Crystal defects creation in Mannitol@CaCl2 metal-organic framework by induced dehydration strategy for enhanced excipient mechanical properties.

The mechanical properties of solid pharmaceutical excipients are important for assisting drug tables production, and they determine the quality of the drug tablets. The purpose of this study was to explore the potential and mechanism of crystal defect engineering to improve the mechanical properties of Mannitol@CaCl2 MOF, a pharmaceutical excipient with metal-organic framework (MOF) structure designed and prepared in our previous study. In this study, a simple and efficient "induced dehydration strategy" was proposed to prepare Mannitol@CaCl2 MOF with crystal defects (DEMOF). SEM, TEM, HRTEM, PXRD, FTIR, DSC-TGA, and N2 adsorption-desorption isotherm revealed the successful introduction of lattice vacancy and macrostructural defects while preserving MOF's skeleton structure. Tabletability profiles indicated that DEMOF presented much better mechanical properties than the original MOF at the powder level. On single crystal and atomic scales, nanoindentation and DFT calculations revealed that the defect structure increased plasticity, decreased brittleness, and improved compressibility, resulting in DEMOF tablets with much higher tensile strength that met the criteria for direct compression excipients. The achieved performance modification illustrated the capability of defect engineering to tune mechanical properties of MOFs, and the Mannitol@CaCl2 DEMOF exhibited great potential to serve as a new direct compression pharmaceutical excipient.

Functional in situ formed deep eutectic solvents improving mechanical properties of powders by enhancing interfacial interactions.

As novel green solvents, deep eutectic solvent (DES) with distinct liquid properties has gained increasing interest in pharmaceutical fields. In this study, DES was firstly utilized for improving powder mechanical properties and tabletability of drugs, and the interfacial interaction mechanism was explored. Honokiol (HON), a natural bioactive compound, was used as model drug, and two novel HON-based DESs were synthesized with choline chloride (ChCl) and l-menthol (Men), respectively. The extensive non-covalent interactions were account for DES formation according to FTIR, 1H NMR and DFT calculation. PLM, DSC and solid-liquid phase diagram revealed that DES successfully in situ formed in HON powders, and the introduction of trace amount DES (99:1 w/w for HON-ChCl, 98:2 w/w for HON-Men) significantly improve mechanical properties of HON. Surface energy analysis and molecular simulation revealed that the introduced DES promoted the formation of solid-liquid interfaces and generation of polar interactions, which increase interparticulate interactions, thus better tabletability. Compared to nonionic HON-Men DES, ionic HON-ChCl DES exhibited better improvement effect, since their more hydrogen-bonding interactions and higher viscosity promote stronger interfacial interactions and adhesion effect. The current study provides a brand-new green strategy for improving powder mechanical properties and fills in the blank of DES application in pharmaceutical industry.

Mechanistic insights into the crystallization of coamorphous drug systems.

In our previous study, the coamorphous formulation of lurasidone hydrochloride (LH) with saccharin (SAC) showed significantly enhanced dissolution and physical stability compared to crystalline/amorphous LH. However, the coamorphous system is still in amorphous state, and has the tendency to recrystallization, which will in turn result in the loss of above advantages. In this study, the crystallization kinetics under isothermal and non-isothermal conditions was investigated. Compared to amorphous LH, coamorphous LH-SAC showed 68.3-361.2 and 2.6-6.1 times lower crystallization rates in glassy state and supercooled liquid state, respectively. After co-amorphization, the addition of SAC changed the crystallization mechanism of amorphous LH from nucleation-controlled to diffusion-controlled manner. Amorphous LH followed the site-saturated nucleation, whereas the coamorphous system exhibited a fixed number of nuclei. The non-isothermal crystallization indicated amorphous LH and coamorphous LH-SAC showed two-dimensional (JMAEK 2) and three-dimensional (JMAEK 3) growth of nuclei, respectively. Furthermore, coamorphous LH-SAC exhibited higher molecular mobility and dynamic fragility (mD) than amorphous LH, which is kinetically unfavorable for its physical stability. However, from thermodynamic perspective, coamorphous LH-SAC had a higher configurational entropy, i.e., a higher entropy barrier for crystallization, which is beneficial to hinder its crystallization. Therefore, it was concluded that the higher configurational entropy rather than the molecular mobility was proposed to be responsible for its improved stability. In addition, molecular dynamics simulations with miscibility, radial distribution function and binding energy calculations suggested coamorphous components exhibited good miscibility and strong intermolecular interactions, which was also conductive to the enhancement in its stability. This study offers an in-depth understanding about the effect of the coformer on the crystallization kinetics of coamorphous systems, and points out the important contribution of the configurational entropy in stabilizing the coamorphous systems.

