Interplay of Drug-Polymer Interactions and Release Performance for HPMCAS-Based Amorphous Solid Dispersions.

The interplay between drug and polymer chemistry and its impact on drug release from an amorphous solid dispersion (ASD) is a relatively underexplored area. Herein, the release rates of several drugs of diverse chemistry from hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based ASDs were explored using surface area normalized dissolution. The tendency of the drug to form an insoluble complex with HPMCAS was determined through coprecipitation experiments. The role of pH and the extent of drug ionization were probed to evaluate the role of electrostatic interactions in complex formation. Relationships between the extent of complexation and the drug release rate from an ASD were observed, whereby the drugs could be divided into two groups. Drugs with a low extent of insoluble complex formation with HPMCAS tended to be neutral or anionic and showed reasonable release at pH 6.8 even at higher drug loadings. Cationic drugs formed insoluble complexes with HPMCAS and showed poor release when formulated as an ASD. Thus, and somewhat counterintuitively, a weakly basic drug showed a reduced release rate from an ASD at a bulk solution pH where it was ionized, relative to when unionized. The opposite trend was observed in the absence of polymer for the neat amorphous drug. In conclusion, electrostatic interactions between HPMCAS and lipophilic cationic drugs led to insoluble complex formation, which in turn resulted in ASDs with poor release performance.

Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Generality of Enhancing the Dissolution Rates of Free Acid Amorphous Solid Dispersions by the Incorporation of Sodium Hydroxide.

The incorporation of a counterion into an amorphous solid dispersion (ASD) has been proven to be an attractive strategy to improve the drug dissolution rate. In this work, the generality of enhancing the dissolution rates of free acid ASDs by incorporating sodium hydroxide (NaOH) was studied by surface-area-normalized dissolution. A set of diverse drug molecules, two common polymer carriers (copovidone or PVPVA and hydroxypropyl methylcellulose acetate succinate or HPMCAS), and two sample preparation methods (rotary evaporation and spray drying) were investigated. When PVPVA was used as the polymer carrier for the drugs in this study, enhancements of dissolution rates from 7 to 78 times were observed by the incorporation of NaOH into the ASDs at a 1:1 molar ratio with respect to the drug. The drugs having lower amorphous solubilities showed greater enhancement ratios, providing a promising path to improve the drug release performance from their ASDs. Samples generated by rotary evaporation and spray drying demonstrated comparable dissolution rates and enhancements when NaOH was added, establishing a theoretical foundation to bridge the ASD dissolution performance for samples prepared by different solvent-removal processes. In the comparison of polymer carriers, when HPMCAS was applied in the selected system (indomethacin ASD), a dissolution rate enhancement of 2.7 times by the incorporated NaOH was observed, significantly lower than the enhancement of 53 times from the PVPVA-based ASD. This was attributed to the combination of a lower dissolution rate of HPMCAS and the competition for NaOH between IMC and HPMCAS. By studying the generality of enhancing ASD dissolution rates by the incorporation of counterions, this study provides valuable insights into further improving drug release from ASD formulations of poorly water-soluble drugs.

Simultaneous Water Sorption and Crystallization in ASDs 2: Modeling Long-Term Stabilities.

The physical stability of amorphous solid dispersions (ASDs) is a major topic in the formulation research of oral dosage forms. To minimize the effort of investigating the long-term stability using cost- and time-consuming experiments, we developed a thermodynamic and kinetic modeling framework to predict and understand the crystallization kinetics of ASDs during long-term storage below the glass transition. Since crystallization of the active phrarmaceutical ingredients (APIs) in ASDs largely depends on the amount of water absorbed by the ASDs, water-sorption kinetics and API-crystallization kinetics were considered simultaneously. The developed modeling approach allows prediction of the time evolution of viscosity, supersaturation, and crystallinity as a function of drug load, relative humidity, and temperature. It was applied and evaluated against two-year-lasting crystallization experiments of ASDs containing nifedipine and copovidone or HPMCAS measured in part I of this work. We could show that the proposed modeling approach is able to describe the interplay between water sorption and API crystallization and to predict long-term stabilities of ASDs just based on short-term measurements. Most importantly, it enables explaining and understanding the reasons for different and sometimes even unexpected crystallization behaviors of ASDs.

Effect of Polymer Architecture and Acidic Group Density on the Degree of Salt Formation in Amorphous Solid Dispersions.

