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The effect of grinding on the pharmaceutical properties of matrix tablets consisting of ground glutinous rice starch (GRS) and theophylline (TH) was predicted by near infrared (NIR) spectroscopy. Ground GRS samples were prepared by grinding GRS in a planetary ball mill for 0-120 min, measured by X-ray diffractometry (XRD) and NIR, and then evaluated for crystallinity (%XRD) based on XRD profiles. Tablets containing TH (5 w/w%), ground GRS (94 w/w%), and magnesium stearate (1 w/w%) were formed by compression. Gel-forming and drug-release processes of the tablets were measured using a dissolution instrument with X-ray computed tomography (XCT). Swelling ratio (SWE) and mean drug-release time (MDT) were evaluated based on XCT and drug-release profiles, respectively. Calibration models for predicting percent %XRD, MDT, and SWE were constructed based on the NIR of ground GRS using partial least-squares. The results indicated the possibility of controlling the pharmaceutical properties of matrix tablets by altering the pre-gelatinization of GRS based on changes in their NIR spectra during the milling process.

The objective of this work is to demonstrate the potential of near-infrared spectroscopy for common screening of falsified medicines in the field by means of a device-independent universal discrimination approach. In order to provide a useful discrimination tool to protect people from low-quality medical products, not only is a low-cost and portable screening device necessary, but a reference library is also essential. The authors believe that a device-dependent reference library inhibits near-infrared spectroscopy from becoming a popular screening tool. In this study, to develop a device-independent method, discrimination performance is evaluated using different devices for training and testing. The training data sets for the reference library were prepared using a bench-top Fourier transform near-infrared spectrophotometer, and predictive discrimination was performed using the spectral data by a low-cost and portable wavelength dispersive near-infrared spectrophotometer. A near-infrared spectrum-based support vector machine was used for these purposes, but the screening resulted in low accuracy thought to be caused by the intrinsically device-dependent features of the spectra data. Thus, principal component analysis was performed to collect the proper components to discriminate low-quality products from standard products. The principal component score-based support vector machine was able to produce highly accurate results, identifying falsified products with no false positive cases.

The manufacturing of solid pharmaceutical dosage forms composed of cocrystals requires numerous processes during which there is risk of dissociation into parent molecules. Resonant acoustic wet granulation (RAG) was devised in an effort to complete theophylline-citric acid (THPCIT) cocrystal formation during the granulation process, thereby reducing the number of operations. In addition, the influence of granulation liquid was investigated. A mixture of anhydrous THP (drug), anhydrous CIT (coformer), and hydroxypropyl cellulose (granulating agent) was processed by RAG with water or ethanol as a granulation liquid. The purposes were to (i) form granules using RAG as a breakthrough method; (ii) accomplish the cocrystallization during the integrated unit operation; and (iii) characterize the final solid product (i.e., tablet). The RAG procedure achieved complete cocrystal formation (>99%) and adequately sized granules (d50: >250 mu m). The granulation using water (GW) facilitated formation of cocrystal hydrate which were then transformed into anhydrous cocrystal after drying, while the granulation using ethanol (GE) resulted in the formation of anhydrous cocrystal before and after drying. The dissolution of the highly dense GW tablet, which was compressed from granules including fine powder due to the dehydration, was slower than that of the GE tablet.

Cocrystallisation can enhance the solubility and bioavailability of active pharmaceutical ingredients (APIs); this method may be applied to improve the availability of materials that were previously considered unsuitable. Terahertz (THz) spectroscopy provides clear, substance-specific fingerprint spectra; the transparency of the THz wave allows us to probe inside a sample to identify medicinal materials. In this study, THz and infrared (IR) spectroscopy were used to characterise cocrystallisation in solid-phase reactions between ibuprofen and nicotinamide. Multivariate curve resolution with alternating least squares (MCR-ALS) was applied to both time-dependent THz and IR spectra to identify the intermolecular interactions between these cocrystallising species. The analytical results revealed cocrystal formation through a two-step reaction, in which the steps were dominated by thermal energy and water vapour, respectively. We infer that the presence of water molecules significantly lowered the activation energy of cocrystal formation.

Hot melt extrusion is a promising technology for producing amorphous solid dispersions, however, there is a risk of thermal degradation or residual crystallinity formation. This caveat may be addressed by optimizing for-mulations and manufacturing conditions. The aim of our study was to explore optimization of formulation by evaluating the thermodynamic and thermal rheological properties of griseofulvin mixed with various carriers, and to investigate the effects of the obtained system. The combination of griseofulvin with 14 varieties of polymers, 1 disaccharide or 4 varieties of sugar alcohols were analyzed using differential scanning calorimetry and rheology. Our results indicated that melting point depression and thermal viscoelasticity were different between each of the formulations tested, and that a ternary system containing hypromellose phthalate (HP) and erythritol (Ery) allowed lowering of the processing temperature. Additionally, the rubber state of HP was maintained within a wide temperature range when mixed with Ery. A promising candidate formulation was manufactured using a twin screw extruder. All extruded products containing HP and Ery showed a reduction in thermal degradation. In addition, the products exhibited improved solubility and maintenance of supersaturated concentration when compared to crystalline griseofulvin, physical mixture or extruded products resulting from binary formulation with HP.

