Language：Japanese   Publisher：Journal of the Australian Ceramic Society  

As society ages, the treatment of osteoporosis has become an issue that must be solved. In this study, we evaluated the effects of hydroxyapatite, βTCP, strontium calcium-deficient apatite, and strontium βTCP on osteoclasts using osteoporosis model zebrafish. Calcium-deficient strontium nanocrystalline apatite was achieved by mechanochemical synthesis. Characterization of the synthesized samples was analyzed by XRD, FTIR, and TG/DTA. In an experiment where zebrafish, used as a model for osteoporosis, were exposed to various apatites, the morphology of osteoclasts was observed by evaluating their scales. The apatites to which the zebrafish were exposed were suggested to influence the differentiation of osteoclasts.

DOI： 10.1007/s41779-025-01323-8

Scopus

Language：Japanese   Publisher：Ceramics International  

This study aims to investigate crystallization of strontium-substituted hydroxyapatite upon sintering. A study of mechanochemically-synthesized hydroxyapatite (HAp), doped with strontium at varying levels from 0 to 20 % is presented. The Sr-doped HAp powders were obtained by a mechanochemical method, followed by sintering at 1000 °C. The sintered samples were characterized using a complimentary set of SEM-EDX, XRD, FTIR, Raman, and solid-state NMR techniques. The FTIR spectra of the sintered samples showed a decreasing ν OH vibrational bands with increasing Sr content. This conflict is resolved by multinuclear solid-state NMR which conclusively demonstrates presence of OH⁻ in all samples, and that the strontium doping does not influence the OH⁻ concentration. Sr doping is demonstrated to not be random, with evidence of clustering, but without phase segregation even at the higher Sr loadings. The structural transformations of HAp revealed herein have significant implications in ongoing development of hydroxyapatite based systems, in monitoring the degree of hydroxylation, phase structure and concomitant effects on crystallinity and bioactivity.

DOI： 10.1016/j.ceramint.2025.04.022

Scopus

Language：Japanese   Publisher：Journal of the Australian Ceramic Society  

In this study, near-infrared (NIR) spectroscopy, a measurement method not widely used in dentistry, was used to monitor the synthesis of calcium phosphate cement. Tetra calcium phosphate and di calcium phosphate dihydrate were mixed at a Ca/P ratio of 1.67, and water was added dropwise to induce the phase transition to HAp. The reaction conditions were evaluated by measuring NIR spectra every minute for 60 min and every 20 min for 24 h. The obtained NIR spectra were analyzed using singular value decomposition. The synthesized apatite was characterized by measuring XRD, FT-IR, and SEM. In the self-setting apatite cement system, 24-hour monitoring revealed that a phase transition was achieved. NIR monitoring was found to be effective and valuable for evaluating calcium phosphate cements.

DOI： 10.1007/s41779-024-01143-2

Scopus

Language：Japanese   Publisher：Journal of Nondestructive Evaluation  

This study aims to investigate the reaction kinetics of polycarboxylate cements using NIR spectroscopy with chemometrics. To achieve 100% inspection of medical devices and drugs, it is desirable to develop non-destructive, non-contact quality control methods. One effective method for this is chemometrics, which uses near-infrared spectroscopy and chemometrics. A dental cement, polycarboxylate cement, was prepared, and the spectral changes from 1 min to 15 min were observed using NIR spectroscopy. The obtained spectra were evaluated by two-dimensional correlation spectroscopy. Carboxylate changes in the cement were analyzed using principal component analysis, and a score plot against loadings and time was shown. It was suggested that the hardening mechanism of cement can be plotted as a pseudo-first-order reaction.

DOI： 10.1007/s10921-025-01185-x

Scopus

Language：Japanese   Publisher：Biomedical Materials (Bristol)  

Because of its superior strength, esthetic properties, and excellent biocompatibility, zirconia is preferred for dental prosthetic such as crowns and bridges. However, zirconia crowns and bridges are susceptible to secondary caries owing to margin leakage. Silver is a well-known antibacterial agent, making it a desirable additive to zirconia crowns and bridges for secondary caries prevention. This study focuses on imparting zirconia composite with antibacterial properties to enhance its protective capacity in dental restorations. We used the sol-gel method to dope Ag into zirconia. Silver-doped zirconia powders were prepared at Zr:Ag molar ratios of 100:0,100:0.1, 100:0.5, 100:1, 100:3, and 100:5 (respective samples denoted as Ag-0, Ag-0.1, Ag-0.5, Ag-1, Ag-3, and Ag-5) and were subjected to firing at various temperatures (400 °C-1000 °C). We performed x-ray diffraction to investigate the crystal phase of these powders and x-ray fluorescence and field emission scanning electron microscopy to analyze their elemental composition and surface morphology, respectively. Moreover, we performed spectrophotometry to determine the L*a*b* color values, conducted dissolution tests, and quantified the Ag content through inductively coupled plasma optical emission spectroscopy. In addition, we studied the antibacterial activity of the samples. Analyses of the samples fired at ⩽600 °C revealed a predominantly white to grayish-white coloration and a tetragonal crystal phase. Firing at ⩾700 °C resulted in gray or dark gray coloration and a monoclinic crystal phase. The Ag content decreased after firing at 900 °C or 1000 °C. Ag-0.5 and above exhibited antibacterial activity against both Escherichia coli and Staphylococcus aureus. Therefore, the minimum effective silver-doped zirconia sample was found to be Ag-0.5. This study allows the exploration of the antimicrobial potential of silver-doped zirconia materials in dental applications such as prosthdontical lining materials, promoting the development of innovative restorations with protective capacity against secondary caries.

DOI： 10.1088/1748-605X/ad6ac3

Scopus

Language：Japanese   Publisher：RSC Advances  

Zirconia ceramics are widely used as dental prosthetics owing to their high biocompatibility, excellent mechanical strength, and aesthetic properties similar to color tones of natural teeth. However, there exists a growing demand for the facile attachment of antibacterial properties in long-term dental restoration. Thus, in this study, we evaluated the adsorption ability of cetylpyridinium chloride (CPC) and benzalkonium chloride (BKC)—quaternary amines widely used as antibacterial substances in commercial toothpaste and other oral care products—onto zirconia surfaces with tetragonal and monoclinic crystal structures. Although tetragonal zirconia has been widely used in dental prosthetic materials such as crowns etc., monoclinic zirconia has also been used under oral conditions because of long-term implantation. When antibacterial molecule loading on zirconia powders under simulated oral conditions, it was revealed that monoclinic zirconia adsorbed approximately five times more CPC and BKC per unit area compared with that of tetragonal zirconia. Moreover, in tetragonal zirconia, the adsorption amounts of both CPC and BKC increased slightly with growing Y2O3 content as a stabilizer. This phenomenon was attributable to the formation of complexes between rare earth elements (REE) such as Y2O3 in zirconia and quaternary amines such as CPC and BKC. In this study, the antibacterial molecular adsorption ability of dental zirconia was observed, and new advantages of zirconia in dental applications were discovered.

DOI： 10.1039/d4ra04084h

Scopus

Language：Japanese   Publisher：Bio-Medical Materials and Engineering  

BACKGROUND: Research using panoramic X-ray images using deep learning has been progressing in recent years. There is a need to propose methods that can classify and predict from image information. OBJECTIVE: In this study, Eichner classification was performed on image processing based on panoramic X-ray images. The Eichner classification was based on the remaining teeth, with the aim of making partial dentures. This classification was based on the condition that the occlusal position was supported by the remaining teeth in the upper and lower jaws. METHODS: Classification models were constructed using two convolutional neural network methods: The sequential and VGG19 models. The accuracy was compared with the accuracy of Eichner classification using the sequential and VGG19 models. RESULTS: Both accuracies were greater than 81%, and they had sufficient functions for the Eichner classification. CONCLUSION: We were able to build a highly accurate prediction model using deep learning scratch sequential model and VGG19. This predictive model will become part of the basic considerations for future AI research in dentistry.

DOI： 10.3233/BME-230217

Scopus

Language：Japanese   Publisher：Journal of the Australian Ceramic Society  

There is demand for the development of highly functional and flexible bone fillers to treat bone defects. This research aimed to fabricate calcium phosphate implants with a flexible porous design and sufficient compressive stress using a three-dimensional 3D printer. A mixed slurry of dicalcium phosphate, calcium hydroxide, photopolymerized resin, and polyethylene glycol (PEG) was prepared using a planetary ball mill. The slurry was formed into a porous model using a stereolithography-type 3D printer. Upon sintering, the resin and PEG evaporated and/or combusted, yielding a β- tricalcium phosphate (TCP) molding with porosity. This study proposes a novel method for freely molding calcium phosphate implants.

