Continuous Monitoring of the Agglomeration and Sedimentation of Indomethacin Nanosuspensions Using T2 Relaxation Time with Time-Domain NMR.

The time-domain NMR technique was utilized to monitor precisely the physicochemical stability of indomethacin (IMC) nanosuspensions using T2 relaxation time (T2). We investigated whether T2 values can distinguish between agglomeration and sedimentation. Nanosuspensions of IMC were prepared using aqueous wet bead milling with polyvinylpyrrolidone as a stabilizer. Prepared nanosuspensions were divided into two fractions: one was stored in the NMR equipment for continuous T2 measurements and the other was stored in the dispersion analyzer. Measurements of both nanosuspensions were carried out, without dilution, over a period of 24 h at 10-min intervals. Transmission profiles based on multilight scattering technology showed that agglomeration predominantly occurred at 25 and 35 °C immediately after wet bead milling up to 4 h, followed by sedimentation from 4 to 24 h. Upon measuring the T2 relaxation, T2 values at both 25 and 35 °C showed a two-step change-there was a significant prolongation in T2 values immediately after preparation of nanosuspensions up to approx. 4 h and a gradual prolongation in T2 values from approx. 4 to 24 h. Considering the results of transmission profiles, these two-step T2 changes correspond to agglomeration and sedimentation. In other words, this study established that monitoring the T2 values of nanosuspensions could be used to evaluate the agglomeration and sedimentation of contained drug particles. This technique does not directly observe the nanoparticles themselves, but the water molecules. Thus, measurement of T2 relaxation is considered to be a general-purpose technique, independent of the type of drug or polymer.

A Data-Driven Approach to Predicting Tablet Properties after Accelerated Test Using Raw Material Property Database and Machine Learning.

The purpose of this study was to develop a model for predicting tablet properties after an accelerated test and to determine whether molecular descriptors affect tablet properties. Tablets were prepared using 81 types of active pharmaceutical ingredients, with the same formulation and three different levels of compression pressure. The tablet properties measured were the tensile strength and disintegration time of tablets after two weeks of accelerated test. The material properties measured were the change in tablet thickness before and after the accelerated test, maximum swelling force, swelling time, and swelling rate. The acquired data were added to our previously constructed database containing a total of 20 material properties and 3381 molecular descriptors. The feature importance values of molecular descriptors, material properties and the compression pressure for each tablet property were calculated by random forest, which is one type of machine learning (ML) that uses ensemble learning and decision trees. The results showed that more than half of the top 25 most important features were molecular descriptors for both tablet properties, indicating that molecular descriptors are strongly related to tablet properties. A prediction model of tablet properties was constructed by eight ML types using 25 of the most important features. The results showed that the boosted neural network exhibited the best prediction accuracy and was able to predict tablet properties with high accuracy. A data-driven approach is useful for discovering intricate relationships hidden within complex and large data sets and predicting tablet properties after an accelerated test.

Determination of the Solid Content of Active Pharmaceutical Ingredient Powders in Suspension-Type Pharmaceutical Oral Jelly Using Time-Domain NMR.

This study determined the content of solid active pharmaceutical ingredient (API) powders dispersed in suspension-type pharmaceutical oral jellies using a low-field time-domain NMR (TD-NMR). The suspended jellies containing a designated API content were prepared and tested. Acetaminophen (APAP), indomethacin (IMC) and L-valine were used as test APIs. First, this study measured the T2 relaxation rate (the reciprocal of T2 relaxation time) by the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, and then evaluated whether the API content could be determined by the acquired T2 relaxation rate. The T2 relaxation rate negatively correlated with API content to a certain extent, but their correlation was not sufficient for achieving a precise determination. Subsequently, the solid-echo pulse sequence measurement was adopted for this study. We found that NMR signals corresponding to solid components strongly correlated with API content. Thus, this method achieved a precise determination of API contents in suspended jellies. In addition, this study confirmed the effect of API particle size on the T2 relaxation rate by using an L-valine-containing jelly: the T2 relaxation rate became faster when a smaller API size was incorporated into the suspended jelly, while there was no difference in terms of the NMR signals measured by solid-echo pulse sequence. From these findings, TD-NMR could be a powerful tool for evaluating the API dispersion state in suspended oral jellies.

