Raman imaging analysis of pharmaceutical tablets by two-dimensional (2D) correlation spectroscopy

Chemical properties of active substances and insoluble excipient within tablets such as crystalline structures can be seen as an important index for solubility of ingredients. Spectroscopic imaging can potentially be a solid solution to understanding mechanisms at the molecular level and it may bring useful insight in terms of process analytical technique. In the present study, generalized two-dimensional (2D) correlation spectroscopy is utilized for the Raman image analysis of pharmaceutical tablets to reveal molecular interactions between chemical components. By using a spatial distance as a perturbation variable in 2D correlation scheme, synchronous and asynchronous correlation analysis becomes possible. Two kinds of pharmaceutical tablets, pentoxifylline (PTX) as an active substance and palmitic acid (PA) as an insoluble excipient, are prepared with different grinding times, 0.5 and 45 min. The 2D correlation analysis of Raman images of the tablets clearly reveals both physical and chemical effects of grinding process on the properties of the tablets. Asynchronous correlations indicate that a specific molecular structural change of PTX related to the crystallinity is induced by the grinding process. Namely, the crystallinity of PTX based on CH₂ structure is a key factor to control the solubility of the tablets. Some properties of pharmaceutical tablets, i.e. solubility or distribution of components in turn may become possible by the simple grinding process. Detailed analysis of Raman images becomes possible by the 2D correlation spectroscopy.     

Nir-chemical imaging study of acetylsalicylic acid in commercial tablets

Near Infrared Chemical Imaging (NIR-CI) is demonstrating an increasing interest in pharmaceutical research since it meets the challenging analytical needs of pharmaceutical quality and may serve as a versatile adjunct to conventional NIR spectroscopy in many fields.The direct analysis of samples by using hyperspectral imaging techniques, which provide a NIR spectrum in each pixel of the image, generates a big amount of information from one sample. Focusing the interest in pharmaceutical research, several chemometric algorithms are demonstrating their usefulness extracting the relevant information (i.e. quantitative determination of the component in one sample) in tablets with only one sample and without damaging it.In this work, a quantitative method to analyze different commercial Acetylsalicylic acid tablets is proposed by using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to the hyperspectral image and without any previous calibration model. For this purpose, a large concentration range of active pharmaceutical ingredient (ASA, Acetylsalicylic acid in this work), between 82% and 12%, was covered depending on the manufacturer. MCR-ALS allowed obtaining a concentration maps for acetylsalicylic acid and therefore, consequent analysis of the ASA distribution in the tablet was developed by using the histograms of the distribution of concentration.Results certified the good distribution of ASA despite the different origins of the tablets. Moreover, the obtained values of concentration showed a very good concordance with the nominal value of ASA. As a matter of fact, the quality of the results demonstrated the useful of encompassing NIR-CI techniques with MCR-ALS and, consequently, the well development on the production of Acetylsalicylic acid tablets.     

Analytical method based on room-temperature phosphorimetry for the determination of rescinamine in pharmaceutical tablets.

An analytical method based on solid surface room temperature phosphorescence (SSRTP) for the determination of rescinamine was developed. Signal enhancements were obtained by heavy atom effect, use of surfactant agent and use of basic medium. Alternatively, an ultraviolet treatment of the analyte was tried in order to induce a phoshor with higher phosphorescence quantum efficiency. A limit of detection of 2.70 ng and linear dynamic range of 2 orders of magnitude were achieved in paper substrate treated for background reduction. A study was performed to verify potential interferences of several pharmacological active ingredients that could be associated with rescinamine in a pharmaceutical preparation. The method was tested by analyzing rescinamine in three different laboratory-made tablets.     

Combined Fourier-transform infrared imaging and desorption electrospray-ionization linear ion-trap mass spectrometry for analysis of counterfeit antimalarial tablets

This paper reports use of a combination of Fourier-transform infrared (FTIR) spectroscopic imaging and desorption electrospray ionization linear ion-trap mass spectrometry (DESI MS) for characterization of counterfeit pharmaceutical tablets. The counterfeit artesunate antimalarial tablets were analyzed by both techniques. The results obtained revealed the ability of FTIR imaging in non-destructive micro-attenuated total reflection (ATR) mode to detect the distribution of all components in the tablet, the identities of which were confirmed by DESI MS. Chemical images of the tablets were obtained with high spatial resolution. The FTIR spectroscopic imaging method affords inherent chemical specificity with rapid acquisition of data. DESI MS enables high-sensitivity detection of trace organic compounds. Combination of these two orthogonal surface-characterization methods has great potential for detection and analysis of counterfeit tablets in the open air and without sample preparation.     

