Publications by authors named "Tatsuo Koide"

46 Publications

Chemical imaging analysis of active pharmaceutical ingredient in dissolving microneedle arrays by Raman spectroscopy.

Drug Deliv Transl Res 2021 Aug 24. Epub 2021 Aug 24.

Division of Drugs, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan.

The purpose of this study was to develop a quality evaluation method for dissolving microneedle arrays (DMNAs) and determine the spatial distribution pattern of drugs in DMNAs. Raman spectroscopy mapping was used to visualize the drug distribution in DMNAs and drug-loaded polymer films as a model. Powder X-ray diffraction (PXRD) and high-pressure liquid chromatography were also performed to characterize DMNAs. Drug-loaded polymer films and DMNAs were prepared by drying the aqueous solutions spread on the plates or casting. PXRD analysis suggested the crystallization of diclofenac sodium (DCF) in several forms depending on its amount in the sodium hyaluronate (HA)-based films. The Raman spectra of HA and DCF showed characteristic and non-overlapping peaks at 1376 and 1579 cm Raman shifts, respectively. The intensity of the characteristic peak of DCF in the DCF-loaded films increased linearly with the increasing drug content in the range of 4.8 to 16.7% (DCF, w/w). Raman imaging analysis revealed a homogenous dispersion of small DCF crystals in these films. Raman imaging indicates the distribution of DCF on the surface of the DMNA needle. This work highlights the benefit of using Raman spectroscopy mapping to reveal the spatial distribution of drugs in DMNAs.
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http://dx.doi.org/10.1007/s13346-021-01052-yDOI Listing
August 2021

Discrimination of ranitidine hydrochloride crystals using X-ray micro-computed tomography for the evaluation of three-dimensional spatial distribution in solid dosage forms.

Int J Pharm 2021 Aug 28;605:120834. Epub 2021 Jun 28.

National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan.

A non-destructive discrimination method for crystals in solid dosage drug forms was first developed using a combination of Raman spectroscopy and X-ray micro-computed tomography (X-ray CT). Identification of the crystal form of an active pharmaceutical ingredient (API) at the appropriate pharmaceutical dosage is crucial, as the crystal form is a determinant of the quality and performance of the final formulation. To develop a non-destructive analytical methodology for the discrimination of solid API crystals in a solid dosage form, we utilized a combination of Raman spectroscopy and X-ray CT to differentiate between ranitidine crystal polymorphs (forms 1 and 2) in tablet formulations containing three excipients. The difference in electron density correlated with the true density between ranitidine polymorphs, thereby enabling the discrimination of crystal forms and visualization of their three-dimensional spatial localization inside the tablets through X-ray CT imaging. Furthermore, X-ray CT imaging revealed that the crystal particles were of varying densities, sizes, and shapes within the same batch. These findings suggest that X-ray CT is not only an imaging tool but also a unique method for quantitative physicochemical characterization to study crystal polymorphs and solid dosage forms.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120834DOI Listing
August 2021

Control strategy and methods for continuous direct compression processes.

Asian J Pharm Sci 2021 Mar 8;16(2):253-262. Epub 2020 Dec 8.

Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Bldg., Tokyo 100-0013, Japan.

We presented a control strategy for tablet manufacturing processes based on continuous direct compression. The work was conducted by the experts of pharmaceutical companies, machine suppliers, academia, and regulatory authority in Japan. Among different items in the process, the component ratio and blended powder content were selected as the items requiring the control method specific to continuous manufacturing different from the conventional batch manufacturing. The control and management of the Loss in Weight (LIW) feeder were deemed the most important, and the Residence Time Distribution (RTD) model were regarded effective for setting the control range and for controlling of the LIW feeder. Based on these ideas, the concept of process control using RTD was summarized. The presented contents can serve as a solid fundament for adopting a new control method of continuous direct compression processes in and beyond the Japanese market.
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http://dx.doi.org/10.1016/j.ajps.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105518PMC
March 2021

Purity Determination of Cyclophosphamide Hydrate by Quantitative P-NMR and Method Validation.

Chem Pharm Bull (Tokyo) 2021 Jul 15;69(7):630-638. Epub 2021 Apr 15.

Sumitomo Dainippon Pharma Co., Ltd.

Recently, quantitative NMR (qNMR), especially H-qNMR, has been widely used to determine the absolute quantitative value of organic molecules. We previously reported an optimal and reproducible sample preparation method for H-qNMR. In the present study, we focused on a P-qNMR absolute determination method. An organophosphorus compound, cyclophosphamide hydrate (CP), listed in the Japanese Pharmacopeia 17th edition was selected as the target compound, and the P-qNMR and H-qNMR results were compared under three conditions with potassium dihydrogen phosphate (KHPO) or O-phosphorylethanolamine (PEA) as the reference standard for P-qNMR and sodium 4,4-dimethyl-4-silapentanesulfonate-d (DSS-d) as the standard for H-qNMR. Condition 1: separate sample containing CP and KHPO for P-qNMR or CP and DSS-d for H-qNMR. Condition 2: mixed sample containing CP, DSS-d, and KHPO. Condition 3: mixed sample containing CP, DSS-d, and PEA. As conditions 1 and 3 provided good results, validation studies at multiple laboratories were further conducted. The purities of CP determined under condition 1 by H-qNMR at 11 laboratories and P-qNMR at 10 laboratories were 99.76 ± 0.43 and 99.75 ± 0.53%, respectively, and those determined under condition 3 at five laboratories were 99.66 ± 0.08 and 99.61 ± 0.53%, respectively. These data suggested that the CP purities determined by P-qNMR are in good agreement with those determined by the established H-qNMR method. Since the P-qNMR signals are less complicated than the H-qNMR signals, P-qNMR would be useful for the absolute quantification of compounds that do not have a simple and separate H-qNMR signal, such as a singlet or doublet, although further investigation with other compounds is needed.
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http://dx.doi.org/10.1248/cpb.c21-00109DOI Listing
July 2021

Advanced Formulation Design for Topical Creams Assisted with Vibrational Spectroscopic Imaging.