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.

Low-Field NMR to Characterize the Crystalline State of Ibuprofen Confined in Ordered or Nonordered Mesoporous Silica.

The crystalline state of ibuprofen (IBU) confined in mesoporous silica was characterized using low-field time-domain nuclear magnetic resonance (TD-NMR). IBU was loaded into ordered (Santa Barbara Amorphous-15 [SBA-15]; SBA) or nonordered mesoporous silica (Sylysia 320; SYL) using a well-known incipient wetness impregnation method. The dissolution profile of IBU from the silica was measured. The IBU-loaded SBA showed a relatively higher drug concentration at 10 and 20 min, which was typical of a supersaturated solution. However, it did not maintain that concentration. By contrast, the IBU-loaded SYL did not show such a dissolution profile in the early stage. To characterize the crystalline state of IBU confined in silica, the T1 relaxation time of IBU-loaded silica powder was measured and analyzed by curve fitting. Monophasic T1 relaxation was observed for IBU-loaded SBA. This may indicate that the amorphous phase, which has various molecular mobilities, was close to within the length of 1H spin diffusion. The TD-NMR technique, even if the sample is powder, can rapidly and easily measure NMR relaxation. Therefore, it can be useful toward fully characterizing the crystalline state of drugs confined in mesopores.

Characterization of the Salt and Free Base of Active Pharmaceutical Ingredients Based on NMR Relaxometry Measured by Time Domain NMR.

NMR relaxometry measurement by time domain NMR (TD-NMR) is a promising technique for characterizing the properties of active pharmaceutical ingredients (APIs). This study is dedicated to identifying the salt and free base of APIs by NMR relaxometry measured by the TD-NMR technique. Procaine (PC) and tetracaine (TC) were selected as model APIs to be tested. By using conventional methods including powder X-ray diffraction and differential scanning calorimetry, this study first confirmed that the salt and free base of the tested APIs differ from each other in their crystalline form. Subsequently, measurements of T1 and T2 relaxation were performed on the tested APIs using TD-NMR. The results demonstrated that these NMR relaxometry measurements have sufficient capacity to distinguish the difference between the free base and salt of the tested APIs. Furthermore, quantification of the composition of the binary powder blends consisting of salt and free bases was conducted by analyzing the acquired T1 and T2 relaxation curves. The analysis of the T1 relaxation curves provided a partly acceptable estimation: a good estimation of the composition was observed from PC powders, whereas for TC powders the estimation accuracy changed with the free base content in the binary blends. For the analysis on T2 relaxation curves, a precise estimation of the composition was observed from all the samples. From these findings, the NMR relaxometry measurement by TD-NMR, in particular the T2 relaxation measurement, is effective for evaluating the properties of APIs having different crystalline forms.

Determination of Hardness of a Pharmaceutical Oral Jelly by Using T2 Relaxation Behavior Measured by Time-Domain NMR.

Hardness is a critical quality characteristic of pharmaceutical oral jelly. In this study, the hardness was determined by using the T2 relaxation curves measured by time-domain NMR. For sample preparation, kappa- and iota-carrageenans, and locust bean gum, were used as gel-forming agents. Ten test jellies with different gel-forming agent composition were prepared, and their hardness and T2 relaxation curves were measured by a texture analyzer and time-domain NMR (TD-NMR). A negative correlation between T2 relaxation time (T2) and hardness was observed; however, it was difficult to determine the hardness directly from the T2 value. That is probably because the T2 relaxation curve contains information about molecular states, not only of water but also of the solute, and T2 values calculated by single-exponential curve fitting only express one property of the test jelly. By considering this issue, partial least squares (PLS) regression analysis was performed on the T2 relaxation curves for hardness determination of the test jellies. According to the analysis, an accurate and reliable PLS model was created that enabled accurate assessment of the hardness of the test jellies. TD-NMR enables the measurement of samples nondestructively and rapidly with low cost, and so could be a promising method for evaluation of the hardness of pharmaceutical oral jellies.