CE as orthogonal technique to HPLC for alprazolam degradation product identification

The control of degradation products is currently a critical issue to the pharmaceutical industry. A degradation product that appeared in alprazolam tablets during their stability assay, 7-chloro-1-methyl-5-phenyl-[1,2,4]triazolo[4,3-a]quinolin-4-amine, also named triazolaminoquinoline, was tested as possible candidate in the HPLC method employed for the study. The impurity showed the same retention time and spectra as the degradation product; but as all these compounds are very closely related, a confirmation with an independent technique was necessary, and CE was chosen for that purpose. Problems related to the adsorption of the analytes to the negatively charged silica surface were solved by employing a new polymeric capillary coating consisting of poly(3-aminopropylmethylsiloxane). The polymer provided EOF towards the anode, and the two compounds were separated in less than 8 min in a 60 cm total-length capillary, 75 microm id capillary with a BGE containing 50 mM phosphate buffer at pH 2.0 with 20% ACN. When the sample containing the degradation product was injected, the presence of triazolaminoquinoline was confirmed.     

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.     

Study of the similarity between distribution maps of concentration in near-infrared spectroscopy chemical imaging obtained by different multivariate calibration approaches

Nowadays, near-infrared spectroscopy chemical imaging (NIR-CI) has been widely used in pharmaceutical analysis since it provides important surface information about the samples. In this work the information of NIR-CI at the pixel level was compared through calculation of the similarity between distribution maps of concentration obtained by different multivariate calibration approaches. The comparison was performed by using four different multivariate methods (MCR, MLR, CLS and PLS) in analysis of carbamazepine pharmaceutical formulations. For global determination, all models developed showed RMSEP below 1.9% (w/w) for active principal ingredient (API) and better than 4.6% (w/w) for excipients. Also, the distribution maps obtained by PLS, CLS and MCR showed great similarity for all compounds of the formulation as well with concentrations in the tablets. However, comparing the distribution maps obtained by MLR with those from the other chemometric tools, a lower similarity was observed. Thus, this fitted model does not ensure, by itself, that the images obtained are reliable or accurate. The paper also compares the distribution maps of concentrations obtained from all constituents present in the pharmaceutical formulation with their respective micrographs.     

Hydrogen/deuterium adsorption and absorption properties on and in palladium using a combined plane wave and localized basis set method

Detailed information on the H/D isotope effects for adsorption on the surface and absorption in the bulk is important for understanding the nuclear quantum effect. To achieve this, we developed a new theoretical approach, namely, the combined plane wave and localized basis set (CPLB) method. By using the multicomponent quantum chemical method, which takes into account the quantum effect of a proton or deuteron, with the localized part of the CPLB method, direct analysis of the H/D isotope effect about adsorption and absorption is carried out. In this study, we performed a theoretical investigation of the H/D isotope effects for adsorption on a Pd(111) surface and absorption in bulk Pd. We clearly showed an H/D isotope effect on geometry during adsorption and absorption. Our developed CPLB approach is a powerful tool for analyzing the quantum nature of H/D in surface, bulk, and inhomogeneous systems.     

Neutron depth profiling applications at The University of Texas research reactor

The neutron depth profiling (NDP) technique has become an increasingly important method to nondestructively measure the absolute concentration versus depth of various elements in substrates. A permanent NDP facility is operational at a tangential beam port of the 1-MW TRIGA Mark II research reactor at The University of Texas at Austin (UT). This facility was developed to perform materials research, specifically measurements of interest to the microelectronics industry. Applications of the UT-NDP facility include measurements of boron-10 profiles in borophosphosilicate glass samples and helium-3 depth profiles of implanted helium-3 in metals, alloys and amorphous materials. A study is underway to determine radiation damage and microstructural changes in stainless steel samples by helium irradiation using NDP and Transmission Electron Microscopy. Another study, currently planned, is to measure surface wear by measuring the depth profiles of implanted beryllium-7 and sodium-22 in various materials.     

光固化粉末涂料中两种复合光引发剂表观量子效率的测定

采用动力学分析方法,测定了几种不同配比光固化粉末涂料引发剂的紫外吸收光谱,并由此进行了量子效率的测定.据此可比较不同引发体系的引发效率.文中详细介绍了计算量子效率的过程.结果表明,不同的引发剂体系不同的配比,其引发效率可相差2—3倍.     