Chem Pharm Bull (Tokyo) 2021 ;69(3):271-277

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University.

Vibrational spectroscopic imaging has become useful analytical tools for quality control of drug products. In this study, we applied microscopic attenuated total reflection (ATR)-IR and confocal Raman microscopy to elucidate microscopic structure of creams and for the formulation design in the development of semi-solid drug products. The model creams were prepared with prednisolone (PRD) and fluconazole (FLC) as active pharmaceutical ingredients and oily solvents such as mineral oil (MO), isopropyl myristate (IPM), benzyl alcohol (BA) and diethyl sebacate (DES). As a result of microscopic ATR-IR imaging, several domains indicating oily internal phase were observed, which had absorption around 1732 and 1734 cm derived from MO, IPM and DES. In addition, domains of BA around 1009 cm were observed at the complemental or similar position in the formulation with MO or DES, respectively. These results suggested that the creams were oil-in-water type and the distribution of domains would reflect the compatibility of the solvents. The contents of PRD and BA were determined quantitatively in each layer after the intentional separation of the creams and the results agreed well with the imaging analysis. Whereas, confocal Raman imaging allowed to visualize the distribution of the components in depth direction as well as two-dimensional plane. In particular, the Raman imaging would ensure the coexistence of FLC and BA as oily phase in the cream. From these results, the feasibility of spectroscopic imaging techniques was successfully demonstrated for the formulation design of semi-solid dosage forms.
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http://dx.doi.org/10.1248/cpb.c20-00979DOI Listing
July 2021

Clarification of the internal structure and factors of poor dissolution of substandard roxithromycin tablets by near-infrared chemical imaging.

Int J Pharm 2021 Mar 20;596:120232. Epub 2021 Jan 20.

Clinical Pharmacy and Healthcare Sciences, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.

The spread of substandard and falsified medicines has become a global problem, especially in low- and middle-income countries (LMICs). Previously, we found that some tablets containing the same active ingredient had large differences in their dissolution even though their contents were comparable. In this study, we investigated the poor dissolution of roxithromycin tablets using near-infrared chemical imaging (NIR-CI) to visualize the internal tablet structure. Roxithromycin tablets collected in LMICs and the pioneer product Rulid® as a reference were cut to a flat surface for analysis. NIR spectral data were normalized, and a principal component analysis was performed to create a tablet internal structure image. For Rulid®, the differences between the spectra with high and low scores were small, and well-defined aggregation of ingredients was not observed. However, large differences in the scores were found for roxithromycin tablets manufactured in some LMICs, and non-uniformity of ingredient distribution and aggregation were observed. Additionally, some pharmaceutical excipients, such as starch or magnesium stearate, were found in certain aggregates by comparing NIR spectra. The NIR-CI results showed some excipients existed as large aggregates, which indicated that the ingredients were not evenly mixed in the roxithromycin tablet, and this contributed to its poor dissolution.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910273PMC
March 2021

Solid-State Analysis of Alpha-Cyclodextrin Inclusion Complexes Using Low-Frequency Raman Spectroscopy.

Anal Chem 2021 01 7;93(2):704-708. Epub 2020 Dec 7.

Coherent Inc., 850 East, Duarte Road, Monrovia, California 91016, United States.

A rapid and nondestructive analytical technique is critical for the analysis of cyclodextrin inclusion complexes in solid dosage forms. This study proposed a newly developed low-frequency Raman spectroscopy as a candidate technique for the analysis of cyclodextrin inclusion complexes. In this study, we selected a typical series of five crystalline cyclodextrin inclusion complexes and reported the usefulness of Raman spectroscopy for analyzing these inclusion complexes. Some inclusion complexes clearly differed from the raw materials in conventional Raman spectra. In another case, though specific differences were not observed between inclusion complexes and raw materials in conventional Raman spectra, clear differences were observed in low-frequency Raman spectra. Moreover, no characteristic differences between inclusion complexes consisting of different guest molecules were observed in conventional Raman spectra. The characteristic differences were observed only in low-frequency Raman spectra. Therefore, low-frequency Raman spectroscopy is a useful technique for solid-state analysis of crystalline inclusion complexes.
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http://dx.doi.org/10.1021/acs.analchem.0c03854DOI Listing
January 2021

Absolute Purity Determination of a Hygroscopic Substance, Indocyanine Green, Using Quantitative NMR (qNMR).

Chem Pharm Bull (Tokyo) 2021 Jan 22;69(1):118-123. Epub 2020 Oct 22.

National Institute of Health Sciences (NIHS).

