Drugs with poor biopharmaceutical performance are the main obstacle to the development and design of medicinal preparations. The anisotropic surface chemistry of different surfaces on the crystal influences its physical and chemical properties, such as solubility, tableting, etc. In this study, the antisolvent crystallization and rapid-cooling crystallization were carried out to tune the crystal habits of ticagrelor (TICA) form II. Different crystal habits of ticagrelor (TICA) form II (TICA-A, TICA-B, TICA-C, TICA-D, and TICA-E) were prepared and evaluated for solubility. The single-crystal diffraction (SXRD) indicated that TICA form II belongs to the triclinic P1 space group with four TICA molecules in the asymmetric unit. The TICA molecules are generated through intermolecular hydrogen bonds along the (010) direction, forming an infinite molecular chain, which are further stacked by hydrogen bonds between hydroxyethoxy side chains, forming molecular circles composed of six TICA molecules along bc directions. Thus, in the case of TICA form II, hydrogen bonds drive growth along one axis (b-axis), which results in the formation of mostly needle-shape crystals. Morphology and face indexation reveals that (001), (010) and (01-1) are the main crystal planes. Powder diffractions showed that five habits have the same crystal structure and different relative intensity of diffraction peak. The solubility of the obtained crystals showed the crystal habits affect their solubility. This work is helpful for studying the mechanism of crystal habit modification and its effect on solubility.Crystals 2019, 9, 556 2 of 15 such as crystal habit, polymorphism and reduction of the particle size [15][16][17][18][19][20]. There have been many studies demonstrating the effect of polymorphism on oral bioavailability and/or dissolution rate [21]. However, the dissolution rate not only differs for different polymorphisms, but also, for different crystal habits [22], which has received scant attention. Meanwhile, crystal habits also influence stability, flowability, suspension, packing, density, compaction, etc. [23][24][25][26][27]. Thus, optimizing crystal properties by modification of the crystal habit of a drug seems to offer an alternative approach to changing the bioavailability of drugs. The relative growth rate of each surface determines the overall shape of the crystal. The growth rate of the crystal surface will be controlled by a combination of structure-related factors, such as dislocations and intermolecular bonds, and by exterior factors such as solvents, rate of agitation, additives, temperature, etc. [28][29][30][31][32][33][34][35].This study aims to systematically investigate how crystal behavior affects the ticagrelor's solubility. TICA form II (TICA-II) with different crystal habits were prepared by controlling the crystallization process. To systematically investigate the relationship between crystal habit and orientation of the molecules of TICA form II in the crystal lattice, single crystals were obtained, and the cr...

The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.

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.

Understanding the host–guest chemistry of α-/β-/γ- cyclodextrins (CDs) and a wide range of organic species are fundamentally attractive, and are finding broad contemporary applications toward developing efficient drug delivery systems. With the widely used β-CD as the host, we herein demonstrate that its inclusion behaviors toward an array of six simple and bio-conjugatable adamantane derivatives, namely, 1-adamantanol (adm-1-OH), 2-adamantanol (adm-2-OH), adamantan-1-amine (adm-1-NH2), 1-adamantanecarboxylic acid (adm-1-COOH), 1,3-adamantanedicarboxylic acid (adm-1,3-diCOOH), and 2-[3-(carboxymethyl)-1-adamantyl]acetic acid (adm-1,3-diCH2COOH), offer inclusion adducts with diverse adamantane-to-CD ratios and spatial guest locations. In all six cases, β-CD crystallizes as a pair supported by face-to-face hydrogen bonding between hydroxyl groups on C2 and C3 and their adjacent equivalents, giving rise to a truncated-cone-shaped cavity to accommodate one, two, or three adamantane derivatives. These inclusion complexes can be terminated as (adm-1-OH)2⊂CD2 (1, 2:2), (adm-2-OH)3⊂CD2 (2, 3:2), (adm-1-NH2)3⊂CD2 (3, 3:2), (adm-1-COOH)2⊂CD2 (4, 2:2), (adm-1,3-diCOOH)⊂CD2 (5, 1:2), and (adm-1,3-diCH2COOH)⊂CD2 (6, 1:2). This work may shed light on the design of nanomedicine with hierarchical structures, mediated by delicate cyclodextrin-based hosts and adamantane-appended drugs as the guests.

