Article

Development of sampling methods for Raman analysis of solid dosage forms of therapeutic and illicit drugs

Authors:
  • J Renwick Beattie Consulting
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Abstract

The results of a study aimed at determining the most important experimental parameters for automated, quantitative analysis of solid dosage form pharmaceuticals (seized and model ‘ecstasy’ tablets) are reported. Data obtained with a macro-Raman spectrometer were complemented by micro-Raman measurements, which gave information on particle size and provided excellent data for developing statistical models of the sampling errors associated with collecting data as a series of grid points on the tablets' surface. Spectra recorded at single points on the surface of seized MDMA–caffeine–lactose tablets with a Raman microscope (λex = 785 nm, 3 µm diameter spot) were typically dominated by one or other of the three components, consistent with Raman mapping data which showed the drug and caffeine microcrystals were ca 40 µm in diameter. Spectra collected with a microscope from eight points on a 200 µm grid were combined and in the resultant spectra the average value of the Raman band intensity ratio used to quantify the MDMA: caffeine ratio, µr, was 1.19 with an unacceptably high standard deviation, σr, of 1.20. In contrast, with a conventional macro-Raman system (150 µm spot diameter), combined eight grid point data gave µr = 1.47 with σr = 0.16. A simple statistical model which could be used to predict σr under the various conditions used was developed. The model showed that the decrease in σr on moving to a 150 µm spot was too large to be due entirely to the increased spot diameter but was consistent with the increased sampling volume that arose from a combination of the larger spot size and depth of focus in the macroscopic system. With the macro-Raman system, combining 64 grid points (0.5 mm spacing and 1–2 s accumulation per point) to give a single averaged spectrum for a tablet was found to be a practical balance between minimizing sampling errors and keeping overhead times at an acceptable level. The effectiveness of this sampling strategy was also tested by quantitative analysis of a set of model ecstasy tablets prepared from MDEA–sorbitol (0–30% by mass MDEA). A simple univariate calibration model of averaged 64 point data had R2 = 0.998 and an r.m.s. standard error of prediction of 1.1% whereas data obtained by sampling just four points on the same tablet showed deviations from the calibration of up to 5%. Copyright © 2004 John Wiley & Sons, Ltd.

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... Since these two channels also gave the best spectra, we can safely conclude that shot noise was the most important factor [7]. The numbers of pixel rows binned for spectral channels 1 to 10 were: 13,14,16,22,55,55,22,16,14, and 13 respectively (Table S-3, SI), which accounted for the noise differences (larger shot noise for more rows binned). This was confirmed by collecting 8410 spectra from a sample under dark conditions (laser off) with the same exposure settings ( Figure S-4, SI). ...
... Since these two channels also gave the best spectra, we can safely conclude that shot noise was the most important factor [7]. The numbers of pixel rows binned for spectral channels 1 to 10 were: 13,14,16,22,55,55,22,16,14, and 13 respectively (Table S-3, SI), which accounted for the noise differences (larger shot noise for more rows binned). This was confirmed by collecting 8410 spectra from a sample under dark conditions (laser off) with the same exposure settings ( Figure S-4, SI). ...
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Article
Full-text available
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Article
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Thesis
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... One of the most important applications of analytical chemistry is the analysis of drugs. Raman spectroscopy became an important tool for this application in its ability to quantify active and inactive pharmaceutical ingredients in manufactured products beginning in the 1990s (Tensmeyer and Heathman, 1989;Tudor et al., 1990;Cutmore and Skett, 1993;Petty et al., 1996;McCreery et al., 1998;Fini, 2004), and its ability to identify illicit and counterfeit products sold over the internet in the past two decades (Ryder et al., 1999;Carter et al., 2000;Bell et al., 2004;de Veij et al., 2008;Sacré et al., 2010;Lanzarotta et al., 2017). However, three significant events have occurred in the past 5 years that require the analysis of trace amounts of drugs. ...