DOI： 10.1007/s41779-024-01076-w

Scopus

Language：Japanese   Publisher：Journal of the Australian Ceramic Society  

The aim of this study is to investigate the effect of the addition of Mg ion on calcium phosphate during mechanochemical synthesis. Ca(OH)2, dicalcium phosphate dihydrate (DCPD), and Mg(OH)2 were mechanochemically synthesized using ball milling with pure water. The prepared samples were evaluated by powder X-ray diffraction analysis (XRD), FT-infrared (IR) spectral analysis, and a TNF alpha test with murine macrophage-like cell line RAW264.7 cells for assessing the immune activation. The cell culture studies indicated that CaMg apatite can be used as bioceramic. Mg ion-doped Ca apatite, which also contains carbonated ions in the crystal, was identified based on the XRD patterns and FTIR spectra. The unique diffraction peaks of apatite at 211, 112, 300, and 202 decreased in the sample containing Mg(OH)2, suggesting a decrease in the rate of crystallization. In addition, the phosphate infrared bands of the samples were different from those of the carbonated apatite. To investigate the details of the effects of Mg ion, multiple spectra combining XRD patterns and FTIR spectra were prepared. The multiple spectra datasets were used for the estimation by multivariate curve resolution-alternating least squares (MCR-ALS). The effects of Mg ion on apatite as calcium phosphate were investigated by multiple spectra multivariate analysis. The analysis postulated that Mg ion decreased the apatite crystallinities possibly by adsorption at the growth sides and that these added ions strongly inhibited the formation of the thermodynamically most stable hydroxyapatite.

DOI： 10.1007/s41779-023-00919-2

Scopus

Language：Japanese   Publisher：Open Ceramics  

Strontium-substituted apatite has been proposed as a promising material for osteoporosis treatment. Several synthesis methods have been attempted in the past. In this study, we investigated a method known as the mechanochemical synthesis method. Characterization was carried out using different amounts of strontium ions in the hydroxyapatite (HAp) matrix with FT-IR spectral analysis, X-ray diffraction, lattice constant measurements, differential thermal analysis (DTA), terahertz spectroscopy, and investigation of the basic morphology using scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX). We report that the development and performance of mechanochemical synthetic pathways are more efficient and economical than other substituted apatite formation methods and are useful in the biomedical field to produce calcium phosphate-based clinical materials. The FTIR spectra, terahertz spectra, and XRD analysis results revealed that the mixture of dicalcium phosphate dihydrate (DCPD), Ca(OH)2 and Sr(OH)2 8H2O was phase-transformed into strontium-containing carbonate amorphous apatite by this simple and economical mechanochemical synthesis method.

DOI： 10.1016/j.oceram.2023.100459

Scopus

Authorship：Lead author,　Corresponding author   Language：English  

DOI： 10.3233/BME-230073

Language：Japanese   Publisher：Physical Chemistry Chemical Physics  

The nonionic surfactants Tween 80 (Tw80) and Triton X-100 (TX100), which are used as components of adjuvants, were used with bovine serum albumin (BSA) and hydroxfypropyl-β-cyclodextrin (HP-β-CD) as model antigens. The interaction patterns of Tw80 and TX100 with the hydrophobic cores of the model antigens were investigated. The fluorescence of 8-anilinonaphthalene-1-sulfonic acid (ANS), a hydrophobic fluorescent probe, was used to evaluate the effect of surfactants on each model antigen. A Hanes Woolf plot was used to analyze the adsorption of ANS to BSA, and an activator-inhibitor model was used to analyze the concentration-dependent increase and decrease of ANS fluorescence intensity. For BSA, TX100 occupies the ANS binding site inside the BSA hydrophobic core, while Tw80 does not contribute to the ANS binding site in the hydrophobic core. For HP-β-CD, the ANS concentration required for analyzable fluorescence intensity extended to the range where ANS concentration-dependent quenching was not negligible. Using the activator inhibitor model, we were able to separate the activators and inhibitors of ANS fluorescence and evaluate the affinity of ANS for HP-β-CD and surfactants. The results obtained showed that TX100 provided a hydrophobic environment to the ANS while being encapsulated by HP-β-CD, while Tw80 did not interact with HP-β-CD and provided a hydrophobic environment to the ANS independently of each other. The interpretations obtained were corroborated by the determination of the CMC of TX100 and Tw80, the effect of salt on ANS fluorescence, and 1H-NMR and ROESY. In summary, the results showed that the large hydrophilic head of Tween, composed of sorbitan and PEG chains, floated in the aqueous phase like a balloon, while Triton pierced the hydrophobic core of the antigen like a spear. In both BSA and HP-β-CD model antigens, TX100 impinged on the hydrophobic core.

DOI： 10.1039/d3cp00094j

Scopus

Language：Japanese   Publisher：Journal of Inclusion Phenomena and Macrocyclic Chemistry  

Ketoprofen is a nonsteroidal anti-inflammatory drug used as mohrus tape which causes unwanted photosensitivity due to UV irradiation. In addition, photodegradation of ketoprofen induces its decarboxylation. Here, we aim to determine the effect of cyclodextrin on the photolysis of ketoprofen. Separation technique using HPLC confirmed that UV irradiation of ketoprofen produced multiple products. A unique reaction proceeded in the presence of β-cyclodextrin. Furthermore, characterization by UV spectroscopy was performed, and the obtained spectra were analyzed using singular value decomposition. By analyzing the trajectory of the singular vector space, we were able to reflect the difference in the reaction pathway of ketoprofen with and without cyclodextrin. This study uses a singular value decomposition analysis, which is useful as a novel approach for solutions of radical reactions and a promising technique for analysis of radical reactions in the future. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s10847-022-01160-3

Scopus

Language：Japanese   Publisher：Food Bioscience  

Background: Among the antioxidant reactions, no correlation (R2 = 0.5468) has been observed between the logarithm of the reciprocal of EC50 obtained by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays, which can measure single electron transfer reactions. Therefore, we attempted to investigate the radical scavenging reaction of each antioxidant in the DPPH and ABTS assays by using electron spin resonance (ESR), and to study an analytical method that can eliminate other than that factor. Results: Singular value decomposition (SVD) of the spectra that were obtained by ESR measurements was used to separate the components and to determine the detailed changes of each component. We calculated the EC50 from the changes in the spectra of the first and second components owing to the change in the antioxidant concentration in the DPPH and ABTS assays to identify which component contributed more to the radical scavenging reaction. The results demonstrated a positive correlation (R2 = 0.8806) between the EC50s of the first component of each of the DPPH and ABTS assays. In this study, common spectral changes were observed for all compounds with radical scavenging activity, so the first component was considered to be radical scavenging activity. Conclusions: Through this study, we could calculate the EC50 that significantly contributed to the radical scavenging reaction by decomposing the spectra that were obtained from ESR measurements of the reactions by the DPPH and ABTS assays into specific values.

DOI： 10.1016/j.fbio.2022.101714

Scopus

Language：Japanese   Publisher：Colloids and Surfaces B: Biointerfaces  

In the present study, we investigated the effect of bile salts (sodium deoxycholate, NaDC) on the conformation of a globular protein (bovine serum albumin, BSA). The two Tryptophan (Trp) residues of BSA and the fluorescence energy of NaDC are in a three-way relationship, and singular value decomposition (SVD) was used to separate each element in the fluorescence spectra. SVD was used to separate the elements in the fluorescence spectra. SVD showed that NaDC had a particularly large effect on the microenvironment around Trp213 and that micellar NaDC enhanced the selectivity for Trp213. In addition, the Stern-Volmer plots of the warfarin (WAR) specific domain (domain I) and ketoprofen (KP) specific domain (domain II) in the presence and absence of NaDC showed that the effect of NaDC was selective for domain II, where Trp213 is located. These results indicate that NaDC induces a localized and selective conformational change in BSA, and that the selectivity varies depending on the aggregation state of NaDC.

DOI： 10.1016/j.colsurfb.2022.112344

Scopus

Language：Japanese   Publisher：Journal of Inclusion Phenomena and Macrocyclic Chemistry  

Abstract: Antioxidants scavenge free radicals and may help prevent disease. However, due to poor stability, continuous intake is required. This study investigates the ability of cyclodextrin inclusion to improve the stability of the novel antioxidant edaravone. Kinetic models of cyclodextrin protection against edaravone oxidative decomposition were assessed and the data obtained was analyzed using Hanes–Woolf plots and Scatchard plots. In addition, complexation was analyzed using phase-solubility diagrams. The results show that cyclodextrin inclusion can control the oxidation rate of antioxidant molecules such as edaravone. This paper also demonstrates a substantial variation in the quantitative stability constant when calculated using different methods. This observation is relevant to determining complexation during the many and varied applications of cyclodextrins. The study establishes mechanisms to enhance the stability of antioxidants, which in turn may be useful to improve their bioavailability and may have translational implications in future. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s10847-021-01122-1

Scopus

Language：Japanese   Publisher：Chemical and Pharmaceutical Bulletin  

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

DOI： 10.1248/cpb.c21-00834

Scopus

Language：English   Publisher：(公社)日本薬学会  

Language：Japanese   Publisher：RSC Advances  

Polytetrafluoroethylene (PTFE) has excellent physical properties and has been used in a wide range of applications in various fields. Adsorption research on PTFE is essential as primary research for the further application of PTFE. We attempted to adsorb coal tar dyes and model drugs such as lidocaine onto PTFE as a guideline to search for medicines that adsorb onto PTFE. Saturation curves were obtained after analyzing the adsorption of coal tar dyes on PTFE using the Hanes-Woolf plot. In addition, we collected multiple cases of ATR-FTIR spectral changes and/or retention depending on TPM derivatives and other adsorbates. Lidocaine matched some coal tar dye for the apparent spectral changes between the adsorbed molecules and its crystalline powder. The apparent spectral changes are blue-shifted, suggesting a hydrophobic interaction between the dyes/lidocaine and porous PTFE. This work provides a promising strategy for further application of PTFE.

