Inert Cores Research Articles

Generalized molecule-like structure in atomic nuclei

Starting from a |ϕ|4 field theory with universal pn interacting angular and distance coordinates (θ,r) to depict nuclear long-range correlations, we have derived a cubic Schrödinger equation for NpNnpn interacting virtual bosons, which are believed to dominate the generic evolution of nuclear structure from spherical multi-nucleon shell-model states to deformed collective rotational states. It is shown that two-soliton solution in θ space manifests two opposite pn-type Ising-like chains existing in ground states and their gradual alignment responsible for nuclear rotational excitations. Of particular prominence is two-soliton solution with respect to r: the mutual relative motion of valence protons and neutrons around valence-nucleon mass centers considered as the dynamic equilibrium positions of a non-linear Schrödinger breather. And the resulting non-vanishing root mean square 〈r2〉 divides half the valence nucleons belonging to a chain into four local mass centers and proposes two chain-corresponding molecule-like tetrads outside inert cores pairwise hidden in ground states. Such solitons turn out to be an analogue of opposite axion fluids around a local mass center in the galactic dark-matter halo outside the soliton core (Garnier et al. (2021) [67]) and the present study facilitates making the latter more clear. The generalized molecule-like structure arouses a requisite to the addition of cluster-interior and cluster-to-core electric dipole moments in particular to pear-shaped nuclei, whose variants Schiff moments play an important role in measuring diamagnetic atomic electric dipole moments and therefore understanding CP-violating new physics beyond the standard model. We put additional parts in evidence by befitting the NpNn scheme verified already by electric quadrupole moments in same nuclei.

Tailoring Mesoporous Silica-Coated Silver Nanoparticles and Polyurethane-Doped Films for Enhanced Antimicrobial Applications.

The global increase in multidrug-resistant bacteria poses a challenge to public health and requires the development of new antibacterial materials. In this study, we examined the bactericidal properties of mesoporous silica-coated silver nanoparticles, varying the core sizes (ca. 28 nm and 51 nm). We also investigated gold nanoparticles (ca. 26 nm) coated with mesoporous silica as possible inert metal cores. To investigate the modification of antimicrobial activity after the surface charge change, we used silver nanoparticles with a silver core of 28 nm coated with a mesoporous shell (ca. 16 nm) and functionalized with a terminal amine group. Furthermore, we developed a facile method to create mesoporous silica-coated silver nanoparticles (Ag@mSiO2) doped films using polyurethane (IROGRAN®) as a polymer matrix via solution casting. The antibacterial effects of silver nanoparticles with different core sizes were analyzed against Gram-negative and Gram-positive bacteria relevant to the healthcare and food industry. The results demonstrated that gold nanoparticles were inert, while silver nanoparticles exhibited antibacterial effects against Gram-negative (Escherichia coli and Salmonella enterica subsp. enterica serovar Choleraesuis) and Gram-positive (Bacillus cereus) strains. In particular, the larger Ag@mSiO2 nanoparticles showed a minimum inhibitory concentration (MIC) and a minimum bactericidal concentration (MBC) of 18 µg/mL in the Salmonella strain. Furthermore, upon terminal amine functionalization, reversing the surface charge to positive values, there was a significant increase in the antibacterial activity of the NPs compared to their negative counterparts. Finally, the antimicrobial properties of the nanoparticle-doped polyurethane films revealed a substantial improvement in antibacterial efficacy. This study provides valuable information on the potential of mesoporous silica-coated silver nanoparticles and their applications in fighting multidrug-resistant bacteria, especially in the healthcare and food industries.

Review on Starter Pellets: Inert and Functional Cores.

A significant proportion of pharmaceuticals are now considered multiparticulate systems. Modified-release drug delivery formulations can be designed with engineering precision, and patient-centric dosing can be accomplished relatively easily using multi-unit systems. In many cases, Multiple-Unit Pellet Systems (MUPS) are formulated on the basis of a neutral excipient core which may carry the layered drug surrounded also by functional coating. In the present summary, commonly used starter pellets are presented. The manuscript describes the main properties of the various nuclei related to their micro- and macrostructure. In the case of layered pellets formed based on different inert pellet cores, the drug release mechanism can be expected in detail. Finally, the authors would like to prove the industrial significance of inert cores by presenting some of the commercially available formulations.