Quantitative NMR (qNMR) is applied to determine the absolute quantitative value of analytical standards for HPLC-based quantification. We have previously reported the optimal and reproducible sample preparation method for qNMR of hygroscopic reagents, such as saikosaponin a, which is used as an analytical standard in the assay of crude drug section of Japanese Pharmacopoeia (JP). In this study, we examined the absolute purity determination of a hygroscopic substance, indocyanine green (ICG), listed in the Japanese Pharmaceutical Codex 2002, using qNMR for standardization by focusing on the adaptation of ICG to JP. The purity of ICG, as an official non-Pharmacopoeial reference standard (non-PRS), had high variation (86.12 ± 2.70%) when preparing qNMR samples under non-controlled humidity (a conventional method). Additionally, residual ethanol (0.26 ± 0.11%) was observed in the non-PRS ICG. Next, the purity of non-PRS ICG was determined via qNMR when preparing samples under controlled humidity using a saturated sodium bromide solution. The purity was 84.19 ± 0.47% with a lower variation than that under non-controlled humidity. Moreover, ethanol signal almost disappeared. We estimated that residual ethanol in non-PRS ICG was replaced with water under controlled humidity. Subsequently, qNMR analysis was performed when preparing samples under controlled humidity in a constant temperature and humidity box. It showed excellent results with the lowest variation (82.26 ± 0.19%). As the use of a constant temperature and humidity box resulted in the lowest variability, it is recommended to use the control box if the reference ICG standard is needed for JP assays.
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http://dx.doi.org/10.1248/cpb.c20-00728DOI Listing
January 2021

[Pharmaceutical Properties of Anti-inflammatory Analgesic Patches Using Acrylic Polymer].

Yakugaku Zasshi 2020 ;140(9):1175-1183

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University.

The mock patches were prepared with novel acrylic polymers as adhesive layer where biphenyl-4-ylacetic acid (BAA) or 2-(2-fluorobiphenyl-4-yl) propanoic acid (FPA) was used as model active pharmaceutical ingredients (APIs). In addition, the mock patches were formulated with typical ester ingredients for transdermal dosage forms. The molecular state of the model APIs in the adhesive layer was observed by polarized microscope and microscopic Raman spectroscopy, which contains both conventional and low frequency (LF) region. Crystallization behavior would be depended on the interaction between API and polymers in the adhesive layer. In particular, LF Raman measurement was useful to discriminate API polymorphs. The pharmaceutical properties including dissolution and skin permeation of APIs were also evaluated for mock patches. The drug release and transdermal permeation were enhanced with the ester ingredients such as isopropyl myristate and diethyl sebacate due to their diffusion to the test solution or the skin stratum corneum as well as reducing the interaction between API and polymers. Further, the tack strength was not changed, but the peel strength was weakened by the additives. Thus, the adhesive properties were controllable by formulation with the additives. These findings could enable to evaluate the interaction between API and the polymers for adhesive layer and select the appropriate polymer and additives for used APIs when designing the drug products.
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http://dx.doi.org/10.1248/yakushi.20-00108DOI Listing
September 2020

Comparison of various pharmaceutical properties of clobetasol propionate cream formulations - considering stability of mixture with moisturizer.

J Pharm Health Care Sci 2020 30;6. Epub 2020 Jan 30.

4Division of Drugs, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501 Japan.

Background: The clobetasol propionate cream formulations (CLB ) belong to the "strongest" group, and are used widely. In addition, those formulations are often used as a mixture with moisturizer. Recently, we evaluated pharmaceutical properties of the CLB using near infrared (NIR) spectroscopy, and characteristic NIR spectra depending on the formulation were observed. In the present study, we attempted to evaluate the more diverse pharmaceutical properties of CLB , including the stability of mixture of CLB and moisturizer.

Method: Pharmaceutical properties of CLB were evaluated using from rheological characteristics, microscopic observation, dye permeability observations, electrical conductivity method, thermogravimetry-differential thermal analysis (TG-DTA) and near infrared (NIR) spectroscopy. Stability of mixtures of CLB and moisturizer were evaluated using from dye method and NIR spectroscopy.

Results: The hardness of Dermovate® (DRM), Glydil® (GDL), and Myalone® (MYA) was greater than that of CLB . High concentrations of white beeswax were considered the reason for the hardness of DRM and GDL. On the other hand, the hardness of MYA may be due to the presence of macrogol 6000. After storage of the cream formulations discharged from the tube at room temperature, mass reduction and attenuation of the peak reflecting water of NIR spectroscopy occurred in a time-dependent manner, except for GDL and MYA. Only GDL was shown to be a w/o-type formulation by dye and electric conductivity measurements, which suggested that this was the reason for the lack of changes in the mass or NIR spectrum of samples after storage. In the NIR spectrum of MYA, the peak reflecting water slightly increased in a time-dependent manner, suggesting the water absorption of macrogol 6000. TG-DTA provided curves indicating the presence of water in each formulation, except for MYA, which was consistent with water quantification previously reported. Finally, when mixing the CLB with a moisturizer, in any CLB , the stability of the mixture with w/o-type moisturizer varies greatly depending on the each CLB .

Conclusion: Thus, even for cream formulations with the same active pharmaceutical ingredient, pharmaceutical properties and stability of mixture with moisturizer may different significantly.
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http://dx.doi.org/10.1186/s40780-020-0158-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990562PMC
January 2020

Determining the Distribution of Active Pharmaceutical Ingredients in Combination Tablets Using Near IR and Low-Frequency Raman Spectroscopy Imaging.

Chem Pharm Bull (Tokyo) 2020 ;68(2):155-160

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University.