Mechanistic Study on Transformation of Coamorphous Baicalein-Nicotinamide to Its Cocrystal Form.

Recently, coamorphization and cocrystal technologies are of particular interest in the pharmaceutical industry due to their ability to improve the solubility/dissolution and bioavailability of poorly water-soluble drugs, while the coamorphous system often tends to convert into the stable crystalline form usually crystalline physical mixture of each component during formulation preparation or storage. In this paper, BCS II drug baicalein (BAI) along with nicotinamide (NIC) were prepared into a single homogeneous coamorphous system with a single transition temperature at 42.5 °C. Interestingly, instead of the physical mixture of crystalline BAI and NIC, coamorphous BAI-NIC would transform to its cocrystal form under stress of temperature and humidity. The transformation rate under isothermal condition was temperature-dependent, since the crystallinity of the cocrystal enhanced as the temperature increased. Further mechanic studies showed the activation energy for the transformation under non-isothermal condition was calculated to be 184.52 kJ/mol. Additionally, water vapor sorption tests with further solid characterizations indicated the transformation was faster under higher humidity condition due to the faster nucleation process of cocrystal BAI-NIC. This research not only discovered the mechanism of transformation from coamorphous BAI-NIC to cocrystal form, but also provided an unusual method for cocrystal preparation from its coamorphous form.

Gelation Elimination and Crystallization Inhibition by Co-Amorphous Strategy for Amorphous Curcumin.

In the previous study, the development of amorphous curcumin (CUR) aimed to enhance the solubility/dissolution of CUR by disrupting its crystal lattice, but it unexpectedly showed a decreased dissolution than its crystalline counterpart on account of gel formation in its dissolution process. Whether such gelation could be eliminated by co-amorphous strategy was answered in this study. Herein, CUR by co-amorphization with chlorogenic acid (CHA) was successfully prepared using quench cooling. The formed co-amorphous material (namely CUR-CHA CM) eliminated the gelation and hence performed superior dissolution performance than crystalline/amorphous CUR. Meanwhile, it exhibited higher physical stability than amorphous CUR during dissolution as well as under long-term/accelerated conditions. To further study the such enhancement mechanism, the internal molecular interactions were investigated for CUR-CHA CM in the solid state as well as in aqueous solution. FTIR and solid-state 13C NMR spectra confirmed that intermolecular hydrogen bonds formed between CUR and CHA after co-amorphization. Furthermore, the nucleation of CUR was significantly inhibited by CHA in an aqueous solution, thus maintaining the supersaturated dissolution for a long time. The present study offers a feasible strategy to eliminate gelation and enhance stability of amorphous solids by co-amorphization and crystallization inhibition.

Recent advances on small molecular gels: formation mechanism and their application in pharmaceutical fields.

INTRODUCTION: As an essential complement to chemically cross-linked macromolecular gels, drug delivery systems based on small molecular gels formed under the driving forces of non-covalent interactions are attracting considerable research interest due to their potential advantages of high structural functionality, lower biological toxicity, reversible stimulus-response, and so on. AREA COVERED: The present review summarizes recent advances in small molecular gels and provides their updates as a comprehensive overview in terms of gelation mechanism, gel properties, and physicochemical characterizations. In particular, this manuscript reviews the effects of drug-based small molecular gels on the drug development and their potential applications in the pharmaceutical fields. EXPERT OPINION: Small molecular-based gel systems, constructed by inactive compounds or active pharmaceutical ingredients, have been extensively studied as carriers for drug delivery in pharmaceutical field, such as oral formulations, injectable formulations, and transdermal formulations. However, the construction of such gel systems yet faces several challenges such as rational and efficient design of functional gelators and the great occasionality of drug-based gel formation. Thus, a deeper understanding of the gelation mechanism and its relationship with gel properties will be conducive to the construction of small molecular gels systems and their future application.