Development of a Biphasic-Release Multiple-Unit Pellet System with Diclofenac Sodium Using Novel Calcium Phosphate-Based Starter Pellets.

Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, sucrose and isomalt were prepared. The developed system consisted of two types of drug-layered pellets attaining different release patterns: delayed-release (enteric-coated) and extended-release. Dissolution characteristics were examined using both compendial and biorelevant methods, which reflected fed and fasting conditions. The results were collated with an equivalent commercial product but prepared with the direct pelletization technique.

Preparation of delayed-release multiparticulate formulations of diclofenac sodium and evaluation of their dissolution characteristics using biorelevant dissolution methods

Diclofenac sodium was used as a model drug for preparation of delayed-release (DR) multiparticulates, which were further processed into solid oral dosage forms such as capsules and tablets. Multiple unit pellets systems (MUPS) were prepared from different types of starter pellets (inert cores) including microcrystalline cellulose pellets, sugar spheres, isomalt pellets and novel calcium phosphate-based pellets. The study results showed that the material of the inert cores affected both mechanical properties of the drug-loaded pellets and the dissolution characteristic of the model drug. Biorelevant dissolution method carried out with the help of a pHysio-grad device allowed thorough examination of the developed formulations in the environment mimicking pH conditions along gastrointestinal tract. This method revealed significant differences between the formulations and their sensitivity to variable hydrodynamic conditions.

Cross-linking of poly (vinyl alcohol) films under acidic and thermal stress

Poly (vinyl alcohol), PVA, a commonly used excipient to coat tablets, forms insoluble films in the presence of acids and thermal stress. This may lead to drug products failing to meet dissolution specifications over time. Studies were conducted to understand the effect of acid strength, processing conditions, and storage stress on the mechanism of insoluble film formation using PVA and OpadryⓇ II as model systems. Aqueous cast films, prepared by incorporating hydrochloric acid (HCl) into the coating solutions or exposing pre-cast “as is” films to HCl vapors, were used as surrogates to develop analytical methods. To understand effect of acid and processing on coatings, acidified OpadryⓇ II was spray coated onto inert cores under “wet” or “dry” conditions. Samples stored at 50-60 °C were analyzed for film disintegration to understand physical/chemical changes in the polymer. Rate and extent of insoluble films formation was dependent on the acid concentration and thermal stress. Analysis of the films indicated significant de-acetylation and ether bond formation in insoluble aqueous cast films. In contrast, acidified coated films showed only ether bond formation, which increased on stress, forming insoluble films. The reduction in the time to form insoluble films for “wet” versus “dry” coated films was rationalized by considering effect of coating, drying, and storage on the microstructure of acidified PVA and ether bond propagation. The results highlight the need to develop an in-depth understanding of the design space for PVA coated products and storage conditions in presence of acids.

Low-energy super Gamow–Teller (LeSGT) and anti-LeSGT transitions

The LS-closed doubly-magic nuclei (DMN) $^{4}_{2}\mathrm{He}_{2}$, $^{16}_{\;\, 8}{\mathrm{O}}_{8}$, and $^{40}_{20}{\mathrm{Ca}}_{20}$ behave as inert cores for Gamow–Teller (GT) excitations. It is known that GT transition strengths from nuclei with DMN + identical two-nucleon particles (2p) to nuclei with DMN + proton-neutron particles ($\pi p$-$\nu p$), i.e., $^{6}_{2}{\mathrm{He}}_{4}\rightarrow ^{6}_{3}{\mathrm{Li}}_{3}$, $^{18}_{\;\, 8}{\mathrm{O}}_{10}$ (or $^{18}_{10}{\mathrm{Ne}}_{8}$) $\rightarrow ^{18}_{\;\, 9}{\mathrm{F}}_{9}$, and $^{42}_{20}{\mathrm{Ca}}_{22}$ (or $^{42}_{22}{\mathrm{Ti}}_{20}$) $\rightarrow ^{42}_{21}{\mathrm{Sc}}_{21}$, concentrate in the lowest GT states called the Low-energy Super GT (LeSGT) states. On the other hand, we notice that the GT strengths from nuclei with DMN + identical two-nucleon holes (2h) to nuclei with DMN + proton-neutron holes ($\pi h$-$\nu h$), i.e., $^{14}_{\;\, 6}{\mathrm{C}}_{8}$ (or $^{14}_{\;\, 8}{\mathrm{O}}_{6}$) $\rightarrow ^{14}_{\;\, 7}{\mathrm{N}}_{7}$, and $^{38}_{18}{\mathrm{Ar}}_{20}$ (or $^{38}_{20}{\mathrm{Ca}}_{18}$) $\rightarrow ^{38}_{19}{\mathrm{K}}_{19}$, concentrate in the second GT states. Accordingly, the lowest GT states, which can be called the anti-LeSGT states, are poorly excited. We find that this seesaw-like GT strength distributions in the 2p and 2h systems are the key to understand the hindered $\beta $ decay of $^{14}$C. The origin of the “Seesaw Mechanism” is analyzed by means of shell-model (SM) calculations.

Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin.

Drug substance degradation kinetics in solid dosage forms is rarely mechanistically modeled due to several potential micro-environmental and manufacturing related effects that need to be integrated into rate laws. The aim of our work was to construct a model capable of predicting individual degradation product concentrations, taking into account also formulation composition parameters. A comprehensive study was done on active film-coated tablets, manufactured by layering of the drug substance, a primary amine compound saxagliptin, onto inert tablet cores. Formulation variables like polyethylene glycol (PEG) 6000 amount and film-coat polymer composition are incorporated into the model, and are connected to saxagliptin degradation, via formation of reactive impurities. Derived reaction equations are based on mechanisms supported by ab initio calculations of individual reaction activation energies. Alongside temperature, relative humidity, and reactant concentration, the drug substance impurity profile is dependent on micro-environmental pH, altered by formation of acidic PEG degradation products. A consequence of pH lowering, due to formation of formic acid, is lower formation of main saxagliptin degradation product epi-cyclic amidine, a better resistance of formulation to high relative humidity conditions, and satisfactory tablet appearance. Discovered insights enhance the understanding of degradational behavior of similarly composed solid dosage forms on overall drug product quality and may be adopted by pharmaceutical scientists for the design of a stable formulation.

Fluidized bed coating of inert cores with a lipid-based system loaded with a polyphenol-rich Rosmarinus officinalis extract

Herbal extracts are used in the food, cosmetic and pharmaceutical sectors, e.g., as natural antioxidants, herbal remedies and active phyto-ingredients. Herbal extract constituents can be lost or suffer degradation due to environmental factors and microbial spoilage. Encapsulation technologies may overcome these limitations and improve product properties. Rosmarinus officinalis is an aromatic plant with proven antioxidant properties linked to their high content of phenolic compounds. In this work, the feasibility of fluidization technology for coating of microcrystalline cellulose cores (Celphere®) with a lipid-based system loaded with polyphenol-rich extract of R. officinalis was studied. The effects of the processing conditions and encapsulating composition on system performance and product properties were evaluated. The coating efficiency ranged from 64.3 to 79.2; although the differences did not show statistical significance (p≤0.05). The percentage of agglomerates in the product ranged from 0.2 to 47.7 and was impacted by processing conditions. Higher retention efficiencies were observed for the monitored marker compounds (caffeic, rosmarinic and carnosic acids and carnosol), reaching values higher than 70%, except for caffeic acid in the composition added with gum arabic (∼60%). Therefore, the fluidization is an effective and promising technology able to engineer innovative granular products loaded with herbal phytochemical compounds.

Bioenhanced advanced third generation solid dispersion of tadalafil: Repurposing with improved therapy in pyelonephritis