Combination tablets containing multiple active pharmaceutical ingredients (APIs) are expected to improve patient convenience by decreasing the number of tablets to be taken; thus, numerous formulations containing multiple APIs have recently been developed. To allow for dose adjustments based on patient conditions, many tablets have a bisection line to allow equal division of tablets. However, there have been no investigations regarding content uniformity among divided combination tablets. Therefore, in this study, the content uniformity of combination tablets after division was investigated using near IR and low-frequency (LF) Raman spectroscopy imaging as well as the Japanese Pharmacopoeia (JP) content uniformity tests. As model drugs, five tablets of three combination drugs containing 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA) and benserazide hydrochloride (BNS) as APIs for treating Parkinson's disease were bisected; the resultant 10 samples were subjected to the JP content uniformity tests. We found that acceptance values of L-DOPA and BNS were 11.0-21.9% and 13.3-17.5%, respectively, with some non-conformity to the maximum allowed acceptance value (15.0%) as per the current JP. Image analyses by near IR showed that L-DOPA, BNS, lactose, and corn starch were uniformly distributed in each tablet; moreover, LF Raman spectroscopy imaging also supported the result that L-DOPA, BNS, and lactose were evenly distributed. Therefore, drug content in the tablets was uniform; thus, careful manipulation was recommended in the tablet bisection. However, the results of bisection line specifications and hardness tests revealed that the ease of division differed depending on the tablets, which warrants attention.
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http://dx.doi.org/10.1248/cpb.c19-00791DOI Listing
March 2020

In situ monitoring of the crystalline state of active pharmaceutical ingredients during high-shear wet granulation using a low-frequency Raman probe.

Eur J Pharm Biopharm 2020 Feb 10;147:1-9. Epub 2019 Dec 10.

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Electronic address:

Optimization of manufacturing processes based on scientific evidence is important in the quality control of active pharmaceutical ingredients (APIs) and drug products, particularly when crystal forms change during production, which could affect subsequent drug performance. In this study, we verified crystalline states using various crystal faces and excipients during high-shear wet granulation based on non-contact low-frequency (LF) Raman probe monitoring. Four model drugs [indomethacin (IND), acetaminophen (APAP), theophylline (TP), and caffeine (CAF) polymorphs and cocrystals] were mixed with microcrystalline cellulose and hydroxypropyl cellulose with the addition of water over time. The LF Raman probe showed comparatively high sensitivity in monitoring 5-20% APAP and IND in a wet mass. Notably, as observed from the characteristic LF Raman peak shifts, form I TP and CAF and their cocrystals were more susceptible to transformation to the monohydrate form than form II. This method was also shown to be applicable in monitoring a commercial formulation of eight excipients and revealed crystalline transformations after 15 min of mixing. Therefore, probe-type LF Raman spectroscopy can be successfully employed to distinguish and monitor the crystalline state of APIs in real time during high-shear wet granulation, in which there is a risk of crystal transformation.
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http://dx.doi.org/10.1016/j.ejpb.2019.12.004DOI Listing
February 2020

Evaluation of the Water Content and Skin Permeability of Active Pharmaceutical Ingredients in Ketoprofen Poultice Formulations Removed from Their Airtight Containers and Left at Room Temperature.

Biol Pharm Bull 2019 ;42(12):2102-2108

Division of Drugs, National Institute of Health Sciences.

The poultice formulation is a patch containing a large amount of water. It is known that the water contained in the adhesive polymer layer (ADPL) of poultice affects the cooling sensation and skin permeability of the active pharmaceutical ingredient (API). In this study, we evaluated the relationship between the water content in a ketoprofen poultice formulation and the amount of time the poultice was left out at room temperature after removal from the airtight container, as well as the influence of the decreasing water content on the skin permeability of the API. After removing the poultice from the container for 1 h, the mass of the ADPL decreased by approximately 40%. When the near-infrared (NIR) spectrum of the ADPL of poultice was measured, the peaks reflecting the hydroxyl group were attenuated depending on the time left out at room temperature. It is suggested that the changes in the mass and NIR spectrum of the ADPL are caused by the change in the water content. Moreover, when the permeability of API was evaluated on hairless mouse skin, the cumulative skin permeation amount and flux decreased, while the lag time was prolonged as the time left out increased. These results suggest that the skin permeability of the API is impaired by water evaporation and that maintaining the water in the ADPL in poultice is very important from not only the viewpoint of cooling sensation, tackiness and moisturizing but also the skin permeability of the API.
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http://dx.doi.org/10.1248/bpb.b19-00758DOI Listing
April 2020

Solid-State Quantification of Cocrystals in Pharmaceutical Tablets Using Transmission Low-Frequency Raman Spectroscopy.

Anal Chem 2019 11 10;91(21):13427-13432. Epub 2019 Oct 10.

Coherent Inc. , 850 East, Duarte Road , Monrovia , California 91016 , United States.

To enable the continuous production of cocrystal-containing pharmaceutical tablets, guaranteeing the cocrystal content of the final pharmaceutical tablets in the solid state is critical. This study demonstrates the quantification of caffeine-glutaric acid cocrystals in model tablets using transmission low-frequency Raman spectroscopy. Although distinguishing between cocrystals and raw materials using conventional Raman spectroscopy is difficult, the use of low-frequency Raman spectroscopy enables the discrimination of cocrystals and raw materials. Low-frequency Raman spectra were analyzed by the partial least-squares method (PLS) to obtain the predicted contents in the model tablets. To evaluate the quantitative ability of this method, the root means square error of cross-validation (RMSECV) was determined by comparing the actual concentration and predicted content with a calibration curve. For cocrystal-containing tablets, the quantitative ability of the transmission mode (RMSECV = 2.06- 3.17) was 13.4-31.4% higher than that of the backscattering mode (RMSECV= 2.37- 3.91). The coexistence of raw crystalline materials did not affect the quantitative ability for cocrystals.
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http://dx.doi.org/10.1021/acs.analchem.9b01895DOI Listing
November 2019

Quantification of a cocrystal and its dissociated compounds in solid dosage form using transmission Raman spectroscopy.