Lenvatinib is a cancer treatment drug approved by the U.S. Food and Drug Administration, which is a multitarget tyrosinase inhibitor. The commercially available form is its mesylate. In this work, five lenvatinib mesylate (LEM) solid-state forms, including two polymorphs (LEM-A, LEM-C) and three pseudopolymorphs (a hydrate (LEM-H) and two iso-structural solvates (LEM-H-EA and LEM-H-THF)), were prepared and characterized using various methods. Powder diffractions of LEM-A and LEM-C have been reported, but their crystal structures were reported for the first time by us. Hydrate and two iso-structural solvates were also first prepared and characterized by thermal analysis, X-ray diffraction, and so forth. The mutual transformation of different forms was studied. Two solvates easily lost their solvent and turned into LEM-B, which provided the possibility for the preparation of LEM-B. In addition, thermal stability and solubility of LEM-A, LEM-C, and LEM-H were determined, along with the respective molecular conformation, their inter-and intramolecular interactions, and packing arrangements.

Baloxavir marboxil (BXM) is a new blockbuster FDA-approved anti-influenza virus agent. However, its poor solubility has limited its oral bioavailability. In this study, BXM was crystallized from several organic solvents, obtaining three polymorphs, and their dissolution behaviors were studied. Detailed crystallographic examination revealed that Form I is monoclinic, space group P21, with unit cell parameters a = 7.1159 (3) Å, b = 20.1967 (8) Å, c = 9.4878 (4) Å, β = 109.033 (1)°, V = 1289.02 (9) Å3, and Z = 2, and Form II is monoclinic, space group P21, with unit cell parameters a = 7.1002 (14) Å, b = 39.310 (7) Å, c = 9.7808 (18) Å, β = 110.966 (5)°, V = 2549.2 (8) Å3, and Z = 4. Form I has a rectangular three-dimensional energy frameworks net, while Form II has a two-dimensional net. On the other hand, Form II has a much larger percentage of its surface area of exposed hydrogen bond acceptors than Form I. These crystallographic features offered increased solubility and dissolution rate to Form II. The results of stability and solubility experiments suggest that Form II may be preferred in the solid form used for the industrial preparation of BXM medicinal products.

The progression of lung cancer is highly associated with the aberrant activation of epidermal growth factor receptor (EGFR) tyrosine kinase and the positive feedback loop between cancer cells and tumor-associated macrophages (TAMs). Hence, we use chitosan (CS) as a backbone and L-Arginine (L-Arg) as lateral chains to synthesize a biocompatible copolymer [(CS)-co-(L-Arg)]. With the electrostatic coupling between Au particles and [(CS)-co-(L-Arg)], the copolymer was further fabricated into [(CS)-co-(L-Arg)]-(AuNPs) nanoparticles with a nest-type perforated structure (CAAu NPs). Owing to the perforated structure and cationic property, CAAu NPs exhibit a high capacity for coloading of gefitinib (GFT) and miR125b, forming GFT-miR125b@CAAu nanomedicine. GFT-miR125b@CAAu shows a pulmonary-anchoring advantage, which is attributed to the mucoadhesion of the CS backbone. Meanwhile, L-Arg residues play a biomimetic role, which endows GFT-miR125b@CAAu with efficient internalization by cancer cells through Arg transportermediated endocytosis. Within the acidic tumor microenvironment, the electrostatic bonding of GFT-miR125b@CAAu cleaves, which facilitates pH-responsive release of GFT and miR125b. By combination of EGFR blocking and miR125b augmenting, GFT-miR125b@CAAu nanomedicine not only inhibits cancer cell survival but also deactivates protumoral TAMs, implementing a combination therapy against lung cancer.

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