Spray freeze drying (SFD) produces suitable particles for the pharmaceutical formulation of dry powders used in dry powder inhalers (DPIs). However, SFD particles have large specific surface area and are partially made up of amorphous solids; this state is hygroscopic and would lead to changes in physicochemical properties by humidity when the particles are stored over the long-term or under high humidity conditions such as in the lungs. This study focused on the application of SFD with a cocrystal technique which can add humidity resistance to the active pharmaceutical ingredients (APIs), and the investigation of the physicochemical properties under high humidity conditions. Cocrystal samples containing theophylline anhydrate (THA) and oxalic acid (OXA) in a molar ratio of 2:1 were prepared by SFD. The crystalline structure, thermal behavior, solid-state, hygroscopicity, stability, and aerodynamic properties were evaluated. Simultaneous in situ measurement by near-infrared and Raman (NIR-Raman) spectroscopy was performed to analyze the humidification process. The SFD sample had a porous particle and an optimal aerodynamic particle size (3.03 µm) although the geometric particle diameter was 7.20 µm. In addition, the sample formed the THAOXA cocrystal with partial coamorphous. The hydration capacity and pseudopolymorphic transformation rate of the SFD sample were much lower than those of THA under conditions of 96.4% relative humidity and 40.0°C temperature because of the cocrystal formation. The reasons were discussed based on the crystalline structure and energy. The SFD technology for cocrystallization would enable the pharmaceutical preparation of DPI products under environmentally friendly conditions.

In this study, we established a robust feed-forward control model for the tableting process by partial least squares regression using the near-infrared (NIR) spectra and physical attributes of the granules to be compressed. The NIR spectra of granules are rich in information about chemical attributes, such as the compositions of any ingredients and moisture content. Polymorphism and pseudo-polymorphism can also be quantitatively evaluated by NIR spectra. We used the particle size distribution, flowability, and loose and tapped density as the physical attributes of the granules. The tableting process was controlled by the lower punch fill depth and the minimum distance between the upper and lower punches at compression, which were specifically related to the tablet weight and thickness, respectively. The feed-forward control of the process would be expected to provide some advantages for automated and semi-automated continuous pharmaceutical manufacturing. As a result, our model, using a combination of NIR spectra and the physical attributes of granules to control the distance between punches, resulted in respectable agreement between the predicted process parameters and actual settings to produce tablets of the desired thickness.

Formulation of a cocrystal into a solid pharmaceutical dosage form entails numerous processing steps during which there is risk of dissociation. In an effort to reduce the number of unit operations, we have attempted the in situ formation of an indomethacin-saccharin (INDSAC) cocrystal during high-shear wet granulation (HSWG). HSWG of IND (poorly water-soluble drug) and SAC (coformer), with polymers (granulating agents), was carried out using ethanol as the granulation liquid and yielded INDSAC cocrystal granules. Therefore, cocrystal formation and granulation were simultaneously accomplished. Our objectives were to (i) evaluate the influence of polymers on cocrystal formation kinetics during wet granulation and (ii) mechanistically understand the role of polymers in facilitating the cocrystal formation. Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO) were chosen to investigate the influence of soluble polymers. The cocrystal formation kinetics was influenced by the polymer (PVP < HPC < PEO) and its concentration. The interaction of the polymer with cocrystal components inhibited the cocrystal formation. Complete cocrystal formation was observed in the presence of PEO, a polymer which does not interact with IND and SAC.

In order to investigate the effect of phytic acid on the improvement of disintegration time (DT) of gelatin-based film sheets, gelatin film sheets and succinylated gelatin film sheets with various concentrations of phytic acid were dipped and stored in polyethylene glycol (PEG) 400 at 60 degrees C. The DT and near infrared (NIR) spectral changes were measured after storage. Gelatin showed a tendency to prolong DT caused by the formation of insoluble thin membranes due to the cross-linking of gelatin molecules, whereas succinylated gelatin did not show prolongation of DT. We also observed the preventive effect of phytic acid on the prolongation of DT of gelatin film sheets as the phytic acid concentration increased. From NIR measurements, it was considered that the -OH groups of phytic acid were coordinated with the hydrogen bonding position of gelatin molecules by replacing H2O or glycerin molecules. It was also thought that structural changes in the gelatin-water-glycerin complexes caused by phytic acid interfered with the access of peroxide or aldehyde generated from PEG 400 to the free epsilon-NH2 groups and prevented the cross-linking of gelatin molecules. On the other hand, because the free epsilon-NH2 groups of succinylated gelatin are protected by acid amidation, the cross-linking of succinylated gelatin was not observed.

Pharmaceutical manufacturing processes are necessary to make solid dosage form even in cocrystal formation. In an effort to reduce the number of unit operations, high-shear wet granulation with cocrystallization system was proposed. In the present study, indomethacin-saccharin was chosen as a model compound, and the cocrystal formation kinetics was investigated during the consistent process. The role of each initial indomethacin crystal state (γ-form, α-form, or amorphous) for the kinetics was explored using in situ Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis as a chemometrics. Obtained granules were characterized by X-ray diffraction and tablet dissolution testing. The Raman peaks assigned to indomethacin-saccharin cocrystal were increased with granulation when ethanol was used as a binding solvent. In addition, the reaction kinetics of run samples which had different indomethacin forms was distinguished by best fitting using Avrami-Erofeev or Ginstling-Brounshtein model. The kinetic variance depended on the initial thermodynamic state of indomethacin because they had a different crystallization mechanism for the cocrystal. The scalable and feasible granulation method is required in the pharmaceutical industry.