J Pharm Biomed Anal 2020 Jan 18;177:112886. Epub 2019 Sep 18.

Division of Drugs, National Institute of Health Sciences, Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan.

The performance of transmission Raman spectroscopy (TRS) for quantifying a cocrystal and its dissociation in solid dosage form was investigated. Some tablets containing 0%-20% (w/w) of a cocrystal of carbamazepine (CBZ)/succinic acid (SUC), 0%-4% of CBZ, 0%-4% of SUC, and 75%-99% of D-mannitol were prepared. The Raman spectra of these tablets were preprocessed using the standard normal variate (SNV) or multiplicative scatter correction (MSC) as well as the Savitzky Golay second derivative, and then, these were used to generate calibration models using partial least squares (PLS) regression. The performance of the model was superior when the MSC preprocessing spectra of the cocrystal between 200 and 1800 cm were used for calibration. The determination coefficient of the PLS calibration curve for the CBZ/SUC cocrystal between 200 and 1800 cm with MSC was 0.97, root mean square error of cross validation (RMSECV) was 1.16, and root mean square error of prediction (RMSEP) was 1.10. As in the case of the CBZ/SUC cocrystal, the performance of the model was superior when the MSC preprocessing spectra of CBZ and SUC between 200 and 1800 cm were used for calibration. These data suggest that TRS is useful for quantifying a cocrystal and its dissociation compounds in solid dosage forms.
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http://dx.doi.org/10.1016/j.jpba.2019.112886DOI Listing
January 2020

Measurement of the Water Content in Semi-solid Formulations Used to Treat Pressure Ulcers and Evaluation of Their Water Absorption Characteristics.

Chem Pharm Bull (Tokyo) 2019 ;67(9):929-934

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University.

We investigated the water contents in commercial semi-solid preparations used for pressure ulcer (PU) treatment using near-IR spectroscopy (NIRS) and compared the results with those measured using the Karl Fischer (KF) method. The aim of this study was to determine a standard method and select the appropriate topical preparation with the optimal moisture for PU treatment. The water absorption properties of bases and formulations were evaluated with a time-dependent factor using Transwell as the model membrane. KF and NIRS were applicable as measurement methods of the water content in semi-solid formulations. NIRS was shown to be a useful, simple, nondestructive tool that is more advantageous than the KF method. The water absorption characteristics tested using Transwell revealed that the rate of and capacity for water absorption are determined not only by the absorption ability of the polymer base but also by other factors, such as the osmotic pressure exerted by additives. KF and NIR measurements can be used to choose external skin preparations to control the amount of water in PU treatment.
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http://dx.doi.org/10.1248/cpb.c18-00746DOI Listing
October 2019

Imaging Analysis Enables Differentiation of the Distribution of Pharmaceutical Ingredients in Tacrolimus Ointments.

Appl Spectrosc 2019 Oct 30;73(10):1183-1192. Epub 2019 Jul 30.

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, Kiyose, Japan.

We demonstrated the difference in the distribution state of pharmaceutical ingredients between tacrolimus (TCR) original ointment and six kinds of generic medicines. Two-dimensional imaging and depth analysis using attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy and confocal Raman microscopy were used, in addition to the evaluation of pharmaceutical properties, including spreading properties, rheological properties, and amount of solvent. The solvents, such as propylene carbonate and triacetin, in TCR ointments formed liquid droplets and dispersed in hydrocarbon oils. Waxes, white beeswax and beeswax, formed other domains. Confocal Raman microscopy could detect liquid droplet size without coalescence of that on germanium or glass surfaces. The combination of ATR FT-IR and confocal Raman imaging would be a powerful tool to reveal the size and shape of liquid droplets of pharmaceutical ingredients in semisolid formulations.
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http://dx.doi.org/10.1177/0003702819863441DOI Listing
October 2019

Pharmaceutical quantification with univariate analysis using transmission Raman spectroscopy.

Drug Dev Ind Pharm 2019 Sep 4;45(9):1430-1436. Epub 2019 Jun 4.

b Division of Drugs , National Institute of Health Sciences , Kawasaki , Japan.

The purpose of this study was to investigate the quantification performance of transmission Raman spectroscopy with univariate analysis. Model dosage forms containing acetaminophen and an excipient, lactose monohydrate, were prepared. The Raman spectra of the tablets were obtained using the modes of transmission, backscattering micro-spectroscopy, and wide area illumination. Calibration curves for quantification of acetaminophen in the tablets were created using peak heights of the Raman spectra. Of the three modes of measurement, the quantitative results by transmission had the highest correlation with those by conventional UV-vis methods. In the validation of quantification by the transmission mode with univariate analysis, a certain degree of daily variation was confirmed. Additionally, quantitative results using peak heights were compared with those of partial least squares (PLSs) multivariate analysis. The root mean square error of prediction (RMSEP) suggested that quantification using PLS provided better precision than the peak height method as expected. However, content uniformity test using large sample sizes by the Raman spectra is not required to be very highly predictive because they usually employ non-parametric criteria and include wide specification ranges. Therefore, univariate analysis using transmission Raman spectroscopy was a suitable quantitative method for conducting content uniformity tests of large sample sizes.
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http://dx.doi.org/10.1080/03639045.2019.1621336DOI Listing
September 2019

Transmission Low-Frequency Raman Spectroscopy for Quantification of Crystalline Polymorphs in Pharmaceutical Tablets.

Anal Chem 2019 02 15;91(3):1997-2003. Epub 2019 Jan 15.

Ondax Incorporated , 850 East Duarte Road , Monrovia , California 91016 , United States.

