Enhancing the Physiochemical Properties of Puerarin via L-Proline Co-Crystallization: Synthesis, Characterization, and Dissolution Studies of Two Phases of Pharmaceutical Co-Crystals

Abstract

Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]∙EtOH∙(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics.

Co-Crystals of Resveratrol and Polydatin with L-Proline: Crystal Structures, Dissolution Properties, and In Vitro Cytotoxicities

“…Meanwhile, the asymmetric unit of RSV-L-Pro contained one RSV and two PRO molecules ( Figure 5 c). In RSV-L-Pro, the L-Pro moiety also was in the zwitterionic form, wherein the H atoms from the –COOH group migrated to the –NH– to yield the –[COO] − and –[NH 2 ] + – pair [ 34 ]. The –[COO] – also was in a conjugated form, serving as the H-bonding acceptors.…”

Solubility Enhancement of Anticancer Drug Belinostat via the Co-crystallization Strategy: Synthesis, Characterization, and Antitumor Activity In Vitro Evaluation

“…The number of formazan products was determined by a microplate reader at 490 nm. The untreated cells served as the 100% cell viability control and the percentage of cell viability was calculated by the formula below: , V % = false[ OD false] exp − false[ OD false] bla false[ OD false] untre − false[ OD false] bla where V % is the percentage of cell viability, [OD] exp is the absorbance of the wells culturing the treated cells, [OD] bla is the absorbance of the blank, and [OD] untre is the absorbance of the wells culturing untreated cells.…”

“…The number of formazan products was determined by a microplate reader at 490 nm. The untreated cells served as the 100% cell viability control and the percentage of cell viability was calculated by the formula below: 29,30 V % OD OD OD OD exp bla untre bla…”

Pharmacological Activity, Pharmacokinetics, and Clinical Research Progress of Puerarin

“…PUE-NSSPE formed a core-shell structure by adsorbing puerarin nanocrystals on the surface of oil droplets. Pueraria can also co-crystallize with L-proline (PRO), lurasidone hydrochloride (LH), and other adjuvants to improve the pharmacokinetics of oral drug preparations [ 156 ]. In addition, the preparation of ultra-small nanocrystals (below 50 nm) by forming hydrogen bonds between puerarin and stabilizers can improve bioavailability and therapeutic efficiency [ 157 ].…”