Development of direct compression Acetazolamide tablet with improved bioavailability in healthy human volunteers enabled by cocrystallization with p-Aminobenzoic acid.

Pharmaceutical cocrystallization has been widely used to improve physicochemical properties of APIs. However, developing cocrystal formulation with proven clinical success remains scarce. Successful translation of a cocrystal to suitable dosage forms requires simultaneously improvement of several deficient physicochemical properties over the parent API, without deteriorating other properties critical for successful product development. In the present work, we report the successful development of a direct compression tablet product of acetazolamide (ACZ), using a 1:1 cocrystal of acetazolamide with p-aminobenzoic acid (ACZ-PABA). The ACZ-PABA tablet exhibits superior biopharmaceutical performance against the commercial tablet, DIAMOX® (250 mg), in healthy human volunteers, leading to more than 50 % reduction in the required dose.

Exploring the Antibacterial Potential of Semisynthetic Phytocannabinoid: Tetrahydrocannabidiol (THCBD) as a Potential Antibacterial Agent against Sensitive and Resistant Strains of Staphylococcus aureus.

Antimicrobial resistance (AMR) is one of the most challenging problems and is responsible for millions of deaths every year. We therefore urgently require new chemical entities with novel mechanisms of action. Phytocannabinoids have been adequately reported for the antimicrobial effect but not seriously pursued because of either stringent regulatory issues or poor drug-like properties. In this regard, the current work demonstrated the antibacterial potential of tetrahydrocannabidiol (THCBD, 4), a semisynthetic phytocannabinoid, against Staphylococcus aureus, the second-most widespread bug recognized by the WHO. THCBD (4) was generated from cannabidiol and subjected to extensive antibacterial screening. In in vitro studies, THCBD (4) demonstrated a potent MIC of 0.25 µg/mL against Gram-positive bacteria, S. aureus ATCC-29213. It is interesting to note that THCBD (4) has demonstrated strong effectiveness against efflux pump-overexpressing (SA-1199B, SA-K2191, SA-K2192, and Mupr-1) and multidrug-resistant (MRSA-15187) S. aureus strains. THCBD (4) has also shown a good effect in kill kinetic assays against ATCC-29213 and MRSA-15187. In the checkerboard assay, THCBD (4) has shown additive/indifference effects with several well-known clinically used antibiotics, tetracycline, mupirocin, penicillin G, and ciprofloxacin. THCBD (4) also exhibited good permeability in the artificial skin model. Most importantly, THCBD (4) has significantly reduced CFU in mice's in vivo skin infection models and also demonstrated decent plasma exposure with 16-17% oral bioavailability. Acute dermal toxicity of THCBD (4) suggests no marked treatment-related impact on gross pathophysiology. This attractive in vitro and in vivo profile of plant-based compounds opens a new direction for new-generation antibiotics and warrants further detailed investigation.

Tuning Caco-2 permeability by cocrystallization: Insights from molecular dynamics simulation.

Emerging evidence suggests that intestinal permeability can be potentially enhanced through cocrystallization. However, a mechanism for this effect remains to be established. In this study, we first demonstrate the enhancement in intestinal permeability, evaluated by the Caco-2 cell permeability assay, of acetazolamide (ACZ) in the presence of a conformer, p-aminobenzoic acid (PABA), delivered in the form of a 1:1 cocrystal. The binding strength of ACZ and PABA with the Pgp efflux transporter, either alone or as a mixture, was calculated using molecular dynamics simulation. Results show that PABA weakens the binding of ACZ with Pgp, which leads to a lower efflux ratio and elevated permeability of ACZ. This work provides molecular-level insights into a potentially effective strategy to improve the intestinal permeability of drugs. If the same cocrystal also exhibits higher solubility, oral bioavailability of BCS IV drugs can likely be improved by forming a cocrystal with a Pgp inhibitor.

Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation.

The significance of stereoselective C-H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.

Study on Sulfamethoxazole-Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties.

Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

Mechanosynthesis of Stable Salt Hydrates of Allopurinol with Enhanced Dissolution, Diffusion, and Pharmacokinetics.

