Improved stability of OPALMON tablets under humid conditions. III: Application of the rotary vacuum drying method to dry Opalmon tablets

In stability studies on moisture-resistant Opalmon tablets in press-through-packages (PTP), which were placed in aluminum bags, we found that the degradation rate of the dextran formulation is faster than that of the lactose formulation. The fast degradation of the dextran formulation is attributed to residual moisture in the package because drying the tablets before packaging suppressed the degradation and there is a good correlation between the stability of the drug and the water-activity of the tablets. Therefore, we developed a new drying method for the tablets, i.e. the rotary vacuum drying method, and investigated the effects of the operating conditions such as heating temperature, rotation speed, and vacuum degree on the drying time, and the appearance of the tablets. Using the rotary vacuum drying method, the tablets were dried over a short time (30 min) on a mass production scale so that the water activity was less than 0.03. Furthermore, the tablets suffered negligible damage such as breaking and chipping during the drying process. These results indicate that the rotary vacuum drying method is useful for drying tablets on mass production scales.     

Measuring Bismuth Oxide Particle Size and Morphology in Film-Coated Tablets

The assessment of active pharmaceutical ingredient (API) particle size and morphology is of great importance for the pharmaceutical industry since it is expected to significantly affect physicochemical properties. However, very few methods are published for the determination of API morphology and particle size of film-coated (FC) tablets. In the current study we provide a methodology for the measurement of API particle size and morphology which could be applied in several final products. Bismuth Oxide 120 mg FC Tabs were used for our method development, which contain bismuth oxide (as tripotassium dicitratobismuthate (bismuth subcitrate)) as the active substance. The sample preparation consists of partial excipient dissolution in different solvents. Following this procedure, the API particles were successfully extracted from the granules. Particle size and morphology identification in Bismuth Oxide 120 mg FC Tabs was conducted using micro-Raman mapping spectroscopy and ImageJ software. The proposed methodology was repeated for the raw API material and against a reference listed drug (RLD) for comparative purposes. The API particle size was found to have decreased compared to the raw API, while the API morphology was also affected from the formulation manufacturing process. Comparison with the RLD product also revealed differences, mainly in the API particle size and secondarily in the crystal morphology.     

Quantitative analysis of pharmaceutical products by laser-induced breakdown spectroscopy

In this paper, the capabilities of laser-induced breakdown spectroscopy (LIBS) for rapid analysis of multi-component pharmaceutical tablets are illustrated using several examples. The atomic line emission from an element present only in a particular component of the tablet (for instance, emission of phosphorus from the drug, or of magnesium from the lubricant) enables the quantitative analysis of that component. It is also demonstrated that simple schemes can significantly improve the analytical performance of LIBS in this context. In particular, internal standardization with a carbon line was found to enable the correction of a matrix effect, apart from improving the precision of measurement. Furthermore, an improvement in the linearity of calibration was observed when the plasma continuum emission was used as internal standard. Finally, in the case of drugs containing halogen species (e.g. F or Cl), producing the plasma in a helium atmosphere caused a seven to eight-fold increase of the signal-to-background ratio, thus improving sensitivity. These data illustrate the strengths of LIBS for fast at-line assessment of the reliability of pharmaceutical manufacturing processes.     

Double pulse laser induced breakdown spectroscopy applied to natural and artificial materials from cultural heritages: A comparison with micro-X-ray fluorescence analysis