Improved Pharmaceutical Properties of Honokiol via Salification with Meglumine: an Exception to Oft-quoted ∆pKa Rule.

Honokiol (HK), a BCS class II drug with a wide range of pharmacological activities, has poor solubility and low oral bioavailability, severely limiting its clinical application. In the current study, incorporating a water-soluble meglumine (MEG) into the crystal lattice of HK molecule was performed to improve its physicochemical properties. The binary mixture of HK and MEG was obtained by anti-solvent method and characterized by TGA, DSC, FTIR, and PXRD. The SCXRD analysis showed that two HK- molecules and two MEG+ molecules were coupled in each unit cell via the ionic interaction along with intermolecular hydrogen bonds, suggesting the formation of a salt, which was further confirmed by the XPS measurements. However, the ∆pKa value between HK and MEG was found to be less than 1, which did not follow the oft-quoted ∆pKa rule for salt formation. After salification with MEG, the solubility and dissolution rate of HK exhibited 3.50 and 25.33 times improvement than crystalline HK, respectively. Simultaneously, the powder flowability, tabletability and stability of HK-MEG salt was also significantly enhanced, and the salt was not more hygroscopic, and that salt formation did not compromise processability in that regard. Further, in vivo pharmacokinetic study showed that Cmax and AUC0-t of HK-MEG salt were enhanced by 2.92-fold and 2.01-fold compared to those of HK, respectively, indicating a considerable improvement in HK oral bioavailability.

Gelation switch of polyamorphic indomethacin depending on the thermal procedure.

Amorphous indomethacin (IMC) prepared under different thermal procedures via melt quenching method showed significantly different dissolution behaviors. This study aims to investigate the influence of thermal procedures on the formation of IMC polyamorphism and to explore the mechanism for their different dissolution behaviors. Amorphous IMC samples were prepared by melting crystalline IMC under a series of temperatures (160-195 °C), respectively, followed by quenching in liquid nitrogen. Samples obtained under 170 °C exhibited bi-halo shapes at ∼15° and ∼26° (2θ), while the ones above 175 °C showed a single halo at ∼21° (2θ), suggesting amorphous IMC prepared under different thermal procedures probably have different local molecular arrangements. In comparison to crystalline IMC, amorphous IMC obtained under 170 °C showed significantly higher dissolution profiles with good dispersibility in aqueous medium, however, all amorphous IMC samples prepared above 175 °C demonstrated much lower dissolution with significant gelation, which seemed like a gelation switch existed for polyamorphic IMC when the preparation temperature was between 170 and 175 °C. Based on physicochemical characterizations, amorphous IMC prepared under 170 °C had higher surface free energy, more surficial hydrophilic groups and better wettability than the ones made above 175 °C. Molecular dynamics simulations revealed that the amorphous samples prepared below 170 °C had similar binding energy values in the range of 310.045-325.479 kcal/mol, while those prepared above 175 °C were significantly lower within 212.193-235.073 kcal/mol. Such binding energy difference might be responsible for their different local molecular arrangements after different thermal procedures. The current study deeply reminds us that the thermal procedure of preparation methods may significantly affect the physicochemical properties of amorphous materials, which should be paid special attention to the polymorphic selection during pharmaceutical development.

Effect of sodium lauryl sulfate-mediated gelation on the suppressed dissolution of crystalline lurasidone hydrochloride and a strategy to mitigate the gelation.