Article
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... The estimation of a repeatability value is related to the best precision that can be achieved using a specific spectrometer and recording conditions, with prefixed values for spectral resolution and number of scans averaged. On the other hand, mapping is a practical solution to overcome the subsampling problem derived from the limited spot size [33] and sample heterogeneity. The differences found between the two recording procedures, in a situation where the subsampling risk is null (tablets are composed by a single compound), may be useful to measure the effect of the particle size and distribution for a given sampled area. ...
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... However, quantification errors caused by non-representative sampling have been reported as an important error source, especially for sensitive techniques analyzing very small samples, e.g., micro-Raman systems with spatial resolution in the micrometer scale [3]. For Raman spectroscopy, larger scattering volumes have been intentionally pursued using various methods [4,5]. A quantitative description of the minimum sample volume required for representative sampling of microparticle based powder samples is presented here. ...
Conference Paper
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Macro-Raman spectroscopy with a large sample volume is suitable for representative composition analysis of bulk powder samples. To achieve less than 3% relative error tolerance with high confidence, the minimum sample volume predicted by the stochastic model for carrier-free metered dose inhaler or dry powder inhaler products is on the order of 10-3 µL, containing millions of particles. However, for dosage forms containing non-respirable large carrier particles and fine components in extremely low concentrations, the required sample volume increases to several microliters. The results are not only instructive for macro-Raman sample preparation of respirable dosage forms but also applicable to any other technique measuring bulk compositions of micro-particle based powder samples. Because the model assumes a perfectly mixed sample, inhomogeneous samples require even larger sample volumes.
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Article
A new macro-Raman system equipped with a motorized translational sample stage and low-frequency shift capabilities was developed for bulk composition and homogeneity analysis of multi-component pharmaceutical powders. Different sampling methods including single spot and scanning measurement were compared. It was found that increasing sample volumes significantly improved the precision of quantitative composition analysis, especially for poorly mixed powders. The multi-pass cavity of the macro-Raman system increased effective sample volumes by 20 times from the sample volume defined by the collection optics, i.e., from 0.02 μL to about 0.4 μL. A stochastic model simulating the random sampling process of polydisperse microparticles was used to predict the sampling errors for a specific sample volume. Comparison of fluticasone propionate mass fractions of the commercial products Flixotide® 250 and Seretide® 500 simulated for different sampling volumes with experimentally measured compositions verified that the effective sample volume of a single point macro-Raman measurement in the multi-pass cavity of this instrument was between 0.3 μL and 0.5 μL. The macro-Raman system was also successfully used for blend uniformity analysis. It was concluded that demixing occurred in the binary mixture of L-leucine and D-mannitol from the observation that the sampling errors indicated by the standard deviations of measured leucine mass fractions increased during mixing, and the standard deviation values were all larger than the theoretical lower limit determined by the simulation. Since sample volume was shown to have a significant impact on measured homogeneity characteristics, it was concluded that powder homogeneity analysis results, i.e., the mean of individual test results and absolute and relative standard deviations, must be presented together with the effective sample volumes of the applied testing techniques for any measurement of powder homogeneity to be fully meaningful.
