A general carbonyl alkylative amination for tertiary amine synthesis.

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3-9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10-14. However, despite extensive efforts, the successful realization of a 'carbonyl alkylative amination' has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.

Microliquid/Liquid Interfacial Sensors: Biomimetic Investigation of Transmembrane Mechanisms and Real-Time Determinations of Clemastine, Cyproheptadine, Epinastine, Cetirizine, and Desloratadine.

Antihistamines relieve allergic symptoms by inhibiting the action of histamine. Further understanding of antihistamine transmembrane mechanisms and optimizing the selectivity and real-time monitoring capabilities of drug sensors is necessary. In this study, a micrometer liquid/liquid (L/L) interfacial sensor has served as a biomimetic membrane to investigate the mechanism of interfacial transfer of five antihistamines, i.e., clemastine (CLE), cyproheptadine (CYP), epinastine (EPI), desloratadine (DSL), and cetirizine (CET), and realize the real-time determinations. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques have been used to uncover the electrochemical transfer behavior of the five antihistamines at the L/L interface. Additionally, finite element simulations (FEMs) have been employed to reveal the thermodynamics and kinetics of the process. Visualization of antihistamine partitioning in two phases at different pH values can be realized by ion partition diagrams (IPDs). The IPDs also reveal the transfer mechanism at the L/L interface and provide effective lipophilicity at different pH values. Real-time determinations of these antihistamines have been achieved through potentiostatic chronoamperometry (I-t), exhibiting good selectivity with the addition of nine common organic or inorganic compounds in living organisms and revealing the potential for in vivo pharmacokinetics. Besides providing a satisfactory surrogate for studying the transmembrane mechanism of antihistamines, this work also sheds light on micro- and nano L/L interfacial sensors for in vivo analysis of pharmacokinetics at a single-cell or single-organelle level.

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery.

Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-dependent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1-7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post-surgery, with 84-88% decreased Cmax, 28-36% decreased Fa, and 24-31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.

Nanosized-Loratadine Embedded Orodispersible Films for Enhanced Bioavailability: Scalable Preparations and Characterizations.

The patient-centric strategy urges the pharmaceutical companies to develop orodispersible films (ODF) as a new approach for pediatrics. However, the most common ODF-fabricated method, solvent casting, is facing the safety challenges of safety during manufacturing. To obtain favorable formulations with the ease of use and rapid dissolution, nanotechnology has been accounted for the development process. In this work, we investigated the wet-milling technique in preparing nanocarriers for loratadine-a hydrophobic anti-histamine drug. The results showed that the wet-milling technique could produce nanocarriers at the size of 400 nm. The reduction of particle size induced the increase of solubility and the dissolution rate of loratadine. Moreover, the pre-formulation of nanosized materials could adapt to the preparation of orodispersible films that disintegrated (less than 60s) and dissolved quickly. The DSC results showed that after the milling process, the crystallinity of loratadine was unchanged; however, the reduction in size induced an enhancement of drug bioavailability. After orally administrated to rats, the drug was quickly reached to the blood circulation, just after 30 min. Cmax increased from 44.97 ng/mL for the raw drug to 101.02 ng/mL for the nanocrystal leading to an enhancement of the AUC0-24h by 5.69-fold when the nanocrystal ODF was administrated. The ease of formulation and the improvement of drug solubility as well as bioavailability potentiated orodispersible films as a promising drug delivery for loratadine. Graphical abstract.

Computational and Experimental Models of Type III Lipid-Based Formulations of Loratadine Containing Complex Nonionic Surfactants.

Type III lipid-based formulations (LBFs) combine poorly water-soluble drugs with oils, surfactants, and cosolvents to deliver the drugs into the systemic circulation. However, the solubility of the drug can be influenced by the colloidal phases formed in the gastrointestinal tract as the formulation is dispersed and makes contact with bile and other materials present within the GI tract. Thus, an understanding of the phase behavior of LBFs in the gut is critical for designing efficient LBFs. Molecular dynamics (MD) simulation is a powerful tool for the study of colloidal systems. In this study, we modeled the internal structures of five type III LBFs of loratadine containing poly(ethylene oxide) nonionic surfactants polysorbate 80 and polyoxyl hydrogenated castor oil (Kolliphor RH40) using long-timescale MD simulations (0.4-1.7 µs). We also conducted experimental investigations (dilution of formulations with water) including commercial Claritin liquid softgel capsules. The simulations show that LBFs form continuous phase, water-swollen reverse micelles, and bicontinuous and phase-separated systems at different dilutions, which correlate with the experimental observations. This study supports the use of MD simulation as a predictive tool to determine the fate of LBFs composed of medium-chain lipids, polyethylene oxide surfactants, and polymers.