Effects of Manufacturing Process Variables on the Tablet Weight Variation of Mini-tablets Clarified by a Definitive Screening Design.

This study investigated the effect of manufacturing process variables of mini-tablets, in particular, the effect of process variables concerning fluidized bed granulation on tablet weight variation. Test granules were produced with different granulation conditions according to a definitive screening design (DSD). The five evaluated factors assigned to DSD were: the grinding speed of the sample mill at the grinding process of the active pharmaceutical ingredient (X1), microcrystalline cellulose content in granules (X2), inlet air temperature (X3), binder concentration (X4) and the spray speed of the binder solution (X5) at the granulation process. First, the relationships between the evaluated factors and the granule properties were investigated. As a result of the DSD analysis, the mode of action of granulation parameters on the granule properties was fully characterized. Subsequently, the variation in tablet weight was examined. In addition to mini-tablets (3 mm diameter), this experiment assessed regular tablets (8 mm diameter). From the results for regular tablets, the variation in tablet weight was affected by the flowability of granules. By contrast, regarding the mini-tablets, no significant effect on the variation of tablet weight was found from the evaluated factors. From this result, this study further focused on other important factors besides the granulation process, and then the effect of the die-hole position of the multiple-tip tooling on tablet weight variation was proven to be significant. Our findings provide a better understanding of manufacturing mini-tablets.

A Novel Approach to Evaluate Amorphous-to-Crystalline Transformation of Active Pharmaceutical Ingredients in Solid Dispersion Using Time-Domain NMR.

The aim of this study was to demonstrate the usefulness of the time-domain NMR (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing a solid dispersion. In this study, indomethacin (IMC) was used as a model for poorly water-soluble API. Solid dispersions of IMC were prepared with polyvinylpyrrolidone (PVP) at different weight ratios. First, we measured the T1 relaxation behavior of solid dispersions. From the result, the T1 relaxation time (T1) changed according to the API content; the T1 tended to increase with increasing API content because the T1 value of amorphous IMC was longer than that of PVP. Next, we tried to monitor the amorphous-to-crystalline transformation of IMC in the solid dispersion during the thermal stress test. In the case of solid dispersion containing 90% IMC, a clear prolongation of the T1 could be observed during the thermal stress test. From the powder X-ray diffraction patterns, the change in T1 relaxation behavior must be caused by the IMC transformation from amorphous to crystalline. From these findings, we were successful in monitoring the IMC amorphous-to-crystalline transformation by the changes in T1 relaxation behavior. Our findings led us to conclude that TD-NMR is a novel approach for the evaluation of crystalline state of APIs in solid dispersions.

T2 Relaxation Study to Evaluate the Crystalline State of Indomethacin Containing Solid Dispersions Using Time-Domain NMR.

The aim of this study was to demonstrate the usefulness of T2 measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. A solid dispersion (SD) and a physical mixture (PM) consisting of indomethacin (IMC) and polyvinylpyrrolidone (PVP) were prepared at different weight ratios as test samples, and then their T2 relaxation curves were measured by TD-NMR. The T2 relaxation curve of IMC was quite different from that of PVP by nature. T2 values of the SD and PM samples became gradually shortened with increasing IMC content. No difference in T2 relaxation curves was observed between SD and PM. By analyzing the T2 relaxation curves in detail, we succeeded in precisely quantifying the IMC contents incorporated in the samples. Next, this study evaluated the T2 relaxation curves of amorphous and crystalline states of powdered IMC. T2 relaxation rate of crystalline IMC was slightly but significantly higher than that of amorphous IMC, proving that the T2 measurement was sensitive enough to detect these differences. Finally, a thermal stress was imposed on SD and PM samples at 60°C for 7 d, and then an amorphous-to-crystalline transformation occurred in IMC in the PM sample and was successfully monitored by T2 measurement. We believe that T2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.