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Article
According to World Health Organization (WHO) low quality, expired and counterfeit medicines are real threat to the health of patients starting from minor allergies to the painful death. Such medicines are affecting patients in developing as well as developed countries. In pharmaceutical industry different techniques are being used for the validation of drugs either at the time of manufacturing or after production. Traditional quality control techniques are time-consuming, destructive and expensive. These techniques also require sample preparation before testing. There is an immense need of a drug validation method that does not require sample preparation and can evaluate quality of medicines nondestructively in real time. The use of Multispectral Imaging (MSI) in the pharmaceutics for quality validation can be very helpful. MSI uses different wavelengths of the electromagnetic spectrum by dividing it into multiple bands. In this paper we are proposing a novel method for nondestructive validation of solid medicines from their surface morphology using MSI. The surface structure captured from MSI is further evaluated using digital image processing techniques and is helpful for the qualitative and quantitative analysis of chemical composition, surface features and interference effects. Different pattern recognition techniques can be used for the classification of this spectral and spatial information of drugs between substandard and genuine drugs. Fast, easy and nondestructive quality control and process monitoring can be achieved using the proposed method. This proposed method will be a contribution to the pharmaceutical industry and will be beneficial for quick, cost-effective and nondestructive quality assessment of the end products. [Tahir F, Fahiem MA, Tauseef H, Farhan S. A Survey of Multispectral High Resolution Imaging Based Drug Surface Morphology Validation Techniques. Life Sci J 2013;10(7s)
... To overcome the quantification error caused by sample inhomogeneity, several methods have been proposed, such as enlarging the illuminated area (sample volume), 33 increasing the length of the beam path through the sample, 34 using transmission Raman spectroscopy, 35,36 increasing the sample homogeneity, 37 averaging multiple spectra recorded from multiple sampling locations, 38 rotating or moving the sample holder, 20,39 and dynamically mixing the sample. 32 With the exception of increasing the degree of homogeneity, which has the potential to introduce modifications to the analyte, all of these methods are intended to increase the number of particles that can be illuminated and monitored using the detector during a Raman measurement. ...
Article
Full-text available
Quantitative macro-Raman spectroscopy was applied to the analysis of the bulk composition of pharmaceutical drug powders. Powders were extracted from seven commercial lactose-carrier-based dry-powder inhalers: Flixotide 50, 100, 250, and 500 μg/dose (four concentrations of fluticasone propionate) and Seretide 100, 250, and 500 μg/dose (three concentrations of fluticasone propionate, each with 50 μg/dose salmeterol xinafoate ). Also, a carrier-free pressurized metered-dose inhaler of the same combination product, Seretide 50 (50 μg fluticasone propionate and 25 μg salmeterol xinafoate per dose) was tested. The applicability of a custom-designed dispersive macro-Raman instrument with a large sample volume of 0.16 μL was tested to determine the composition of the multicomponent powder samples. To quantify the error caused by sample heterogeneity, a Monte Carlo model was developed to predict the minimum sample volume required for representative sampling of potentially heterogeneous samples at the microscopic level, characterized by different particle-size distributions and compositions. Typical carrier-free respirable powder samples required a minimum sample volume on the order of 10−4 μL to achieve representative sampling with less than 3% relative error. In contrast, dosage forms containing non-respirable carriers (e.g., lactose) required a sample volume on the order of 0.1 μL for representative measurements. Error analysis of the experimental results showed good agreement with the error predicted by the simulation.
... These not only cause fluorescence issues, but mixture interferences as well. There are published accounts of using Raman microscopy to " map " ecstasy tablets, but this is both time consuming and not applicable to portable technology [33]. Analysis of plant materials using portable Raman technology and some bench-top instruments has been regarded as difficult or impossible by researchers in the past. ...
Thesis
Full-text available
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... One solution to this problem is to measure several small volumes at random and try to estimate the actual concentrations from the average spectrum. Different approaches have been tested with different success rates, such as rotation of the sample (Vandenabeele et al., 2000) or mapping larger areas (Bell et al., 2004). By doing so, one of the major advantages of the technique is lost: By focussing a laser beam on a specific micrometre-sized particle, the technique is able to identify it. ...
Article
Raman spectroscopy is one of the techniques that is being advocated for adoption in astrobiology for the detection of extinct or extant life on planetary surfaces extraterrestrially. A discussion on the definition of the Raman spectroscopic limits of detection and the operational factors which influence the data observed is needed for the evaluation of the results. This research paper forms a starting point for the discussion of the meaning of detection limits of biomarker molecules – solids dispersed in solid matrices – and the consequences for astrobiological research as this will have implications on the analytical protocols and spectrometer design for remote field-operated spectrometers.