The laser-induced breakdown spectroscopy (LIBS) is an applied physical technique that has shown in recent years its great potential for rapid qualitative analysis of materials. Thanks to the possibility to implement a portable instrument that perform LIBS analysis, this technique is revealed to be particularly useful for in situ analysis in the field of cultural heritages. The purpose of this work is to evaluate the potentiality of LIBS technique in the field of cultural heritages, with respect to the chemical characterization of complex matrix as calcareous and refractory materials for further quantitative analyses on cultural heritages. X-Ray Fluorescence (XRF) analyses were used as reference. Calibration curves of certified materials used as standards were obtained by XRF analyses. The LIBS measurements were performed with a new mobile instrument called Modì (Mobile Double pulse Instrument for LIBS Analysis). The XRF analyses were performed with a portable instrument ArtTAX. LIBS and XRF measurement were performed on both reference materials and samples (bricks and mortars) sampled in the ancient Greek–Roman Theatre of Taormina. Although LIBS measurements performed on reference materials have shown non linear response to concentrations, and so we were not able to obtain quantitative results, an integrated study of XRF and LIBS signals permitted us to distinguish among chemical features and degradation state of measured building materials.     

Double pulse laser induced breakdown spectroscopy applied to natural and artificial materials from cultural heritages : A comparison with micro-X-ray fluorescence analysis

The laser-induced breakdown spectroscopy (LIBS) is an applied physical technique that has shown in recent years its great potential for rapid qualitative analysis of materials. Thanks to the possibility to implement a portable instrument that perform LIBS analysis, this technique is revealed to be particularly useful for in situ analysis in the field of cultural heritages. The purpose of this work is to evaluate the potentiality of LIBS technique in the field of cultural heritages, with respect to the chemical characterization of complex matrix as calcareous and refractory materials for further quantitative analyses on cultural heritages. X-Ray Fluorescence (XRF) analyses were used as reference. Calibration curves of certified materials used as standards were obtained by XRF analyses. The LIBS measurements were performed with a new mobile instrument called Modì (Mobile Double pulse Instrument for LIBS Analysis). The XRF analyses were performed with a portable instrument ArtTAX. LIBS and XRF measurement were performed on both reference materials and samples (bricks and mortars) sampled in the ancient Greek–Roman Theatre of Taormina. Although LIBS measurements performed on reference materials have shown non linear response to concentrations, and so we were not able to obtain quantitative results, an integrated study of XRF and LIBS signals permitted us to distinguish among chemical features and degradation state of measured building materials.     

Use of spectroscopic techniques for the chemical analysis of biomorphic silicon carbide ceramics

Biomorphic silicon carbide ceramics are a new class of materials prepared by several complex processing steps including pre-processing (shaping, drying, high-temperature pyrolysis in an inert atmosphere) and reaction with liquid silicon to obtain silicon-carbide. The results of industrial process of synthesis (measured by the SiC content) must be evaluated by means of fast analytical methods. In the present work, diverse samples of biomorphic ceramics derived from wood are studied for to evaluate the capability of the different analytical techniques (XPS, LIBS, FT-IR and also atomic spectroscopy applied to previously dissolved samples) for the analysis of these materials. XPS and LIBS gives information about the major components, whereas XPS and FT-IR can be used to evaluate the content of SiC. On the other hand, .the use of atomic techniques (as ICP-MS and ETA-AAS) is more adequate for the analysis of metal ions, specially at trace level. The properties of ceramics depend decisively of the content of chemical elements. Major components found were C, Si, Al, S, B and Na in all cases. Previous dissolution of the samples was optimised by acid attack in an oven under microwave irradiation.     

Effect of supercritical CO2 plasticization on the degradation and residual crystallinity of melt‐extruded spironolactone

Immediate‐release solid dispersions of a slowly dissolving active pharmaceutical ingredient, spironolactone, were prepared by supercritical‐CO₂‐assisted melt extrusion (a solvent‐free and continuous manufacturing technology) using Eudragit E as matrix. Through optimizing process parameters (i.e. temperature, melt throughput, pressure and CO₂ flow), stable foams with high porosity, homogeneous structure and thin (even submicronic) walls could be prepared, as revealed by scanning electron microscopy. The samples were found to be rigid enough to mill, enabling further processing, as is necessary to formulate tablets. The influence of extrusion temperature and melt throughput on residual drug crystallinity was measured using non‐invasive confocal Raman mapping coupled with chemometric analysis, while the influence on the degree of drug degradation was determined using high performance liquid chromatography. The plasticizing effect of supercritical CO₂ was shown to reasonably improve the purity of the prepared solid dispersions by enabling high‐yield production at lower temperature ranges. At the same time, shorter residence time and lower temperature slightly increased residual drug crystallinity. The obtained foamy structures ensured immediate drug dissolution in an acidic medium. Copyright © 2014 John Wiley & Sons, Ltd.     