Allopurinol (ALO) is a medication that treats gout and kidney stones by lowering uric acid synthesis in the blood. The biopharmaceutics classification system (BCS) IV drug exhibits poor aqueous solubility, permeability, and bioavailability. To overcome the bottlenecks of ALO, salts with maleic acid (MLE) and oxalic acid (OXA) were synthesized using the solvent-assisted grinding method. The novel multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SEM images. The crystal structures of these salts with variable stoichiometry were obtained using Rietveld refinement from the high-resolution PXRD data. The proton from the dicarboxylic acid is transferred to the most basic pyrimidine "N" of ALO. The N-H···N hydrogen-bonded ALO homodimer is replaced by the N+-H···O- ionic interactions in ALO-OXA (2:1:0.4) and ALO-MLE (1:1:1) salt hydrates. The organic salts improved solubility and dissolution up to 5-fold and the diffusion permeability up to 12 times compared to the native drug in a luminal pH 6.8 phosphate buffer medium. The salt hydrates were exceptionally stable during storage at 30 ± 5 °C and 75 ± 5% relative humidity. Superior dissolution and diffusion permeability of the ALO-MLE salt resulted in improved pharmacokinetics (peak plasma concentration) that offers a promising solid dosage form with enhanced bioavailability and lower dosage formulation.

Access to unsaturated bicyclic lactones by overriding conventional C(sp3)-H site selectivity.

Transition metal catalysis plays a pivotal role in transforming unreactive C-H bonds. However, regioselective activation of distal aliphatic C-H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C-H bond in the presence of methyl C-H is underexplored. Here we show activation of a methylene C-H bond in the presence of methyl C-H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C-H bond activation. Computational studies suggest that reversible C-H activation is followed by ß-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C-O cyclization, and subsequent ß-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C-H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.

Synthesis and Evaluation of Metal Lipoate Adhesives.

The development of new bioadhesives with integrated properties remains an unmet clinical need to replace staples or sutures. Current bioadhesives do not allow electronic activation, which would allow expansion into laparoscopic and robotic surgeries. To address this deficiency, voltage-activated adhesives have been developed on both carbene- and catechol-based chemical precursors. Herein, a third platform of voltage-activated adhesive is evaluated based on lipoic acid, a non-toxic dithiolane found in aerobic metabolism and capable of ring-opening polymerization. The electro-rheological and adhesive properties of lithium, sodium, and potassium salts of lipoic acid are applied for wet tissue adhesion. At ambient conditions, potassium lipoate displays higher storage modulus than lithium or sodium salt under similar conditions. Voltage stimulation significantly improves gelation kinetics to Na- and K-lipoates, while Li-lipoate is found to not require voltage stimulation for gelation. Lap shear adhesion strength on wetted collagen substrates reveals that the synthetic metal lipoates have comparable adhesion strength to fibrin sealants without viral or ethical risks.

Broad Dual Emission by Codoping Cr3+ (d→d) and Bi3+ (s→p) in Cs2 Ag0.6 Na0.4 InCl6 Double Perovskite.

A phosphor emitting both white light and broad near-infrared (NIR) radiation can simultaneously provide visual inspection and early signs of rotting of food products. The broad NIR emission is absorbed by the vibrational overtones of water molecules present in food items, providing the non-invasive image contrast to assess the food freshness. Here we design a phosphor, namely, Cr3+ -Bi3+ -codoped Cs2 Ag0.6 Na0.4 InCl6 , that simultaneously emit warm white light and broad NIR (1000 nm) radiation with quantum yield 27 %. This dual emitter is designed by combining the features of s2 -electron (Bi3+ ) and d3 -electron (Cr3+ ) doping in a weak crystal field of the halide perovskite host. 6 s 2 → 6 s 1 6 p 1 ${6{s}^{2}\to 6{s}^{1}6{p}^{1}}$ excitation of Bi3+ , using a commercial 370 nm ultraviolet light-emitting-diodes (UV-LED), yields both the emissions. A fraction of the excited Bi3+ dopants emit the warm white light, and the other fraction transfers its energy non-radiatively to Cr3+ . Then the Cr3+ de-excites emitting broad NIR emission. Temperature dependent (6.4-300 K) photoluminescence in combination with Tanabe-Sugano diagram show that the Cr3+ experiences a weak crystal field ( D q / B ${{D}_{q}/B}$ =2.2), yielding the 4 T 2 → 4 A 2 ${{{\rm \ }}^{4}{{\rm T}}_{2}\to {{\rm \ }}^{4}{{\rm A}}_{2}}$ NIR emission. As a proof of concept, we fabricated a panel containing 122 phosphor-converted LEDs, demonstrating its capability to inspect food products.

Development of ezetimibe eutectic with improved biopharmaceutical and mechanical properties to design an optimized oral solid dosage formulation.