... For toxicological screening, some surface analysis techniques have been developed to identify or quantify analytes in unknown tablets. Infrared (IR) [10], near infrared (NIR) [11] [12], Raman [13] and fluorescence [14][15] spectroscopy have been described for the analysis of pharmaceutical solid forms or illicit drugs, such as Ecstasy tablets. Other techniques like nuclear quadrupole resonance (NQR) also show perspectives as non-destructive analysis techniques [16]. ...
Article
Full-text available
Desorption electrospray ionization (DESI) is a new ionization technique recently introduced in analytical chemistry for the ambient analysis of surfaces by mass spectrometry. We present here new developments in this field, focusing on their use for the analysis of solid forms, as pharmaceutical tablets or illicit drug tablets. Results recently published by ourselves are discussed in the context of related publications.
Chapter
The widespread availability of effective enhancing substrates means that the challenge for practical SERS studies has now moved to making the measurements reliable. Here, we first consider the factors which need to be controlled to minimise variability in SERS measurements. This is followed by discussion of methods, such as use of internal standards, which can further reduce uncertainty and increase the robustness of SERS measurements.
Article
Reproducibility is still a great challenge for surface-enhanced Raman scattering (SERS), because the uncontrollable fabrication of SERS substrates or the uneven distribution of samples on the substrate result in the signal fluctuation with or between the substrates. Herein, a novel SERS quantitative method with good reproducibility was proposed. It is based on the basic principle that the SERS signal intensity is not only related to electromagnetic enhancement and the concentration of sample, but also related to the specific surface area of the substrate. The surface area information of the substrate is obtained through electrochemical technology, and then introduced into the standard curve with the linear relationship of concentration of sample and SERS intensity as a new variable to obtain a 3D standard curved surface, which effectively corrects the signal difference between the substrates, and combines the wide area Raman method to reduce the difference within the substrate, thereby improving the reproducibility of SERS quantitative detection. Using malachite green (MG) as the probe molecule and using cyclic voltammetry to calculate the substrate area fitted plane model (CV-standard curved surface), the root mean square error (RMSE) of the predicted result is 0.26 and the relative error (RE) is 0.25. It shows that the detection error significantly reduces comparing with the traditional standard curve method. Also, the proposed method can be used in other SERS quantitative detection and has potential application prospects.
Article
Raman spectroscopy is a commonly applied technique for identifying the molecular nature of the constituents of solid samples. However, the quantification of the intensity associated with a particular molecular solute in solid dispersions requires analytical strategies to integrate the possible microheterogeneity in terms of composition. Many quantitative applications of solid dispersions rely on large spectral datasets. However, analytical procedures with limited data acquisition must be developed in preparation for future robotic planetary exploration missions or for field applications on earth, both of which involve miniaturised instrumentation. Based on statistical models, we evaluate the minimum number of spectra required to deliver robust data for quantitative measurements associated with differing concentrations of β‐carotene or L‐cysteine dispersed in gypsum. In this respect, reference materials were prepared, and we investigated an analytical methodology based on a large, automated multipoint scanning approach enabling the representative interrogation of the samples. We demonstrate from a comprehensive and reproducible model that the intensity associated with different organic contents within a mineral matrix can be estimated from a reduced number of spectra. Calibration curves were established for our reference dispersions of L‐cysteine in gypsum in the range 1–10 wt%, using both confocal benchtop and nonconfocal miniaturised portable instruments. We propose a reference system and a Raman analytical strategy, that is, adaptable for planetary exploration constraints, and which allows quantitative comparison of performance of instrumentation in terms of signal detection.
Chapter
There is a wide range of applications of confocal Raman microscopy in pharmaceutical development. It is a powerful tool to probe the distribution of components within a formulation, to characterize homogeneity of pharmaceutical samples, to determine solid state of drug substances and excipients as well as to characterize contaminations and foreign particulates. The information obtained by confocal Raman microscopy is extremely useful, sometimes even crucial, for drug substance design, for the development of solid and liquid formulations, as a tool for process analytics and for patent infringements and counterfeit analysis. In this chapter, those aspects and applications will be presented, focusing on solid drug formulations. This chapter will also reveal the advantages and demonstrate the synergies of Raman mapping as compared to/with similar imaging methods such as SEM/EDX, NIR and MIR imaging.
