Lamellar Liquid Crystal Research Articles

Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs.

Aggregation behavior of pyrrolidinium-based surface active ionic liquids in H2O-EAN binary solvents

Pyrrolidinium-based surface active ionic liquid (SAIL), N-butyl-N-methylpyrrolidinium dodecyl sulfate ([C4MP][C12H25SO4]), was synthesized and its aggregation behavior was regulated by varying the concentration of SAIL and composition of H2O-ethylammonium nitrate (EAN) mixed solvent. Particularly interesting is that [C4MP][C12H25SO4] could not only form diverse lyotropic liquid crystals (LLCs), viz. hexagonal (H1) and lamellar liquid crystal (Lα) phases, in the water-rich environment, but also serve as an effective small molecule gelator and construct weak gel (W) and gel (G) in EAN-abundant binary solvent. The microstructures of LLC phases (H1 and Lα phases) were observed by polarized optical microscopy (POM). Small-angle X-ray scattering (SAXS) results affirm that the gels formed by different concentration of SAIL have the nearly constant interlayer spacing, and the H1 phase at higher [C4MP][C12H25SO4] concentration has a lower distance between the neighboring cylinders. Rheological measurements testify that the viscoelasticity of LLC phase reduces with the increasing content of EAN in the mixed solvent whereas increases with increase in concentration of SAIL. This work provides new insights into the aggregation behavior of SAILs in mixed solvents and the aggregates investigated may have potential applications in some fields, e.g. materials preparation and drug delivery, etc.

Interaction between organized assemblies of amphiphilic molecules and biological active molecules

Organized assemblies formed by amphiphilic molecules have various structures, including micelles, microemulsions, vesicles, lamellar liquid crystals, and hydrogel. Due to the similarity between the basic structure of the life system and molecular organized assemblies, these organized assemblies are of much importance as a convenient model for studying the biomacromolecules such as protein and phospholipids bilayer and also of great significance from the viewpoint of various promising practical applications. Therefore, it is of great theoretical and practical significance to study the interaction between organized assemblies of amphiphilic molecules and biological active molecules. In recent years, we have carried out a series of work in this area. We designed and synthesized some amino acid, glucoside and ionic liquid based functional green surfactants. These new surfactants can self-assemble into organized assemblies having various structures, such as micelles, vesicles, lamellar liquid crystals, and hydrogel. The mutual transformation among these different molecular ordered assemblies can be regulated by the molecular structure of surfactants and environmental factors. The molecular self-assembly of surfactants based on noncovalent interactions, such as hydrogen-bond, static electricity, solvophobic interaction and π-π stacking, etc, provides a powerful tool for the creation of well-defined structures in certain dimensions, and the transform among these organized assemblies. Furthermore, the interaction relationship between amphiphilic molecules and biological active molecules has been revealed by studying their thermodynamic and kinetic characteristics. Methemoglobin and GDA/ n -C5H11OH/H2O assemblies can affect their structures and properties, and the change in behavior is dependent on the content of methemoglobin and the composition and structure of the GDA/ n -C5H11OH/H2O system. The existence of methemoglobin reduces the hexagonal liquid crystal region, while the lamellar liquid crystal region is little changed in the presence of methemoglobin. The addition of amino acid does not change the structure of the microemulsions ultimately, but results in the redistribution of surfactants between the upper and lower phases. Furthermore, the distribution of amino acid between the phases can be adjusted by changing the total surfactant content. The exact location of the drugs depends on both the micellar structure and the molecular structure. The different locations of drugs in the micelle influence the structure-function of the drugs. Flavonoids show selective dimerization with the micelle structure change. It is always in the form of a dimer in spherical micelles, while it is in the form of a monomer in the rodlike micelles. The antihydrolysis and antioxidation activity of drug molecules can be modulated by changing and adjusting the microstructure of the molecular ordered assemblies. The clearance of hydroxyl radicals by morin and the protection of human serum albumin against hydroxyl radical induced damage by morin have been reduced in the Triton X-100 micelles. This dynamic process of puerarin’s localization in micelles causes the acid–base equilibrium of puerarin to move to the deprotonation reaction, enhancing the interaction between puerarin and surfactants, and promoting the formation of the puerarin–surfactant associate. With the changes of membrane hydrophobicity the effect of puerarin on membrane-water interfaces enhances and puerarin can locate more internally in the region of membranes, favoring the deprotonation of puerarin. Based on this, the relationship between the structure-function of bioactive molecules and the microenvironment is clarified from molecular level. This provides important theory and application basis for life sciences, medicine, pharmacy and other related fields.