In dissolution test, the surfactant sodium lauryl sulfate (SLS) is usually added to increase the dissolution of insoluble drugs and achieve the sink condition. However, the current study found that 0.1 % SLS would significantly decrease the dissolution of crystalline lurasidone hydrochloride (LH, a BCS Ⅱ drug). The aim of this study was to clarify the mechanism of this unexpected phenomenon and explore a strategy for mitigating the negative effect of SLS on the dissolution of LH. Sample characterizations (such as PLM, DSC, PXRD, IR and NMR) confirmed that the insoluble single-phase amorphous LH-SLS complex (with a single Tg at 35.2 °C) formed during dissolution in 0.1 % SLS aqueous solution via electrostatic interaction, tetrel bond interaction, and hydrophobic effect. Due to the plasticization effect of water, the transition of amorphous LH-SLS from its glassy state to viscous supercooled liquid state led to the gel formation, and suppressd the dissolution of LH. Meanwhile, the solubility curve of LH in SLS aqueous solution at various concentrations exhibited an unusual V-shaped feature, with the CMC value of SLS serving as the inflection point, since the gel degree was attenuated due to the micelle solubilization of SLS. Additionally, an innovative strategy was developed to alleviate the inhibiting effect of SLS on LH dissolution based on the potential competitive interactions. This study not only enriches the internal mechanism of surfactant-inhibited drug dissolution but also informs an effective strategy to mitigate the gelation.

A novel soluble lornoxicam-sodium chelate monohydrate with improved plasticity and tabletability.

Lornoxicam (LOR), a BCS II nonsteroidal anti-inflammatory drug, has been clinically utilized for moderate to severe acute pain management. However, it has poor water solubility and insufficient tabletability, leading to erratic absorption and challenge in tablet processability. This study reported a novel solid state of LOR (i.e., LOR sodium chelate monohydrate, LOR-Na·H2O) with significantly improved solubility, dissolution rate and tabletability. The prepared chelate (CCDC No.: 2125157) contains LOR-, Na+, and H2O in a molar ratio of 1:1:1, where Na+ ions bridged with O(5) of amide group, and N(2) of pyridine group on LOR-, as well as O(4) on H2O through coordination bonds. LOR-Na·H2O displayed a superior dissolution rate (5 âˆ¼ 465 folds) than commercial LOR due to its increased wettability (contact angle: 74.5° vs 85.6°) and lower solvation free energy (∼2-fold). In addition, the significant improvement in tabletability was caused by high plasticity and deformability, which was attributed to its special interlayer gliding with weak bonding interactions across layers but strong coordination bonding interactions within layers. The novel LOR-Na·H2O with significantly enhanced pharmaceutical performance offers a promising strategy for further product development.

The bending behavior of an L-phenylalanine monohydrate soft crystal via reversible hydrogen bond rupture and remodeling.

The present study reports a novel L-phenylalanine monohydrate (L-Phe·H2O) soft crystal, which has the potential to be developed as a medical microdevice owing to its flexibility and biosafety. Structure analysis indicated that there were plenty of directional hydrogen bonds distributed along almost every direction of the L-Phe·H2O crystal, which appeared to be a rigid and brittle crystal. However, the L-Phe·H2O crystal could be easily bent heavily and repeatedly. The aim of this study was to systematically investigate the bending mechanism of the L-Phe·H2O soft crystal from the viewpoint of hydrogen bond variations. In situ micro-Raman and in situ micro-infrared spectra showed that the hydrogen bonds ruptured and rearranged during the bending process. According to the micro-X-ray diffraction results, the order of the L-Phe·H2O lattice decreased in the bending region, and the varied lattice could return to its original state after straightening. Additionally, energy calculations suggested that the non-directional Coulomb attraction was the major force maintaining the macroscopic crystal integrity of L-Phe·H2O when it was bent.

Mechanistic insight into gel-induced aggregation of amorphous curcumin during dissolution process.

Amorphous curcumin (CUR) exhibited a decreased dissolution rate in comparison with the crystalline counterpart due to its gel formation during dissolution. The main purpose of the present study is to explore the mechanism of such gelation phenomenon. It was found that the dissolution of amorphous CUR and gel properties were influenced by the temperature and pH of the media. The formed gels were characterized by TPA, SEM, DSC, XRPD, FTIR and PLM. The results indicated that the gelation process led to the formation of a porous structure in which water molecules infiltrate, and entered into its supercooled liquid state with high viscosity when contacting aqueous media, accompanied by decreased Tg and crystalline transformation. In addition, mixing with hydrophilic excipients (such as hydrophilic silica) accelerated the gel formation of amorphous CUR, while the addition of hydrophobic excipients (such as hydrophobic silica and magnesium stearate) could effectively weaken and even eliminate the gelation, hence significantly improving its dissolution. Furthermore, according to contact angle measurement and fluorescence microscope observation, hydrophilic excipients were found to be able to accelerate water entering into the interior of amorphous CUR, hence facilitating the gelation, while hydrophobic excipients would hinder water infiltration into the powder and thus achieve degelation. In conclusion, it is important to recognize that the gelation potential of some amorphous materials should be considered in developing robust amorphous drug product of high quality and performance.