A Time-Domain NMR Study of the State of Water in Wet Granules with Different Fillers and Its Contribution to the Wet Granulation Process and to the Characteristics of Granules.

The different states of water incorporated in wet granules were studied by a low-field benchtop 1H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T2) was measured using the NMR relaxation technique. The experimental T2 relaxation curves were analyzed by the two-component curve fitting, and then the individual T2 relaxation behaviors of solid and water in wet granules were identified. According to the observed T2 values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.

Nondestructive Monitoring of the Dispersion State of Titanium Dioxide Nanoparticles in Concentrated Suspensions Using Magnetic Resonance Imaging.

The purpose of the present study is to demonstrate the applicability of magnetic resonance imaging, especially T2 relaxation time mapping, for nondestructive monitoring of the dispersion state of nanoparticles (NPs) in concentrated suspensions. TiO2 15-nm-diameter NPs, for use in sunscreen lotion products, were examined as a test NP. First, this study investigated whether T2 is sensitive to the NP concentration. In experiments with pulsed nuclear magnetic resonance on TiO2 NP suspensions with different organic solvents (ethanol, acetone, and decamethylcyclopentasiloxane), the T2 of each solvent varied in the suspensions according to the NP concentration. This study also confirmed that T2 mapping was effective for visualizing differences in NP concentration. Subsequently, gravitational sedimentation of the test suspensions was investigated. T2 mapping exhibited better detection sensitivity to sedimentation occurring in concentrated suspensions than visual observation, as it enabled the detection of changes in NP distributions that could not be visible to the naked eye. In addition, measurements of backscattered light enabled the full understanding of the dispersion stability of the TiO2 NPs in each solvent. Finally, the present study evaluated the centrifuge sedimentation of a commercial TiO2 NP suspension. T2 mapping clearly showed the complicated sedimentation behavior induced by the centrifugation treatment. The simulated fluid flow was consistent with the particle distribution in the centrifuged sample; thus, the sedimentation was believed to have developed in accordance with the vorticity generated by the centrifugation.

MRI Monitoring of the Mixed State of Admixtures Consisting of Moisturizing Cream and Steroid Ointment during the Mixing Process by a Revolution/Rotation-Type Hybrid Mixer.

The admixture of a steroid ointment and a moisturizing cream is frequently prescribed to patients suffering from atopic dermatitis. For the mixing operation, a revolution/rotation-type hybrid mixer is widely used in pharmacy. The purpose of this study was to monitor the mixed state of the admixtures during the mixing process of the hybrid mixer. The key technology used in this study was magnetic resonance imaging (MRI). Two different commercial mometasone furoate-containing ointments were used as a test steroid ointment. After layering the moisturizing cream and the steroid ointment in an ointment bottle, the sample was mixed for a predetermined period using the hybrid mixer. According to MRI transverse relaxation time (T2) mapping for nondestructive monitoring, it was confirmed that the Flumeta® ointment-containing admixture became homogeneous by mixing for 60 s or more. As for the mometasone furoate ointment 0.1%-containing admixture, the mixed state, after becoming homogeneous, was separated into two layers again by the prolonged mixing process. From the 1H-NMR spectra of the phase-separated layers, re-separation was caused by removing aqueous components from the bottom of the samples. MRI is a powerful tool for monitoring the mixed state of the admixture during the mixing process. We believe that our findings offer profound insights into the clinical practice of the mixing operation using a hybrid mixer.

Inhibition of Gastric H+,K+-ATPase Activity in Vitro by Dissolution Media of Original Brand-Name and Generic Tablets of Lansoprazole, a Proton Pump Inhibitor.

