Rational Design, Synthesis, and Characterization of a Solid Δ9-Tetrahydrocannabinol Nanoformulation Suitable for "Microdosing" Applications.

Background: This article highlights the formulation of a solid Δ9-tetrahydrocannabinol (THC)-loaded ingestible prepared from pure THC distillate. Methods: A THC-containing ethanol-assisted cannabinoid nanoemulsion (EACNE) was created using a solvent displacement technique. Subsequently, the EACNE was converted to a solid powdery material while still retaining its THC potency, a format uniquely suited for "microdosing" applications. Results: EACNE had an average lipid droplet size of ∼190 nm, with a polydispersity index of 0.15, and an average droplet ζ potential of -49±10 mV. The nanoemulsion (NE) was colloidally stable for at least 6 weeks, with no meaningful change in cannabinoid potency over the experimental period, as determined by high-performance liquid chromatography analysis. The EACNE remained stable when subjected to physical stresses such as heat, freeze/thaw cycles, carbonation, dilution to beverage concentrations, high sucrose concentrations, and a pH range between 5 and 8. The microencapsulated EACNE demonstrated limited free-flowing behavior but was freely redispersible in water without any visible phase separation. Conclusions: We report the design, creation, and characterization of a THC NE generated without the use of specialized equipment, such as a microfluidizer or a high-pressure homogenizer. This emulsion could readily be converted to a water-redispersible powder. This embodiment is particularly suited for THC "microdosing," a practice that might decouple the health benefits of THC from its psychotropic effects.

"Breaking bud": the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential.

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two "major cannabinoids". However, their incorporation into clinical and nutraceutical preparations is challenging, owing to their limited bioavailability, low water solubility, and variable pharmacokinetic profiles. Understanding the organic chemistry of the major cannabinoids provides us with potential avenues to overcome these issues through derivatization. The resulting labile pro-drugs offer ready cannabinoid release in vivo, have augmented bioavailability, or demonstrate interesting pharmacological properties in their own right. This review identifies and discusses a subset of these advanced derivatization strategies for the major cannabinoids, where the starting material is the pure phytocannabinoid itself, and the final product either a cannabinoid pro-drug, or a novel pharmacoactive material.

Synthesis, characterization and stress-testing of a robust quillaja saponin stabilized oil-in-water phytocannabinoid nanoemulsion.

BACKGROUND: This study describes the design, optimization, and stress-testing of a novel phytocannabinoid nanoemulsion generated using high-pressure homogenization. [Formula: see text], a plant-derived commercial emulsifier containing quillaja saponin, was used to stabilize the lipid phase droplets in water. Stress-testing was performed on this nanoemulsion in order to evaluate its chemical and colloidal stability under the influence of different environmental factors, encompassing both physical and chemical stressors. METHODS: Extensive optimization studies were conducted to arrive at an ideal nanoemulsion formulation. A coarse emulsion containing 16.6 wt% CBD-enriched cannabis distillate and 83.4 wt% carrier (soybean) oil dispersed in 10 wt% [Formula: see text] (1.5 wt% quillaja saponin) solution after 10 homogenization cycles at a pressure of 30,000 psi produced a stable nanoemulsion. This nanoemulsion was then subjected to the stress studies. RESULTS: The optimized nanoemulsion had an average droplet diameter of ca. 120 nm and average droplet surface ζ potentials of ca. -30 mV. It was imaged and characterized by a variety of protocols. It proved to be stable to droplet agglomeration and phase separation upon storage under ambient conditions for 6 weeks, as well as under a variety of physical stressors such as heat, cold, dilution, and carbonation. pH values ≤2 and moderately high salt concentrations (> 100 mM), however, destabilized the nanoemulsion, eventually leading to phase separation. Cannabis potency, determined by HPLC, was detrimentally affected by any changes in the nanoemulsion phase stability. CONCLUSIONS: Quillaja saponin stabilized cannabidiol(CBD)-enriched nanoemulsions are stable, robust systems even at low emulsifier concentrations, and are therefore significant from both a scientific as well as a commercial perspective.

Cannabinoids and Cannabinoid Receptors: The Story so Far.

Like most modern molecular biology and natural product chemistry, understanding cannabinoid pharmacology centers around molecular interactions, in this case, between the cannabinoids and their putative targets, the G-protein coupled receptors (GPCRs) cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Understanding the complex structure and interplay between the partners in this molecular dance is required to understand the mechanism of action of synthetic, endogenous, and phytochemical cannabinoids. This review, with 91 references, surveys our understanding of the structural biology of the cannabinoids and their target receptors including both a critical comparison of the extant crystal structures and the computationally derived homology models, as well as an in-depth discussion about the binding modes of the major cannabinoids. The aim is to assist in situating structural biochemists, synthetic chemists, and molecular biologists who are new to the field of cannabis research.

Three Sequential Hydrolysis Products of the Ubiquitous Cu24 Isophthalate Metal-Organic Polyhedra.