Study on the formation and rheological properties of sucrose stearate lamellar liquid crystals

ABSTRACTThe phase diagrams of S1570–Brij 97/oleic acid/water system at two different S1570/Brij 97 mass ratios of 1/1 (system S) and 7/3 (system P) were determined at 37°C, respectively. The microstructures and rheological properties of liquid crystals at constant surfactants/water mass ratio of 1/1 were studied with increase in oil content. Small-angle x-ray scattering measurements showed that system S exhibited a typical lamellar liquid crystals and the repeat distance (d) decreased as oil content increased. While for system P, two couples of scattering peaks were observed when oil content reached 28 wt%. This indicated that adding oil content may give rise to a multilamellar structures in the higher S1570/Brij 97 mass ratio system. The rheological tests indicated that a transition from elastic gel-like properties to viscoelastic liquid-like properties appeared in both system S and P when oil content reached 20 wt%, corresponding to the polarizing optical microscopy textures changing from oily streak to cruciate flower. This supplies a way to adjust structure, rheological properties, and even phase transition by altering the S1570/Brij 97 mass ratio and oleic acid content in system.

Phase equilibria of mixtures of surfactants and viscoelastic properties of the liquid crystal phases

Mixtures of surfactants are widely used in many industrial and pharmaceutical products. Whereas diluted mixtures of surfactants have been studied in deep, much lesser studies at high surfactant concentrations have been made. A comparative study among the different systems of tetraoxyethylene dodecyl ether (C12E4) with different nonionic and anionic surfactants has been carried out. Four phase diagrams of C12E4/C12E10/water, C12E4/S40P/water, C12E4/SDS/water and C12E10/SDS/water systems at 30 °C are reported. In all of them, mixed micelles in water and reverse micelles have been found. Lamellar and hexagonal are the liquid crystals which appear in these ternary systems. Liquid crystals have been characterized by polarized light microscopy and rheology. Viscoelastic properties of the liquid crystals have been determined. Lamellar phase behaves like a gel with both mechanical moduli (G′ and G″) independent on frequency. The elastic properties of the lamellar phase are strongly dependent of the presence of ionic charges. Lamellar liquid crystals for the mixture with the anionic surfactant (SDS) have the higher elastic modulus. For hexagonal phase, elastic and viscous moduli increase with increasing frequency but with different slopes. Its elastic properties are strongly dependent of critical packing parameter of surfactants. Hexagonal liquid crystals for the mixtures with C12E4 (surfactant with the smaller area of the head group) show the more important elastic properties.

Optically Isotropic Homochiral Structure Produced by Intercalation of Achiral Liquid Crystal Trimers.

Dark conglomerates of domains with opposite handedness, which are designated dark conglomerate phases (DC phases), have attracted much attention. We prepared an achiral liquid crystal trimer, 4,4'-bis{9-[4-(5-octyloxypyrimidin-2-yl)phenyloxy]nonyloxy}biphenyl (I-9), and investigated the physical properties. A droplet of trimer I-9 formed a conventional nematic phase on cooling from the isotropic liquid, and then changed to an optical isotropic phase with homochirality. X-ray diffraction measurements reveal that the isotropic phase has an intercalated layer structure with a correlation length of 95 nm. We prepared binary mixtures with a nematic liquid crystal, 4'-hexyloxy-4-cyanobiphenyl (6OCB). The mixtures containing 30-75 mol % of 6OCB exhibited smectic phases above the isotropic phase. We investigated mesogenic properties of trimer I-n (n = 5-9) depending on the parity of the linking group. Only trimer I-9 possessing the longest odd-numbered spacers showed the chiral isotropic phase, suggesting that a rigid bent structure is not necessary for the appearance of the isotropic phase. The experimental results reveal that trimer I-9 exhibits a soft crystalline DC phase representing a new modification of chiral symmetry breaking in lamellar liquid crystal phases.

Liquid Crystal Observations in Emulsion Fractions from Brazilian Crude Oils by Polarized Light Microscopy

The observation of lamellar liquid crystals (LCs) is reported in fractions of Brazilian crude oil emulsions. Through polarized light microscopy, several structures exhibiting Maltese cross-optical pattern were observed, mostly in aqueous-rich fractions (bottom fractions). Microscopy observations were carried out immediately after emulsion preparation and after a destabilization protocol by centrifugation. Four oils were used: two waxy crude oils and two non-paraffinic oils. The experimental variables investigated were oil composition, aqueous content, and saline solution concentration. The liquid crystalline structures had a similar pattern for all samples observed with a thickness of 1.77 ± 0.14 μm surrounding droplets of 4.57 ± 0.47 μm diameter. Neither the presence of wax nor NaCl (up to 35 g/L) exhibited any correlation with liquid crystal (LC) appearance. However, the increase of the aqueous phase added to the systems favoring LC formation.