To investigate the inhibitory effect of a commercial proton pump inhibitor (lansoprazole) on the gastric proton pump H+,K+-ATPase in vitro, we used orally disintegrating (OD) tablets including original brand-name and generic tablets. In the course of the development of generic products, dissolution and clinical tests are necessary to ensure their bioequivalence to the original brand-name products; by contrast, there is almost no opportunity to demonstrate their activity in vitro. This study initially compared the similarity of the dissolution of test generic tablets with that of the original brand-name tablets. The dissolution tests for 15 and 30-mg lansoprazole tablets found their dissolution properties were similar. Subsequently, the dissolution media were sampled and then their effects on the H+,K+-ATPase activity were measured using tubulovesicles prepared from the gastric mucosa of hogs. We confirmed that the inhibitory effects of the generic tablets on H+,K+-ATPase activity were consistent with those of the original brand-name tablets. Furthermore, lansoprazole contents in each tablet estimated from their inhibitory effects were in good agreement with their active pharmaceutical ingredient content. To our knowledge, this is the first technical report to compare the in vitro biochemical activity of lansoprazole OD tablets between the original brand-name and generic commercial products.

Use of Time-Domain NMR for 1H T1 Relaxation Measurement and Fitting Analysis in Homogeneity Evaluation of Amorphous Solid Dispersion.

This study examined the usefulness of 1H T1 relaxation measurements for evaluating the homogeneity of amorphous solid dispersion (ASD). Indomethacin and polyvinylpyrrolidone were used to prepare two kinds of ASDs. One was inhomogeneous ASD (ASDmelt) prepared by a melt-quenching method, and the other was homogeneous ASD (ASDsolvent) prepared by a solvent evaporation method. The T1 relaxation was measured by the time-domain NMR (TD-NMR) technique using a low-field NMR system. Curve-fitting analysis of T1 relaxation plots was conducted using the Akaike information criterion. This fitting analysis revealed that the T1 relaxation of ASDmelt and ASDsolvent was biphasic and monophasic, respectively. ASDmelt and ASDsolvent were inhomogeneous and homogeneous on a nanometer scale, respectively, considering the spin diffusion of 1H nuclei. These T1 results were consistent with the Raman mapping of ASDs. From the fitting analysis of 1H T1 relaxation, we conclude that TD-NMR is a promising technique for evaluating ASD homogeneity.

TGA and NMR relaxation measurement of nonmesoporous silica to investigate the amount of hydrolysis product in acetylsalicylic acid adsorbed on silica.

This study investigated a crucial surface property of silica that contributes to the chemical stability of acetylsalicylic acid (ASA) physically adsorbed on silica. Hydrophilic nonmesoporous types of silica were selected, and the number of hydroxyl groups on silica (N(OH)) was evaluated using thermogravimetric analysis (TGA). The ASA-containing silica was stored at 40 °C in drying conditions, and the amount of ASA degradation was quantified based on salicylic acid. From the scatterplots between the number of hydroxyl groups per unit weight (specific surface area (SSA) × N(OH)) and the amount of ASA degradation, it was clarified that in ASA adsorbed on silica, the ASA chemical stability was determined by the formula (the SSA × N(OH)). In addition, a time-domain nuclear magnetic resonance measurement verified the N(OH) result by estimating the interaction between the silica surface and water in an aqueous silica suspension. The N(OH) result was found to be reasonable.

[Time-Domain NMR Study to Evaluate Physical Properties of Pharmaceutical Dosage Forms for Process Analysis].