Tadalafil (TDL) a BCS-II drug is recently reported for repurposing nephroprotective effect in Pyelonephritis (PN). However, poor water solubility and dissolution rate limited oral bioavailability pose serious challenges in its therapeutic applications. We present an advanced third generation Solid Dispersion (SD) of TDL comprising a polymer in combination with a Self Micro-emulsifying Composition (SMEC) to achieve high drug loading, improved stability and rapid dissolution of TDL for enhancing bioavailability and efficacy in PN. TDL-SMEC-SD was coated onto rapidly disintegrating inert tablet cores which disintegrated rapidly in water to release SD as a film. TDL-SMEC-SD was evaluated for in-vivo oral bioavailability and in-vivo efficacy in lipopolysaccharide-induced PN in rats. TDL exhibited high solubility (45.6 mg/ml) in the SMEC. TDL-SMEC-SD exhibited remarkably high TDL loading (45%w/w), exceptionally low contact angle (9°), rapid in-vitro release (t50 7.3 min), microemulsion formation (globule size ~100 nm) in aqueous dispersion, and stability as per ICH guidelines. SEM, DSC, and XRD confirmed high physical stability. A relative bioavailability of 350% and 150% compared to TDL and TDL-SD without SMEC respectively, established the superiority of TDL-SMEC-SD. A significant reduction in serum creatinine, blood urea nitrogen and nitric oxide levels in the lipopolysaccharide-induced PN confirmed the benefit of the TDL-SMEC-SD. The advanced third generation SMEC SDs presents the possibility of platform technology for bioenhancement of poorly water soluble drugs.

Controlled Release Oral Delivery of Apigenin Containing Pellets with Antioxidant Activity.

Drug delivery of phytochemicals has gained interest recently due to their remarkable health effects. Apigenin, a plant flavonoid, has antioxidant, anti-inflammatory and anticancer activities but its delivery is challenging. It could be absorbed through the whole intestine, however, it has poor bioavailability due to its low aqueous solubility. In Europe, the daily intake was estimated to be as low as 3 ± 1 mg. Pellets offer several advantages such as improved bioavailability and various resultant drug release profiles can be obtained by simply mixing pellets with different coatings. The objective of our study was to develop a carrier system containing 20 mg apigenin thus enhancing intake and to offer reduction of oxidative stress which can cause inflammation in the intestine. The apigenin powder was dispersed in aqueous solution of binding material and layered onto the inert cores in a fluidized bed apparatus. The layered cores were further coated with enteric polymers and the process parameters were optimized. The prepared pellets met with the requirements and have good physical characteristic. 10% (w/w) Eudragit® L was suitable for enteric coating with a complete release at pH 6.8 within 1 hour. 15% (w/w) Eudragit® FS coating ensured acid resistance ability and colonic delivery. The therapeutic efficiency was confirmed with antioxidant activity measurement by using DPPH* assay. Enteric coated spheres allow targeted delivery into the intestine and colon thus reaching the main absorption site. Pellets were proved to be an optimal delivery system for apigenin thus providing enhanced apigenin intake.

Development of oral site-specific pellets containing flavonoid extract with antioxidant activity

Herbal medicines are recognized as an effective treatment of common diseases, mainly associated with oxidative stress. Therefore developing drug delivery systems of these biological active ingredients are gaining interest. Parsley (Petroselinum crispum L.) is a well-known culinary herb and its leaf contains high amount of apigenin, therefore it is suitable as a natural source of this flavonoid. Apigenin possess many health effects such as antioxidant, anti-inflammatory and anticancer activities. Unfortunately, these benefits are limited due to the low water solubility and bioavailability, it was recently classified as BCS II group compound. Therefore the aim of this study was to develop a carrier system for Petroselinum crispum extract, containing high amount of apigenin. Microcrystalline cellulose inert pellet cores were chosen and enteric coatings were applied. The produced multiparticulates had spherical shape, narrow size distribution and low moisture content. 10% (w/w) Eudragit® L 30 D-55 and 15% (w/w) Eudragit® FS 30 D coating was adequate for the modified release in vitro. The layered pellets demonstrated antioxidant activity. It was concluded that development of oral site-specific pellets containing flavonoid extract successful and the therapeutic effectiveness could be hypothesized.