It is important to quantify amorphous solid in active pharmaceutical ingredients (API) of formulations to guarantee high-quality pharmaceutical products. In this study, we aimed to quantify amorphous solid in API by transmission Raman spectroscopy (TRS) and transmission near-infra-red spectroscopy (NIRS). To quantify the amount of trace amorphous solids contained in the API of a formulation, calibration curves of tablets containing 40% or 3% solifenacin succinate (SLFS) in the pharmaceutical formulations were prepared. The tablets varied in the ratio of amorphous solids in the API. TRS and NIRS were carried out with the calibration tablets and partial least square regression (PLSR) analysis was performed. Good results were obtained by both TRS and NIRS with the calibration model containing 40% SLFS. On the contrary, with the calibration model containing 3% SLFS, the PLSR analysis results using the TRS data were better than those using the NIRS data. The low content calibration model based on TRS showed good results with R2 of 0.999, RMSECV of 1.236, and LOD of 0.12. TRS can be used to specifically detect trace amorphous solids contained in the API of a formulation.

A continuous-spray granulator (CTS-SGR) is a one-step granulation technology capable of using solutions or suspensions. The present research objectives were, (1) to reduce the manufacturing operations for solid dosage formulations, (2) to make amorphous solid dispersion (ASD) granules without pre-preparation of amorphous solids of active pharmaceutical ingredients (API), and (3) to characterize the obtained SGR granules by comprehensive pharmaceutical analysis. Rebamipide (RBM), a biopharmaceutical classification system class IV drug, that has low solubility or permeability in the stomach, was selected as a model compound. Five kind of granules with different concentrations of polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA) were prepared using a one-step SGR process. All of the SGR granules could be produced in amorphous or ASD form and their thermodynamic stability was very high because of high glass transition temperatures (&gt;178 °C). They were unstable in 20 °C/75%RH; however, their stability was improved according to the proportion of polymer. The carboxy group of RBM was ionized in the granules and interactions appeared between RBM and PVP-VA, with the formation of an ASD confirmed and the solubility was enhanced compared with bulk RBM crystals. The SGR methodology has the possibility of contributing to process development in the pharmaceutical industry.

In order to investigate the properties of gelatin film sheets for soft gelatin shell capsules, we compared gelatin and succinylated gelatin film sheets using dynamic vapor sorption (DVS), static near infrared (NIR), and dynamic NIR during tensile strength measurements. A steep increase in the amount of water vapor absorbed was observed with relative humidity > 70% for both gelatin and succinylated gelatin film sheets. From the static NIR measurement, it was considered that the -OH alcohol groups in glycerin were coordinated with gelatin or succinylated gelatin molecules by replacing H2O in the gelatin or succinylated gelatin film sheets as the glycerin concentration increased. It was found that gelatin molecules showed a change in the molecular net structure before and after stress, but this phenomenon was not observed for the succinylated gelatin film sheets. The properties of gelatin simultaneously explained the flexibility and stronger resistance to contortion. In relation to these results, we considered that the gelatin molecules made a stronger net structure among gelatin-water-glycerin complexes because of the free epsilon-NH2 groups compared with succinylated gelatin.

In order to establish a pharmaceutical manufacturing process control system based on a Quality-by-Design concept, the pharmaceutical properties of tablets during the tablet-coating process were monitored in real time and predicted using values recorded by in-line near-infrared (NIR) spectroscopy. Coating amount (C%), thickness (L), tablet hardness (HT), and tablet dissolution parameters with elution times (T0, T50, and T80) were measured using individual pharmaceutical tests. Tablet coating was performed by spraying F-A (25 w/w%) or F-B (17.8 w/w%) containing EUDRAGIT® L 30 D-55, and monitored using an in-line NIR spectroscopy instrument. Calibration models to predict tablet properties (C%, L, HT, T0, T50, and T80) were obtained based on NIR spectroscopy using a partial least-squares regression (PLS). Chemometric parameters were found to be sufficiently accurate. Correlations between the predicted and measured values of each tablet property showed satisfactory linear relationships. Therefore, the pharmaceutical properties (C%, L, HT, T0, T50, and T80) of tablets may be monitored in real time during the coating process with an in-line NIR spectroscopy method.

We developed a method for the optimization of dissolution properties of solid oral dosage forms manufacturing using high shear wet granulation (HSWG) by using near-infrared spectroscopy (NIRS) with chemometrics in small-scale experiments. The changes in rheology and NIR spectra of the granules were monitored to verify the granulation mechanism and determine the suitable water amount for model formulation during the HSWG. Tablets were manufactured by altering the added water amount to investigate the impact of the granulation mechanism on drug product qualities. Model formulation granules were prepared with 10–20% w/w water in a funicular state, corresponding to the plateau region in score plots obtained by principal component analysis (PCA). The dissolution rate of model formulation tablets manufactured with more than 20% w/w of water was significantly delayed while tablets manufactured with 15% w/w water showed 100% dissolution at 15 min. NIRS and PCA are applicable to the optimization of dissolution properties via the process understanding of HSWG at the early formulation development stage and could facilitate drug development.

Ulinastatin (UTI) is a trypsin inhibitor derived from human urine. UTI has inhibitory activities against many enzymes, and is clinically effective and safe for the treatment of acute pancreatitis. Administration of UTI into the vagina is an effective treatment for threatened premature delivery. Traditional UTI-containing vaginal suppositories may have adverse effects on the stability and quality of UTI because of the properties of Witepsol® W-35. Therefore, we sought to develop UTI-containing vaginal suppositories with good UTI uniformity using a UTI injection solution and Witepsol® S-55. We investigated the influence of moisture content and hardness on the quality of UTI-containing vaginal suppositories. The residual moisture content of vaginal suppositories using S-55 decreased as mixing time increased. In addition, suppository hardness increased as mixing time increased because moisture content decreased. The water phase, which contains UTI, was dispersed uniformly by mixing for 5 h, and prepared vaginal suppositories had uniform UTI content. These results suggest that we can prepare UTI-containing vaginal suppositories with good quality control, and this will be beneficial for patients.