Recent work has shown that an amorphous drug-polymer salt can be highly stable against crystallization under hot and humid storage conditions (e.g., 40 °C/75% RH) and provide fast release and that these advantages depend on the degree of salt formation. Here, we investigate the salt formation between the basic drug lumefantrine (LMF) and several acidic polymers: poly(acrylic acid) (PAA), hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), Eudragit L100, and Eudragit L100-55. Salt formation was performed by "slurry synthesis" where dry components were mixed at room temperature in the presence of a small quantity of an organic solvent, which was subsequently removed. This method achieved more complete salt formation than the conventional methods of hot-melt extrusion and rotary evaporation. The acidic group density of a polymer was determined by nonaqueous titration in the same solvent used for slurry synthesis; the degree of LMF protonation was determined by X-ray photoelectron spectroscopy. The polymers studied show very different abilities to protonate LMF when compared at a common drug loading, following the order PAA > (HPMCP ∼ CAP ∼ L100 ∼ L100-55) > HPMCAS, but the difference largely disappears when the degree of protonation is plotted against the concentration of the available acidic groups for reaction. This indicates that the extent of salt formation is mainly controlled by the acidic group density and is less sensitive to the polymer architecture. Our results are relevant for selecting the optimal polymer to control the degree of ionization in amorphous solid dispersions.

Understanding Self-Assembly and Molecular Packing in Methylcellulose Aqueous Solutions Using Multiscale Modeling and Simulations.

We present a multiscale molecular dynamics (MD) simulation study on self-assembly in methylcellulose (MC) aqueous solutions. First, using MD simulations with a new coarse-grained (CG) model of MC chains in implicit water, we establish how the MC chains self-assemble to form fibrils and fibrillar networks and elucidate the MC chains' packing within the assembled fibrils. The CG model for MC is extended from a previously developed model for unsubstituted cellulose and captures the directionality of H-bonding interactions between the -OH groups. The choice and placement of the CG beads within each monomer facilitates explicit modeling of the exact degree and position of methoxy substitutions in the monomers along the MC chain. CG MD simulations show that with increasing hydrophobic effect and/or increasing H-bonding strength, the commercial MC chains (with degree of methoxy substitution, DS, ∼1.8) assemble from a random dispersed configuration into fibrils. The assembled fibrils exhibit consistent fibril diameters regardless of the molecular weight and concentration of MC chains, in agreement with past experiments. Most MC chains' axes are aligned with the fibril axis, and some MC chains exhibit twisted conformations in the fibril. To understand the molecular driving force for the twist, we conduct atomistic simulations of MC chains preassembled in fibrils (without any chain twists) in explicit water at 300 and 348 K. These atomistic simulations also show that at DS = 1.8, MC chains adopt twisted conformations, with these twists being more prominent at higher temperatures, likely as a result of shielding of hydrophobic methyl groups from water. For MC chains with varying DS, at 348 K, atomistic simulations show a nonmonotonic effect of DS on water-monomer contacts. For 0.0 < DS < 0.6, the MC monomers have more water contacts than at DS = 0.0 or DS > 0.6, suggesting that with few methoxy substitutions, the MC chains are effectively hydrophilic, letting the water molecules diffuse into the fibril to participate in H-bonds with the MC chains' remaining -OH groups. At DS > 0.6, the MC monomers become increasingly hydrophobic, as seen by decreasing water contacts around each monomer. We conclude based on the atomistic observations that MC chains with lower degrees of substitutions (DS ≤ 0.6) should exhibit solubility in water over broader temperature ranges than DS ∼ 1.8 chains.

Effect of Food Viscosity on Drug Dissolution.

PURPOSE: The purpose of the present study was to investigate the effect of food viscosity on the dissolution rate of a drug. There are two types of viscosity, macroviscosity and microviscosity. Macroviscosity affects the diffusion layer thickness, whereas microviscosity affects the molecular diffusion coefficient. The mass transfer coefficient (kc) in the intrinsic dissolution rate (IDR) depends on the viscosity (η) as kc ∝ ηa (a is an exponent on η). In theory, for rotating flow over a disk, if a thickener increases only macroviscosity, a = -1/6, and if it increases both macroviscosity and microviscosity equally, a = -7/6. METHOD: Benzocaine was used as a model drug. Hydroxypropyl cellulose (HPC) and methylcellulose (MC) were employed as control thickeners that increase only macroviscosity. Sucrose was employed as a control thickener for both macroviscosity and microviscosity. The FDA breakfast homogenate (BFH) was diluted with distilled water or 1 mM HCl with/without pepsin digestion. The IDR value was measured by the paddle-over-disk method. RESULTS: The η value of 30% BFH distilled water was 209 mPa∙s, about 300 times higher than distilled water. It was further increased by HCl (430 mPa∙s), and reduced by pepsin digestion (35 mPa∙s). The kc value was little affected by BFH (a = 0.00 to -0.09), slightly less than those in HPC (a = -0.19) and MC (a = -0.21). Sucrose decreased the kc value more significantly (a = -0.70). CONCLUSION: The IDR and kc values of benzocaine were little affected by BFH, suggesting that BFH increased only macroviscosity.