Here, we sought to investigate the usefulness of time-domain NMR (TD-NMR) for evaluating the physical properties of drug formulations. TD-NMR measures NMR relaxation and is mainly performed using a bench-top low-field NMR system (e.g., 20 MHz); thus, it does not require any specific sample shape for measurement if the sample is not gas. Taking advantage of these features, TD-NMR has been widely used for quality control in food science. However, it has rarely been used in the pharmaceutical field. The T1 and T2 relaxations are not spectra like those obtained by a high-field NMR system (e.g., 300-600 MHz) but only curves in which the NMR signal recovers or decays according to a specific rule. Therefore, selecting the equation used in the fitting analysis is crucial to estimate the time constants, T1 and T2 relaxation times. As the result of a series of studies, the T1 relaxation measurement by TD-NMR was shown to help evaluate the crystallinity of drugs in solid dosage forms and the miscibility of a drug and excipient in a binary mixture. The T2 relaxation measurement was also helpful for quantitatively evaluating the solid form of drugs in a physical mixture with or without moisture adsorption. TD-NMR is an excellent technique widely applied to evaluating the physical properties of various formulations, whether solid or liquid, and is expected to be applied to process analysis and quality control in the pharmaceutical field.

Usefulness of Applying Partial Least Squares Regression to T2 Relaxation Curves for Predicting the Solid form Content in Binary Physical Mixtures.

This study applied partial least squares (PLS) regression to nuclear magnetic resonance (NMR) relaxation curves to quantify the free base of an active pharmaceutical ingredient powder. We measured the T2 relaxation of intact and moisture-absorbed physical mixtures of tetracaine free base (TC) and its hydrochloride salt (TC·HCl). The obtained T2 relaxation curves were analyzed by two methods, one using a previously reported T2 relaxation time (T2), and the other using PLS regression. The accuracy of estimating TC was inadequate when using previous T2 values because the moisture-absorbed physical mixtures showed biphasic T2 relaxation curves. By contrast, the entire measured whole of the T2 relaxation curves was used as input variables and analyzed by PLS regression to quantify the content of TC in the moisture-absorbed TC/TC·HCl. Based on scatterplots of theoretical versus predicted TC, the obtained PLS model exhibited acceptable coefficients of determination and relatively low root mean squared error values for calibration and validation data. The statistical values confirmed that an accurate and reliable PLS model was created to quantify TC in even moisture-absorbed TC/TC·HCl. The bench-top low-field NMR instrument used to apply PLS regression to the T2 relaxation curve may be a promising tool in process analytical technology.

Application of unsupervised and supervised learning to a material attribute database of tablets produced at two different granulation scales.

The purpose of this study is to demonstrate the usefulness of machine learning (ML) for analyzing a material attribute database from tablets produced at different granulation scales. High shear wet granulators (scale 30 g and 1000 g) were used and data were collected according to the design of experiments at different scales. In total, 38 different tablets were prepared, and the tensile strength (TS) and dissolution rate after 10 min (DS10) were measured. In addition, 15 material attributes (MAs) related to particle size distribution, bulk density, elasticity, plasticity, surface properties, and moisture content of granules were evaluated. By using unsupervised learning including principal component analysis and hierarchical cluster analysis, the regions of tablets produced at each scale were visualized. Subsequently, supervised learning with feature selection including partial least squares regression with variable importance in projection and elastic net were applied. The constructed models could predict the TS and DS10 from the MAs and the compression force with high accuracy (R2= 0.777 and 0.748, respectively), independent of scale. In addition, important factors were successfully identified. ML can be used for better understanding of similarity/dissimilarity between scales, for constructing predictive models of critical quality attributes, and for determining critical factors.

Formation of higher-order structures of chiral poly(ethynylpyridine)s depending on size, temperature, and saccharide recognition.

Amphiphilic 2,6-pyridylene ethynylene "meta-ethynylpyridine" polymers having chiral oligo(oxyethylene) side chains were developed as hosts for saccharide recognition. The polymers were prepared via a Sonogashira reaction and fractionated by gel permeation chromatography (GPC). They showed circular dichroism (CD) activity due to their higher-order chiral helical structures, and their CD and UV-vis spectra changed depending on not only saccharide recognition but also molecular size, temperature, and metal cation recognition.