DOI： 10.1039/d1ra09086k

Scopus

Language：Japanese   Publisher：BBA Advances  

Amyloid fibrillation is provoked by the conformational rearrangement of its source. In our previous study, we claimed that the conformational rearrangement of hen egg white lysozyme requires intermolecular aggregation/packing induced. Our proposed causality of the aggregation and amyloid formation was demonstrated by the quantitative dependence of amyloid fibrillation on pH difference from its isoelectric point (pI) and on the square root of ionic strength in order to reduce the intermolecular repulsion due to the shielding effect of electrolytes (DLVO effect). When Congo red has dianionic form at the pH higher than its pKa, it forms ribbon-like micelle colloids under lower ionic strength, while it loses electrostatic repulsion and aggregates to be emulsified in the octanolic phase under the higher ionic strength. These behaviors of Congo red were resembling to molecular assembly of surfactants. In contrast, the amyloid formation of insulin was proportional to the square root of ionic strength at the pH lower than its isoelectric point. Therefore, the trigger for conformational rearrangement of amyloid fibrillation is predominantly gripped by hydrophobic hydration and an electrostatic shielding effect. We concluded that the both behaviors of Congo red and insulin were derived from a driving force related to the hydrophobic hydration.

DOI： 10.1016/j.bbadva.2021.100036

Scopus

Language：Japanese   Publisher：Journal of Drug Delivery Science and Technology  

The purpose of this study was to evaluate effects of dry mechanochemical synthesizes on ethenzamide (EZ) and saccharin (SA) mixture. EZ and SA mixture were evaluated after grinding by mid and near infrared spectroscopy, powder X-ray diffraction (PXRD) and thermal analysis. During the grind, EZ and SA mixture was transformed into their 1:1 cocrystal form. Measurement time course data was applied to multi variate analysis of principal component analysis (PCA). Their cocrystallization could decompose two steps reactions. At first, EZ crystal transform into amorphous phase and their amorphous react with SA molecules after them, hydrogen bond networks were constructed and produce cocrystal was suggested. Combination PCA and several measurement data enable to extract useful chemical information.

DOI： 10.1016/j.jddst.2021.102918

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

The purpose of this study is to investigate the effects of dry and wet mechanochemical synthesis on piroxicam (PX) and saccharin (SA) mixtures. For this purpose, PX and SA mixtures prepared by wet mechanochemical processes using three solvents and by dry mechanochemical synthesis were evaluated by mid-and near-infrared spectroscopy, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). The mixtures of wet-type products were transformed into PX/SA 1:1 co-crystals. The effect of the solvent was key to the co-crystallization of PX and SA. The products from the dry process were transformed into the amorphous phase. For the sample of the amorphous mixture, two exothermic peaks due to crystallization were observed in the thermal analysis. Bulk PX was ground for the same number of times for transformation, but was not successfully transformed to the amorphous bulk; the same was observed for SA. It is suggested that the mutual existence of PX and SA promotes mutual amorphization.

DOI： 10.1016/j.xphs.2021.06.024

Scopus

Language：Japanese   Publisher：Bio-Medical Materials and Engineering  

BACKGROUND: Control of the pharmaceutical manufacturing process and active pharmaceutical ingredients (API) is essential to product formulation and bioavailability. OBJECTIVE: The aim of this study is to predict tablet surface API concentration by chemometrics using integrating sphere UV-Vis spectroscopy, a non-destructive and contact-free measurement method. METHODS: Riboflavin, pyridoxine hydrochloride, dicalcium phosphate anhydrate, and magnesium stearate were mixed and ground with a mortar and pestle, and 100 mg samples were subjected to direct compression at a compaction pressure of 6 MPa at 7 mm diameter. The flat surface tablets were then analyzed by integrating sphere UV-Vis spectrometry. Standard normal variate (SNV) normalization and principal component analysis were applied to evaluate the measured spectral dataset. The spectral ranges were prepared at 300-800 nm and 500-700 nm with SNV normalization. Partial least squares (PLS) regression models were constructed to predict the API concentrations based on two previous datasets. RESULTS: The regression vector of constructed PLS regression models for each API was evaluated. API concentration prediction depends on riboflavin absorbance at 550 nm and the excipient dicalcium phosphate anhydrate. CONCLUSION: Integrating sphere UV-Vis spectrometry is a useful tool to process analytical technology.

DOI： 10.3233/BME-211269

Scopus

Language：Japanese   Publisher：Biochemistry and Biophysics Reports  

Amyloid fibril formation occurs in restricted environment, such as the interface between intercellular fluids and bio-membranes. Conformational interconversion from α-helix to β-structure does not progress in fluids; however, it can occur after sedimentary aggregation during amyloid fibril formation induced by heat treatment of hen egg white lysozyme (HEWL). Secondary structures of various proteins and denatured proteins titrated with 2,2,2-trifluoroethanol (TFE) were examined using their CD spectra. Gaussian peak/trough and singular value decompositions (SVD) showed that the spectral pattern of the α-helix comprised a sharp trough at wavelength 207 nm and a broad trough at 220 nm. Conversely, we distinguished two patterns for β-sheet—a spread barrel type, corresponding to ConA, and a tightly weaved type, corresponding to the soybean trypsin inhibitor. Herein, we confirmed that the spectral/conformational interconversion of the heat-treated HEWL was not observed in the dissolved fluid.

DOI： 10.1016/j.bbrep.2021.101153

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-β-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-β-CD. In the solid state, it was compared the physical properties of INM/HP-β-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-β-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-β-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC–XRPD demonstrated that INM crystals from the INM/HP-β-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-β-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-β-CD to INM enhanced INM solubility.

DOI： 10.1016/j.xphs.2021.07.002

Scopus

Language：Japanese   Publisher：Journal of Oleo Science  

In this study, we aimed to investigate imine emulsification using Raman spectroscopy with chemometrics. The imine emulsification samples were obtained by mixing aldehydes and amines in methanol and aqueous methanol. The Raman spectra of the samples were measured over time between 400 and 2300 cm–1 every 40 s using a Raman spectrometer. The obtained spectra were regarded as a dataset matrix. A multivariate curve resolution with alternating least squares was applied to the dataset. A multivariate analysis based on the Raman spectrum revealed that raw materials, emulsions, and products were decomposed when the water-rich samples were emulsified. Additionally, we evaluated the kinetics of the synthesis. The effect of water content on emulsification was investigated using Raman spectroscopy. The molecular dynamics of the co-solvent model were also investigated. The phase-layer construction was consistent with the phase transition in the water-methanol imine samples.

DOI： 10.5650/jos.ess21073

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

This study investigated the effect of phase transformation on indomethacin (IMC), cimetidine (CIM), and their 1:1 eutectic mixture, using FTIR spectra and multivariate analysis. The IMC form γ, CIM form A, and IMC-CIM 1:1 mixture molar ratio samples were heated on a hot plate at 303–453 K for 5 min and cooled till room temperature. The prepared samples were investigated by powder X-ray diffraction analysis and infrared spectroscopy with KBr powder. The PXRD patterns suggested the bulk IMC form γ, bulk CIM form A, and 1:1 physical mixture samples phase transformed into low-crystallinity IMC form γ, amorphous CIM, and eutectic mixture, respectively. FTIR spectra combined with singular value decomposition (SVD) suggested by absorbance peak shifts of several vibration modes that the polymorphic transformations of the samples affect their molecular interactions. The estimated melting points of heated samples were evaluated by sigmoid fitting based on the SVD results. The principal components of SVD show that the process of phase transformation of IMC-CIM 1:1 mixture samples affect the IR vibration of the C[dbnd]O stretch of IMC and the C-C stretch and C-H bending of CIM. These results suggest that molecular interaction is an important factor in the eutectic condition of IMC-CIM 1:1 mixture. This observation enables to evaluate for in co-amorphous formulations or stability of drug combinations in a poly pill.

DOI： 10.1016/j.xphs.2020.09.049

Scopus

Language：Japanese   Publisher：Journal of Drug Delivery Science and Technology  

The aim of this study was to investigate the effects of the molecular weight (Mw) of hydroxypropyl cellulose (HPC) and grinding duration on solid dispersions (SDs) formation and their characteristics. In this study, ternary amorphous SD systems containing curcumin (CUR), HPC, and sodium dodecyl sulfate (SDS) were developed using the milling method and characterized their physicochemical and mechanochemical properties. After 120-min grinding, the particle size reduced to under 1 μm and the GMs totally transformed into amorphous phase. The release behavior of CUR depended on the grade of HPCs due to their Mw and corresponding viscosity. During the SD formation process, the grinding time and Mw of HPC could be monitored by analyzing data obtained from MIR and NIR spectra based on chemometrics. There were two steps in SD formation: (1) simple dispersion with grinding time under 30 min and (2) random dispersion of mixtures with grinding time from 30 to 120 min. The HPC-M (700,000 Da) resulted in more effectively forming SD systems.