The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using a novel transmission low-frequency Raman spectroscopy method. We developed a novel transmission geometry for low-frequency Raman spectroscopy and compared quantitative ability in transmission mode versus backscattering mode using chemometrics. We prepared two series of tablets, (1) containing different weight-based contents of carbamazepine form III and (2) including different ratios of carbamazepine polymorphs (forms I/III). From the relationship between the contents of carbamazepine form III and partial least-squares (PLS) predictions in the tablets, correlation coefficients in transmission mode ( R = 0.98) were found to be higher than in backscattering mode ( R = 0.97). The root-mean-square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. The tablets containing a mixture of carbamazepine (I/III) polymorphs were measured by transmission low-frequency Raman spectroscopy, and it was found that the spectral shape changed according to the ratio of polymorphs: the relationship between the actual content and the prediction showed high correlation. These findings indicate that transmission low-frequency Raman spectroscopy possesses the potential to complement existing analytical methods for the quantification of polymorphs.
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http://dx.doi.org/10.1021/acs.analchem.8b04365DOI Listing
February 2019

Molecular State of Active Pharmaceutical Ingredients in Ketoprofen Dermal Patches Characterized by Pharmaceutical Evaluation.

Biol Pharm Bull 2018 ;41(9):1348-1354

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University.

The molecular states of ketoprofen and the interaction between ketoprofen and other pharmaceutical excipients in the matrix layer were examined to determine their effect on the pharmaceutical properties of original and generic ketoprofen dermal patches (generic patches A and B). Molecular states of ketoprofen were evaluated using polarized light microscopy, Raman spectroscopy and powder X-ray diffraction. For the original ketoprofen patch, crystalline components were not observed in the matrix layer. However, crystalline ketoprofen was observed in the two generic ketoprofen patches. Moreover, the ketoprofen exhibited hydrogen bonding with the pharmaceutical excipients or patch materials in the generic products. Skin permeation of ketoprofen from the patches was evaluated using hairless mouse skin. Twelve hours after application, the original patch demonstrated the highest level of cumulative skin permeation of ketoprofen. This was followed by generic patch B while generic patch A showed the lowest level of permeation. Fluxes were calculated from the skin permeation profiles. The original patch was approx. 2.4-times faster compared with generic patch A and approximately 1.9-times faster compared with generic patch B. This investigation suggested that pharmaceutical properties such as skin permeability for these types of products are affected by the precipitation of crystalline ketoprofen in the matrix layer and the interaction of ketoprofen with the pharmaceutical excipients or patch materials.
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http://dx.doi.org/10.1248/bpb.b18-00019DOI Listing
November 2018

Mixtures of betamethasone butyrate propionate ointments and heparinoid oil-based cream: Physical stability evaluation.

Eur J Pharm Sci 2018 Nov 29;124:199-207. Epub 2018 Aug 29.

Division of Drugs, National Institute of Health Sciences, Japan.

Betamethasone butyrate propionate ointment (BBP) is mainly used for adult patients in dermatology and is often prescribed as a mixture containing a base or moisturizing cream for various reasons. However, in the case of a moisturizing cream, since this formulation is composed of various ingredients, a physical change is expected to occur by mixing it with an ointment. Therefore, in the present study, the physical stability of a mixture of four BBP formulations and heparinoid oily cream (HP) was examined. Layer separation was observed in all mixtures following centrifugation. The near-infrared (NIR) measurement showed a peak at 5200 cm on the lower layer side, which strongly suggests the presence of water. The peak at 5200 cm in the middle layer was hardly observed in the mixtures of two BBP generic formulations and HP, thus suggesting that the separation was more advanced in those mixtures than in the others. These two mixtures separated into a semisolid layer (upper side) and a liquid layer (lower side) after 3 h of storage at 37 °C. The NIR measurement of each layer revealed that most of the semisolid layer was oil while the liquid layer was water. Furthermore, backscattered light measurements were conducted to monitor the behavior of the mixture's layer separation. An evaluation using model formulations revealed that the layer separation of the mixtures was due to the propylene glycol (PG) and surfactant content of the two generic BBP formulations. Thus, these findings suggest that excipients need to be considered in selecting formulations for mixtures of skin preparations.
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http://dx.doi.org/10.1016/j.ejps.2018.08.040DOI Listing
November 2018

In situ monitoring of cocrystals in formulation development using low-frequency Raman spectroscopy.

Int J Pharm 2018 May 7;542(1-2):56-65. Epub 2018 Mar 7.

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, 522-1, Noshio 2-chome, Kiyose, Tokyo 204-8588, Japan.

In recent years, to guarantee a quality-by-design approach to the development of pharmaceutical products, it is important to identify properties of raw materials and excipients in order to determine critical process parameters and critical quality attributes. Feedback obtained from real-time analyses using various process analytical technology (PAT) tools has been actively investigated. In this study, in situ monitoring using low-frequency (LF) Raman spectroscopy (10-200 cm), which may have higher discriminative ability among polymorphs than near-infrared spectroscopy and conventional Raman spectroscopy (200-1800 cm), was investigated as a possible application to PAT. This is because LF-Raman spectroscopy obtains information about intermolecular and/or lattice vibrations in the solid state. The monitoring results obtained from Furosemide/Nicotinamide cocrystal indicate that LF-Raman spectroscopy is applicable to in situ monitoring of suspension and fluidized bed granulation processes, and is an effective technique as a PAT tool to detect the conversion risk of cocrystals. LF-Raman spectroscopy is also used as a PAT tool to monitor reactions, crystallizations, and manufacturing processes of drug substances and products. In addition, a sequence of conversion behaviors of Furosemide/Nicotinamide cocrystals was determined by performing in situ monitoring for the first time.
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http://dx.doi.org/10.1016/j.ijpharm.2018.03.008DOI Listing
May 2018

Stability of Mixed Preparations Consisting of Commercial Moisturizing Creams with an Ointment Base Investigated by Magnetic Resonance Imaging.