Design and optimization of disintegrating pellets of MCC by non-aqueous extrusion process using statistical tools

The objective of the study was to design and optimize a disintegrating pellet formulation of microcrystalline cellulose by non-aqueous extrusion process for a water sensitive drug using various statistical tools. Aspirin was used as a model drug. Disintegrating matrix pellets of aspirin using propylene glycol as a non-aqueous granulation liquid and croscarmellose as a disintegrant was developed. Plackett–Burman design was initially conducted to screen and identify the significant factors. Final optimization of formula was performed by response surface methodology using a central composite design. The critical attributes of the pellet dosage forms (dependent variables); disintegration time, sphericity and yield were predicted with adequate accuracy based on the regression model. Pareto charts and contour charts were studied to understand the influence of factors and predict the responses. A design space was constructed to meet the desirable targets of the responses in terms of disintegration time <5min, maximum yield, sphericity >0.95 and friability <1.7%. The optimized matrix pellets were enteric coated using Eudragit L 100. The drug release from the enteric coated pellets after 30min in the basic media was ~93% when compared to ~77% from the marketed pellets. The delayed release pellets stored at 25°C/60% RH were stable for a period of 10mo. In conclusion, it can be stated that the developed process for disintegrating pellets using non-aqueous granulating agents can be used as an alternative technique for various water sensitive drugs, circumventing the application of volatile organic solvents in conventional drug layering on inert cores. The scope of this study can be further extended to hydrophobic drugs, which may benefit from the rapid disintegration property and the use of various hydrophilic excipients used in the optimized pellet formulation to enhance dissolution and in turn improve bioavailability.

Unified studies of structure and reactions in light unstable nuclei

The generalized two-center cluster model (GTCM), which can treat covalent, ionic and atomic configurations in general systems with two inert cores plus valence nucleons, is formulated in the basis of the microscopic cluster model. In this model, the covalent configurations constructed by the molecular orbital (MO) method and the atomic (or ionic) configuration obtained by the valence bonding (VB) method can be described in a consistent manner. GTCM is applied to the light neutron-rich system, 10,12 Be = α + α + XN (X = 2,4), and the unified studies of the structural changes and the reaction problem are performed. In the structure study, the calculated energy levels are characterized in terms of the chemical bonding like structures, such as the covalent MO or ionic VB structures. The chemical bonding structures changes from level to level within a small energy interval. In the unbound region, the structure problem with the total system of α + α + XN and the reaction problem, induced by the collision of an asymptotic VB state of α +6,8 He, are combined by GTCM. The properties of unbound resonant states are discussed in a close connection to the reaction mechanism, and some enhancement factors originated from the properties of the intrinsic states are predicted in the reaction observables. The unified calculation of the structures and the reactions is applied to the Coulomb shift problem in the mirror system, such the 10 Be and 10 C nuclei. The Coulomb displacement energy of the mirror systems are discussed.

Improvement of mechanical properties of pellet containing tablets by thermal treatment

Batches of partially spray-dried lactose tablets with three different initial tensile strength (∼20N, ∼35N, ∼50N) were made. Changes along a 24h long thermal treatment at 100°C in tensile strength, friability, individual mass, water content, disintegration time, average free volume and wetting properties were evaluated. Caffeine containing gastroresistant pellets were gained by drug layering and filmcoating of inert microcrystalline cellulose pellet cores in fluid bed equipment. Shape, size, mechanical properties, drug content and dissolution profile of the coated pellets were determined. Batches of pellet containing tablets with three different pellet-filler ratios were compressed where partially spray-dried lactose was used as a filler-binder material.Characteristics of pellet containing tablets were evaluated before and after a 24h long thermal treatment at 100°C. Results shown that the poor initial mechanical properties (friability, tensile strength) were improved by thermal exposure while there were no remarkable alterations in drug release profiles.

Pediatric drug formulation of sodium benzoate extended-release granules

Urea cycle disorders are a group of inherited orphan diseases leading to hyperammonemia. Current therapeutic strategy includes high doses of sodium benzoate leading to three or four oral intakes per day. As this drug is currently available in capsules or in solution, children are either unable to swallow the capsule or reluctant to take the drug due to its strong bitter taste. The objective of the present study was to develop solid, multiparticulate formulations of sodium benzoate, which are suitable for pediatric patients (i.e. flavor-masked, easy to swallow and with a dosing system). Drug layering and coating in a fluidized bed were applied for preparing sustained-release granules. Two types of inert cores (GalenIQ® and Suglets®) and three different polymers (Kollicoat®, Aquacoat® and Eudragit®) were tested in order to select the most appropriate polymer and starter core for our purpose. Physical characteristics and drug release profiles of the pellets were evaluated. A Suglets® core associated with a Kollicoat® coating seems to be the best combination for an extended release of sodium benzoate. A curing period of 8 h was necessary to complete film formation and the resulting drug release pattern was found to be dependant of the acidity of the release medium.