DOI： 10.1016/j.jddst.2020.102278

Scopus

Language：Japanese   Publisher：BBA Advances  

Many natural compounds mop up radicals and limit radical reactions and may prove useful in reducing or preventing oxidative stress-related diseases in vivo. Several assays have been developed to measure antioxidant or anti-radical activity. Here, we measured the anti-radical activities of representative antioxidants using different assays. The oxygen radical absorption capacity (ORAC) assay has two mechanistic stages. We classified antioxidant behavior using two characteristic values thought to be related to the two stages — peroxyl radical formation time (lag time) and fluorescein annihilation rate (kobs) — by applying Voronoi polyhedral division. We focused on four class-representative antioxidants, Trolox ®, vitamin C, L-cysteine, and 2,6-di‑tert‑butyl‑p-cresol, and compared their characteristic activities with those of edaravone. Our analysis indicates that edaravone is in the same group as cysteine and may function via a similar mechanism. Our results suggest that analyzing lag time and kobs is a useful method to characterize antioxidants.

DOI： 10.1016/j.bbadva.2021.100030

Scopus

Language：Japanese   Publisher：Bunseki Kagaku  

We applied a partial least squares regression (PLS) to overlapped peaks to develop a rapid flow injection analysis by the PLS method (RFP method) that quantifies the analytes of interest both accurately and rapidly. Spectrophotometric determination of Fe2+ with 1,10-phenanthroline was used as an evaluation model of the RFP method. Two Fe2+ standard samples (S1 and S2) were sequentially injected at a 30-sec interval, and the overlapped peaks were obtained. A calibration curve was constructed by applying the PLS to the overlapped peaks. The slopes of the calibration curve for S1 and S2 were both almost unity with good linearity. The concentrations of Fe2+ in surface water samples were determined by the RFP method. The Fe2+ concentrations measured were in good agreement with the values calculated by applying an absolute calibration curve method to non-overlapped peaks (ACC method). The sample throughput of the RFP method was about 1.7-times faster than that of the ACC method. We concluded that the RFP method achieves both accurate and rapid quantification.

DOI： 10.2116/bunsekikagaku.70.451

Scopus

Language：Japanese   Publisher：International Journal of Pharmaceutics  

This study focused on the physicochemical interactions between acidic and basic drugs in aqueous solutions. Their ion pair interactions were evaluated in an in vitro study. The model non-steroid anti-inflammatory drugs (NSAIDs), indomethacin (INM) and diclofenac (DIC), were used as acidic and hydrophobic drugs, whereas cimetidine (CIM), famotidine (FAM), and imidazole (IMD) were used as basic additives with heterocyclic moieties. The drug mixtures were evaluated by thermal analysis, dissolution test, nuclear magnetic resonance (NMR) spectroscopy, and mass spectroscopy. The fusion enthalpy of DIC-CIM, INM-CIM, and INM-arginine (ARG) sample was calculated based on melting temperature transformation. The DIC mixture with CIM, IMD, antipyrine (ANT), and ARG showed enhanced solubility, whereas the DIC-FAM mixture sample showed a decreased solubility. Electrospray ionization mass spectroscopy was carried out to detect binary mixtures. The interactions in DIC-FAM mixture sample were found between the carboxyl group of DIC and the amine groups of FAM by NMR. These findings were suggested that DIC-FAM mixture samples construct ion pair complexes based on the theory of Bjerrum. Moreover, the acid model drug and basic model drug also can be constructed 1:1 complexes that affects their solubility in the solvent of water type.

DOI： 10.1016/j.ijpharm.2020.119841

Scopus

Language：Japanese   Publisher：International Journal of Pharmaceutics  

This study focused on the physicochemical interactions between acidic and basic drugs in aqueous solutions. Their ion pair interactions were evaluated in an in vitro study. The model non-steroid anti-inflammatory drugs (NSAIDs), indomethacin (INM) and diclofenac (DIC), were used as acidic and hydrophobic drugs, whereas cimetidine (CIM), famotidine (FAM), and imidazole (IMD) were used as basic additives with heterocyclic moieties. The drug mixtures were evaluated by thermal analysis, dissolution test, nuclear magnetic resonance (NMR) spectroscopy, and mass spectroscopy. The fusion enthalpy of DIC-CIM, INM-CIM, and INM-arginine (ARG) sample was calculated based on melting temperature transformation. The DIC mixture with CIM, IMD, antipyrine (ANT), and ARG showed enhanced solubility, whereas the DIC-FAM mixture sample showed a decreased solubility. Electrospray ionization mass spectroscopy was carried out to detect binary mixtures. The interactions in DIC-FAM mixture sample were found between the carboxyl group of DIC and the amine groups of FAM by NMR. These findings were suggested that DIC-FAM mixture samples construct ion pair complexes based on the theory of Bjerrum. Moreover, the acid model drug and basic model drug also can be constructed 1:1 complexes that affects their solubility in the solvent of water type.

DOI： 10.1016/j.ijpharm.2020.119841

Scopus

Language：Japanese   Publisher：Pharmaceuticals  

Solubility is an important physicochemical property affecting drug bioavailability. One approach to improve drug solubility is using amorphous formulations, which can improve solubility by up to a 1000-fold. Herein, amorphous curcumin (CUR) and amorphous solid dispersions (SDs) consisting of CUR, hydroxypropyl cellulose (HPC) and/or sodium dodecyl sulfate (SDS) were developed using vibrational ball milling. The resulting ground mixtures (GMs) were characterized using powder X-ray diffractometry, Fourier transform infrared spectroscopy, differential scanning calorimetry and a dissolution test. The 60-min GM containing 90% HPC significantly increased the drug solubility. Presence of SDS in the GMs containing 90% HPC reduced the grinding duration from 60 min to 30 min in forming a ground SD that significantly increased the CUR dissolution rate. This amorphous state was stable for 30 days when stored at 40^◦C/RH 75%.

DOI： 10.3390/ph13110383

Scopus

Language：Japanese   Publisher：Pharmaceuticals  

Solubility is an important physicochemical property affecting drug bioavailability. One approach to improve drug solubility is using amorphous formulations, which can improve solubility by up to a 1000-fold. Herein, amorphous curcumin (CUR) and amorphous solid dispersions (SDs) consisting of CUR, hydroxypropyl cellulose (HPC) and/or sodium dodecyl sulfate (SDS) were developed using vibrational ball milling. The resulting ground mixtures (GMs) were characterized using powder X-ray diffractometry, Fourier transform infrared spectroscopy, differential scanning calorimetry and a dissolution test. The 60-min GM containing 90% HPC significantly increased the drug solubility. Presence of SDS in the GMs containing 90% HPC reduced the grinding duration from 60 min to 30 min in forming a ground SD that significantly increased the CUR dissolution rate. This amorphous state was stable for 30 days when stored at 40^◦C/RH 75%.

DOI： 10.3390/ph13110383

Scopus

Language：Japanese   Publisher：Pharmaceuticals  

This study aimed to investigate the effect of polymers and storage relative humidity on amorphous rebamipide (RB) and its solid dispersion phase transformation using chemometrics based on multiple datasets. The amorphous RB was prepared using particle mixture and grinding methods with hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium dodecyl sulfate. Prepared amorphous RB and solid dispersion samples were stored under a relative humidity of 30% and 75% for four weeks. Infrared spectra of the dispersion samples suggested that the hydrogen bond network was constructed among quinolinone, carbonyl acid, and amide of RB and other polymers. The dataset combining near-infrared (NIR) spectra and powder X-ray diffractograms were applied to principal component analysis (PCA). The relationship between diffractograms and NIR spectra was evaluated using loadings and the PCA score. The multiple spectra analysis is useful for evaluating model amorphous active pharmaceutical ingredients without a standard sample.

DOI： 10.3390/ph13070147

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

Cyclodextrins (CDs) form complex crystals with drugs and improve physicochemical properties of drugs. However, only few reports have summarized relationships between crystal structures of drug/CD and dissolution behavior. In this study, we developed cimetidine (CIM)/CD complex crystals to achieve sustained drug release and investigated the relationship between the dissolution behavior of CIM/CD complexes and their crystal structures. CIM and 3 types of CDs (α-, β-, and γ-CD) formed a complex crystal when subjected to solvent mixing. The CIM/CD complexes had a highly reduced dissolution rate compared to that of the physical mixture of CIM and CD. β-CD improved the solubility of CIM, whereas γ-CD decreased its solubility. Based on the phase solubility diagram, CIM and α-, β-, and γ-CD indicated A-type positive (A<inf>P</inf>) and A<inf>L</inf> deviation, and B-type limited solubility (B<inf>S</inf>) profiles, respectively. In γ-CD, the saturated concentration of CIM decreased owing to the formation of a low-solubility complex with CIM. CIM/α-CD formed cage-type crystals, and CIM/β-CD and CIM/γ-CD formed channel-type crystals. The dissolution rate constant (k) of CIM/α-CD and CIM/β-CD were 0.045 and 0.04 h⁻¹, respectively. CIM/γ-CD and CIM/β-CD displayed channel-type crystals; however, the channel-type crystals of CIM/γ-CD were stabilized by the presence of additional water molecules.