Development of a rapid process monitoring method for dry-coated tableting process by using near-infrared spectroscopy

A nondestructive transmittance near-infrared (NIR) method for detecting off-centered cores in dry-coated (DC) tablets was developed as a monitoring system in the DC tableting process. Caffeine anhydrate was used as a core active pharmaceutical ingredient (API), and DC tablets were made by the direct compression method. NIR spectra were obtained from these intact DC tablets using the transmittance method. The reference assay was performed with HPLC. Calibration models were generated by partial least squares (PLS) regression and principal component regression (PCR) utilizing external validations. Hierarchical cluster analysis (HCA) of the results confirmed that NIR spectroscopy correctly detected off-centered cores in DC tablets. We formulated and used the Centering Index (CI) to evaluate the precision of core alignment and generated an NIR calibration model that could correctly predict this index. The principal component (PC) 1 loading vector of the final calibration model indicated that it could specifically detect the misalignment of tablet cores. The model also had good linearity and accuracy. The CIs of unknown sample tablets predicted by the final calibration model and those calculated through the HPLC analysis were closely parallel with each other. These results demonstrate the validity of the final calibration model and the utility of the transmittance NIR spectroscopic method developed in this study as a monitoring system in DC tableting process.     

Investigation into classification/sourcing of suspect counterfeit Heptodin™ tablets by near infrared chemical imaging

Near infrared chemical imaging (NIR-CI) analysis was performed on 55 counterfeit Heptodin™ tablets obtained from a market survey and an additional 11 authentic Heptodin™ tablets for comparison. The aim of the study was to investigate whether NIR-CI can be used to detect the counterfeit tablets and to classify/source them so as to understand the possible number of origins to aid investigators and authorities to shut down counterfeiting operations. NIR-CI combined with multivariate analysis is particularly suited to compare chemical and physical properties of samples, since it is a quick and non-destructive method of analysis. Counterfeit tablets were easily distinguished from the authentic ones. Principal component analysis (PCA) and k-means clustering were performed on the data set. The results from both analyses grouped the counterfeit tablets in 13 main groups. The main groups found with both methods were quite consistent. Out of the 55 tablets only 18% contained the correct active pharmaceutical ingredient (API), i.e., the anti-viral drug lamivudine. The remaining 82% of counterfeit tablets contained talc and starch as main excipients. The API containing tablets classified into three main groups, based mainly on the amount of lamivudine present in the tablet. The group which had close to the correct amount of lamivudine sub-classified into three groups. From the analysis carried out, it is likely that the counterfeit tablets originate from as many as 15 different sources.     

Near infrared and Raman spectroscopy as Process Analytical Technology tools for the manufacturing of silicone-based drug reservoirs