The relationships between the physicochemical properties of milled starch and drug release from tablets were investigated quantitatively using a drug release kinetic method and X-ray computed tomography (XCT). The samples were prepared from raw β-starch by milling in a planetary ball mill. The tablets, containing 5% theophylline (TH), 94% milled starch, and 1% magnesium stearate, were compressed at 6 kN. The drug-release and gel-forming processes were measured simultaneously using an original dissolution tester with an XCT instrument. Drug release from the tablet was delayed with increasing milling time, because the TH tablet formed a typical gel-layer on the outside of the tablet. The relationship between the crystallinity of milled starch and mean drug release time (MDT) for the TH tablets showed almost a straight inverse proportional relationship. The plots of MDT against area under the curve of the swelling ratio profiles of the TH tablets had a good straight line.

Although near infrared (NIR) spectra are primarily influenced by undesired variations, i.e., baseline shifts and non-linearity, and many applications of NIR spectroscopy to the real-time monitoring of wet granulation processes have been reported, the granulation mechanisms behind these variations have not been fully discussed. These variations of NIR spectra can be canceled out using appropriate pre-processing techniques prior to spectral analysis. The present study assessed the feasibility of directly using baseline shifts in NIR spectra to monitor granulation processes, because such shifts can reflect changes in the physical properties of the granular material, including particle size, shape, density, and refractive index. Specifically, OPUSGRAN®, a novel granulation technology, was investigated by in-line NIR monitoring. NIR spectra were collected using a NIR diffuse reflectance fiber optic probe immersed in a high-shear granulator while simultaneously examining the morphology, particle size, density, strength, and Raman images of the mixture during granulation. The NIR baseline shift pattern was found to be characteristic of the OPUSGRAN® technology and was attributed to variations in the light transmittance, reflection, and scattering resulting from changes in the physicochemical properties of the samples during granulation. The baseline shift also exhibited an inflection point around the completion of granulation, and therefore may be used to determine the endpoint of the process. These results suggest that a specific pattern of NIR baseline shifts are associated with the unique OPUSGRAN® granulation mechanism and can be applied to monitor the manufacturing process and determine the endpoint.

A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0–8h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0–8h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.

In the present study, the dehydration process of caffeine hydrate (CAH) was investigated by calibrating the moisture content in the caffeine tablet using backscattering Raman spectroscopy (BRS) and transmission Raman spectroscopy (TRS). The detectable depth of BRS is limited by its shallow laser penetration, while TRS is a powerful tool to determine the content of active pharmaceutical ingredients in a tablet. Our results suggest that the accuracy of a TRS-based calibration model falls beyond that of a BRS-based model. Based on the calibration used, the model was built by calculating the differences in the crystalline structures between hydrate and anhydrous caffeine. Moreover, it was demonstrated that the dehydration process occurred by switching water molecules between hydration sites of caffeine. (C) 2017 Elsevier B.V. All rights reserved.

The coating layer thickness of enteric-coated tablets is a key factor that determines the drug dissolution rate from the tablet. Near-infrared spectroscopy (NIRS) enables non-destructive and quick measurement of the coating layer thickness, and thus allows the investigation of the relation between enteric coating layer thickness and drug dissolution rate. Two marketed products of aspirin enteric-coated tablets were used in this study, and the correlation between the predicted coating layer thickness and the obtained drug dissolution rate was investigated. Our results showed correlation for one product; the drug dissolution rate decreased with the increase in enteric coating layer thickness, whereas, there was no correlation for the other product. Additional examination of the distribution of coating layer thickness by X-ray computed tomography (CT) showed homogenous distribution of coating layer thickness for the former product, whereas the latter product exhibited heterogeneous distribution within the tablet, as well as inconsistent trend in the thickness distribution between the tablets. It was suggested that this heterogeneity and inconsistent trend in layer thickness distribution contributed to the absence of correlation between the layer thickness of the face and side regions of the tablets, which resulted in the loss of correlation between the coating layer thickness and drug dissolution rate. Therefore, the predictability of drug dissolution rate from enteric-coated tablets depended on the homogeneity of the coating layer thickness. In addition, the importance of micro analysis, X-ray CT in this study, was suggested even if the macro analysis, NIRS in this study, are finally applied for the measurement. (C) 2017 Elsevier B.V. All rights reserved.

Objectives: The adsorption kinetics of urine-like-toxin indole-3-acetic acid (IA) by spherical carbonaceous adsorbent (SC) was inhibited by competitive effect of atorvastatin calcium (AT). Methods: Competitive effect of AT on the adsorption behavior of IA by SC was investigated by ultraviolet (UV) absorption/chemometrics method. In order to predict the adsorbed amounts of IA and AT to SC, the calibration models to predict drug concentrations (IA and AT) were obtained based on UV profiles of standard sample solutions by the classical least squares (CLS) method. Key findings: The IA and AT adsorption behaviors of SC followed first-order kinetics. The drug adsorption kinetic rate constants for IA and AT (k(IA) and k(AT)) were obtained for the single- and multiple-drug administrations (SA and MA) by the least-squares method. In the case of the MA, the k(IA) was 75% suppression by the coexistence of AT, but the k(AT) was 44% suppression by the IA. Conclusion: Adsorption rate to the SC of the IA or AT, respectively, was significantly inhibited by the presence of coexistence drug. (C) 2017 Elsevier B.V. All rights reserved.