DOI： 10.1016/j.xphs.2020.03.029

Scopus

Language：Japanese   Publisher：Pharmaceuticals  

This study aimed to investigate the effect of polymers and storage relative humidity on amorphous rebamipide (RB) and its solid dispersion phase transformation using chemometrics based on multiple datasets. The amorphous RB was prepared using particle mixture and grinding methods with hydroxypropyl cellulose, polyvinylpyrrolidone, and sodium dodecyl sulfate. Prepared amorphous RB and solid dispersion samples were stored under a relative humidity of 30% and 75% for four weeks. Infrared spectra of the dispersion samples suggested that the hydrogen bond network was constructed among quinolinone, carbonyl acid, and amide of RB and other polymers. The dataset combining near-infrared (NIR) spectra and powder X-ray diffractograms were applied to principal component analysis (PCA). The relationship between diffractograms and NIR spectra was evaluated using loadings and the PCA score. The multiple spectra analysis is useful for evaluating model amorphous active pharmaceutical ingredients without a standard sample.

DOI： 10.3390/ph13070147

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

Cyclodextrins (CDs) form complex crystals with drugs and improve physicochemical properties of drugs. However, only few reports have summarized relationships between crystal structures of drug/CD and dissolution behavior. In this study, we developed cimetidine (CIM)/CD complex crystals to achieve sustained drug release and investigated the relationship between the dissolution behavior of CIM/CD complexes and their crystal structures. CIM and 3 types of CDs (α-, β-, and γ-CD) formed a complex crystal when subjected to solvent mixing. The CIM/CD complexes had a highly reduced dissolution rate compared to that of the physical mixture of CIM and CD. β-CD improved the solubility of CIM, whereas γ-CD decreased its solubility. Based on the phase solubility diagram, CIM and α-, β-, and γ-CD indicated A-type positive (A<inf>P</inf>) and A<inf>L</inf> deviation, and B-type limited solubility (B<inf>S</inf>) profiles, respectively. In γ-CD, the saturated concentration of CIM decreased owing to the formation of a low-solubility complex with CIM. CIM/α-CD formed cage-type crystals, and CIM/β-CD and CIM/γ-CD formed channel-type crystals. The dissolution rate constant (k) of CIM/α-CD and CIM/β-CD were 0.045 and 0.04 h⁻¹, respectively. CIM/γ-CD and CIM/β-CD displayed channel-type crystals; however, the channel-type crystals of CIM/γ-CD were stabilized by the presence of additional water molecules.

DOI： 10.1016/j.xphs.2020.03.029

Scopus

Language：Japanese   Publisher：Colloids and Surfaces B Biointerfaces  

In this study, the combined effects of pH and salt concentration on the aggregation and amyloid formation of a charge-bearing protein (hen egg white lysozyme, HEWL) were investigated, as well as the inhibition of amyloid formation by using dithiothreitol (DTT) as a denaturing agent. Amyloid formation was found to depend on the ion strength and pH of the sample solution. Rather than the total charge, the partial charge of the amyloid related residues contributes to amyloid formation at pH < isoelectric point (pI). On the other hand, at pH> pI HEWL only undergoes alkaline denaturation regardless of the ionic strength. The effect of adding different amounts of DTT at different times on amyloid formation was also investigated. These results suggested that the positions of charges on a protein and the protein secondary structure are critical for protein aggregation and amyloid formation.

DOI： 10.1016/j.colsurfb.2020.110845

Scopus

Language：Japanese   Publisher：Colloids and Surfaces B Biointerfaces  

In this study, the combined effects of pH and salt concentration on the aggregation and amyloid formation of a charge-bearing protein (hen egg white lysozyme, HEWL) were investigated, as well as the inhibition of amyloid formation by using dithiothreitol (DTT) as a denaturing agent. Amyloid formation was found to depend on the ion strength and pH of the sample solution. Rather than the total charge, the partial charge of the amyloid related residues contributes to amyloid formation at pH < isoelectric point (pI). On the other hand, at pH> pI HEWL only undergoes alkaline denaturation regardless of the ionic strength. The effect of adding different amounts of DTT at different times on amyloid formation was also investigated. These results suggested that the positions of charges on a protein and the protein secondary structure are critical for protein aggregation and amyloid formation.

DOI： 10.1016/j.colsurfb.2020.110845

Scopus

Language：Japanese   Publisher：Journal of Drug Delivery Science and Technology  

The effect of temperature on terahertz (THz) spectra of caffeine/oxalic 2:1 cocrystal and its vibrational mode was analyzed. Caffeine anhydrate and oxalic acid dihydrate were dissolved in an organic solvent, after which the solution was evaporated to produce caffeine/oxalic acid 2:1 (CA/OX) cocrystal. The prepared CA/OX cocrystals were measured by a continuous wave gallium phosphide THz spectrometer at several low temperatures. The peak resolutions of the cocrystal spectra were found to depend on the temperature. To assign the vibrational modes, a density functional theory simulation was applied. The measured THz spectra of CA/OX cocrystal at low temperatures agreed with the calculated vibrational mode.

DOI： 10.1016/j.jddst.2019.101215

Scopus

Language：Japanese   Publisher：Journal of Drug Delivery Science and Technology  

The effect of temperature on terahertz (THz) spectra of caffeine/oxalic 2:1 cocrystal and its vibrational mode was analyzed. Caffeine anhydrate and oxalic acid dihydrate were dissolved in an organic solvent, after which the solution was evaporated to produce caffeine/oxalic acid 2:1 (CA/OX) cocrystal. The prepared CA/OX cocrystals were measured by a continuous wave gallium phosphide THz spectrometer at several low temperatures. The peak resolutions of the cocrystal spectra were found to depend on the temperature. To assign the vibrational modes, a density functional theory simulation was applied. The measured THz spectra of CA/OX cocrystal at low temperatures agreed with the calculated vibrational mode.

DOI： 10.1016/j.jddst.2019.101215

Scopus

Language：Japanese   Publisher：Bio Medical Materials and Engineering  

BACKGROUND: To ensure quality and stability, monitoring systems are recommended to analyze pharmaceutical manufacturing processes. OBJECTIVE: This study was performed to predict powder X-ray diffraction (PXRD) patterns of formulation powders through attenuated total reflectance (ATR)-infrared (IR) spectroscopy in a nondestructive manner along with chemometrics. RESULTS: Caffeine anhydrate, acetaminophen, and lactose monohydrate were grinded at six weight ratios. The six sample groups were evaluated using ATR-IR spectroscopy and PXRD analysis. Partial least squares models were constructed to predict the PXRD intensities of the samples from the ATR-IR spectra. The prediction accuracy on the prepared PLS regression models was as high as R2 = 0.993. CONCLUSIONS: Linear relationships were obtained between the prediction data set and reference PXRD intensity at each degree. 2D PLS regression coefficient analysis enabled the analysis of the correlation between PXRD patterns and IR spectra.

DOI： 10.3233/BME-206003

Scopus

Language：Japanese   Publisher：Rsc Advances  

Polymers have been recognized to have the function of sustaining the supersaturated state of drugs. This function has been widely studied because it will improve the absorption of poorly water-soluble drugs. However, clarifying the mechanism of this sustaining pharmaceutical effect (parachute effect) on the supersaturated state as a result of polymers is remains a task. We have found that oxybuprocaine, which is a small molecule, has a parachute effect on the supersaturated state (due to an anhydrate-to-hydrate transformation) of piroxicam-anhydrate in the aqueous phase. We consider that oxybuprocaine controls the environment of the solution and the network of polymers is unnecessary. Therefore, oxybuprocaine not only becomes a clue for elucidating the essential mechanism of the parachute effect of polymers but also enables us to rationally propose a new type of solubilizer.

DOI： 10.1039/c9ra09952b

Scopus

Language：Japanese   Publisher：Bio Medical Materials and Engineering  

BACKGROUND: To ensure quality and stability, monitoring systems are recommended to analyze pharmaceutical manufacturing processes. OBJECTIVE: This study was performed to predict powder X-ray diffraction (PXRD) patterns of formulation powders through attenuated total reflectance (ATR)-infrared (IR) spectroscopy in a nondestructive manner along with chemometrics. RESULTS: Caffeine anhydrate, acetaminophen, and lactose monohydrate were grinded at six weight ratios. The six sample groups were evaluated using ATR-IR spectroscopy and PXRD analysis. Partial least squares models were constructed to predict the PXRD intensities of the samples from the ATR-IR spectra. The prediction accuracy on the prepared PLS regression models was as high as R2 = 0.993. CONCLUSIONS: Linear relationships were obtained between the prediction data set and reference PXRD intensity at each degree. 2D PLS regression coefficient analysis enabled the analysis of the correlation between PXRD patterns and IR spectra.