Increasing Angiogenesis Factors in Hypoxic Diabetic Wound Conditions by siRNA Delivery: Additive Effect of LbL-Gold Nanocarriers and Desloratadine-Induced Lysosomal Escape.

Impaired wound healing in people with diabetes has multifactorial causes, with insufficient neovascularization being one of the most important. Hypoxia-inducible factor-1 (HIF-1) plays a central role in the hypoxia-induced response by activating angiogenesis factors. As its activity is under precise regulatory control of prolyl-hydroxylase domain 2 (PHD-2), downregulation of PHD-2 by small interfering RNA (siRNA) could stabilize HIF-1α and, therefore, upregulate the expression of pro-angiogenic factors as well. Intracellular delivery of siRNA can be achieved with nanocarriers that must fulfill several requirements, including high stability, low toxicity, and high transfection efficiency. Here, we designed and compared the performance of layer-by-layer self-assembled siRNA-loaded gold nanoparticles with two different outer layers-Chitosan (AuNP@CS) and Poly L-arginine (AuNP@PLA). Although both formulations have exactly the same core, we find that a PLA outer layer improves the endosomal escape of siRNA, and therefore, transfection efficiency, after endocytic uptake in NIH-3T3 cells. Furthermore, we found that endosomal escape of AuNP@PLA could be improved further when cells were additionally treated with desloratadine, thus outperforming commercial reagents such as Lipofectamine® and jetPRIME®. AuNP@PLA in combination with desloratadine was proven to induce PHD-2 silencing in fibroblasts, allowing upregulation of pro-angiogenic pathways. This finding in an in vitro context constitutes a first step towards improving diabetic wound healing with siRNA therapy.

Asymmetric Catalysis upon Helically Chiral Loratadine Analogues Unveils Enantiomer-Dependent Antihistamine Activity.

Analogues of the conformationally dynamic Claritin (loratadine) and Clarinex (desloratadine) scaffolds have been enantio- and chemoselectively N-oxidized using an aspartic acid containing peptide catalyst to afford stable, helically chiral products in up to >99:1 er. The conformational dynamics and enantiomeric stability of the N-oxide products have been investigated experimentally and computationally with the aid of crystallographic data. Furthermore, biological assays show that rigidifying the core structure of loratadine and related analogues through N-oxidation affects antihistamine activity in an enantiomer-dependent fashion. Computational docking studies illustrate the observed activity differences.

Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs.

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.

Molecular Origin of the Distinct Tabletability of Loratadine and Desloratadine: Role of the Bonding Area - Bonding Strength Interplay.

PURPOSE: To explain the different tabletability of two structurally similar H1-receptor antihistamine drugs, loratadine (LOR) and desloratadine (DES), based on the molecular basis of bonding area and bonding strength. METHODS: LOR and DES were characterized by powder X-ray diffractometry, thermal analysis, and dynamic water sorption. The compressibility, tabletability, compactibility, and Heckel analysis of their bulk powders and formulations were evaluated. A combined energy framework and topological analysis was used to characterize the crystal structure - mechanical property relationship. Surface energy of bulk powder was assessed by contact angle measurement using the Owens/Wendt theory. RESULTS: Both LOR and DES bulk powders are phase pure and stable under compaction. The superior tabletability of LOR is attributed to both larger bonding area (BA) and higher interparticle bonding strength (BS). The larger BA of LOR results from its experimentally established higher plasticity, which is explained by the presence of more densely packed molecular layers with smooth surface topology. The higher BS of LOR corresponded to its significantly higher dispersive component of the surface energy. CONCLUSIONS: This work provides new insights into the molecular origins of BA and BS, which can be applied to improve mechanical properties and tableting performance of drugs through appropriate crystal engineering.