Phase Behavior of Ascorbyl Palmitate Coagels Loaded with Oligonucleotides as a New Carrier for Vaccine Adjuvants

AbstractIn this work, the phase behavior variations of an ascorbyl palmitate (Asc16) system in aqueous solution were analyzed when immunologically active hydrophilic compounds (CpG and OVA) were introduced. This study was carried out through optical polarizing microscopy (OPM) and differential scanning calorimetry (DSC) at different temperatures and over a broad range of concentrations. The combination of both techniques allowed the determination of a complete phase diagram which was compared with those built for Asc16‐water system and it was demonstrated that fixed concentrations of hydrophilic compounds (300 and 24 µg/g for CpG‐ODN and OVA respectively) generate two lamellar liquid crystals, a cubic liquid crystal phase, and also other aggregates. However, no changes were observed in the phase diagram in terms of formation of new mesophases. The aqueous phase behavior was also studied as a function of surfactant and temperature. DSC and Fourier transform infrared spectroscopy (FT‐IR) measurements show differences in the free water and mainly in the secondary hydration layer, which confirm that the studied compounds are situated in the aqueous domain. The construction and analysis of Asc16 phase diagrams with a fixed concentration of CpG‐ODN/OVA allows the comprehension of Asc16 phase behavior and could be easily adapted to other concentrations. Moreover, these findings could be extrapolated to other hydrophilic substances in aqueous solution introduced in liquid crystal phases since they follow a similar behavior as those reported in the literature.

Liquid crystal nanoparticle formulation as an oral drug delivery system for liver-specific distribution.

Liquid crystal nanoparticles have been utilized as an efficient tool for drug delivery with enhanced bioavailability, drug stability, and targeted drug delivery. However, the high energy requirements and the high cost of the liquid crystal preparation have been obstacles to their widespread use in the pharmaceutical industry. In this study, we prepared liquid crystal nanoparticles using a phase-inversion temperature method, which is a uniquely low energy process. Particles prepared with the above method were estimated to be ~100 nm in size and exhibited a lamellar liquid crystal structure with orthorhombic lateral packing. Pharmacokinetic and tissue distribution studies of a hydrophobic peptide-based drug candidate formulated with the liquid crystal nanoparticles showed a five-fold enhancement of bioavailability, sustained release, and liver-specific drug delivery compared to a host–guest complex formulation.

Development of nanotechnology-based drug delivery systems with olive vegetable oil for cutaneous application

ABSTRACT Liquid-Crystalline Systems represent active compounds delivery systems that may be able to overcome the physical barrier of the skin, especially represented by the stratum corneum. To obtain these systems, aqueous and oily components are used with surfactants. Of the different association structures in such systems, the liquid-crystalline offer numerous advantages to a topical product. This manuscript presents the development of liquid-crystalline systems consisting, in which the oil component is olive oil, its rheological characterizations, and the location of liquid crystals in its phase map. Cytotoxic effects were evaluated using J-774 mouse macrophages as the cellular model. A phase diagram to mix three components with different proportions was constructed. Two liquid crystalline areas were found with olive oil in different regions in the ternary diagram with two nonionic surfactants, called SLC1 (S1) and SLC2 (S2). These systems showed lamellar liquid crystals that remained stable during the entire analysis time. The systems were also characterized rheologically with pseudoplastic behavior without thixotropy. The texture and bioadhesion assays showed that formulations were similar statistically (p < 0.05), indicating that the increased amount of water in S2 did not interfere with the bioadhesive properties of the systems. In vitro cytotoxic assays showed that formulations did not present cytotoxicity. Olive oil-based systems may be a promising platform for skin delivery of drugs.

Solubility dynamic of methyl yellow and carbon black in microemulsions and lamellar liquid crystal of water, non ionic surfactants and cyclohexane system

Solubility dynamics of methyl yellow and carbon black in microemulsions and liquid crystals of water, non-ionic surfactants and cyclohexane system, have been investigated. Actually, solubility dynamics of these dyes both in microemulsion (w/o microemulsions) and the lamellar liquid crystal (LLC) were strongly related to the chemical composition, nature and characteristics of microemulsions and the lamellar liquid crystals.