In the pharmaceutical industry, the implementation of continuous manufacturing has been widely promoted in lieu of the traditional batch manufacturing approach. More specially, in recent years, the innovative concept of feed-forward control has been introduced in relation to process analytical technology. In the present study, we successfully developed a feed-forward control model for the tablet compression process by integrating data obtained from near-infrared (NIR) spectra and the physical properties of granules. In the pharmaceutical industry, batch manufacturing routinely allows for the preparation of granules with the desired properties through the manual control of process parameters. On the other hand, continuous manufacturing demands the automatic determination of these process parameters. Here, we proposed the development of a control model using the partial least squares regression (PLSR) method. The most significant feature of this method is the use of dataset integrating both the NIR spectra and the physical properties of the granules. Using our model, we determined that the properties of products, such as tablet weight and thickness, need to be included as independent variables in the PLSR analysis in order to predict unknown process parameters. (C) 2017 Elsevier B.V. All rights reserved.

Carbonated apatite cement can be a potential biomaterial to be used as a drug carrier. We reported previously that sustainable release of simvastatin (SIM) from poly(lactic-co-glycolic acid) (PLGA) formulations could induce bone formation. The aim of this study was to develop a SIM-loaded PLGA microspheres (SPLGAMs)/carbonated hydroxyapatite (CHAP) composite, and investigate the effect of SIM released from that composite in comparison with a SIM/CHAP composite used as a control. X-ray diffraction analysis (XRD) and Fourier-transformed infrared spectroscopy (FT-IR) results showed most parts of the cement bulk powder transformed into carbonated hydroxyapatite. The SPLGAMs and SPLGAMs/CHAP composites were able to produce sustained release of SIM for 1 month, whereas the SIM/CHAP composite released SIM for 2 weeks. The mechanisms of the drug release patterns from these composites were confirmed by several mathematical models. The proliferation of MC3T3-E1 cells on the SPLGAMs/CHAP composite showed no significant difference in comparison with the SIM/CHAP composite. However, the SPLGAMs/CHAP composite significantly increased alkaline phosphate activity, a differentiation marker of MC3T3-E1 cells, compared with the SIM/CHAP composite. These results suggested that the SPLGAMs/CHAP composite could release SIM sustainably and induce proliferation and differentiation of MOT3-E1 more effectively than the SIM/CHAP composite. (C) 2016 Published by Elsevier B.V.

We developed an in-line near-infrared spectroscopy (NIRS) monitoring method enabling a rapid and non-invasive analysis of granule properties during the high shear wet granulation (HSWG) process. Eleven batches were manufactured and used as the calibration dataset and an additional batch was manufactured and used as the validation dataset. The HSWG process was directly monitored using an acousto-optical tunable filter (AOTF)-NIR spectrometer and the NIR spectra related to the physical and chemical changes of the granules were acquired. The particle size, tapped density, bulk density, and powder flowability of the granules were qualitatively and quantitatively evaluated by a chemometrics approach. Principal component analysis (PCA) and partial least square regression (PLSR) were applied for the qualitative and quantitative modelling of the granule properties. The PCA score plots showed a clear relationship between the granule properties and the granulation progress and provided an effective means for the endpoint determination of the manufacturing process. The PLSR models constructed for the quantitative evaluation of the granule properties were demonstrated to be predictive with high accuracy. These findings allow HSWG to be monitored in-line and controlled effectively. A better understanding of the process by NIRS with chemometrics will contribute to developing high-quality drug products using the required quality-by-design approach.

BACKGROUND: Since it can take an enormous amount of time and cost to discriminate counterfeit medicines by using conventional methods, counterfeit medicines has been spread in the world markets. OBJECTIVE: The purpose of this study was to develop a rapid and simple analytical method to discriminate counterfeit drugs using near infrared (NIR) spectroscopy. METHODS: Seven types of brand name tablet and generic tablets containing atorvastatin calcium sesquihydrate (AT) preparations were used as simulated counterfeit medicines. NIR spectra of 35 AT tablet products were measured using a diffuse reflection method. RESULTS: The NIR spectral data were analyzed by principal component analysis (PCA). The PCA results suggested that the model had sufficient accuracy to discriminate the 7 types for AT tablets. The NIR spectral data were also analyzed using a soft independent modeling of class analogy (SIMCA) method. Predicting the classification of the AT tablet samples was performed based on all the validated AT tablet data using the SIMCA model, and the probability of classification of 7 types was 100%. The discrimination power spectrum of the SIMCA model indicated significant patterns based on diluents. CONCLUSIONS: The PCA and SIMCA classification of the AT tablets were depended on the major excipient combinations.

The bone remodeling process plays an essential part of the calcium homeostatic system and provides a crucial mechanism for adaptation to physical stress, the repair of damaged bone and the removal of old bone. We reported previously that sustainable release of simvastatin (SIM) from poly (lactic-co-glycolic acid) (PLGA) formulations could induce bone formation. The aim of this study was to develop a simvastatin-releasing PLGA/β-TCP composite microspheres (β-SPMs) sintered scaffolds (β-SPMSS) as a synthetic bone substitute, and investigate the influence of the dissolution medium on the drug release capabilities of these device based on a physicochemical model for bone remodeling. X-ray diffraction analysis (XRD) results showed β-TCP and SIM could be encapsulated into the PLGA microspheres. The β-SPMs and the β-SPMSS were able to produce sustained release of SIM for 1 month in simulated body fluid (SBF), whereas these composites released SIM for 10 days in acetate buffer (AB). The release rate of SIM from β-SPMSS in AB was faster than in SBF, indicating that the β-SPMSS could control drug release with bone cells activity response, and could be used as a scaffold in bone remodeling area. These results suggested that the β-SPMSS could release SIM sustainably, with bone cells activity response, and could be used as a scaffold in bone remodeling area.