Chem Pharm Bull (Tokyo) 2017 ;65(5):487-491

Department of Pharmaceutics, Hoshi University.

A moisturizing cream mixed with a steroid ointment is frequently prescribed to patients suffering from atopic dermatitis. However, there is a concern that the mixing operation causes destabilization. The present study was performed to investigate the stability of such preparations closely using magnetic resonance imaging (MRI). As sample preparations, five commercial moisturizing creams that are popular in Japan were mixed with an ointment base, a white petrolatum, at a volume ratio of 1 : 1. The mixed preparations were stored at 60°C to accelerate the destabilization processes. Subsequently, the phase separations induced by the storage test were monitored using MRI. Using advanced MR technologies including spin-spin relaxation time (T) mapping and MR spectroscopy, we successfully characterized the phase-separation behavior of the test samples. For most samples, phase separations developed by the bleeding of liquid oil components. From a sample consisting of an oil-in-water-type cream, Urepearl Cream 10%, a distinct phase-separation mode was observed, which was initiated by the aqueous component separating from the bottom part of the sample. The resultant phase separation was the most distinct among the test samples. To investigate the phase separation quantitatively and objectively, we conducted a histogram analysis on the acquired T maps. The water-in-oil type creams were found to be much more stable after mixing with ointment base than those of oil-in-water type creams. This finding strongly supported the validity of the mixing operation traditionally conducted in pharmacies.
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http://dx.doi.org/10.1248/cpb.c16-00986DOI Listing
June 2017

Characterization and Quality Control of Pharmaceutical Cocrystals.

Chem Pharm Bull (Tokyo) 2016 Oct 18;64(10):1421-1430. Epub 2016 Jun 18.

Division of Drugs, National Institute of Health Sciences.

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.
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http://dx.doi.org/10.1248/cpb.c16-00233DOI Listing
October 2016

Analysis of the Stability of External-Application Dermatologic Preparations: Consideration from Rheological Measurements.

Chem Pharm Bull (Tokyo) 2016 Jul 22;64(7):1047-55. Epub 2016 Apr 22.

Faculty of Pharmaceutical Sciences, Teikyo Heisei University.

The present study examined the stability of mixtures of various combinations of moisturizers, water in oil (w/o)-type or oil in water (o/w)-type cream preparations containing heparinoids, and steroidal ointments or creams (o/w-type) frequently used in children. Centrifugation at room temperature led to separation of mixtures of w/o-type moisturizers and steroidal ointments into three layers. Polarized microscopic observations, near-infrared (NIR) spectroscopy, and dye-based analyses revealed the presence of oily components in the upper and middle layers and water-soluble components in the lower layer. Separation into three layers upon centrifugation was also observed for mixtures of o/w-type moisturizers and steroidal ointments. In contrast, neither the o/w-type moisturizer and steroidal cream nor the w/o-type moisturizer and steroidal cream mixtures separated into layers upon centrifugation. Consideration of the characteristics of each preparation is necessary when mixing external-application dermatologic preparations. Centrifugation at 4°C did not result in layer separation of the w/o-type moisturizer and steroidal ointment mixture, suggesting that cold storage of such mixtures provides superior stability compared with room temperature storage. However, despite no obvious layer separation, the NIR spectra indicated that water movement was induced within the mixture. These results clearly indicate that methods such as NIR spectroscopy are useful for early determinations of the stability of mixed external-application dermatologic preparations.
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http://dx.doi.org/10.1248/cpb.c16-00216DOI Listing
July 2016

Analysis of Distribution of Ingredients in Commercially Available Clarithromycin Tablets Using Near-Infrared Chemical Imaging with Principal Component Analysis and Partial Least Squares.

Chem Pharm Bull (Tokyo) 2015 ;63(9):663-8

Division of Drugs, National Institute of Health Sciences.

The aim of this study was to evaluate pharmaceuticals using a near-infrared chemical imaging (NIR-CI) technique for visualizing the distribution of ingredients in solid dosage forms of commercially available clarithromycin tablets. The cross section of a tablet was measured using the NIR-CI system for evaluating the distribution of ingredients in the tablet. The chemical images were generated by performing multivariate analysis methods: principal component analysis (PCA) and partial least squares (PLS) with normalized near-infrared (NIR) spectral data. We gained spectral and distributional information related to clarithromycin, cornstarch, and magnesium stearate by using PCA analysis. On the basis of this information, the distribution images of these ingredients were generated using PLS analysis. The results of PCA analysis enabled us to analyze individual components by using PLS even if sufficient information on the products was not available. However, some ingredients such as binder could not be detected using NIR-CI, because their particle sizes were smaller than the pixel size (approximately 25×25×50 µm) and they were present in low concentrations. The combined analysis using both PCA and PLS with NIR-CI was useful to analyze the distribution of ingredients in a commercially available pharmaceutical even when sufficient information on the product is not available.
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http://dx.doi.org/10.1248/cpb.c14-00811DOI Listing
June 2016

Collagenous gastroduodenitis with recurrent gastric ulcer in 12-year-old girl.

Pediatr Int 2015 Aug 22;57(4):754-7. Epub 2015 May 22.

Department of Pediatrics, Osaka Police Hospital, Osaka, Japan.