Effect of Coformer Selection on In Vitro and In Vivo Performance of Adefovir Dipivoxil Cocrystals.

PURPOSE: This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important role of coformer selection on the cocrystal's properties. METHODS: ADD was cocrystallized with three small molecules (i.e., paracetamol (PA), saccharin (SAC) and nicotinamide (NIC)), respectively. The obtained ADD-PA cocrystal was characterized by DSC, TGA, PXRD and FTIR. Comparative study on dissolution rates among the three ADD cocrystals were conducted in water and pH 6.8 phosphate buffer. Besides, effects of coformers on intestinal permeability of ADD were evaluated via in vitro Caco-2 cell model and in situ single-pass intestinal perfusion model in rats. Furthermore, in vivo pharmacokinetic study of ADD cocrystals was also compared. RESULTS: Dissolution rates of ADD cocrystals were improved with the order of ADD-SAC cocrystal > ADD-PA cocrystal > ADD-NIC cocrystal. The permeability studies on Caco-2 cell model and single-pass intestinal perfusion model indicated that PA could enhance intestinal absorption of ADD by P-gp inhibition, while SAC and NIC did not. Further in vivo pharmacokinetic study showed that ADD-SAC cocrystal exhibited higher Cmax (1.4-fold) and AUC0-t (1.3-fold) of ADD than administration of ADD alone, and Cmax and AUC0-t of ADD-PA cocrystal were significantly enhanced by 2.1-fold and 2.2-fold, respectively, which was attributed to its higher dissolution and improved intestinal permeability. CONCLUSION: Coformer selection had an important role on cocrystal's properties, and cocrystallization of ADD with a suitable coformer was an effective approach to enhance both dissolution and bioavailability of ADD.

Charge-assisted bond and molecular self-assembly drive the gelation of lenvatinib mesylate.

Lenvatinib mesylate (LM) is a first-line anticancer agent for the treatment of unresectable hepatocellular carcinoma, while it formed viscoelastic hydrogel when contacting with aqueous medium, which would significantly hinder its in vitro dissolution. The aim of this study was to systematicly explore the gelation mechanism and gel properties via thermal analysis, rheology, morphology and spectroscopy studies. The formed hydrogel was found to be composed of a new polymorph of crystalline LM, and its mechanical strength depended on the cross-linking degree of the fibrillar network structure. Spectroscopy analyses revealed that the intermolecular hydrogen bonds (the bifurcated hydrogen bond between the adjacent urea groups and the NH⋯OC hydrogen bond between the primary amide groups) as well as π-π stacking interactions (between the benzene ring and the quinoline ring) were suggested to be the driving forces for the self-assembly of LM during gelation process. Additionally, no gelation phenomenon was observed when suspending the base form lenvatinib in water, while it could form gel in various acidic solutions (e.g. hydrochloric acid, phosphoric acid and methanesulfonic acid) because the regenerated N+-H group increased the solubility of lenvatinib and promoted the balance between the dissolution or aggregation of LX (X: acid radical ion) molecules in solutions. In conclusion, the charge-assisted bond N+-H in LM molecule and intermolecular non-covalent interactions drived the hydrogel formation of LM in aqueous media. This study elucidates the gelation mechanism and gel properties of LM hydrogel, which would be helpful to figure out strategy to eliminate its gelation fundamentally and pave the way for its further formulation development in future.

Puerarin-Na Chelate Hydrate Simultaneously Improves Dissolution and Mechanical Behavior.