DOI： 10.3233/BME-206003

Scopus

Language：Japanese   Publisher：Rsc Advances  

Polymers have been recognized to have the function of sustaining the supersaturated state of drugs. This function has been widely studied because it will improve the absorption of poorly water-soluble drugs. However, clarifying the mechanism of this sustaining pharmaceutical effect (parachute effect) on the supersaturated state as a result of polymers is remains a task. We have found that oxybuprocaine, which is a small molecule, has a parachute effect on the supersaturated state (due to an anhydrate-to-hydrate transformation) of piroxicam-anhydrate in the aqueous phase. We consider that oxybuprocaine controls the environment of the solution and the network of polymers is unnecessary. Therefore, oxybuprocaine not only becomes a clue for elucidating the essential mechanism of the parachute effect of polymers but also enables us to rationally propose a new type of solubilizer.

DOI： 10.1039/c9ra09952b

Scopus

Language：Japanese   Publisher：Chemical Physics  

Drug solubility is an important characteristic affecting its bioavailability. The properties of ionic drugs affect their sensitivity to buffer composition. We aimed to elucidate the variations in ibuprofen solubility due to different buffers and buffer concentrations. We also examined the intermolecular interaction between IBP and lidocaine (LDC) in the presence or absence of phosphate ion to determine whether phosphate in buffer modifies IBP hydration and LDC hydrophobic hydration. The IBP/LDC mixture formed a complex in phosphate buffer, as confirmed by van't Hoff plot and diffusion-ordered NMR spectroscopy, where dissolving behavior changed from endothermic to an exothermic process. This behavior was only achieved in the presence of phosphate ion. We also examined the dependence of a drug's solubility on the solubility of other drugs. Phosphate ion can greatly affect drug solubility behavior. This knowledge gives us to ensure comparative assessment that is suitable for the Electrolyte environment of patients.

DOI： 10.1016/j.chemphys.2019.110415

Scopus

Language：Japanese   Publisher：Chemical Physics  

Drug solubility is an important characteristic affecting its bioavailability. The properties of ionic drugs affect their sensitivity to buffer composition. We aimed to elucidate the variations in ibuprofen solubility due to different buffers and buffer concentrations. We also examined the intermolecular interaction between IBP and lidocaine (LDC) in the presence or absence of phosphate ion to determine whether phosphate in buffer modifies IBP hydration and LDC hydrophobic hydration. The IBP/LDC mixture formed a complex in phosphate buffer, as confirmed by van't Hoff plot and diffusion-ordered NMR spectroscopy, where dissolving behavior changed from endothermic to an exothermic process. This behavior was only achieved in the presence of phosphate ion. We also examined the dependence of a drug's solubility on the solubility of other drugs. Phosphate ion can greatly affect drug solubility behavior. This knowledge gives us to ensure comparative assessment that is suitable for the Electrolyte environment of patients.

DOI： 10.1016/j.chemphys.2019.110415

Scopus

Language：Japanese   Publisher：Journal of Drug Delivery Science and Technology  

The aim of this study was to predict Differential Scanning Calorimetry (DSC) curves of pharmaceutical direct compression model tablet by chemometrics using Raman spectroscopy, measured in a nondestructive and contact-free manner. Theophylline anhydrate, theophylline hydrate, and micro-crystalline cellulose were ground and mixed with a mortar and pestle to obtain various formulations. The tablets were then measured with a handheld Raman spectrometer. DSC curves of the ground powder were measured, and the first-order derivative DSC curves were calculated. The Partial Least Squares (PLS) models were constructed to predict the calories at each temperature from the Raman spectra, and the regression vector of the constructed PLS models was plotted with 2D mapping (Raman wavenumber, Temperature, Regression coefficient). This mapping system allowed for the analysis of the correlations between Raman shift and DSC endothermic peaks.

DOI： 10.1016/j.jddst.2018.11.003

Scopus

Language：Japanese   Publisher：Journal of Drug Delivery Science and Technology  

The aim of this study was to predict Differential Scanning Calorimetry (DSC) curves of pharmaceutical direct compression model tablet by chemometrics using Raman spectroscopy, measured in a nondestructive and contact-free manner. Theophylline anhydrate, theophylline hydrate, and micro-crystalline cellulose were ground and mixed with a mortar and pestle to obtain various formulations. The tablets were then measured with a handheld Raman spectrometer. DSC curves of the ground powder were measured, and the first-order derivative DSC curves were calculated. The Partial Least Squares (PLS) models were constructed to predict the calories at each temperature from the Raman spectra, and the regression vector of the constructed PLS models was plotted with 2D mapping (Raman wavenumber, Temperature, Regression coefficient). This mapping system allowed for the analysis of the correlations between Raman shift and DSC endothermic peaks.

DOI： 10.1016/j.jddst.2018.11.003

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

The effects of amino acids on calcium phosphate phase transformation were investigated by using attenuated total reflection (ATR)-infrared (IR) spectroscopy. A self-setting apatite cement, which consisted of tetracalcium phosphate and dicalcium phosphate, was transformed into hydroxyapatite (HAp) by kneading with a phosphoric acid solution. Phosphate buffer (0.2 M, pH 6.8) or aqueous solutions of 0.1 w/v% amino acids (alanine, asparagine, serine, and o-phospho-l-serine) were used as the kneading solutions. The kneaded samples were analyzed by ATR-IR spectroscopy. The amount of HAp produced was determined by the multivariate curve resolution alternative least-squares method based on the ATR-IR spectra. The phase transformations to HAp were fitted to several solid-state kinetic models. The results indicate that o-phospho-l-serine inhibits the crystal growth of HAp. A simulation model of HAp surface interaction was developed by using the molecular dynamics method. The total energy of the HAp surface with amino acids was sufficient to explain the o-phospho-l-serine inhibition model. The inhibition is attributed to the specific adsorption of o-phospho-l-serine on the surface of HAp seed crystals.

DOI： 10.1007/s00396-018-4438-0

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

The effects of amino acids on calcium phosphate phase transformation were investigated by using attenuated total reflection (ATR)-infrared (IR) spectroscopy. A self-setting apatite cement, which consisted of tetracalcium phosphate and dicalcium phosphate, was transformed into hydroxyapatite (HAp) by kneading with a phosphoric acid solution. Phosphate buffer (0.2 M, pH 6.8) or aqueous solutions of 0.1 w/v% amino acids (alanine, asparagine, serine, and o-phospho-l-serine) were used as the kneading solutions. The kneaded samples were analyzed by ATR-IR spectroscopy. The amount of HAp produced was determined by the multivariate curve resolution alternative least-squares method based on the ATR-IR spectra. The phase transformations to HAp were fitted to several solid-state kinetic models. The results indicate that o-phospho-l-serine inhibits the crystal growth of HAp. A simulation model of HAp surface interaction was developed by using the molecular dynamics method. The total energy of the HAp surface with amino acids was sufficient to explain the o-phospho-l-serine inhibition model. The inhibition is attributed to the specific adsorption of o-phospho-l-serine on the surface of HAp seed crystals.

DOI： 10.1007/s00396-018-4438-0

Scopus

Language：Japanese   Publisher：Chemical and Pharmaceutical Bulletin  

Dissolution kinetics of a bilayer direct compress tablet was evaluated by using degassing cyclic flow UV-visible (Vis) spectroscopy with chemometrics. The model bilayer nicotinamide (NA)–pyridoxine hydrochloride (PH) 100.0mg tablets were prepared via the dual compress method. The fast diffusion layer of the bilayer tablet contained nicotinamide, microcrystal cellulose, beta-lactose, magnesium stearate, and croscar-mellose sodium. The slow release layer contained pyridoxine hydrochloride and carnauba wax. The monolayer direct compress tablets were prepared as dual ingredient (API)s formulation tablets. The degassing cyclic flow UV-Vis spectroscopy dissolution test was carried out using the prepared tablets. The dissolution test conditions were as follows: time, 60min; temperature, 37°C; paddle method, 50rpm, and UV-Vis spectra measurement 1 time/min. The UV-Vis spectra of the flow solution were measured in the range of 240–380nm. API concentration was predicted by partial least squares (PLS) regression models based on UV-Vis spectra. The dissolution kinetics of the bilayer and monolayer tablets were evaluated based on the UV-Vis spectra with the predicted API concentration profile. The degassing flow system could prevent air bubbles in the flow cell at 1800min. Therefore, simultaneous determination of NA and PH concentration based on the PLS regression was suggested to have high accuracy. PLS regression has advantages over the conventional λ<inf>max</inf> absorbance method of simultaneous determination. We found that the kinetics of the separated bilayer tablet can be evaluated by the same kinetic analysis method used for the single layer model tablet.