Using near infrared (NIR) and Raman spectroscopy as PAT tools, 3 critical quality attributes of a silicone-based drug reservoir were studied. First, the Active Pharmaceutical Ingredient (API) homogeneity in the reservoir was evaluated using Raman spectroscopy (mapping): the API distribution within the industrial drug reservoirs was found to be homogeneous while API aggregates were detected in laboratory scale samples manufactured with a non optimal mixing process. Second, the crosslinking process of the reservoirs was monitored at different temperatures with NIR spectroscopy. Conformity tests and Principal Component Analysis (PCA) were performed on the collected data to find out the relation between the temperature and the time necessary to reach the crosslinking endpoints. An agreement was found between the conformity test results and the PCA results. Compared to the conformity test method, PCA had the advantage to discriminate the heating effect from the crosslinking effect occurring together during the monitored process. Therefore the 2 approaches were found to be complementary. Third, based on the HPLC reference method, a NIR model able to quantify the API in the drug reservoir was developed and thoroughly validated. Partial Least Squares (PLS) regression on the calibration set was performed to build prediction models of which the ability to quantify accurately was tested with the external validation set. The 1.2% Root Mean Squared Error of Prediction (RMSEP) of the NIR model indicated the global accuracy of the model. The accuracy profile based on tolerance intervals was used to generate a complete validation report. The 95% tolerance interval calculated on the validation results indicated that each future result will have a relative error below ±5% with a probability of at least 95%. In conclusion, 3 critical quality attributes of silicone-based drug reservoirs were quickly and efficiently evaluated by NIR and Raman spectroscopy.     

Evaluation of laser induced breakdown spectroscopy for multielemental determination in soils under sewage sludge application

Laser induced breakdown spectroscopy (LIBS) is an atomic emission spectroscopy technique for simple, direct and clean analysis, with great application potential in environmental sustainability studies. In a single LIBS spectrum it is possible to obtain qualitative information on the sample composition. However, quantitative analysis requires a reliable model for analytical calibration. Multilayer perceptron (MLP), an artificial neural network, is a multivariate technique that is capable of learning to recognize features from examples. Therefore MLP can be used as a calibration model for analytical determinations. Accordingly, the present study proposes to evaluate the traditional linear fit and MLP models for LIBS calibration, in order to attain a quantitative multielemental method for contaminant determination in soil under sewage sludge application. Two sets of samples, both composed of two kinds of soils were used for calibration and validation, respectively. The analyte concentrations in these samples, used as reference, were determined by a reference analytical method using inductively coupled plasma optical emission spectrometry (ICP OES). The LIBS-MLP was compared to a LIBS-linear fit method. The values determined by LIBS-MLP showed lower prediction errors, correlation above 98% with values determined by ICP OES, higher accuracy and precision, lower limits of detection and great application potential in the analysis of different kinds of soils.     

Calibration-Free Laser-Induced Breakdown Spectroscopy: State of the art

The aim of this paper is offering a critical review of Calibration-Free Laser-Induced Breakdown Spectroscopy (CF-LIBS), the approach of multi-elemental quantitative analysis of LIBS spectra, based on the measurement of line intensities and plasma properties (plasma electron density and temperature) and on the assumption of a Boltzmann population of excited levels, which does not require the use of calibration curves or matrix-matched standards. The first part of this review focuses on the applications of the CF-LIBS method. Quantitative results reported in the literature, obtained in the analysis of various materials and in a wide range of experimental conditions, are summarized, with a special emphasis on the departure from nominal composition values. The second part is a discussion of the simplifying assumptions which lie at the basis of the CF-LIBS algorithm (stoichiometric ablation and complete atomization, thermal equilibrium, homogeneous plasma, thin radiation, detection of all elements). The inspection of the literature suggests that the CF-LIBS method is more accurate in analyzing metallic alloys rather than dielectrics. However, the full exploitation of the method seems to be still far to come, especially for the lack of a complete characterization of the effects of experimental constraints. However, some general directions can be suggested to help the analyst in designing LIBS measurements in a way which is more suited for CF-LIBS analysis.     

