The first structural characterization of glycyrrhizic acid, its monoammonium salt (AGA), and the complex of the salt with p-aminobenzoic acid in the solid state is reported. X-ray crystallography reveals that neutral and ionic forms of GA have similar supramolecular organization, with aglycon groups protruding from the 2D hydrogenbonded sugar platform. Interpenetration of these assemblies leads to the generation of intersecting channels where solvent and guest molecules are enclosed. It is worth noting that small solvent molecules or cations can functionally replace three water molecules which are an integral part of the sugar platform in GA. The crystal structures indicate the drug and cation binding sites and explain the similar properties of glycyrrhizic acid and its salts. The presented structures provide information about the supramolecular organization of amphiphilic GA molecule in the solid state, giving a guide into a possible aggregation mode in gels and solutions.

Rifampicin belongs to the family of naphthalenic ansamycin antibiotics. The first crystal structure of rifampicin in the form of the pentahydrate was reported in 1975 [Gadret, Goursolle, Leger & Colleter (1975). Acta Cryst. B 31, 1454-1462] with the rifampicin molecule assumed to be neutral. Redetermination of this crystal structure now shows that one of the phenol -OH groups is deprotonated, with the proton transferred to a piperazine N atom, confirming earlier spectroscopic results that indicated a zwitterionic form for the molecule, namely (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)-21-acetyloxy-6,9,17,19-tetrahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[(E)-N-(4-methylpiperazin-4-ium-1-yl)formimidoyl]-1,11-dioxo-1,2-dihydro-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-5-olate pentahydrate, C(43)H(58)N(4)O(12)·5H(2)O. The molecular structure of this antibiotic is stabilized by a system of four intramolecular O-H···O and N-H···N hydrogen bonds. Four of the symmetry-independent water molecules are arranged via hydrogen bonds into helical chains extending along [100], whereas the fifth water molecule forms only one hydrogen bond, to the amide group O atom. The rifampicin molecules interact via O-H···O hydrogen bonds, generating chains along [001]. Rifampicin pentahydrate is isostructural with recently reported rifampicin trihydrate methanol disolvate.

The aim of our research was to improve the solubility and antioxidant activity of pterostilbene (PTR) by developing a novel amorphous solid dispersion (ASD) with Soluplus® (SOL). DSC analysis and mathematical models were used to select the three appropriate PTR and SOL weight ratios. The amorphization process was carried out by a low-cost and green approach involving dry milling. An XRPD analysis confirmed the full amorphization of systems in 1:2 and 1:5 weight ratios. One glass transition (Tg) observed in DSC thermograms confirmed the complete miscibility of the systems. The mathematical models indicated strong heteronuclear interactions. SEM micrographs suggest dispersed PTR within the SOL matrix and a lack of PTR crystallinity, and showed that after the amorphization process, PTR-SOL systems had a smaller particle size and larger surface area compared with PTR and SOL. An FT-IR analysis confirmed that hydrogen bonds were responsible for stabilizing the amorphous dispersion. HPLC studies showed no decomposition of PTR after the milling process. PTR’s apparent solubility and antioxidant activity after introduction into ASD increased compared to the pure compound. The amorphization process improved the apparent solubility by ~37-fold and ~28-fold for PTR-SOL, 1:2 and 1:5 w/w, respectively. The PTR-SOL 1:2 w/w system was preferred due to it having the best solubility and antioxidant activity (ABTS: IC50 of 56.389 ± 0.151 µg·mL−1 and CUPRAC: IC0.5 of 82.52 ± 0.88 µg·mL−1).

The present study reports amorphous solid dispersions (ASDs) of hesperidin (Hes) prepared by ball milling to improve its solubility and apparent solubility over the unmodified compound. The carriers were Soluplus® (Sol), alginate sodium (SA), and hydroxypropylmethylcellulose (HPMC). XRPD analysis confirmed full amorphization of all binary systems in 1:5 w/w ratio. One glass transition (Tg) observed in DSC thermograms of hesperidin:Soluplus® (Hes:Sol) and hesperidin:HPMC (Hes:HPMC) 1:5 w/w systems confirmed complete miscibility. The mathematical model (Gordon–Taylor equation) indicates that the obtained amorphous systems are characterized by weak interactions. The FT-IR results confirmed that hydrogen bonds are responsible for stabilizing the amorphous state of Hes. Stability studies indicate that the strength of these bonds is insufficient to maintain the amorphous state of Hes under stress conditions (25 °C and 60 °C 76.4% RH). HPLC analysis suggested that the absence of degradation products indicates safe hesperidin delivery systems. The solubility and apparent solubility were increased in all media (water, phosphate buffer pH 6.8 and HCl (0.1 N)) compared to the pure compound. Our study showed that all obtained ASDs are promising systems for Hes delivery, wherein Hes:Sol 1:5 w/w has the best solubility (about 300-fold in each media) and apparent solubility (about 70% in phosphate buffer pH 6.8 and 63% in HCl).

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The nutraceutical system of curcumin-piperine in 2-hydroxypropyl-b-cyclodextrin was prepared by using the kneading technique. Interactions between the components of the system were defined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR). Application of hydroxypropyl-b-cyclodextrin as a carrier-solubiliser improved solubility of the curcumin-piperine system, its permeability through biological membranes (gastrointestinal tract, blood-brain barrier) as well as the antioxidant, antimicrobial and enzyme inhibitory activities against acetylcholinesterase and butyrylcholinesterase.

CMTI-I, a small-protein trypsin inhibitor, has been crystallized as a 4:1 protein-zinc complex. The metal is coordinated in a symmetric tetrahedral fashion by glutamate/glutamic acid side chains. The structure was solved by direct methods in the absence of prior knowledge of the special position metal centre and refined with anisotropic displacement parameters using diffraction data extending to 1.03 A. In the final calculations, the main-chain atoms of low B(eq) values were refined without restraint control. The two molecules in the asymmetric unit have a conformation that is very similar to that reported earlier for CMTI-I in complex with trypsin, despite the Met8Leu mutation of the present variant. The only significant differences are in the enzyme-binding epitope (including the Arg5 residue) and in a higher mobility loop around Glu24. The present crystal structure contains organic solvent molecules (glycerol, MPD) that interact with the inhibitor molecules in an area that is at the enzyme-inhibitor interface in the CMTI-I-trypsin complex. A perfectly ordered residue (Ala18) has an unusual Ramachandran conformation as a result of geometrical strain introduced by the three disulfide bridges that clamp the protein fold. The results confirm deficiencies of some stereochemical restraints, such as peptide planarity or the N-C(alpha)-C angle, and suggest a link between their violations and hydrogen bonding.

The crystal structures of three ester derivatives of glycyrrhetinic acid (GE) are reported. X-ray crystallography revealed that despite differences in the size of the ester substituents (ethyl, isopropyl and 2-morpholinoethyl) the scheme of molecular self-assembly is similar in all three cases but differs significantly from that observed in other known GE esters. According to our analysis, the two basic patterns of self-assembly of GE esters observed in their unsolvated crystals correspond to two distinct orientations of the ester groups relative to the triterpene backbone. Moreover, comparison of the self-assembly modes of GE esters in their unsolvated forms with the supramolecular organization of GE and carbenoxolone in their solvated crystals revealed that ester substituents replace solvent molecules hydrogen bonded to the COOH group at the triterpene skeleton, resulting in similar packing arrangements of these compounds.