Skin Permeation of Testosterone from Viscoelastic Lecithin Reverse Wormlike Micellar Solution.

We evaluated testosterone-containing lecithin reverse wormlike micelles (reverse worms) composed of a polar substance/lecithin/isopropyl myristate for transdermal application. Water, D-ribose, or tetraglycerol were used as the polar substance and were key ingredients for forming the reverse worms. Using the reverse worms, 1 wt% of testosterone could be stably solubilized. When using D-ribose as polar substance, the maximum zero-shear viscosity of the reverse worms solution was higher than that of systems using water or tetraglycerol as the polar substance. The mechanism of skin permeation of testosterone from reverse worms solution was elucidated using skin permeation experiments with hairless mouse skin. When the structure of the reverse worms transitioned to lamellar liquid crystals at the skin/formulation interface, testosterone became supersaturated in the formulations. The structural transition occurred in systems using water or D-ribose as the polar substance, increasing the flux of testosterone. The flux of testosterone from reverse worms solution thus depends on the type of polar substance used.

Sandwich organization of non-ionic surfactant liquid crystalline phases as induced by large inorganic K4Nb6O17 nanosheets.

While retaining its lamellar liquid crystal phase, K4Nb6O17 nanosheets were used as a template to sandwich and stabilize an alkylpoly(ethylene oxide) nonionic surfactant-water system showing monodomain (lamella) formation within the inorganic niobate sheets that appears to be not dependent on the surfactant liquid crystalline state in solution but more its concentration.

Effect of different hydrocarbons on phase behavior of dihydrogenated tallowalkyl dimethyl ammonium chloride, hydrocarbon and water

The phase behaviors of dihydrogenated tallowalkyl dimethyl ammonium chloride (DHTDMAC), water and different hydrocarbons were studied. Addition of different hydrocarbons to DHTDMAC and water system formed rich aggregates, including two liquid crystal aggregates and water in oil microemulsion. The polarity of hydrocarbon affects stability and phase behavior of hydrocarbon–DHTDMAC–water. The polar hydrocarbons, cyclohexane and benzene stabilize the phase structure. Interaction of different hydrocarbon molecules with liquid crystal phase was studied by the small angle X-ray diffraction. The results indicate that the variable hydrocarbon and water fraction penetrate into surfactant association structure with the different hydrocarbons, which affects the stability and Kraft point of surfactant aggregates. Less water penetrates into lamellar liquid crystal where more oil penetrates into the same area, which stabilizes the aggregate's phase structure.

Lamellar Liquid Crystal Improves the Skin Retention of 3-O-Ethyl-Ascorbic Acid and Potassium 4-Methoxysalicylate In Vitro and In Vivo for Topical Preparation.

The study aimed at increasing the skin retention of 3-O-ethyl-ascorbic acid (EA) and potassium 4-methoxysalicylate (4-MSK) via topical administration for effective skin-whitening. To achieve this goal, EA and 4-MSK were formulated into lamellar liquid crystalline (LLC) cream, and response surface methodology (RSM) was employed to optimize the formulation. Polarized light microscopy (PLM), differential scanning calorimetry (DSC), and rheological experiments were performed to confirm the presence of the LLC structure in the base of cream. In addition, a comparison analysis of the skin retention of the two drugs between the LLC cream and the common o/w (COW) cream was made through in vitro permeation and in vivo drug distribution experiments. As a result, the optimal formulation was defined as 1.2% of EA, 1.48% of 4-MSK, 14.05% of Schercemol™ DISM Ester (DISM) as the oil, 4.0% of Emulium® Delta as the emulsifier, and 3.0% of stearyl alcohol as the co-emulsifier. In comparison with the COW cream, the LLC cream significantly increased the skin retention of EA and 4-MSK both in vitro and in vivo. In conclusion, the LLC carrier serves as a promising choice for topical preparation by enhancing skin retention and providing desirable rheological characteristics.

Preparation and characterization of monodisperse zirconia spherical nanometer powder via lamellar liquid crystal template method

Cubic phase spherical zirconia nano-powder was prepared by a direct template route in the lamellar liquid crystal formed by polyoxyethylene tert-octylphenyl ether (Triton X-100)/sodium dodecyl sulfate (SDS)/H2O. The precursor powder and zirconia powder were characterized by XRD, FT-IR, TG/DSC, TEM, and SEM methods. Results show that the stability of the lamellar liquid crystal is controlled by NH3·H2O concentration. The size of nanoparticles is greatly affected by NH3·H2O and ZrOCl2·8H2O concentrations. The zirconia nanoparticles show narrow particle size distribution of 10–30nm.

Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice

To distinguish the lithogenic effect of the classical estrogen receptor α (ERα) from that of the G protein-coupled receptor 30 (GPR30), a new estrogen receptor, on estrogen-induced gallstones, we investigated the entire spectrum of cholesterol crystallization pathways and sequences during the early stage of gallstone formation in gallbladder bile of ovariectomized female wild-type, GPR30((-/-)), ERα((-/-)), and GPR30((-/-))/ERα((-/-)) mice treated with 17β-estradiol (E2) at 6 µg/day and fed a lithogenic diet for 12 days. E2 disrupted biliary cholesterol and bile salt metabolism through ERα and GPR30, leading to supersaturated bile and predisposing to the precipitation of cholesterol monohydrate crystals. In GPR30((-/-)) mice, arc-like and tubular crystals formed first, followed by classical parallelogram-shaped cholesterol monohydrate crystals. In ERα((-/-)) mice, precipitation of lamellar liquid crystals, typified by birefringent multilamellar vesicles, appeared earlier than cholesterol monohydrate crystals. Both crystallization pathways were accelerated in wild-type mice with the activation of GPR30 and ERα by E2. However, cholesterol crystallization was drastically retarded in GPR30((-/-))/ERα((-/-)) mice. We concluded that E2 activates GPR30 and ERα to produce liquid crystalline versus anhydrous crystalline metastable intermediates evolving to cholesterol monohydrate crystals from supersaturated bile. GPR30 produces a synergistic lithogenic action with ERα to enhance E2-induced gallstone formation.

Study on the Thermal Stability of Viscoelastic Surfactant-Based Fluids Bearing Lamellar Structures

A detailed study has been done on the phase behavior and rheological properties of viscoelastic surfactant (VES)-based fracturing fluids bearing lamellar liquid crystal structures that are developed from two surfactants (SDS and NaOA) and three co-surfactants (propan-2-ol, iso-amyl alcohol, and 2-ethyl hexanol) in the presence of clove oil as the organic phase and water as the aqueous phase. Lamellar liquid crystals prepared from NaOA/2-ethyl hexanol/clove oil/water system demonstrated the best viscoelastic properties among all the developed fluids, because it exhibited resistance to high temperature and shear conditions. The addition of alkali and nanoparticles enhanced the viscoelastic properties, which were observed from static and dynamic rheological tests.

The Effect of Electroporation of a Lyotroic Liquid Crystal Genistein-Based Formulation in the Recovery of Murine Melanoma Lesions.

A lamellar lyotropic liquid crystal genistein-based formulation (LLC-Gen) was prepared in order to increase the aqueous solubility of the lipophilic phytocompound genistein. The formulation was applied locally, in a murine model of melanoma, with or without electroporation. The results demonstrated that, when the formulation was applied by electroporation, the tumors appeared later. During the 21 days of the experiment, the LLC-Gen formulation decreased the tumor volume, the amount of melanin and the degree of erythema, but when electroporation was applied, all these parameters indicated a better prognosis even (lower tumor volume, amount of melanin and degree of erythema). Although hematoxylin–eosin (HE) staining confirmed the above events, application of the LLC-Gen formulation by electroporation did not lead to a significant effect in terms of the serum concentrations of the protein S100B and serum neuron specific enolase (NSE), or the tissue expression of the platelet-derived growth factor receptor β (PDGFRβ) antibody.

Effect of water soluble molecules on the stability and flexibility of lyotropic lamellar structures. Polymer molecular weight influence

Two neutral hydrophilic substances, acrylamide and the corresponding homopolymer, polyacrylamide, with different molecular weights, have been incorporated in the lamellar liquid crystal formed by the anionic surfactant sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and water. The study of the elastic properties of the lamellae, through the analysis of the power law exhibited by the Bragg peaks, indicates that the presence of monomer does not modify the interaction between the lamellae until near the macroscopic phase separation, whereas the progressive incorporation of polymer weakens the effective interlaying interaction. A fraction of acrylamide lower than 5wt% can be solubilized into the lamellar structures and at higher concentrations a macroscopic phase separation occurs. Regarding the polymers, it has been shown that only the chains with coil sizes smaller than the water layer thickness are dissolved between the lamellae, while larger chains segregate with part of the water developing an isotropic phase. Combining small angle X-ray scattering data and the distribution of macromolecular sizes, obtained by size exclusion chromatography, the fraction of polymer excluded from the lamellae has been estimated.