DOI： 10.1248/cpb.c18-00867

Scopus

Language：Japanese   Publisher：Chemical and Pharmaceutical Bulletin  

Dissolution kinetics of a bilayer direct compress tablet was evaluated by using degassing cyclic flow UV-visible (Vis) spectroscopy with chemometrics. The model bilayer nicotinamide (NA)–pyridoxine hydrochloride (PH) 100.0mg tablets were prepared via the dual compress method. The fast diffusion layer of the bilayer tablet contained nicotinamide, microcrystal cellulose, beta-lactose, magnesium stearate, and croscar-mellose sodium. The slow release layer contained pyridoxine hydrochloride and carnauba wax. The monolayer direct compress tablets were prepared as dual ingredient (API)s formulation tablets. The degassing cyclic flow UV-Vis spectroscopy dissolution test was carried out using the prepared tablets. The dissolution test conditions were as follows: time, 60min; temperature, 37°C; paddle method, 50rpm, and UV-Vis spectra measurement 1 time/min. The UV-Vis spectra of the flow solution were measured in the range of 240–380nm. API concentration was predicted by partial least squares (PLS) regression models based on UV-Vis spectra. The dissolution kinetics of the bilayer and monolayer tablets were evaluated based on the UV-Vis spectra with the predicted API concentration profile. The degassing flow system could prevent air bubbles in the flow cell at 1800min. Therefore, simultaneous determination of NA and PH concentration based on the PLS regression was suggested to have high accuracy. PLS regression has advantages over the conventional λ<inf>max</inf> absorbance method of simultaneous determination. We found that the kinetics of the separated bilayer tablet can be evaluated by the same kinetic analysis method used for the single layer model tablet.

DOI： 10.1248/cpb.c18-00867

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

We report the effects of dry mechanochemical synthesis conditions on the crystallization of caffeine (CA) and oxalic acid (OX) 2:1 cocrystal. CA anhydrate and OX dihydrate were grinded at various temperatures, rotation speeds, and grinding time. The cocrystal was also synthesized by an organic solvent evaporation method, as a reference. The produced samples were measured by a powder X-ray diffraction (PXRD) analysis. The PXRD spectra suggest that the grinded cocrystal has a lower crystallinity than the evaporated one. The diffractograms for the cocrystals synthesized by 2 kinds of methods were further evaluated by multivariate curve resolution-alternating least squares method. Sources of the mathematical models constructed were assigned to the cocrystal and unreacted mixture of CA and OX dihydrate. The present approach is concluded to be useful for the improvement of pharmaceutical property because cocrystallization is closely relating to the solubility characteristics, bioavailability, stability, and so on of drugs.

DOI： 10.1016/j.xphs.2017.07.025

Scopus

Language：Japanese   Publisher：Journal of Pharmaceutical Sciences  

We report the effects of dry mechanochemical synthesis conditions on the crystallization of caffeine (CA) and oxalic acid (OX) 2:1 cocrystal. CA anhydrate and OX dihydrate were grinded at various temperatures, rotation speeds, and grinding time. The cocrystal was also synthesized by an organic solvent evaporation method, as a reference. The produced samples were measured by a powder X-ray diffraction (PXRD) analysis. The PXRD spectra suggest that the grinded cocrystal has a lower crystallinity than the evaporated one. The diffractograms for the cocrystals synthesized by 2 kinds of methods were further evaluated by multivariate curve resolution-alternating least squares method. Sources of the mathematical models constructed were assigned to the cocrystal and unreacted mixture of CA and OX dihydrate. The present approach is concluded to be useful for the improvement of pharmaceutical property because cocrystallization is closely relating to the solubility characteristics, bioavailability, stability, and so on of drugs.

DOI： 10.1016/j.xphs.2017.07.025

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

Chloroapatite (ClAp), which is more soluble than hydroxyapatite (HAp), was synthesized in order to improve the inert nature of HAp as implant material. Two mechanochemical synthetic methods were investigated. In one method, CaCl<inf>2</inf> was added after the formation of amorphous calcium phosphate from CaHPO<inf>4</inf>·2H<inf>2</inf>O and CaO in a planetary ball mill; in the other method, CaCl<inf>2</inf>, CaHPO<inf>4</inf>·2H<inf>2</inf>O, and CaO were mixed from the beginning in the mill. Thus, obtained products were evaluated by a powder X-ray diffractometry and an attenuated total reflection-infrared spectroscopy. The mechanochemical synthetic method is found to be useful for the synthesis of ClAp because of its simplicity in operation and equipment. The ClAp produced by the former method is contaminated with carbonate ion and its crystallinity is lower than that produced by the latter method. The carbonate ion also affects the behavior of ClAp in pure water and in a simulated body fluid.

DOI： 10.1007/s00396-017-4177-7

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

Chloroapatite (ClAp), which is more soluble than hydroxyapatite (HAp), was synthesized in order to improve the inert nature of HAp as implant material. Two mechanochemical synthetic methods were investigated. In one method, CaCl<inf>2</inf> was added after the formation of amorphous calcium phosphate from CaHPO<inf>4</inf>·2H<inf>2</inf>O and CaO in a planetary ball mill; in the other method, CaCl<inf>2</inf>, CaHPO<inf>4</inf>·2H<inf>2</inf>O, and CaO were mixed from the beginning in the mill. Thus, obtained products were evaluated by a powder X-ray diffractometry and an attenuated total reflection-infrared spectroscopy. The mechanochemical synthetic method is found to be useful for the synthesis of ClAp because of its simplicity in operation and equipment. The ClAp produced by the former method is contaminated with carbonate ion and its crystallinity is lower than that produced by the latter method. The carbonate ion also affects the behavior of ClAp in pure water and in a simulated body fluid.

DOI： 10.1007/s00396-017-4177-7

Scopus

Language：Japanese   Publisher：Chemical and Pharmaceutical Bulletin  

We propose an approach for the simultaneous determination of multiple components in pharmaceutical mixed powder based on powder X-ray diffraction (PXRD) method coupled with chemometrics. Caffeine anhydrate, acetaminophen and lactose monohydrate were mixed at various ratios. The samples were analyzed by PXRD method in the ranges of 2θ=5.00-30.0 and 35.0-45.0 degrees. Obtained diffractograms were analyzed by conventional peak intensity method, multi curve resolution (MCR)-alternating least squares (ALS) method and partial least squares (PLS) method. Constructed PLS models can most accurately predict the concentrations among different methods used. Each regression vector of PLS correlates not only to the compound of interest but also to the coexisting compounds. The combination of PXRD and PLS methods is concluded to be powerful approach for analyzing multi components in pharmaceutical formulations.

DOI： 10.1248/cpb.c16-00151

Scopus

Language：Japanese   Publisher：Chemical and Pharmaceutical Bulletin  

We propose an approach for the simultaneous determination of multiple components in pharmaceutical mixed powder based on powder X-ray diffraction (PXRD) method coupled with chemometrics. Caffeine anhydrate, acetaminophen and lactose monohydrate were mixed at various ratios. The samples were analyzed by PXRD method in the ranges of 2θ=5.00-30.0 and 35.0-45.0 degrees. Obtained diffractograms were analyzed by conventional peak intensity method, multi curve resolution (MCR)-alternating least squares (ALS) method and partial least squares (PLS) method. Constructed PLS models can most accurately predict the concentrations among different methods used. Each regression vector of PLS correlates not only to the compound of interest but also to the coexisting compounds. The combination of PXRD and PLS methods is concluded to be powerful approach for analyzing multi components in pharmaceutical formulations.

DOI： 10.1248/cpb.c16-00151

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

The effect of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) on carbamazepine (CBZ) polymorphic transformation has been investigated by an attenuated total reflectance-infrared (ATR-IR) spectroscopy and chemoinformatics. CBZ anhydrate samples were each kneaded with 35.0 μL of pure water, aqueous solution of 0.005 w/v% HPC, or that of 0.005 w/v% HPMC. Each paste was put on a germanium glass of an ATR accessory and was covered with a sheet of Parafilm® at 20 ± 2 °C. Measured IR spectra were analyzed by a multivariate curve resolution-alternating least squares (MCR-ALS) and a two-dimensional correlation spectroscopic analysis. Source vectors of MCR-ALS were assigned to CBZ anhydrate and dihydrate. Concentration data of MCR-ALS were evaluated for the kinetics of CBZ polymorphic transformation. The combination of ATR-IR spectroscopy and MCR-ALS is concluded to be useful for the elucidation of rapid polymorphic transformation in suspension. The transformation rate is delayed by HPC and HPMC.

DOI： 10.1007/s00396-015-3698-1

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

The effect of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) on carbamazepine (CBZ) polymorphic transformation has been investigated by an attenuated total reflectance-infrared (ATR-IR) spectroscopy and chemoinformatics. CBZ anhydrate samples were each kneaded with 35.0 μL of pure water, aqueous solution of 0.005 w/v% HPC, or that of 0.005 w/v% HPMC. Each paste was put on a germanium glass of an ATR accessory and was covered with a sheet of Parafilm® at 20 ± 2 °C. Measured IR spectra were analyzed by a multivariate curve resolution-alternating least squares (MCR-ALS) and a two-dimensional correlation spectroscopic analysis. Source vectors of MCR-ALS were assigned to CBZ anhydrate and dihydrate. Concentration data of MCR-ALS were evaluated for the kinetics of CBZ polymorphic transformation. The combination of ATR-IR spectroscopy and MCR-ALS is concluded to be useful for the elucidation of rapid polymorphic transformation in suspension. The transformation rate is delayed by HPC and HPMC.