Resonant acoustic (R) mixing (RAM) technology is a system that performs high-speed mixing by vibration through the control of acceleration and frequency. In recent years, real-time process monitoring and prediction has become of increasing interest, and process analytical technology (PAT) systems will be increasingly introduced into actual manufacturing processes. This study examined the application of PAT with the combination of RAM, near-infrared spectroscopy, and chemometric technology as a set of PAT tools for introduction into actual pharmaceutical powder blending processes. Content uniformity was based on a robust partial least squares regression (PLSR) model constructed to manage the RAM configuration parameters and the changing concentration of the components. As a result, real-time monitoring may be possible and could be successfully demonstrated for in-line real-time prediction of active pharmaceutical ingredients and other additives using chemometric technology. This system is expected to be applicable to the RAM method for the risk management of quality.

ObjectivesThe purposes of this study were to clarify the amorphization by ball milling of atorvastatin calcium sesquihydrate (AT) and to analyse the change in dissolution kinetics. MethodsThe amorphous AT was prepared from crystal AT by ball milling and analysed in terms of the changes of its physicochemical properties by powder X-ray diffraction analysis (XRD), thermal analysis and infrared spectroscopy (IR). Moreover, to evaluate the usefulness of the amorphous form for pharmaceutical development, intrinsic solubility of the ground product was evaluated using a dissolution kinetic method. Key findingsThe XRD results indicated that crystalline AT was transformed into amorphous solids by more than 30-min milling. The thermal analysis result suggested that chemical potential of the ground AT are changed significantly by milling. The IR spectra of the AT showed the band shift from the amide group at 3406 cm(-1) with an intermolecular hydrogen bond to a free amide group at 3365 cm(-1) by milling. The dissolution of amorphous AT follows a dissolution kinetic model involving phase transformation. ConclusionsThe initial dissolution rate of the ground product increased with the increase in milling time to reflect the increase in the intrinsic solubility based on the amorphous state.

Here, we report on near-infrared and ATR/FT-IR spectroscopic measurements of magnesium stearate and potato starch powder blends. In the pharmaceutical and food industries, magnesium stearate is commonly used as a supplement in powder blends or granules for the purpose of lubrication and to minimize aggregation and adherence. However, excessive blending of magnesium stearate (MgSt) may lead to unwanted effects, and more particularly during the manufacturing of products. Upon blending, the IR bands due to both CH symmetric and anti-symmetric stretching modes decreased and displayed a frequency shift to higher wavenumber as the blending duration increased. The NW and the auto-correlation spectra were collected during the duration of blending in real-time. The auto-correlation spectra indicated the disaggregation of starch particles and a following effect of excessive blending. We suggest that the disaggregation of starch and the following process can be monitored by NIR and the auto-correlation spectra.

Non-destructive and quantitative investigation of density distribution of round tablets was the objectives of this study. The density distribution of round tablets was observed using X-ray computed tomography (X-ray CT). The distribution images were visualized by fractionating the CT images into 25 unit cells and averaging the CT number for each cell. The profiles of the distribution were analyzed with respect to the compression pressure by partial least squares (PLS) method. Analysis using the PLS method resulted in regression and loading vectors depicting the contribution of the change in density due to the variation of compression pressure. The vectors were also composed of 25 positions and used to reconstruct density mapping. The reconstructed maps quantitatively indicated the regions reflecting changes in density. At the upper and lower surface of tablets, increasing the compression pressure increased density in the edge region and decreased density in the center region. The center region under the upper surface was weakly affected by the pressure change. These results well agreed with the simulation results of finite elemental method. We suggest that the effects of compression pressure visually revealed in each region of the tablet by the X-ray CT and PLS methods are generated by density imbalance resulting from high pressure compression. (C) 2016 Elsevier B.V. All rights reserved.

Magnesium stearate (Mg-St) is a common lubricant used for solid pharmaceutical formulations and is known for its property to cause delay of tablet dissolution. In this study, the mechanism underlying the delay caused by Mg-St was investigated with model metformin hydrochloride (HCl) tablets containing Mg-St by using the stationary disk method, scanning electron microscopy with energy dispersive X-ray spectrometry (SEM-EDS), and Fourier transform infrared spectroscopy (FTIR). The results revealed the process and mechanism of delay: the exposed amount of Mg-St on the tablet surface increases during the dissolution process, and tablet dissolution is limited by the diffusion of Mg-St. In addition, in the case of dissolution in acidic medium, stearic acid derived from Mg-St was detected on the tablet surface by FTIR. Because the solubility of stearic acid is lower than that of Mg-St, the slower dissolution in acidic medium than in neutral medium may be attributed to the generation of stearic acid. (C) 2016 Published by Elsevier B.V.

In this study, formations of pi-pi and CH-pi interactions in the crystallization of amorphous indomethacin (IMC) were investigated by simultaneous Raman spectroscopy and X-ray diffraction (XRD) measurements. The activation energy obtained from the change in the peak at 1616 cm(-1) corresponded to the energy obtained from the XRD diffraction peak at 21.6. We suggest that the stable IMC crystal forms by carboxyl-carboxyl interactions, which is followed by CH-pi and TC-pi interactions supporting stabilization in the indole and chlorophenyl rings. (C) 2016 Elsevier B.V. All rights reserved.