基于双脉冲LIBS结合偏最小二乘回归的稀土元素定量分析

激光诱导击穿光谱(LIBS)是一种以激光为激发源的等离子体发射光谱分析技术,已有将其用于稀土元素的定量分析研究,但由于稀土矿基体差异大、元素含量低,定量分析灵敏度和准确度仍有待提高。通过使用单激光分束构造双脉冲LIBS系统,并结合偏最小二乘回归(PLSR)算法实现对稀土矿石样品中的稀土元素La、Dy、Yb和Y的定量分析。结果表明,双脉冲LIBS结合PLSR可建立更加稳定的定标模型,与常规基本定标法相比,La、Dy、Yb和Y元素的相对均方根预测误差(RMSEP)从0.0061 %、0.0037%、0.0045%、0.0280 %降低至0.0044%、0.0016%、0.0029%、0.0134%,平均相对预测误差(AREP)从10.88%、15.27%、6.42%、17.20%降低至6.67%、3.62%、4.10%、7.98%。因此,双脉冲LIBS结合PLSR方法可以有效地提高LIBS对稀土矿石中稀土元素的定量分析能力。     

Evaluation of laser induced breakdown spectroscopy for the determination of macronutrients in plant materials

Laser induced breakdown spectroscopy (LIBS) has become an analytical tool for the direct analysis of a large variety of materials in order to provide qualitative and/or quantitative information. However, there is a lack of information for LIBS analysis of agricultural and environmental samples. In this work a LIBS system has been evaluated for the determination of macronutrients (P, K, Ca, Mg) in pellets of vegetal reference materials. An experimental setup was designed by using a Nd:YAG laser operating at 1064 nm and an Echelle spectrometer with ICCD detector. The plasma temperature was estimated by Boltzmann plots and instrumental parameters such as delay time, lens-to-sample distance and pulse energy were evaluated. Certified reference materials as well as reference materials were used for analytical calibrations of P, K, Ca, and Mg. Most results of the direct analysis of plant samples by LIBS were in reasonable agreement with those obtained by ICP OES after wet acid decomposition.     

Laser-induced breakdown spectroscopy for semi-quantitative and quantitative analyses of artworks—application on multi-layered ceramics and copper based alloys

In the present work, we report on the analyses of different types of artworks, such as medieval glazed Umbrian pottery and copper based alloys from Roman and modern periods, performed by means of Laser Induced Breakdown Spectroscopy (LIBS). The semi-quantitative analyses on the multi-layered ceramic findings regard glaze, luster and pigment decorations present on the surface. The composition for each decorative layer was determined by estimating the contribution of the ceramic layer beneath the examined one to the whole plasma emission. Two types of ancient luster have been considered: red and gold, while the pigments examined include painted decorations of different blue tonalities. The measured elemental composition of the decorative layers resulted partially correlated with the color of the painted surface, measured by a standard UV-VIS spectrometer. In LIBS analyses of bronze samples, a procedure was developed, which improves data repeatability and extends quantitative measurements to minor elemental constituents. Results of the quantitative analyses gave indications about the manufacturing process of the artwork, its actual degree of conservation and the presence of residual surface decorations.     

Validation of a Stability Indicating LC Method for Amiodarone HCL and Related Substances

A simple, rapid and sensitive isocratic high performance liquid chromatographic (HPLC) method has been developed for the estimation of purity and quantitative determination of Amiodarone HCl active pharmaceutical ingredient (API).The method describes a quantitative estimation of five process related impurities of Amiodarone HCl with a resolution of more than or near to 3.0 between each impurity. These five known related substances are estimated by a simple, rapid and accurate reverse phase isocratic HPLC method. The method has been validated for the determination of assay and related substances in Amiodarone HCl API, using a C₈ column. The elution is carried out using a mobile phase consisting of water-methanol-acetic acid with a pH 5.8. For the quantitative determination of these relative substances, a relative response factors have been determined for all five related substances with respect to Amiodarone HCl. The precision (system precision, method precision and intermediated precision) is demonstrated for both the assay as well as related substances on six independent sample preparations. Accuracy of the method (recovery) is demonstrated for both Amiodarone and each of the five related substances. Specificity of the method is demonstrated by forced degradation study of Amiodarone HCl API under various stress conditions. The method is found to be stability indicating and useful for the analysis of assay and related substances of Amiodarone HCl API in a routine quality control laboratory and for the stability studies of drug substance.     