Puerarin monohydrate (PUEM), as the commercial solid form of the natural anti-hypertension drug puerarin (PUE), has low solubility, poor flowability, and mechanical properties. In this study, a novel solid form as PUE-Na chelate hydrate was prepared by a reactive crystallization method. Crystal structure analysis demonstrated that PUE-Na contains PUE-, Na+, and water in a molar ratio of 1:1:7. It crystallizes in the monoclinic space group P21, and Na+ is linked with PUE- and four water molecules through Na+ ← O coordination bonds. Another three crystal water molecules occupy channels along the crystallographic b-axis. Observing along the b-axis, the crystal structure features a distinct tubular helix and a DNA-like twisted helix. The complexation between Na+ and PUE- in aqueous solution was confirmed by the Na+ selective electrode, indicating that PUE-Na chelate hydrate belongs to a type of chelate rather than organic metal salt. Compared with PUEM, PUE-Na exhibited a superior dissolution rate (i.e., ∼38-fold increase in water) owing to its lower solvation free energy and clear-enriched exposed polar groups. Moreover, PUE-Na enhanced the tabletability and flowability of PUEM, attributing to its better elastoplastic deformation and lower-friction crystal habit. The unique PUE-Na chelate hydrate with significantly enhanced pharmaceutical properties is a very promising candidate for future product development of PUE.

Thermodynamic and kinetic studies on the polymorphic transformations of puerarin hydrates.

Puerarin (PUE), a bioactive flavonoid from the plant Pueraria lobata, exists in two hydrated forms: monohydrate (PUEMH) and dihydrate (PUEDH). The aim of the present work was to explore the thermodynamic and kinetic mechanism of the polymorphic transformation of PUE, including the solvent-mediated polymorphic transformation (SMPT) of PUEMH to PUEDH and the solid-state polymorphic transformations (SSPTs) of PUEMH and PUEDH. PUEMH and PUEDH were identified as isolated and channel hydrate, respectively. The thermodynamic parameters (ΔG < 0, ΔH < 0, and ΔS < 0) indicated that the SMPT was a spontaneous, exothermic and entropy-decreased reaction. The facilitating roles of stirring rate and temperature on the SMPT were favored by the primary and secondary nucleation process of PUEDH. In addition, the results of SSPTs suggested that PUEMH and PUEDH would transform to two different anhydrates (PUEAH-I and PUEAH-II) upon heating, respectively. The dehydration rate of PUEMH was slower than that of PUEDH due to the stronger hydrogen bond interactions. The rate-limiting step for the dehydration of PUEMH was the diffusion of water molecules, resulting in the increased dehydration activation during the dehydration process, while the dehydration activation energy of PUEDH showed opposite trend due to the complicated crystallization process of PUEAH-II.

Gel formation of puerarin and mechanistic study during its cooling process.

Recently, low molecular weight gelators are getting increasing interests in pharmaceutical field. In the current study, puerarin (PUE), a natural and bioactive flavonoid from the plant Pueraria lobata, was found to be able to gelate water to form hydrogel during cooling down process of its hot solution. In order to explore its gelation mechanism, the crystallization process, characterization, interaction force, morphology, rheological properties of PUE hydrogel were investigated by polarized light microscopy (PLM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Karl Fischer (KF), Raman spectrum, 1H-NMR, environmental scanning electron microscope (ESEM) and rheometer. The results indicated that at a high supersaturation condition, the gelation process of PUE was initiated by nucleation, and then fibers emanated rapidly from the nucleation center. The types of fiber growth changed from "fiber-like" growth to "less-linear" growth as the increase of supersaturation, leading to a denser structure with higher fractal dimension and stronger mechanical properties. Notably, the CO⋯π interaction facilitated the gelation assembly process, and the crystallographic mismatch branching played a vital role in constructing the network of PUE hydrogel.

The advances in research on the pharmacological effects of Fructus Ligustri Lucidi.

Fructus Ligustri Lucidi is a well-known invigorator in Chinese materia medica with hepatoprotective effect, anticancer activity, antioxidant activity, and so on. And oleanolic acids are the major pharmacologically active components in Fructus Ligustri Lucidi. So it has great value in medical health, and may be developed to a complementary and alternative medicine through further research. In this paper, the advances in research on pharmacological effects of Fructus Ligustri Lucidi were summarized by reviewing the recent related literature.