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Sulfathiazole Forms II, III and IV are polytypes where common monolayers accumulate in different stacking modes. These polytypes are difficult to identify using conventional analytical techniques when they concomitantly crystallize. However, the use of low-frequency Raman spectroscopy enables discrimination of these polytypes and can determine the ratio of Forms III and IV, which are the most challenging pair for quantification. A Hydrogen/Deuterium exchange study suggests that characteristic patterns below 100 cm‒1 predominantly come from differences of superstructure geometries, especially layer stacking, rather than hydrogen-bond geometries. This study demonstrates that low-frequency Raman spectroscopy has advantages for both polytypic discrimination and quantification.
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Global regulatory agencies have encouraged the use of process analytical technology (PAT) to assure quality in the pharmaceutical industry. A frequently cited obstacle to the implementation of spectroscopy-based PAT methods is the difficulty associated with directly transferring calibration models between PAT instruments. The goal of this study was to compare model transfer strategies for method transfer between two transmission Raman spectroscopy (TRS) instruments. The calibration and test samples were pharmaceutical compacts of acetaminophen and excipients. The experimental design was a 3 factor by 5 level circumscribed central composite design of active pharmaceutical ingredient, lactose, and microcrystalline cellulose concentrations. The calibration and test data were collected using two instruments. Quantitative models were constructed using partial least squares regression. Global calibration modeling and direct model transfer were compared to evaluate opportunities for situations involving method transfer, calibration update, and line extension. Models were compared using a t test-based method to evaluate performance statistics. Statistical analysis demonstrated equivalent performance of the global modeling and direct transfer methods. This work demonstrated that a quantitative transmission Raman model could be directly transferred across instruments, thus avoiding the challenges and resources necessary when creating global models.
Article
Chemical Imaging (CI) is an emerging platform technology that integrates conventional imaging and spectroscopy to attain both spatial and spectral information from an object. Vibrational spectroscopic methods, such as Near Infrared (NIR) and Raman spectroscopy, combined with imaging are particularly useful for analysis of biological/pharmaceutical forms. The rapid, non-destructive and non-invasive features of CI mark its potential suitability as a process analytical tool for the pharmaceutical industry, for both process monitoring and quality control in the many stages of drug production. This paper provides an overview of CI principles, instrumentation and analysis. Recent applications of Raman and NIR-CI to pharmaceutical quality and process control are presented; challenges facing CI implementation and likely future developments in the technology are also discussed.
Article
The potential of IR absorption and Raman spectroscopy for rapid identification of novel psychoactive substances (NPS) has been tested using a set of 221 unsorted seized samples suspected of containing NPS. Both IR and Raman spectra showed large variation between the different sub-classifications of NPS and smaller, but still distinguishable, differences between closely related compounds within the same class. In initial tests, screening the samples using spectral searching against a limited reference library allowed only 41% of the samples to be fully identified. The limiting factor in the identification was the large number of active compounds in the seized samples for which no reference vibrational data were available in the libraries rather than poor spectral quality. Therefore, when 33 of these compounds were independently identified by NMR and mass spectrometry and their spectra used to extend the libraries, the percentage of samples identified by IR and Raman screening alone increased to 76%, with only 7% of samples having no identifiable constituents. This study, which is the largest of its type ever carried out, therefore demonstrates that this approach of detecting non-matching samples and then identifying them using standard analytical methods has considerable potential in NPS screening since it alllows rapid identifcation of the constituents of the majority of street quality samples. Only one complete feedback cycle was carried out in this study but there is clearly the potential to carry out continuous identification/updating when this system is used in operational settings.