Many pharmaceutical bulk powders are known to have various solid states, such as polymorphic forms, solvates, and amorphous forms. The amorphous form is known to be recrystallized by absorbing various solvent vapors depending on the chemical properties. It is possible to perform a search for polymorphs of drugs by utilizing this property. In this study, the solvent properties of solvent vapor by using amorphous indomethacin (A-IMC) as a model drug were measured using X-ray diffraction (XRD) in terms of the effect on crystallization. A-IMC was exposed for 2 h at 30 degrees C in a sealed container with normal alcohols with different carbon number (ethanol, 1-propanol, 1-butanol, 1-pentanol, and 1-octanol), and changed to the stable crystalline form (gamma-IMC) and the metastable form (alpha-IMC). Exposure to alcohol vapor with a long alkyl chain provided a high yield of the gamma-form and a long induction period. It was considered that the rapid generation of crystal nuclei was performed by increasing the polarity of alcohol. (C) 2015 Published by Elsevier B.V. on behalf of The Society of Powder Technology Japan. All rights reserved.

In this study, in order to control zinc (Zn)-release from calcium phosphate (CaP), the crystalline forms of CaP-containing Zn were modified by wet ball milling and/or heat treatment. The CaP (CaO:CaHPO4:ZnO=7:20:3, molar ratio) was ground in a ball mill with the addition of purified water, and the ground products were heated to 400 degrees C and 800 degrees C. The physicochemical properties of these ground products were measured by powder X-ray diffraction (XRD), infrared spectroscopy (IR), scanning electron microscopy and energy-dispersive X-ray spectroscopy. Zn release characteristics from the samples were evaluated using a dissolution tester. The results of XRD and IR suggested that the structures of the starting materials were destroyed after 2.5h of grinding, and new apatite-like amorphous solid containing Zn was generated. The Zn-release from the ground products was markedly suppressed after 2.5h of grinding.

Mixing processes are important for making high-quality pharmaceutical formulations and are related to dissolution and chemical stability in pharmaceutical manufacturing. The resonant acoustic (R) mixing (RAM) technology is a blending method, and it has been reported that it has a unique mixing action for various samples. In this study, in order to apply the RAM method to the pharmaceutical blending process, optimization of the operating conditions of RAM (acceleration and frequency) was conducted by numerical simulation. Powder mixing experiments were carried out using various RAM conditions and also a modified V-shaped mixing device with a powder material of theophylline powder and lactose or magnesium oxide and lactose. The angle of repose of the mixed powder sample was measured as an index of powder flowability and also the degree of powder mixing. A drug uniformity test of the mixed powders was performed to measure theophylline content using high-performance liquid chromatography. The results of these experiments indicate that the optimum values for acceleration and frequency in RAM mixing are 90-100 G and approximately 60 Hz, respectively, which prove the superiority of the RAM method over the ordinary mixing method. The RAM method was estimated to throw the powder upward into the air and perform mixing by utilizing free-fall, possibly by inducing a weightless state without depending on the density and mass of the sample. Therefore, RAM may be applicable to pharmaceutical manufacturing processes.

The objectives of this study were to characterize and investigate the differences in amorphous states of gatifloxacin. We prepared two types of gatifloxacin amorphous solids coded as M and MQ using milling and melt-quenching methods, respectively. The amorphous solids were characterized via X-ray diffraction (XRD), nonisothermal differential scanning calorimetry (DSC) and time-resolved near-infrared (NIR) spectroscopy. Both the solids displayed halo XRD patterns, the characteristic of amorphous solids; however, in the non-isothermal DSC profiles, these amorphous solids were distinguished by their crystallization and melting temperatures. The Kissinger-Akahira-Sunose plots of non-isothermal crystallization temperatures at various heating rates indicated a lower activation energy of crystallization for the amorphous solid M than that of MQ. These results support the differentiation between two amorphous states with different physical and chemical properties.

ObjectivesObjectives of this study are investigating the initial dissolution kinetics of the cocrystal of carbamazepine (CBZ) with nicotinamide (NIC) and understanding its initial dissolution process. MethodsCocrystal solids of CBZ with NIC were prepared by co-milling and solvent evaporation methods. The formation of cocrystal solid was verified via X-ray diffraction measurement. Dissolution tests of the solids were performed using an original flow cell and ultraviolet-visible spectroscopic detector. The spectra monitored in situ were analyzed to determine the dissolved compounds separately using the classical least squares regression method. The initial dissolution profiles were interpreted using simultaneous model of dissolution and phase changes. Key findingsIn the initial dissolution, CBZ in the cocrystal structure dissolved in water and it was suggested that CBZ reached a metastable intermediate state simultaneously with dissolution. The cocrystal solid prepared by solvent evaporation provided a higher rate constant of the phase change than that prepared by co-milling. Our results thus support the use of evaporation as the method of choice to produce ordered cocrystal structures. ConclusionWe suggest that CBZ forms dihydrate during the dissolution process; however, during the initial phase of dissolution, CBZ changes to a metastable intermediate phase.

The objective of this research was to quantify the alpha-mangostin content in mangosteen pericarp (MP) ointment as a colloidal dispersion using near-infrared (NIR) spectroscopy. Various concentrations of MP (IP and EP) ointments containing both internal and external pericarps were prepared and the NIR spectra of these ointments were measured. The NIR spectrum of each ointment was correlated with alpha-mangostin concentration by partial least square (PLS) regression. Validation of the models was performed and their predictive ability was also investigated. The equation and R-2 value for the prediction of alpha-mangostin concentration in IP ointment were y=0.9843x+0.4441 and 0.9730 and those in EP ointment were y = 0.9569x + 0.1142 and 0.9136, respectively. The biases of the IP and EP ointment models were 0.23 and 0.00, respectively. The results showed that NIR could be a useful tool for the quality control of herbal medicine in hydrophilic ointment without any sample preparation. It could predict alpha-mangostin content in hydrophilic ointment at very low concentration with sufficient accuracy.