Retinoprotective Effect of SkQ1, Visomitin Eye Drops, Is Associated with Suppression of P38 MAPK and ERK1/2 Signaling Pathways Activity.

Visomitin eye drops are the first and, so far, the only drug based on SkQ1 - the mitochondria-targeted antioxidant 10-(6'-plastoquinonyl) decyltriphenylphosphonium, developed in the laboratories of Moscow State University under the leadership of Academician V. P. Skulachev. SkQ1 is considered as a potential tool to combat the aging program. We have previously shown that it is able to prevent and/or suppress development of all manifestations of accelerated senescence in OXYS rats, including retinopathy, similar to the age-related macular degeneration (AMD). Here, we assessed the effect of Visomitin instillations on progression of the AMD-like pathology and p38 MAPK and ERK1/2 activity in the OXYS rat retina (from the age of 9 to 12 months). Wistar and OXYS rats treated with placebo (composition identical to Visomitin with the exception of SkQ1) were used as controls. Ophthalmological examination showed that in the OXYS rats receiving placebo, retinopathy progressed and severity of clinical manifestations did not differ from the intact OXYS rats. Visomitin suppressed progression of the AMD-like pathology in the OXYS rats and significantly improved structural and functional parameters of the retinal pigment epithelium cells and state of microcirculation in the choroid, which, presumably, contributed to preservation of photoreceptors, associative and ganglion neurons. It was found that the activity of p38 MAPK and ERK1/2 in the retina of 12-month-old OXYS rats is higher than that of the Wistar rats of the same age, as indicated by the increased content of phosphorylated forms of p38 MAPK and ERK1/2 and their target protein tau (at position T181 and S396). Visomitin decreased phosphorylation of p38 MAPK, ERK1/2, and tau indicating suppression of activity of these MAPK signaling cascades. Thus, Visomitin eye drops are able to suppress progression of the AMD-like pathology in the OXYS rats and their effect is associated with the decrease in activity of the MAPK signaling cascades.

Modification of bentonite with black cotton soil and carboxyl methyl cellulose for the enhancement of hydraulic performance of geosynthetic clay liners.

Geosynthetic clay liners (GCLs) are mostly used as flow barriers in landfills and waste containments due to their low hydraulic conductivity to prevent the leachate from reaching the environment. The self-healing and swell-shrink properties of soft clays (expansive soils) such as bentonite enable them as promising materials for the GCL core layers. However, it is important to modify their physico-chemical properties in order to overcome the functional limitations of GCL under different hydraulic conditions. In the present study, locally available black cotton soil (BCS) is introduced in the presence of an anionic polymer named carboxymethyl cellulose (CMC) as an alternative to bentonite to enhance the hydraulic properties of GCL under different compositions. The modified GCL is prepared by stitching the liner with an optimum percentage of CMC along with various percentages of BCS mixed with bentonite. Hydraulic conductivity tests were performed on the modified GCL using the flexi-wall permeameter. The results suggest that the lowest hydraulic conductivity of 4.58 × 10-10 m/s is obtained when 25% of BCS is blended with bentonite and an optimum 8% CMC and further addition of BCS results in the reduction of the hydraulic conductivity.

[Research progress of methylcellulose-based thermosensitive hydrogels applied in biomedical field].

Methylcellulose is a semi-flexible cellulose ether derivative, whose hydrogels are thermosensitive and reversible, with good biocompatibility and adjustable function, and its application has attracted much attention in the biomedical field. In this paper, the application of methylcellulose-based thermo-sensitive hydrogels in biomedical field was reviewed. Based on the mechanism of gelation and influencing factors of methylcellulose, this paper focused on the recent advances in biomedical applications of methylcellulose-based hydrogels, including drug delivery, regenerative medicine, and other related fields. The current achievements in these fields were summarized in the form of lists in this paper to provide ideas and tendencies for future research. Finally, the future development of multifunctional methylcellulose-based hydrogel materials with improved performance was also discussed.