Article
IntroductionBulk DrugsTrace DetectionConclusions References
Article
A robust and accurate analytical methodology for low-content (<0.1%) quantification in the solid-state using Raman spectroscopy, sub-sampling, and chemometrics was demonstrated using a piracetam-proline model. The method involved a 5-step process: collection of relatively large number of spectra (8410) from each sample by Raman mapping, meticulous data pretreatment to remove spectral artefacts, use of a 0-100% concentration range partial least squares (PLS) regression model to estimate concentration at each pixel, use of a more-accurate, reduced concentration range PLS model to accurately calculate analyte concentration at each pixel, and finally statistical analysis all 8000+ concentration predictions to produce an accurate overall sample concentration. The relative prediction accuracy was ~2.4% for a 0.05~1.0% concentration range and the limit of detection was comparable to high performance liquid chromatography (0.03% versus 0.041%). For data pretreatment, we developed a unique cosmic ray removal method and used an automated baseline correction method, neither of which required subjective user intervention and thus were fully automatable. The method is applicable to systems, which cannot be easily analyzed chromatographically such as hydrate, polymorph, or solvate contamination.
Article
The present paper describes the application of solid probe assisted nanoelectrospray ionization mass spectrometry (SPA-nanoESI-MS) for the direct analysis of samples in solid or dried form. The experimental procedure is simple and requires a metallic needle to touch the sample surface followed by inserting the needle into a solvent preloaded nano-capillary. A number of real-world samples in solid or dried form comprising proteins, drugs in tablets, illicit drugs in dried urine, and lipids in tissues were analyzed to evaluate the applicability of the technique in diverse fields. This technique can produce high quality mass spectra without clogging the capillary tip. The quantitative aspect of this technique was evaluated using morphine from dried urine. In addition, biofluids/biomolecules captured on the needle tip and stored for several days at room temperature produced almost similar spectra to those obtained for fresh samples of cancerous and noncancerous tissues. The high sensitivity, versatile applicability and capability of dried sample analysis extend the scope of SPA-nanoESI to new ventures like bioanalytical and forensic analysis as well as clinical diagnosis.
Article
Introduction: In recent years, Raman spectroscopy has become increasingly important as an analytical technique in various scientific areas of research and development. This is partly due to the technological advancements in Raman instrumentation and partly due to detailed fingerprinting that can be derived from Raman spectra. Its versatility of applications, rapidness of collection and easy analysis have made Raman spectroscopy an attractive analytical tool. Areas covered: The following review describes Raman spectroscopy and its application within the pharmaceutical industry. The authors explain the theory of Raman scattering and its variations in Raman spectroscopy. The authors also highlight how Raman spectra are interpreted, providing examples. Expert opinion: Raman spectroscopy has a number of potential applications within drug discovery and development. It can be used to estimate the molecular activity of drugs and to establish a drug's physicochemical properties such as its partition coefficient. It can also be used in compatibility studies during the drug formulation process. Raman spectroscopy's immense potential should be further investigated in future.
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The identification of benzodiazepine drugs is important in the Forensics field because they are used in drug-facilitated crimes. Raman spectroscopy has been proven as a non-invasive, fast and reliable technique highly promising for the analysis of drug products. Up to date, attention has been paid on the active ingredient, but the spectral drug product signature has rarely been used in spite of having potential valuable information. In this work, confocal Raman microscopy was used to obtain the spectral signature of the most widely used benzodiazepine products. Firstly, the study aimed at determining an appropriate Raman mapping spectra to obtain each benzodiazepine signature with low sampling error. Then, PCA scores and loadings showed that the variability, measured on the variance, among batches of the same benzodiazepine drug was similar to the variability of the spectral signature of the same tablet (or capsule content) and the same batch, mainly attributed to the heterogeneity of such drug product. Interestingly, differentiation among doses of the same active ingredient (AI), benzodiazepine drugs with different AI manufactured by the same pharmaceutical company, and drugs with the same AI but manufactured by different companies were demonstrated. It is remarkable that for low doses, the active ingredient is almost absent of the spectral signature, but the differentiation is mainly achieved by the excipients. As consequence, spectral signature obtained by confocal Raman microscopy can be used for discriminating among these benzodiazepine drugs without requiring a clearly identifiable band related to the active ingredient in the corresponding Raman spectra.