Near-infrared determination of active substance content in intact low-dosage tablets

Near-infrared (NIR) spectroscopy can be applied to determine the active substance content of tablets. Its great advantage lies in the minimal sample preparation required, which helps to reduce the potential for error. The aim of this study is to show the feasibility of this method on low-dosage tablets. The influence of various spectral pretreatments [standard normal variate (SNV), multiplicative scatter correction (MSC), second derivative (D2), orthogonal signal correction (OSC), separately and combined] and regression methods on prediction error are compared. Partial least square (PLS) regression provided better prediction than principal component regression (PCR). SNV was applied to the first data set and SNV and a second derivative to the second set to maximise model accuracy for quantifying the active substance of intact pharmaceutical products using diffuse reflectance NIR. The models yielded standard errors of prediction (SEP) of 0.1768 and 0.0682 mg for the two products. The experiments were conducted with two low-dosage pharmaceutical forms and results of NIR predictions were comparable to currently approved methods. Diffuse reflectance NIR has the potential to become a reliable and robust quality control method for determining active tablet content.     

Analytical performance of a fast multi-element method for titanium and trace elements determination in cosmetics and pharmaceuticals by ICP-AES

A multi-element analytical method based on inductively coupled plasma atomic emission spectrometry (ICP-AES) was developed for trace elements in pharmaceutical tablets and cosmetics. Titanium was also included in the analytes since it is widely used in pharmaceuticals. Critical ICP conditions, like RF incident power, argon gas flow rate and nebulizer sample uptake flow rate were optimized. The most sensitive spectral line of each analyte was selected as optimum for further study. Detection limits in the low μg g⁻¹ range were obtained. Prior to chemical analysis, the samples were decomposed by acid digestion, using various mixtures of HCl, HNO₃ and HF. Yttrium was used as a suitable internal standard in order to correct for possible matrix effects. The method was applied to the analysis of six different pharmaceutical products (anti-biotic, anti-inflammatory, anti-hypertensive) in the form of tablets with film coating and also three cosmetic products like hair and face masks.     

Validation of a Quantitative Method Determination of Estradiol in Pharmaceutical Products using UV-Vis Molecular Absorption Spectrometry

Abstract

This article describes the development and validation of a quantitative analytical method for determination of estradiol in several pharmaceutical products (powder, tablets, cream, solutions for injection) using UV-vis molecular absorption spectrometry. The proposed method is accurate, precise, sensitive, and selective and can be used in quality control laboratories.     

Electron probe X-ray microanalysis as a non-destructive method for the quantitative determination of ion-implanted impurities in silicon

An urgent need exists for non-destructive methods of analysis which can provide information both on the depth distributions and cumulative quantity of impurity in semiconductors. A proposal for using electron probe X-ray microanalysis is presented in this paper. The method is based on the equation which relates the X-ray intensity of impurity atoms to their depth distribution in the specimen.Two different approaches are presented:     

Identification of pharmaceutical tablets by Raman spectroscopy and chemometrics

Raman spectroscopy has become an attractive tool for the analysis of pharmaceutical solid dosage forms. In the present study it is used to ensure the identity of tablets. The two main applications of this method are release of final products in quality control and detection of counterfeits. Twenty-five product families of tablets have been included in the spectral library and a non-linear classification method, the Support Vector Machines (SVMs), has been employed. Two calibrations have been developed in cascade: the first one identifies the product family while the second one specifies the formulation. A product family comprises different formulations that have the same active pharmaceutical ingredient (API) but in a different amount. Once the tablets have been classified by the SVM model, API peaks detection and correlation are applied in order to have a specific method for the identification and allow in the future to discriminate counterfeits from genuine products. This calibration strategy enables the identification of 25 product families without error and in the absence of prior information about the sample. Raman spectroscopy coupled with chemometrics is therefore a fast and accurate tool for the identification of pharmaceutical tablets.     

Modeling of glancing incidence X-ray for depth profiling of thin layers

In this work, we present a method to obtain quantitative information about the thickness of thin, polycrystalline layers. This non-destructive method is based on Glancing-Incidence X-ray Diffraction (GIXRD) experiments at different incidence angles. At different incidence angles, information about phases lying at different depths is obtained. The diffracted X-ray intensities' dependence on the glancing angle was analyzed and compared with simulations performed by means of a simple optico-geometrical model taking into account the Fresnel coefficients, X-ray absorption, and the effective scattered volume. The depth profile of polycrystalline Au layers was evaluated to test the procedure. The results of the GIXRD and the simulations are in very good agreement with the thickness obtained by means of X-ray reflectivity (XRR) technique.     