Minimization of Acid-Catalyzed Degradation in KinetiSol Processing through HPMCAS Neutralization.

Hypromellose acetate succinate (HPMCAS) is an enteric polymer that has been successfully employed as a carrier in amorphous solid dispersions (ASDs). Deprotonation of succinic acid substituents at intestinal pH levels results in solubilization of the polymer. However, the acidic moieties responsible for favorable pH-dependent solubility can also result in incompatibilities between acid-sensitive drugs and HPMCAS. Solution-state conversion of the carboxylic acid substituents of enteric polymers into carboxylate salts to reduce acid-mediated drug degradation is a demonstrated effective strategy for generating ASDs in enteric polymers. This work aimed to extend the use of a pre-ionized enteric polymer to KinetiSol solvent-free processing to reduce acid- or base-mediated drug degradation during processing. Pre-ionization of HPMCAS was accomplished by reaction with a stoichiometric quantity of sodium carbonate (Na2CO3) delivered as a saturated aqueous solution. The resulting ionized polymer, HPMCAS-Na, was dried thoroughly before processing. Tetrabenazine (TBZ) was chosen as a model drug for its susceptibility to degradation via both acid- and base-catalyzed reaction mechanisms and for its tendency to form a single impurity by these mechanisms. The use of HPMCAS-Na in KinetiSol solid dispersions (KSDs) of TBZ resulted in a 6- to 8-fold reduction of the acid- and base-generated TBZ impurity compared with KSDs formulated with untreated HPMCAS.

Does Media Choice Matter When Evaluating the Performance of Hydroxypropyl Methylcellulose Acetate Succinate-Based Amorphous Solid Dispersions?

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a weakly acidic polymer that is widely used in the formulation of amorphous solid dispersions (ASDs). While the pH-dependent solubility of HPMCAS is widely recognized, the role of other solution properties, including buffer capacity, is less well understood in the context of ASD dissolution. The goal of this study was to elucidate the rate-limiting steps for drug and HPMCAS release from ASDs formulated with two poorly water soluble model drugs, indomethacin and indomethacin methyl ester. The surface area normalized release rate of the drug and/or polymer in a variety of media was determined. The HPMCAS gel layer apparent pH was determined by incorporating pH sensitive dyes into the polymer matrix. Water uptake extent and rate into the ASDs were measured gravimetrically. For neat HPMCAS, the rate-limiting step for polymer dissolution was observed to be the polymer solubility at the polymer-solution interface. This, in turn, was impacted by the gel layer pH which was found to be substantially lower than the bulk solution pH, varying with medium buffer capacity. For the ASDs, the HPMCAS release rate was found to control the drug release rate. However, both drugs reduced the polymer release rate with indomethacin methyl ester having a larger impact. In low buffer capacity media, the presence of the drug had less impact on release rates when compared to observations in higher strength buffers, suggesting changes in the rate-limiting steps for HPMCAS dissolution. The observations made in this study can contribute to the fundamental understanding of acidic polymer dissolution in the presence and absence of a molecularly dispersed lipophilic drug and will help aid in the design of more in vivo relevant release testing experiments.

Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation.

In an earlier investigation, the critical cooling rate to prevent drug crystallization (CRcrit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CRcrit N) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (tC) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CRcrit N). The strength of the drug-polymer interactions as well as the polymer concentration affected the CRcrit N, with PVP having a stronger interaction than HPMCAS. The CRcrit of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CRcrit of ∼0.05 and 0.2 °C/min and CRcrit N of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.

Structure and Conformation of Hydroxypropylmethyl Cellulose with a Wide Range of Molar Masses in Aqueous Solution─Effects of Hydroxypropyl Group Addition.