Eutectics are multicomponent systems which are an alternative to the conventional techniques for modulating the biopharmaceutical properties of a pharmaceutical. Ezetimibe (ETZ) is a hypocholesterolemic agent with limited dissolution, poor water solubility, and subsequently demonstrates low oral bioavailability. Additionally, ETZ exhibits poor mechanical properties, leading to difficulties in developing dosage forms through direct compression. The present work highlights the applicability of eutectics in the simultaneous improvement of physicochemical along with mechanical properties of ETZ. A pharmaceutical eutectic of ETZ with succinimide (SUC) was prepared by mechanochemical grinding and thoroughly characterized using thermoanalytical, X-ray diffraction, and spectroscopic methods. Intrinsic dissolution rate and pharmacokinetic analysis were also performed for ezetimibe-succinimide (ETZ-SUC) eutectic in contrast to pure ETZ. The eutectic demonstrated ∼2-fold increase in the solubility and dissolution rate. In pharmacokinetic studies, the area under the curve (AUC) for ETZ-SUC eutectic (28.03 ± 2.22 ng*h/mL) was found to be higher than ETZ (8.98 ± 0.36 ng*h/mL), indicating improved oral bioavailability for eutectics. Also, it was observed that enhanced material functionality aids in designing directly compressed tablets, where the eutectic formulation showed an improved dissolution profile over the ETZ formulation. The study demonstrates that eutectic conglomerates could be utilized to develop ideal oral solid dosage formulations.

Substrate-Rhodium Cooperativity in Photoinduced ortho-Alkynylation of Arenes.

In the realm of metallaphotocatalytic C-H activation strategy, the direct excitation of the transition metal which plays the dual role of light energy harnessing alongside performing the bond breaking and forming is a rare phenomenon. In this context we have developed the first photo-induced Rh-catalyzed ortho-alkynylation under ambient conditions without the requirement of silver salt, photocatalyst (PC) or any engineered substrate or catalyst. The transformation functions by the specific cooperative effect of a six-membered rhodacycle which is the photo-responsive species. The catalytic system allows the conjugation of arenes with sp3 -rich pharmacophoric fragments. The control experiments as well as the computational studies resolve the mechanistic intricacies for this transformation. An outer sphere electron transfer process from Rh to alkynyl radical is operative for the present photo-induced transformation over the more common oxidative addition or 1,2-migratory insertion pathways.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Sustained release matrix tablet of 100 mg losartan potassium: Formulation development and in vitro characterization

Abstract Sustained release matrix tablets of 100 mg losartan potassium HCl were fabricated with two release retarding polymers namely HPMC K100 M and affinisol by direct compression method. Nine trial formulations were prepared by varying content of these polymers, each from 50 mg to 100 mg; keeping the total weight of the tablet 310 mg. The best formulation was selected based on in vitro drug release profile for 12 hours conducted in Type II dissolution apparatus at 50 rpm and water as dissolution medium. Pre-compression parameters such as bulk density, tap density, Carr's index and Hausner ratio were evaluated for the selected tablet. The tablets were subjected to thickness, weight variation test, drug content, hardness and friability. Drug release kinetics, surface morphology and accelerated stability study were investigated for that selected formulation. Formulation F4 with the composition of 75 mg HPMC K100M and 100 mg affinisol was selected as the best formulation that extended the drug release up to 12 hours. Pre-compression parameters and other tableting properties were within the Pharmacopoeia limit. Release kinetics analysis proved non-fickian zero-order drug release and that was further confirmed by surface morphology of the tablets before and after dissolution study visualized by SEM. The developed formulation was found to be stable for one month stored at 60 ○C.

Organocatalytic Asymmetric Synthesis of Spirooxindole Embedded Oxazolidines.

The first organocatalytic asymmetric synthesis of spirooxindole embedded oxazolidines has been developed via a domino reaction involving hemiaminal formation, followed by an unprecedented aza-Michael reaction between isatin derived N-Boc ketimines and γ-hydroxy enones. A quinine derived bifunctional squaramide catalyst was found to be efficient for this reaction, and the products were obtained in good diastereoselectivity and with high enantioselectivity.

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C-H activation.

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years. Several unique features of HFIP compared to its non-fluoro analogue isopropanol have helped this solvent to make a difference in various subdomains of organic chemistry. One such area is transition metal-catalyzed C-H bond functionalization reactions. While, on one side, HFIP is emerging as a green and sustainable deep eutectic solvent (DES), on the other side, a major proportion of Pd-catalyzed C-H functionalization is heavily relying on this solvent. In particular, for distal aromatic C-H functionalizations, the exceptional impact of HFIP to elevate the yield and selectivity has made this solvent irreplaceable. Recent research studies have also highlighted the H-bond-donating ability of HFIP to enhance the chiral induction in Pd-catalyzed atroposelective C-H activation. This perspective aims to portray different shades of HFIP as a magical solvent in Pd-catalyzed C-H functionalization reactions.