This report describes a rare case of collagenous gastroduodenitis found in a 12-year-old Japanese girl who had recurrent hematemesis. Gastrointestinal endoscopy showed many lotus leaf-like lesions on the gastric mucosa surrounded by atrophic gastric mucosa in the antrum, with a cobblestone appearance and a scarred duodenal ulcer in the duodenal bulb. A biopsy of the gastric mucosa indicated subepithelial collagen band. The patient was treated with H2-blockers for her symptoms for 4 years following the endoscopic findings. Follow-up endoscopy showed the same appearance as before. The pathology, however, showed a more prominent subepithelial collagen deposition. To make the correct diagnosis, it is critical to know from which part the pathological biopsy specimens were taken because there were numerous collagen bands in the atrophic membrane. It is important to monitor the patient regularly for evaluation of the etiology, pathogenesis and prognosis of this rare disease.
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http://dx.doi.org/10.1111/ped.12615DOI Listing
August 2015

Magnetic resonance imaging of the phase separation in mixed preparations of moisturizing cream and steroid ointment after centrifugation.

Chem Pharm Bull (Tokyo) 2015 ;63(5):377-83

Department of Pharmaceutics, Hoshi University.

A mixed preparation consisting of a water-in-oil emulsion-type moisturizing cream and a steroid ointment is frequently prescribed for the treatment of atopic dermatitis. We have investigated the compatibility of moisturizing creams and ointments because there are concerns regarding the physical stability of these mixed preparations. The key technology used in this study was magnetic resonance imaging (MRI). A commercial moisturizing cream and white petrolatum or clobetasone butyrate (CLB) ointment samples were mixed in a weight ratio of 1 : 1. A centrifugation test protocol (20000×g for 3 min) was implemented to accelerate the destabilization processes in the samples. After centrifugation, the mixed preparations separated into three distinct layers (upper, middle, and lower), while no phase separation was observed using moisturizing cream alone. The phase separation was monitored using chemical shift selective images of water and oil and quantitative T2 maps. In addition, MR and near-infrared spectroscopy were employed for component analysis of each phase-separated layer. Collectively, it was confirmed that the lower layer contained water, oils, and organic solvent, while the upper and middle layers were composed solely of oils. Furthermore, this study investigated the distribution of CLB in the phase-separated samples and showed that a heterogeneous distribution existed. From our results, it was confirmed that the mixed preparation became unstable because of the incompatibility of the moisturizing cream and ointment.
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http://dx.doi.org/10.1248/cpb.c15-00088DOI Listing
February 2016

Studies on uniformity of the active ingredients in acetaminophen suppositories re-solidified after melting under high temperature conditions.

Chem Pharm Bull (Tokyo) 2015 5;63(4):263-72. Epub 2015 Feb 5.

Faculty of Pharmaceutical Sciences, Teikyo Heisei University.

The target of the present pharmaceutical study was the antipyretic analgesic, acetaminophen; its suppository form is usually split when used in pediatric patients. We focused on the active ingredient uniformity in these products, which were re-solidified after melting under high temperature condition. When sections of the cut surfaces of the seven acetaminophen suppository products (SUP-A-G) commercially available in Japan were visualized by polarized microscopy, acetaminophen crystals that were dispersed in the base were identified. The results of the quantitative determination of agent concentration for each cut portion (mg/g) suggested uniform dispersion of these crystals in the base of each product. The agent concentration in each portion of the suppositories that was re-solidified after melting at high temperatures was measured. Segregation of the active ingredient was observed in four products at a temperature of 40°C for 1 h, while active ingredient uniformity was maintained in the other three products (SUP-C, SUP-F and SUP-G). The latter three products also showed high viscosity at 40°C. At 50°C for 4 h, only the uniformity of the active ingredient in SUP-C was maintained. These results suggest that the uniformity of the active ingredient is lost in some acetaminophen suppositories that were re-solidified after melting under high temperature conditions. The degree of loss varies depending on the product.
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http://dx.doi.org/10.1248/cpb.c14-00803DOI Listing
December 2015

Comparative pharmaceutical evaluation of brand and generic clobetasone butyrate ointments.

Int J Pharm 2014 Mar 7;463(1):62-7. Epub 2014 Jan 7.

School of Pharmacy, Nihon University, Japan.

In the present study, we performed comprehensive pharmaceutical evaluation among an original clobetasone butyrate (CLB) ointment product and three generic products. Although spherocrystal images were observed under a polarizing microscope for only Kindavate®, the original product, distribution of active and inactive ingredients was chemically equivalent between the original and generic medicine by the attenuated total reflection infrared spectroscopy. These results suggest that the spherocrystals observed in Kindavate® are composed of hydrocarbon. On GC/MS, it was revealed that linear alkanes having 25-27 carbon atoms are densely present in Sun White®, the base used in Kindavate®. On the other hand, linear alkanes having 22-31 carbon atoms were broadly distributed in most other white petrolatums. In the CLB ointment products, the distribution equivalent of linear alkane to Sun White® was observed only in Kindavate®. Thus, the GC/MS method is extremely useful for identification of white petrolatum used in the ointment. A similar amount of CLB among the pharmaceutical products was detected in the skin tissue by skin accumulation test, although there were the differences in rheological properties and the quality of white petrolatum. The present results will be very useful for pharmacists in selecting medicine products that match the needs of the patient. Such pharmaceutical information will help spread objective knowledge about products in the future, and will contribute to the appropriate selection of medication.
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http://dx.doi.org/10.1016/j.ijpharm.2013.12.054DOI Listing
March 2014
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