The structure of hydroxypropylmethyl cellulose (HpMC) samples with a wide range of weight average molar masses (Mw) from 23 to 5000 kg mol-1, a controlled degree of substitution (DS) of 1.9 by methyl groups, and a molar substitution number (MS) of 0.25 by hydroxypropyl groups dissolved in aqueous solution was examined using static light scattering (SLS), dynamic light scattering (DLS), small-to-wide angle neutron scattering (S-WANS) techniques, and intrinsic viscosity ([η]) measurements. The determined Mw and the radius of gyration (Rg) showed the relationships Rg ∝ Mw1.0 and [η] ∝ Mw1.7 in a range of Mw < 100 kg mol-1, similar to rigid rod molecules in solution. However, exponents in the relationships decreased gradually with increasing Mw and reached ∼0.5 in a high Mw region, which is a typical value of flexible chain molecules for both Rg and [η]. These observations suggest that the HpMC samples behave as semiflexible rods with a certain persistence length (lp). The ratios of the hydrodynamic radius via DLS measurements to Rg also supported semiflexible rod behavior. Particle form factors and the average lengths (L) resulting from SLS and S-WANS experiments are well described with rigid rod particles in the range of Mw < 100 kg mol-1 and semiflexible rods with lp ∼ 100 nm in Mw > 100 kg mol-1. Because the average contour length (lc) calculated from Mw is approximately twice as long as L in the Mw range < 100 kg mol-1, the formed HpMC particles possess a folded hairpin-like elongated rigid rod structure. However, the lc/L value increases gradually in the range Mw > 200 kg mol-1, where the formed HpMC particles behave as semiflexible rods. The formed particle structure was substantially different from that found in methyl cellulose samples with a similar DS value, which showed rod-like behavior over a wide Mw range. The addition of hydroxypropyl groups only at MS = 0.25 effectively changed the formed particle structure.

Development of Sustained Release System Based on High Water-Absorbable Gel Formation Using Croscarmellose Sodium, Alkaline Excipients and HPMC (ACSH SR System); Novel Application of Croscarmellose Sodium as a Gel Former.

PURPOSE: Croscarmellose sodium, generally used as a superdisintegrant in pharmaceutical formulations, is hydrolyzed to form the gel structure under basic pH conditions. Utilizing this property of croscarmellose sodium, we developed a novel sustained release (SR) system. METHODS: Immediate release (IR) and SR tablets containing croscarmellose sodium, alkaline excipients and/or hydroxypropyl methylcellulose (HPMC) were prepared and examined for wet strength and in vitro drug release behavior. In vivo oral drug absorption was evaluated for IR tablets, HPMC tablets and our novel SR tablets in fasted Beagle dogs. RESULTS: To form the gel structure even under the physiological condition, alkaline excipients were added into the formulation containing croscarmellose sodium. Furthermore, HPMC was used to make the gel structure strong enough against mechanical destructive forces. The novel alkalized croscarmellose sodium-HPMC (ACSH) SR tablet, consisting of croscarmellose sodium, alkaline excipients, and HPMC, successfully sustained the release of acetaminophen, ibuprofen, or nicardipine hydrochloride, compared with the IR tablets. The ACSH SR system provided a better release of acetaminophen than the HPMC tablet without croscarmellose sodium in the release study using a small volume of liquid, suggesting that substantial release and subsequent absorption would be expected in the distal intestinal segments after oral dosing. The in vivo oral absorption study revealed that the ACSH SR system successfully suppressed and prolonged the plasma concentrations of acetaminophen. CONCLUSION: This novel ACSH SR system prepared with croscarmellose sodium, alkaline excipients, and HPMC, would be a promising SR formulation for enabling substantial drug absorption in the distal intestinal segments.

Genome-directed discovery of antiproliferative bafilomycins from a deepsea-derived Streptomyces samsunensis.

Genomic bioinformatics analysis identified a bafilomycin biosynthetic gene cluster (named bfl) in the deepsea-derived S. samsunensis OUCT16-12, from which two new (1 and 2, named bafilomycins R and S) along with four known (3-6) bafilomycins were targetly obtained. The structure of 3 was clearly identified for the first time, thus named bafilomycin T herein. Differ from the fumarate substitution at C-21 of known bafilomycins, its location on C-23 is a unique feature of 1 and 2. The stereochemistry of the compounds was established based on NOE correlations, ketoreductase (KR)-types in PKS modules of bfl, and ECD calculations. Moreover, a detailed biosynthetic model of 1-6 in S. samsunensis OUCT16-12 was provided based on the gene function prediction and sequence identity. Compared with the positive control doxorubicin, 1-6 showed more potent antiproliferative activities against drug-resistant lung cancer cell line A549-Taxol, with IC50 values ranging from 0.07 µM to 1.79 µM, which arrested cell cycle in G0/G1 phase to hinder proliferation.

Tensile bond strength of adhesive mortars with hydroxypropyl methyl cellulose and vinyl acetate-ethylene polymers after thermal storage.