Synthesis of azahelicenes through Mallory reaction of imine precursors: corannulene substrates provide an exception to the rule in oxidative photocyclizations of diarylethenes.

Typically, the synthesis of phenanthrene-based polycyclic aromatic hydrocarbons relies on the Mallory reaction. In this approach, stilbene (PhCH[double bond, length as m-dash]CHPh)-based precursors undergo an oxidative photocyclization reaction to join the two adjacent aromatic rings into an extended aromatic structure. However, if one C[double bond, length as m-dash]C carbon atom is replaced by a nitrogen atom (C[double bond, length as m-dash]N), the synthesis becomes practically infeasible. Here, we show the very first examples of a successful Mallory reaction on stilbene-like imine precursors involving the molecularly curved corannulene nucleus. The isolated yields exceed 90% and the resulting single and double aza[4]helicenes exhibit adjustable high affinity for electrons.

Cocrystallization: Cutting Edge Tool for Physicochemical Modulation of Active Pharmaceutical Ingredients.

Cocrystallization is a widely accepted and clinically relevant technique that has prospered very well over the past decades to potentially modify the physicochemical properties of existing active pharmaceutic ingredients (APIs) without compromising their therapeutic benefits. Over time, it has become an integral part of the pre-formulation stage of drug development because of its ability to yield cocrystals with improved properties in a way that other traditional methods cannot easily achieve. Cocrystals are solid crystalline materials composed of two or more than two molecules which are non-covalently bonded in the same crystal lattice. Due to the continuous efforts of pharmaceutical scientists and crystal engineers, today cocrystals have emerged as a cutting edge tool to modulate poor physicochemical properties of APIs such as solubility, permeability, bioavailability, improving poor mechanical properties and taste masking. The success of cocrystals can be traced back by looking at the number of products that are getting regulatory approval. At present, many cocrystals have obtained regulatory approval and they successfully made into the market place followed by a fair number of cocrystals that are currently in the clinical phases. Considering all these facts about cocrystals, the formulation scientists have been inspired to undertake more relevant research to extract out maximum benefits. Here in this review cocrystallization technique will be discussed in detail with respect to its background, different synthesis approaches, synthesis mechanism, application and improvements in drug delivery systems and its regulatory perspective.

Structure-Activity Relationships of Voltaglue Organic Blends.

Voltage-activated, one-pot adhesives are an emerging platform with many potential advantages, but require multicomponent grafting of electrochemical donors and acceptors for operation in organic environments. This formulation strategy reduces throughput efficiency, organic solubility, and requires additional purification of the grafted dendrimers. A more advanced strategy is proposed for setting up the donor-acceptor conductive network by exploiting a flexible blending design, providing faster throughput of structure-activity analyses with less synthetic investment. The blend method investigates the ampere-dependent storage modulus and gelation time as a function of both donor and acceptor concentration. This blend strategy allows a rapid evaluation of donor-acceptor parameters involved in voltage-activated adhesive formulations.

Development of a Thermoresponsive Polymeric Composite Film Using Cross-Linked ß-Cyclodextrin Embedded with Carbon Quantum Dots as a Transdermal Drug Carrier.

Polymeric nanocomposite films are used as promising transdermal drug carriers because of the improved patient compliance, easy application on skin, and noninvasiveness. A thermoresponsive polymeric composite film has been developed here through the deposition of carbon quantum dots (CQDs) on functionalized ß-cyclodextrin (ß-CD). The composite has been developed by grafting of poly(N-vinyl caprolactam) on ß-CD, followed by cross-linking of diethylene glycol dimethacrylate and subsequent deposition of CQDs. CQDs have been prepared from waste pomegranate peels via a hydrothermal method. To enlighten the thermoresponsive nature of the composite film, lower critical solution temperature, as well as temperature-dependent swelling behavior, has been studied. The composite demonstrates excellent rheological features. The developed polymeric composite film is nontoxic toward NIH 3T3 fibroblast cell lines. On the deposition of CQDs on the copolymer, the penetration power and fluorescent property have been improved, which help to track the cells in vitro. This film is worthy to be applied to the skin. It can efficiently load lidocaine hydrochloride monohydrate (LHM). In vitro and ex vivo skin permeation profiles reveal the sustained release behavior of loaded LHM at average skin temperature and pH.