Article
In this paper, the author reported two methods to extract spectral or spatial information inherited in the Raman chemical images for linear quantification calibration of crystallinity. The two approaches reported quantification results according to the spectral mean score of overall pixels or the spatial percentage of the pixels with a score greater than and equal to the threshold of the chemical images, respectively. From this study, it can be concluded that, first, sampling method for data collection in mapping has to be optimized to achieve linear quantification calibration through simple univariate analysis approaches. Second, the ordinary way of evaluating/validating a linear quantification technique by best linear correlation coefficient (R2) and root-mean-square error of calibration is disputable and has to be reconsidered. Lastly, with further consideration of root-mean-square relative error of calibration and predicted crystallinity at subpercent, it was found that the spectral mean score method cannot generate reliable quantification results at subpercent crystallinity. Copyright © 2014 John Wiley & Sons, Ltd.
Article
It is common belief that in Raman mapping, the sampling depth from which Raman signal is collected originates from a probe laser spot size of approximately 1–5 µm3. Actually, the active pharmaceutical ingredient (API) crystals detected by mapping on the sample surface distribute from surface to over a few tens to hundreds of microns into the sample, as determined by z‐slices mapping in this context. It was also found that the score of API crystals detected in a chemical image decrease with their depth into the sample. Therefore, a larger threshold of the binary chemical images can be used to restrict the sampling depth and consequently eliminate the problem of ‘saturation’ by quantifying merely the amount of API crystals within a sampling volume equivalent to a smaller sampling depth rather than the overall detected crystalline API in the chemical images. Eventually, one single linear quantification calibration was established over the crystallinity from sub‐percent ( Document Type: Research Article DOI: http://dx.doi.org/10.1002/jrs.4370 Publication date: November 1, 2013 (document).ready(function() { var shortdescription = (".originaldescription").text().replace(/\\&/g, '&').replace(/\\, '<').replace(/\\>/g, '>').replace(/\\t/g, ' ').replace(/\\n/g, ''); if (shortdescription.length > 350){ shortdescription = "" + shortdescription.substring(0,250) + "... more"; } (".descriptionitem").prepend(shortdescription);(".descriptionitem").prepend(shortdescription); (".shortdescription a").click(function() { (".shortdescription").hide();(".shortdescription").hide(); (".originaldescription").slideDown(); return false; }); }); Related content In this: publication By this: publisher By this author: Wu, Jianping GA_googleFillSlot("Horizontal_banner_bottom");
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Quantitative monitoring of a mechanochemical reaction by Raman spectroscopy leads to a surprisingly straightforward second-order kinetic model in which the rate is determined simply by the frequency of reactive collisions between reactant particles.
Article
Raman spectroscopy is increasingly often used for the investigation of archaeological and art objects. Often, questions are asked concerning achievable limits of detection. However, the definition of Raman spectroscopic detection limits is not straightforward, especially in art analysis where the investigation of solid particles, often dispersed in a solid matrix, is involved. Moreover, apart from the definition of the limit of detection, as often qualitative analysis is performed, it is equally necessary to establish a definition for the limit of identification of a product. Moreover, some ideas are discussed on the description of relative Raman band intensities and on how to include this in the definition of the limit of identification. In this paper, some topics are raised, and we hope to initiate with this paper future discussions in the Raman spectrometry community on this topic. Copyright © 2012 John Wiley & Sons, Ltd.
Article
Full-text available
Antisense oligonucleotide to NF-κB sequence: 5'-GGA AAC ACA TCC TCC ATG-3', was microencapsulated in an albumin matrix by the method of spray dryingTM. Spectral analysis was performed on varying drug loading formulations of both drugs by mid-IR attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). An out of plane O–H bending vibration at 948 cm−1, unique to both the native and microencapsulated drugs was identified. The calculated peak areas corresponded to the drug loadings in the microsphere formulations. A standard curve could then be used to determine the drug content of an unknown microsphere formulation. Accuracy and precision were determined to be comparable to other analytical techniques such as HPLC.