DOI： 10.1007/s00396-015-3698-1

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

Rapid self-setting apatite cement (SSAC) formation from tetracalcium phosphate (TeCP) and dicalcium phosphate dihydrate (DCPD) has been investigated by an attenuated total reflection Fourier transform infrared (ATR-IR) spectroscopy coupled with a principal component analysis (PCA). After TeCP and DCPD were kneaded with phosphoric acid, the peaks of ATR-IR spectra for the kneaded sample shift significantly in the ranges of 2250–2400 and 850–1150 cm⁻¹ due to the crystalline transformation into hydroxyapatite (HAp). The PCA results indicate that the loadings of principal components 1 and 2 (PC1 and PC2, respectively) are ascribed to CO<inf>2</inf> and phosphate group, respectively, in the transforming cement. The PC1 score initially increases to reach a maximum at around 1000 s and then decreases. In contrast, the PC2 score increases continuously, but its increment became lesser with time. Although the profiles of PC2 score against PC1 score are similar in shape, there are deviations among the profiles obtained through quadruplicate experiments. The scores are, therefore, time differentiated, and the relationship between the differentiated scores is analyzed. The time differentiation approach is found to be useful for understanding complicated chemical reactions. The PCA results suggest that SSAC formation can be divided into three major stages. In the first stage, CO<inf>2</inf> concentration in the transforming cement rapidly increases, which triggers HAp crystallization. In the second stage, CO<inf>2</inf> concentration still increases, but its increasing rate drastically decreases; HAp crystallization continues with increasing rate. In the last stage, CO<inf>2</inf> concentration decreases, and HAp crystallization significantly slows down.

DOI： 10.1007/s00396-015-3616-6

Scopus

Language：Japanese   Publisher：Colloid and Polymer Science  

Rapid self-setting apatite cement (SSAC) formation from tetracalcium phosphate (TeCP) and dicalcium phosphate dihydrate (DCPD) has been investigated by an attenuated total reflection Fourier transform infrared (ATR-IR) spectroscopy coupled with a principal component analysis (PCA). After TeCP and DCPD were kneaded with phosphoric acid, the peaks of ATR-IR spectra for the kneaded sample shift significantly in the ranges of 2250–2400 and 850–1150 cm⁻¹ due to the crystalline transformation into hydroxyapatite (HAp). The PCA results indicate that the loadings of principal components 1 and 2 (PC1 and PC2, respectively) are ascribed to CO<inf>2</inf> and phosphate group, respectively, in the transforming cement. The PC1 score initially increases to reach a maximum at around 1000 s and then decreases. In contrast, the PC2 score increases continuously, but its increment became lesser with time. Although the profiles of PC2 score against PC1 score are similar in shape, there are deviations among the profiles obtained through quadruplicate experiments. The scores are, therefore, time differentiated, and the relationship between the differentiated scores is analyzed. The time differentiation approach is found to be useful for understanding complicated chemical reactions. The PCA results suggest that SSAC formation can be divided into three major stages. In the first stage, CO<inf>2</inf> concentration in the transforming cement rapidly increases, which triggers HAp crystallization. In the second stage, CO<inf>2</inf> concentration still increases, but its increasing rate drastically decreases; HAp crystallization continues with increasing rate. In the last stage, CO<inf>2</inf> concentration decreases, and HAp crystallization significantly slows down.

DOI： 10.1007/s00396-015-3616-6

Scopus

Language：Japanese   Publisher：Bio Medical Materials and Engineering  

BACKGROUND: Theophylline anhydrate (TA) in tablet formulation is transformed into monohydrate (TH) at high humidity and the phase transformation affected dissolution behavior. OBJECTIVE: Near-infrared spectroscopic (NIR) method is applied to predict the change of pharmaceutical properties of TA tablets during storage at high humidity. METHODS: The tablet formulation containing TA, lactose, crystalline cellulose and magnesium stearate was compressed at 4.8 kN. Pharmaceutical properties of TA tables were measured by NIR, X-ray diffraction analysis, dissolution test and tablet hardness. RESULTS: TA tablet was almost 100% transformed into TH after 24 hours at RH 96%. The pharmaceutical properties of TA tablets, such as tablet hardness, 20 min dissolution amount (D20) and increase of tablet weight (TW), changed with the degree of hydration. Calibration models for TW, tablet hardness and D20 to predict the pharmaceutical properties at high-humidity conditions were developed on the basis of the NIR spectra by partial least squares regression analysis. The relationships between predicted and actual measured values for TW, tablet hardness and D20 had straight lines, respectively. CONCLUSIONS: From the results of NIR-chemometrics, it was confirmed that these predicted models had high accuracy to monitor the tablet properties during storage at high humidity.

DOI： 10.3233/BME-151278

Scopus

Language：Japanese   Publisher：Bio Medical Materials and Engineering  

BACKGROUND: Theophylline anhydrate (TA) in tablet formulation is transformed into monohydrate (TH) at high humidity and the phase transformation affected dissolution behavior. OBJECTIVE: Near-infrared spectroscopic (NIR) method is applied to predict the change of pharmaceutical properties of TA tablets during storage at high humidity. METHODS: The tablet formulation containing TA, lactose, crystalline cellulose and magnesium stearate was compressed at 4.8 kN. Pharmaceutical properties of TA tables were measured by NIR, X-ray diffraction analysis, dissolution test and tablet hardness. RESULTS: TA tablet was almost 100% transformed into TH after 24 hours at RH 96%. The pharmaceutical properties of TA tablets, such as tablet hardness, 20 min dissolution amount (D20) and increase of tablet weight (TW), changed with the degree of hydration. Calibration models for TW, tablet hardness and D20 to predict the pharmaceutical properties at high-humidity conditions were developed on the basis of the NIR spectra by partial least squares regression analysis. The relationships between predicted and actual measured values for TW, tablet hardness and D20 had straight lines, respectively. CONCLUSIONS: From the results of NIR-chemometrics, it was confirmed that these predicted models had high accuracy to monitor the tablet properties during storage at high humidity.

DOI： 10.3233/BME-151278

Scopus

Language：Japanese   Publisher：Colloids and Surfaces B Biointerfaces  

The effect of high humidity on the pharmaceutical properties of direct compression tablets containing theophylline anhydrate (TA) was investigated to prepare high quality pharmaceuticals. A mixed powder (230. mg) containing the TA, β-lactose anhydrate, microcrystalline cellulose (MCC) and magnesium stearate was compressed in a die by 8-mm diameter punches with flat surfaces at 4.8. kN. The TA tablets were stored in desiccators at 96% relative humidity and 20°C. Physicochemical properties of the tablets were measured using, powder X-ray diffraction (XRD), X-ray computed tomography (XCT), the tablet hardness test and the dissolution test. The water absorption process could be divided into two stages: 1.0% absorption at for 0-6. h due to absorption of MCC, and 4% absorption at 6-24. h due to hydration of TA. The XRD and XCT results were supported be tablet weight changes in the initial and later stages, respectively. The relationship between tablet hardness and water absorption indicated that the first stage of absorption was more significant. In contrast, the relationship between the dissolved amount at 20. min (D20) and water absorption indicated that the first stage was less effective. The first stage of absorption was due to MCC, but the second was due to hydration of the TA bulk powder. © 2012 Elsevier B.V.

DOI： 10.1016/j.colsurfb.2012.07.049

Scopus

Language：Japanese   Publisher：Colloids and Surfaces B Biointerfaces  

The effect of high humidity on the pharmaceutical properties of direct compression tablets containing theophylline anhydrate (TA) was investigated to prepare high quality pharmaceuticals. A mixed powder (230. mg) containing the TA, β-lactose anhydrate, microcrystalline cellulose (MCC) and magnesium stearate was compressed in a die by 8-mm diameter punches with flat surfaces at 4.8. kN. The TA tablets were stored in desiccators at 96% relative humidity and 20°C. Physicochemical properties of the tablets were measured using, powder X-ray diffraction (XRD), X-ray computed tomography (XCT), the tablet hardness test and the dissolution test. The water absorption process could be divided into two stages: 1.0% absorption at for 0-6. h due to absorption of MCC, and 4% absorption at 6-24. h due to hydration of TA. The XRD and XCT results were supported be tablet weight changes in the initial and later stages, respectively. The relationship between tablet hardness and water absorption indicated that the first stage of absorption was more significant. In contrast, the relationship between the dissolved amount at 20. min (D20) and water absorption indicated that the first stage was less effective. The first stage of absorption was due to MCC, but the second was due to hydration of the TA bulk powder. © 2012 Elsevier B.V.

DOI： 10.1016/j.colsurfb.2012.07.049

Scopus