The properties of adhesive mortars can change due to heating, compromising the durability of the coating systems. The aim of this article was to evaluate the influence of cement and polymer contents on the tensile bond strength of adhesive mortars after thermal storage. Ceramic tiling system specimens were prepared with seventeen formulations of adhesive mortars. These specimens were stored under dry (reference) at temperature of 23 ± 2 °C and 60 ± 5% of relative humidity and thermal (temperature of 70 ± 2 °C) conditions. The results showed that the cement content was the major factor concerning tensile bond strength. The vinyl acetate-ethylene (VAE) polymer improved the tensile bond strength of mortars under thermal storage. However, the hydroxypropyl methyl cellulose (HPMC) content contributed to the tensile bond strength only when higher cement contents were used. Besides, microstructure analysis showed that ettringite was degraded during thermal storage.

Continuous Monitoring of the Hydration Behavior of Hydrophilic Matrix Tablets Using Time-Domain NMR.

Time-domain NMR (TD-NMR) was used for continuous monitoring of the hydration behavior of hydrophilic matrix tablets. The model matrix tablets comprised high molecular weight polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG). The model tablets were immersed in water. Their T2 relaxation curves were acquired by TD-NMR with solid-echo sequence. A curve-fitting analysis was conducted on the acquired T2 relaxation curves to identify the NMR signals corresponding to the nongelated core remaining in the samples. The amount of nongelated core was estimated from the NMR signal intensity. The estimated values were consistent with the experiment measurement values. Next, the model tablets immersed in water were monitored continuously using TD-NMR. The difference in hydration behaviors of the HPMC and PEO matrix tablets was then characterized fully. The nongelated core of the HPMC matrix tablets disappeared more slowly than that of the PEO matrix tablets. The behavior of HPMC was significantly affected by the PEG content in the tablets. It is suggested that the TD-NMR method has potential to be utilized to evaluate the gel layer properties, upon replacement of the immersion medium: purified (nondeuterated) water is replaced with heavy (deuterated) water. Finally, drug-containing matrix tablets were tested. Diltiazem hydrochloride (a highly water-soluble drug) was employed for this experiment. Reasonable in vitro drug dissolution profiles, which were in accordance with the results from TD-NMR experiments, were observed. We concluded that TD-NMR is a powerful tool to evaluate the hydration properties of hydrophilic matrix tablets.

Simplified PCR-Based Quantification of Proteins with DNA Aptamers and Methylcellulose as a Blocking Agent.

Due to their unique three-dimensional structure, DNA or RNA oligonucleotide aptamers bind to various molecules with high affinity and specificity. Aptamers, alone or in combination with antibodies, can be used to sensitively quantify target molecules by quantitative real-time polymerase chain reaction (qPCR). However, the assays are often complicated and unreliable. In this study, we explored the feasibility of performing the entire assay on wells of routinely used polypropylene PCR plates. We found that polypropylene wells efficiently bind proteins. This allows the entire assay to be run in a single well. To minimize nonspecific binding of the assay components to the polypropylene wells, we tested various blocking agents and identified methylcellulose as an effective alternative to the commonly used BSA. Methylcellulose not only demonstrates comparable or superior blocking capabilities but also offers the advantage of a well-defined composition and non-animal origin. Our findings support the utilization of aptamers, either alone or in combination with antibodies, for sensitive quantification of selected molecules immobilized in polypropylene PCR wells in a streamlined one-well qPCR assay under well-defined conditions.

Apple Pomace Compositional Data Highlighting the Proportional Contribution of Polymeric Procyanidins.

Recent years have seen an increase in research focusing on the amelioration of apple pomace waste for use in the food and nutraceutical industries. Much of this work has concentrated on the characterisation of the polyphenol composition of apple pomace materials to determine their role in conferring nutritional and health benefits. Although apples contain substantial quantities of polymeric procyanidins (condensed tannins), this class of compounds has received limited attention in apple research. This study quantified the polymeric procyanidins in apple pomace extracts using a rapid, methyl-cellulose precipitation (MCP) approach for the first time. In addition, a non-targeted metabolomics approach was applied to determine the most abundant phenolic classes present. Polymeric procyanidins were found to be the most abundant type of polyphenol in apple pomace extracts and were generally oligomeric in nature. Multivariate statistical analysis revealed that the ferric-reducing antioxidant power (FRAP) was most strongly correlated with the polymeric procyanidin concentration. Noting that polymeric procyanidins may not cross the cell layer to exert antioxidant activity in vivo, their presence in apple pomace extracts may therefore overestimate the FRAP. This work highlights the importance of polymeric procyanidins in the phenolic diversity of apple pomaces, and it is proposed that in future studies, rapid MCP assays may be used for their quantification.