Quantitative Analysis of Fe Content in Iron Ore via External Calibration in Conjunction with Internal Standardization Method Coupled with LIBS

The external calibration in conjunction with internal standardization(ECIS) coupled with laser-induced breakdown spectroscopic(LIBS) technique was proposed to perform the quantitative analysis of Fe content in iron ore. The plasma temperature and the electron number density were calculated to prove that the plasma was under local thermodynamic equilibrium(LTE) conditions and to ensure that the integral intensities of Fe I lines were reasonable. In addition, the result of the quantitative analysis shows a content of (20.26±0.59)% by mass of Fe in the iron ore. It was determined by four calibration curves, drawn for four emission lines of Fe I(373.48, 373.71, 404.58 and 438.35 nm) normalized by Mn I line, base on the ECIS method which can eliminate the influence of matrix effect and improve the accuracy of quantitative analysis, compared with the standard addition method. Both the results of these two analytical methods were compared with that listed in the Standard Substance Certificate. The percentage content of Fe in the same sample of iron ore by the ECIS method was (20.17±0.08)% by mass, which shows a good performance to analyze the Fe content of iron ore in combination with LIBS.     

A new approach for generic screening and quantitation of potential genotoxic alkylation compounds by pre-column derivatization and LC-MS/MS analysis

A generic LC-MS/MS method was developed for the analysis of potentially genotoxic alkyl halides. A broad selection of alkyl halides were derivatized using 4-dimethylaminopyridine in acetonitrile. The reaction conditions for derivatization, i.e., solvent, reaction time, temperature and concentration of alkyl halide, active pharmaceutical ingredient (API), and reagent, were optimized for sensitivity and robustness. The interference of the matrix and the API and the presence of water on the derivatization reaction were investigated for a model drug product (paracetamol/caffeine tablets). Hydrophilic interaction liquid chromatography was used to allow a quantitative determination of the derivatives by tandem mass spectrometry. The derivatization reaction was shown to be selective for alkyl halides, although some reactivity was also observed for an aromatic sulfonate, which is also genotoxic. Even though differences in reaction efficiencies have been observed, the enhanced sensitivity obtained by the derivatization allows the majority of the alkyl halides to be detected by MS/MS at relevant levels for genotoxic impurity evaluation, i.e., 10 mg kg(-1). Another key advantage is that for the majority of derivatives, reagent-related fragments are produced, which allows low-level screening for alkyl halides. Highly specific MS detection can be performed using neutral loss and precursor ion scan experiments. The applicability of a generic screening method will make the genotox evaluation less dependent on the quality of assessments based on predictions only, and it will provide essential information during the development of new chemical entities. In addition to screening, target analysis in the low milligrams per kilogram range can be performed. A similar response of the derivatized compounds was obtained in the range of 1-100 mg kg(-1) with a reproducibility better than 10%, which is sufficient for the determination of alkyl halides in APIs and drug products.     

Chemical imaging of pharmaceutical granules by Raman global illumination and near-infrared mapping platforms

Raman global illumination and near-infrared (NIR) mapping instruments were used to chemically image pharmaceutical granules obtained by the wet granulation process in order to determine whether the API was mixed with the major excipient or granulates on its own. The granules were randomly distributed onto a microscope slide and an average area of about 3.5 mm × 3.5 mm, covering 50-100 granules, was analyzed by both instruments. Light microscopy images of the separated granules were collected before the spectroscopic data acquisition. Both Raman and NIR signals of API and major excipient (mannitol) were easily detected by both techniques which allowed the chemical structure of the granules to be characterised. Most of the granules were found to contain both API and mannitol but pure mannitol and a few pure API granules were also identified. Raman global illumination was found to provide a comprehensive insight into chemical structure of the granules being able to more clearly determine the API in comparison with NIR mapping. Owing to the differences in shapes of the particles and reflection characteristics, visual microscopy and methods based on reflection can be potentially useful for analyzing this particular formulation.