoid, naringenin that shows improved hydration over an extended period of 30 days stored at 93% RH compared to anhydrous carbamazepine. 97 Cocrystal of AMG 517. AMG 517 is a potent VR1 antagonist that exists as a hydrate along with the anhydrate forms.…”

“…Rahman et al addressed that the carbamazepine–nicotinamide cocrystal has better stability compared to anhydrous carbamazepine even at extreme humidity conditions (40 °C/94% RH) over a month (Figure ). In a very recent report, Lee and co-workers synthesized a new cocrystal with a natural flavonoid, naringenin that shows improved hydration over an extended period of 30 days stored at 93% RH compared to anhydrous carbamazepine …”