Molecular Structures and monopole excitations in light neutron-excess systems

The generalized two-center cluster model (GTCM), which can treat covalent, ionic and atomic configurations in general systems with two inert cores plus valence nucleons, is formulated on the basis of the microscopic cluster model. In this model, the covalent configurations constructed by the molecular orbital (MO) method and the atomic (or ionic) configuration obtained by the valence bonding (VB) method can be handled in a consistent manner. GTCM is applied to the light neutron-rich system, 12Be = α + α + 4N. The energy spectra are characterized in terms of the excitation degrees of freedom, such as the the excitation of two a relative motion and the neutrons' single particle excitation. A large enhancement in a monopole transition from a ground MO state to the excited states is found, which seems to be consistent to a recent observation. The systematics of the 0+ states in even Be isotopes over a wide range of the excitation energy is also discussed.

Organic-aqueous crossover coating process for the desmopressin orally disintegrating microparticles

The purpose of the present study was to prepare desmopressin orally disintegrating microparticles (ODMs) using organic-aqueous crossover coating process which featured an organic sub-coating followed by an aqueous active coating. Sucrose beads and hydroxypropyl cellulose (HPC) were used as inert cores and a coating material, respectively. Characterizations including size distribution analysis, in-vitro release studies and in-vitro disintegration studies were performed. A pharmacokinetic study of the ODMs was also conducted in eight beagle dogs. It was found that sucrose beads should be coated using organic solvents to preserve their original morphology. For the active coating, the aqueous coating solution should be used for drug stability. When sucrose beads were coated using organic-aqueous crossover coating process, double-layer ODMs with round shapes were produced with detectable impurities below limit of US Pharmacopeia. The median size of ODMs was 195.6 μm, which was considered small enough for a good mouthfeel. The ODMs dissolved in artificial saliva within 15 s because of hydrophilic materials including sucrose and HPC in the ODMs. Because of its fast-dissolving properties, 100% release of the drug was reached within 5 min. Pharmacokinetic parameters including Cmax and AUC24 indicated bioequivalence of the ODMs and the conventional immediate release tablets. Therefore, by using the organic-aqueous crossover coating process, double-layer ODMs were successively prepared with small size, round shapes and good drug stability.

Permeability thickening fluids for improved secondary oil recovery

Waterflooding is limited by zones of spatially varying permeability which cause channelling. More crude oil could be produced by a more uniform water/brine front across layers of different permeabilities. Novel non-polymeric water additives (CTAB+NaSal in brine) are used to selectively slow down flow of water in high permeability zones. In order to isolate rheological effects from rock fluid interactions, we have carried out experiments on inert glass cores. A monotonic increase of viscosity as function of permeability is observed for the range 45–2200 mD (covering typical reservoir ranges). This effect can be referred to as permeability thickening. This result opens up the possibility of tunable fluid engineering for any given permeability distribution of reservoirs. Low additive concentrations (<1000 ppm) yield in-situ permeability dependent viscosities up to 40 times that of brine. Flow in high permeability zones is retarded more than in low permeability ones which results in typically 15–36% extra sweep area based on single phase experiments.

Supramolecular elucidation of the quality attributes of microcrystalline cellulose and isomalt composite pellet cores

The major objective of this study was to disclose the relationships between the physical quality attributes and supramolecular structure of novel composite pellet cores containing microcrystalline cellulose (MCC) and isomalt in different ratios.The novel composite pellet cores were manufactured by an extrusion/spheronisation process. The micro or supramolecular structure of pellets was tracked by positron annihilation lifetime spectroscopy (PALS) based on the o-Ps lifetime values. The results indicate a correlation between the examined macro and microstructural properties of the inert cores. The higher free volume holes indicated by the higher o-Ps lifetime values resulted in a more mobile micro- and supramolecular structure of MCC cores thus increasing the plastic deformation and the tensile strength of the cores. A physical interaction was found between the microcrystalline cellulose and isomalt which supports the osmotic effect of the water soluble sugar alcohol in the composite pellet cores regarding drug release.