Design, synthesis and biological evaluation of novel desloratadine derivatives with anti-inflammatory and H1 antagonize activities.

To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H1 antagonistic activities. Among them, compound 2c showed the strongest H1 antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.

Design, synthesis and bioevaluation of tricyclic fused ring system as dual binding site acetylcholinesterase inhibitors.

Due to recently discovered non-classical acetylcholinesterase (AChE) function, dual binding-site AChE inhibitors have acquired a paramount attention of drug designing researchers. The unique structural arrangements of AChE peripheral anionic site (PAS) and catalytic site (CAS) joined by a narrow gorge, prompted us to design the inhibitors that can interact with dual binding sites of AChE. Eighteen homo- and heterodimers of desloratadine and carbazole (already available tricyclic building blocks) were synthesized and tested for their inhibition potential against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE). We identified a six-carbon tether heterodimer of desloratadine and indanedione based tricyclic dihydropyrimidine (4c) as potent and selective inhibitor of eeAChE with IC50 value of 0.09 ±â€¯0.003 µM and 1.04 ±â€¯0.08 µM (for eqBChE) with selectivity index of 11.1. Binding pose analysis of potent inhibitors suggest that tricyclic ring is well accommodated into the AChE active site through hydrophobic interactions with Trp84 and Trp279. The indanone ring of most active heterodimer 4b is stabilized into the bottom of the gorge and forms hydrogen bonding interactions with the important catalytic triad residue Ser200.

Ecotoxic effects of loratadine and its metabolic and light-induced derivatives.

Loratadine and desloratadine are second-generation antihistaminic drugs. Because of human administration, they are continuously released via excreta into wastewater treatment plants and occur in surface waters as residues and transformation products (TPs). Loratadine and desloratadine residues have been found at very low concentrations (ng/L) in the aquatic environment but their toxic effects are still not well known. Both drugs are light-sensitive even under environmentally simulated conditions and some of the photoproducts have been isolated and characterized. The aim of the present study was to investigate the acute and chronic ecotoxicity of loratadine, desloratadine and their light-induced transformation products in organisms of the aquatic trophic chain. Bioassays were performed in the alga Pseudokirchneriella subcapitata, the rotifer Brachionus calyciflorus and in two crustaceans, Thamnocephalus platyurus and Ceriodaphnia dubia. Loratadine exerted its acute and chronic toxicity especially on Ceriodaphnia dubia (LC50: 600 µg/L, EC50: 28.14 µg/L) while desloratadine showed similar acute toxicity among the organisms tested and it was the most chronically effective compound in Ceriodaphnia dubia and Pseudokirchneriella subcapitata. Generally, transformation products were less active in both acute and chronic assays.

Report: A comparative study of loratidine physiochemical properties from different brands.

Loratidine is a piperidine derivative resemble to azatadine long acting non sedating commonly used for the treatment of allergic condition like watery or itchy eyes, runny nose, chronic urticaria or throat itching. In the present study different brands of loratidine were evaluated for the weight variation, hardness, friability, disintegration time and dissolution. Dissolution release study performed by using paddle method (USP 2) in 900 ml of 0.1N HCl at 50 rpm. The physicochemical of loratidine did not give any variation. By this study we conclude that all parameter for physicochemical properties like weight variation, hardness of tablets, friability, their disintegration time and the dissolution release study for all the brands of loratidine that are available in Karachi meet the British pharmacopoeia (BP) and United State pharmacopoeia (USP) specification for quality control analysis.Weight variation, hardness and friability value requirement was complied by all brands .Disintegration time for all brands was less than 15 minutes complying the BP/USP recommendation. All brands showed more than 80% drug release within 45 minutes. The present findings suggest that almost all the brands of loratidine meet the BP/USP specification for QC analysis.

Interaction of Approved Drugs with Synaptic Vesicle Protein 2A.

Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [3 H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 µM. Subsequent concentration-inhibition curves revealed the antihistaminic prodrug loratadine (Ki = 1.16 µM) and the antimalarial drug quinine (Ki = 2.03 µM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (Ki = 1.74 µM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure-activity relationships were determined. The anti-convulsive effects of the natural product quinine may - at least in part - be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development.

Coamorphous Loratadine-Citric Acid System with Enhanced Physical Stability and Bioavailability.

Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T g over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T g over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.

PREPARATION AND CHARACTERIZATION OF ORALLY DISINTEGRATING LORATADINE TABLETS MANUFACTURED WITH CO-PROCESSED MIXTURES.

The aim of this study was to develop orally disintegrated tablets (ODT) with loratadine using Parteck ODT and Ludiflash--new commercially available tableting excipients based on co-processed mannitol. ODT containing loratadine were prepared with 3% addition of various superdisintegrants (AcDiSol, Kollidon CL-F and Kollidon CL-SF) by direct compression method. Obtained tablets were characterized for friability, pore structure, and wetting and disintegration time measured by four independents methods. In order to identify possible interactions between loratadine and the excipients, differential scanning calorimetry was used. The results showed that all formulated ODT were characterized by appropriate mechanical properties (friability < 1%), the uniform content of the drug substance and pleasant mouth feeling. Disintegration time below 30 s was observed in formulations with crospovidones as disintegrant.

Synthesis of (18) F-Difluoromethylarenes from Aryl (Pseudo) Halides.

A general method for the synthesis of [(18) F]difluoromethylarenes from [(18) F]fluoride for radiopharmaceutical discovery is reported. The method is practical, operationally simple, tolerates a wide scope of functional groups, and enables the labeling of a variety of arenes and heteroarenes with radiochemical yields (RCYs, not decay-corrected) from 10 to 60 %. The (18) F-fluorination precursors are readily prepared from aryl chlorides, bromides, iodides, and triflates. Seven (18) F-difluoromethylarene drug analogues and radiopharmaceuticals including Claritin, fluoxetine (Prozac), and [(18) F]DAA1106 were synthesized to show the potential of the method for applications in PET radiopharmaceutical design.

Loratadine analogues as MAGL inhibitors.

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24 µM) and 35-fold higher selectivity over human α/ß-hydrolase-6 (hABHD6, IC50=1.79 µM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽ 10 µM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

Similar substrate specificity of cynomolgus monkey cytochrome P450 2C19 to reported human P450 2C counterpart enzymes by evaluation of 89 drug clearances.

Cynomolgus monkeys are used widely in preclinical studies as non-human primate species. The amino acid sequence of cynomolgus monkey cytochrome P450 (P450 or CYP) 2C19 is reportedly highly correlated to that of human CYP2C19 (92%) and CYP2C9 (93%). In the present study, 89 commercially available compounds were screened to find potential substrates for cynomolgus monkey CYP2C19. Of 89 drugs, 34 were metabolically depleted by cynomolgus monkey CYP2C19 with relatively high rates. Among them, 30 compounds have been reported as substrates or inhibitors of, either or both, human CYP2C19 and CYP2C9. Several compounds, including loratadine, showed high selectivity to cynomolgus monkey CYP2C19, and all of these have been reported as human CYP2C19 and/or CYP2C9 substrates. In addition, cynomolgus monkey CYP2C19 formed the same loratadine metabolite as human CYP2C19, descarboethoxyloratadine. These results suggest that cynomolgus monkey CYP2C19 is generally similar to human CYP2C19 and CYP2C9 in its substrate recognition functionality.

Dissolution evaluation in vitro and bioavailability in vivo of self-microemulsifying drug delivery systems for pH-sensitive drug loratadine.

The aim of this study was to improve the oral absorption of loratadine, a pH-sensitive drug, by self-microemulsifying drug delivery systems (SMEDDSs). The optimal SMEDDS was analysed and evaluated after emulsification in distilled water with diameter of 26.57 ± 0.71 nm and zeta potential of -30.5 ± 4.5 mV. Dissolution experiments in vitro were carried out in different released media of pH values and the SMEDDS formulations were able to release loratadine completely in different media while market tablets just performed similarly in the media of pH 1.2. Furthermore, the oral bioavailability and the pharmacokinetic behaviour of loratadine formulations in vivo were studied after a single dose of 1 mg/kg loratadine in beagle dogs. The SMEDDS formulations displayed higher Cmax and AUC, approximately 9 and 5 times increase than those of market tablets (p < 0.01) respectively. These results demonstrated that SMEDDS formulations had significantly increased the oral absorption of loratadine in beagle dogs.