高聚物包覆法抑制NTO酸性腐蚀的XPS实验研究

采用高聚物包覆方法制得了NTO/F2311药柱,用XPS测试了药柱与不锈钢、铝、铜等金属高温接触贮存期间的NTO酸性腐蚀作用.结果表明,NTO/F2311药柱与金属在高温接触贮存期间未发生酸性腐蚀,F2311具有抑制NTO酸性腐蚀的作用;样品表面各种原子的迁移变化不明显,F2311中含氯链段发生取向为药柱深层的迁移,而含氟链段发生取向为药柱表面的迁移;药柱表面组分的迁移存在着的取向性使表面层组分的电子云密度降低以及峰位结合能增大,起到了抑制NTO酸性腐蚀的作用.     

Content uniformity of pharmaceutical solid dosage forms by near infrared hyperspectral imaging: A feasibility study

Near-infrared imaging systems simultaneously record spectral and spatial information. Each measurement generates a data cube containing several thousand spectra. Chemometric methods are therefore required to extract qualitative and quantitative information. The aim of this study was to determine the feasibility of quantifying active pharmaceutical ingredient (API) and excipient content in pharmaceutical formulations using hyperspectral imaging.Two kinds of tablets with a range of API content were analysed: a binary mixture of API and cellulose, and a pharmaceutical formulation with seven different compounds. Two pixel sizes, 10 μm/pixel and 40 μm/pixel, were compared, together with two types of spectral pretreatment: standard normal variate (SNV) normalization and Savitzky-Golay smoothing. Two methods of extracting concentrations were compared: the partial least squares 2 (PLS2) algorithm, which predicts the content of several compounds simultaneously, and the multivariate classical least squares (CLS) algorithm based on pure compound reference spectra without calibration.Best content predictions were achieved using 40 μm/pixel resolution and the PLS2 method with SNV normalized spectra. However, the CLS method extracted distribution maps with higher contrast and was less sensitive to noisy spectra and outliers; its API predictions were also highly correlated to real content, indicating the feasibility of predicting API content using hyperspectral imaging without calibration.     

Recent theoretical and practical applications of micellar liquid chromatography (MLC) in pharmaceutical and biomedical analysis

Micellar liquid chromatography (MLC) is an analytical technique belonging to the wide range of reversed-phase liquid chromatographic (RP-LC) separation techniques. MLC with the use of surfactant solutions above its critical micellar concentration (CMC) and the addition of organic modifiers is currently an important analytical tool with still growing theoretical considerations and practical applications in pharmaceutical analysis of drugs and other biologically active compounds. The use of MLC as an alternative, relatively much faster in comparison to conventional chromatographic separation techniques has several advantages, especially as being suitable for screening pharmaceutical analysis. The analytical data received from MLC analysis are considered a useful source of information to predict passive drug absorption, drug transport and other pharmacokinetics and physicochemical measures of pharmaceutical substances.     

A novel rapid quantitative analysis of drug migration on tablets using laser induced breakdown spectroscopy

There have been few reports wherein drug migration from the interior to the surface of a tablet has been analyzed quantitatively until now. In this paper, we propose a novel, rapid, quantitative analysis of drug migration in tablets using laser induced breakdown spectroscopy (LIBS). To evaluate drug migration, model tablets containing nicardipine hydrochloride as active pharmaceutical ingredient (API) were prepared by a conventional wet granulation method. Since the color of this API is pale yellow and all excipients are white, we can observe the degree of drug migration by visual inspection in these model tablets. In order to prepare tablets with different degrees of drug migration, the temperature of the drying process after tableting was varied between 50 to 80 °C. Using these manifold tablets, visual inspection, Fourier transform (FT)-IR mapping and LIBS analysis were carried out to evaluate the drug migration in the tablets. While drug migration could be observed using all methods, only LIBS analysis could provide quantitative analysis wherein the average LIBS intensity was correlated with the degree of drug migration obtained from the drying temperature. Moreover, in this work, we compared the sample preparation, data analysis process and measurement time for visual inspection, FT-IR mapping and LIBS analysis. The results of the comparison between these methods demonstrated that LIBS analysis is the simplest and the fastest method for migration monitoring. From the results obtained, we conclude that LIBS analysis is one of most useful process analytical technology (PAT) tools to solve the universal migration problem.