Metal-organic polyhedra (MOPs) are increasingly studied as host-guest capsules, linked into networks, or incorporated into composite materials. As such, understanding the decomposition of MOP structures is of fundamental importance. The degradation of the ubiquitous copper(II) MOP Cu24[5-(hydroxy)isophthalate]24 (1) is studied in liquid water. At different intervals of water exposure, powder X-ray diffraction (PXRD) is performed and stepwise conversion of the MOP into three different coordination polymers is observed. First, the formation of a 2D coordination polymer, 2, is observed, which upon further exposure gives a 1D coordination polymer, 3, and finally a trinuclear copper(II) complex, 4. Compound 2 is characterized by PXRD owing to its transient nature, while 3 and 4 are characterized crystallographically. The final structure, 4, contains copper(II) trimers, and so its magnetic behavior is also investigated.

Bifunctional Pyrrolidin-2-one Terminated Manganese Oxide Nanoparticles for Combined Magnetic Resonance and Fluorescence Imaging.

Multimodal probes are an asset for simplified, improved medical imaging. In particular, fluorescence and magnetic resonance imaging (MRI) are sought-after combined capabilities. Here, we show that pyrrolidin-2-one-capped manganese oxide nanoparticles (MnOpyrr NPs) combine MRI with fluorescence microscopy to function as efficient bifunctional bio-nanoprobes. We employ a one-pot synthesis for ca. 10 nm MnO NPs, wherein manganese(II) 2,4-pentadionate is thermally decomposed using pyrrolidin-2-one as a solvent and capping ligand. The MnOpyrr NPs are soluble in water without any further postsynthetic modifications. The r1 relaxivity and r2 /r1 ratio indicate that these NPs are potential T1 MRI contrast agents at clinical (3 T) and ultrahigh (9.4 T) magnetic fields. Serendipitously, the as-prepared NPs are photoluminescent. The unexpected luminescence is ascribed to the modification of the pyrrolidin-2-one during the thermal treatment. MnOpyrr NPs are successfully used to enable fluorescence microscopy of HeLa cells, demonstrating bifunctional imaging capabilities. A low cytotoxic response in two distinct cell types (HeLa, HepG2) supports the suitability of MnOpyrr NPs for biological imaging applications.

Spectroscopic and photophysical study of the demetallation of a zinc porphyrin and the aggregation of its free base in a tetraalkylphosphonium ionic liquid.

Dissolving zinc tetraphenylporphyrin in the tetraalkylphosphonium chloride ionic liquid P4448Cl results in progressive demetallation of the solute and quantitative production of the free base porphyrin. Aggregation of the free base occurs in which the monomer and J aggregates are in fully reversible thermal equilibrium in the ionic liquid. The thermodynamic, kinetic and spectroscopic behaviour of this system is described based on absorption, emission and excited state lifetime measurements. Both the thermodynamics of the ground state aggregation and the kinetics of the excited state relaxation processes are unusual due to the particular role played by the ionic liquid solvent.

Redispersion of transition metal nanoparticle catalysts in tetraalkylphosphonium ionic liquids.

Despite the fact that particle sintering is one of the most common events leading to the deactivation of metal nanoparticle (NP) catalysts, there is a paucity of studies investigating potential routes for the regeneration of smaller, catalytically active nanoparticles from larger particles formed after repeated catalytic cycles. Here, we reveal a simple yet elegant technique for the 'redispersion' of sintered NPs in tetraalkylphosphonium halide ionic liquids (ILs). The procedure described can use environmentally benign oxidants, be carried out at mild temperatures, and is shown to be applicable to a large number of catalytically important transition metals. TEM and UV-Vis spectroscopy reveal that this methodology can indeed regenerate smaller NPs from sintered systems. A sample catalytic reaction reveals that the redispersed NPs are as catalytically active as they were prior to sintering.

Highly stable noble-metal nanoparticles in tetraalkylphosphonium ionic liquids for in situ catalysis.

Gold and palladium nanoparticles were prepared by lithium borohydride reduction of the metal salt precursors in tetraalkylphosphonium halide ionic liquids in the absence of any organic solvents or external nanoparticle stabilizers. These colloidal suspensions remained stable and showed no nanoparticle agglomeration over many months. A combination of electrostatic interactions between the coordinatively unsaturated metal nanoparticle surface and the ionic-liquid anions, bolstered by steric protection offered by the bulky alkylated phosphonium cations, is likely to be the reason behind such stabilization. The halide anion strongly absorbs to the nanoparticle surface, leading to exceptional nanoparticle stability in halide ionic liquids; other tetraalkylphosphonium ionic liquids with non-coordinating anions, such as tosylate and hexafluorophosphate, show considerably lower affinities towards the stabilization of nanoparticles. Palladium nanoparticles stabilized in the tetraalkylphosphonium halide ionic liquid were stable, efficient, and recyclable catalysts for a variety of hydrogenation reactions at ambient pressures with sustained activity. Aerial oxidation of the metal nanoparticles occurred over time and was readily reversed by re-reduction of oxidized metal salts.