Starch is a natural polymeric with high chemical stability and no toxicity, so it is used widely as an additive in pharmaceutical manufacturing and the food industry. In this study, the effect of heat treatment on the controlled theophylline (TH) release rate of spray-dried pre-gelatinised glutinous rice starch (pGRS) was evaluated predictively by near infrared (NIR) spectroscopy. Spray-dried particles (SGRS) were obtained by spray-drying of TH ethanolic aqueous solution (TH :pGRS = 1:1). The obtained SGRS was heat-treated to control drug release by chemical modification at 40-100 degrees C. TH release test of the SGRS was performed to evaluate the drug release rate constant (K-H) in water at 37 degrees C - body temperature. NIR spectra of heat-treated SGRS were recorded by diffuse reflectance NIR spectroscopy. The best calibration model consisted of five latent variables to predict K-H and was determined by partial least squares (PLS) regression. Since the drug release profiles of TH from SGRS followed a Higuchi-type plot (diffusion-controlled sustained drug release), it was indicated that the rate-determining step of TH release is diffusion in polymeric matrices of SGRS. The K-H of SGRS was evaluated based on Higuchi plots. It decreased with increasing temperature. X-ray diffraction and NIR results of SGRS suggested that TH recrystallised in SGRS after heat treatment. The relationship between actual and predicted k(H) values by our best PLS model based on NIR spectra gave a straight line with r(2) = 0.990, with the slopes being close to 1. The K-H of SGRS could be controlled by heat treatment. The K-H could be predicted from NIR spectra and a chemometric method.

Real-time monitoring of adsorbed water content (FW) and hydrate formation of theophylline anhydrate (THA) in tablet formulation during agitated granulation was investigated by near-infrared (NIR) spectroscopy. As the wet-granulation process of THA tablet formulation involves change in pseudo-polymorphs between THA and theophylline monohydrate (THM), the pharmaceutical properties of THA tablet depend on the degree of hydration during granulation. After mixing of the powder materials (4 g) containing THA, and excipients and the addition of 600 mu L of binding water, the powder was kneaded at 27 degrees C, 40 degrees C, and 50 degrees C and then dried. The mixing, granulating, and drying processes were monitored using NIR. The calibration models to predict THM and total water contents during granulation in THA tablet formulation were obtained by partial least-squares regression. The FW in the formulation was determined by subtracting THM from the water content. The results of the THA formulation powder bed during granulation by NIR monitoring indicated that the transformation pathway of the THA powder was THA. THM. THA at 27 degrees C and 40 degrees C, but that at 50 degrees C was THA. THA. THA. The pharmaceutical properties, such as tablet porosity, hardness, tablet disintegration time, and dissolution rate of the final THA tablet products, were affected by the degree of crystalline transformation during granulation. (C) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

Simultaneous real-time monitoring of water content and mean particle size in the powder bed of a fluidized-bed granulator was performed by near-infrared (NIR) spectroscopy through a window, and the findings were used to evaluate the granular properties. A powder mixture containing acetaminophen bulk and additive powders was granulated by spraying with 10, 8.5 and 7.5% binder solutions in a lab-size fluid-bed granulator. Change of water content and mean particle size of the granules during fluid-bed granulation were evaluated by weight loss and sieving of the removed granule samples, respectively. The NIR spectra were recorded during the granulation processes, and calibration models to evaluate water content and mean particle size of the granules were developed based on NIR spectra using the partial least squares regression method. The best calibration models to predict water content and mean particle size were obtained by multiplicative scatter correction treatment. The validation results based on external validation NIR spectra also had sufficiently linear relationships. In the predicted water content-time profiles during the granulation processes, the water content increased in the granulation process, and it decreased in the drying process; the predicted values fitted very well to the actual values in all processes. The maximum water content in the processes using 8.5 and 7.5% binder solutions was around 6-7%, but that using 10% binder solution was around 3%. In terms of the predicted mean particle size-time profiles, they increased during the granulation process, and remained constant during the drying process; the predicted profile fitted very well to the actual values in all processes.

The purpose of this study was an attempt to adapt the audible acoustic emission (AAE) sound measurement method for the on-line monitoring of the fluid-bed drying progress of pharmaceutical granules. The granules were prepared by extrusion-granulation based on a formulation of 6.7 : 2 : 1 lactose-starch-crystalline cellulose. After the granulation process, the drying process was performed in a fluid-bed dryer at 27 or 42 degrees C, and AAE sound was measured using a digital voice recorder. The recorded signals were transformed into frequency spectra by using the fast Fourier transformation function. Samples were collected every 60 seconds to determine the moisture content of the granules. The calibration models to predict the moisture content of the granules were constructed based on AAE frequency spectra by using the partial least squares regression method after area normalized function. In order to test the robustness of the calibration model obtained under different dry operating conditions (air temperature) with various acoustic environments (noise), the moisture content of the granules was predicted based on AAE frequency spectra containing noise. The external validation results suggested that the calibration model could be applied to any data set. The regression vector indicated that the sound in the low frequency range might have been caused by the contact of the granules upon over-hydration at the initial stage of the drying process. In contrast, the sound at high frequencies might have been caused by friction of the dried granules later in the drying process.

Disintegrating agents, such as microcrystalline cellulose (MCC), starch, carboxymethyl cellulose (CMC) and polyvinylpyrrolidone, are often used as drug additives to make the tablet swell and disintegrate in water. Here, we investigated the swelling process of these agents via near infrared and two-dimensional correlation spectroscopic analysis. The traditional agents MCC and starch showed increments of loose hydration prior to strong hydration. However, strong hydration increases were followed by loose hydration for CMC. In conclusion, the distinguishing swelling property of CMC is provided by the first strong hydration of water molecules, which may avoid polymer-polymer interaction and induce water penetration into the drug tablet.