Article
Benzodiazepines are among the most prescribed compounds and are commonly present in many toxicological screens. They are also of concern forensically in cases of drug facilitated sexual assault. Currently these compounds are predominantly analyzed using immunoassay techniques; however more specific screening methods are needed. This paper demonstrates the applicability of surface enhanced Raman spectroscopy as a method for the analysis and detection of benzodiazepines. The procedure involves mixing urine extracts with gold nanoparticles and appropriate aggregating agents for trace detection of these compounds and their metabolites. In this paper we will discuss the optimization of various parameters of this technique as well as its application to screening urine samples. Eleven different benzodiazepines and metabolites were examined, including 1,2-triazolo-benzodiazepines and 1,4-benzodiazpines. Experiments were performed using four different chloride salts, MgCl2, CaCl2, KCl, and NaCl, as aggregating agents for the colloidal gold nanoparticles. Overall it was found that each aggregating agent produced different levels of signal enhancement for each drug. MgCl2 provided the lowest limit of detection at 2.5 ng mL(-1), and linearity over a wide range of concentrations for a variety of drugs chosen. It was also determined that the optimum MgCl2 concentration was 1.67 M. This method has shown the applicability of SERS for the detection of trace quantities of benzodiazepines in aqueous solutions as well as the optimization of the technique over a wide range of compounds. This technique can be utilized in the detection of trace benzodiazepines in toxicological samples following extraction of the analyte.
Article
Raman spectroscopy provides a very effective method of identifying an illicit substance in situ without separation or contact other than with a laser beam. The equipment required is steadily improving and is now reliable and simple to operate. Costs are also coming down and hand held portable spectrometers are proving very effective. The main limitations on the use of the technique are that it is insensitive in terms of the number of incident photons converted into Raman scattered photons and fluorescence produced in the sample by the incident radiation interferes. Newer methods, still largely in the development phase, will increase the potential for selected applications. The use of picosecond pulsed lasers can discriminate between fluorescence and Raman scattering and this has been used in the laboratory to examine street samples of illicit drugs. Surface-enhanced Raman scattering, in which the analyte requires to be adsorbed onto a roughened metal surface, creates a sensitivity to compete with fluorescence and quenches fluorescence for molecules on a surface. This provides the ability to detect trace amounts of substances in some cases. The improving optics, detection capability and the reliability of the new methods indicate that the potential for the use of Raman spectroscopy for security purposes will increase with time.
Article
This review summarizes recent studies to improve sample representation in Raman measurement by covering a large area of a sample in spectral collection. Three different schemes have been mainly investigated to fulfill the goal: (1) averaging of Raman spectra collected at many different locations on a sample, (2) rotation of a sample during spectral collection and (3) simultaneous wide area illumination (WAI) for spectral collection. The use of a wide area illumination scheme, simultaneously illuminating a laser over a large area for spectral acquisition without any further assistance such as sample rotation, has increased in diverse fields. Applications employing the WAI scheme in pharmaceutical, polymer/chemical/petrochemical and other areas are described in this review.
Chapter
The sections in this article are The New Paradigm of Process Control Overview of Spectroscopic Techniques Commonly Used The Need for Multivariate Data Analysis Pre‐Processing Exploration Techniques Regression, Resolution and Classification Techniques Image Processing Techniques Applications in Pharmaceutical Process Monitoring and Quality Control Spray Formulations Powders Polymorphism Solid Dosage Forms Root Cause Analysis API Distribution Coatings Counterfeit Identification High Throughput Analysis Issues Facing the Implementation of Spectroscopic Techniques in the Pharmaceutical Industry Sampling Spatial Resolution Representativeness of the Measured Surface Irregularities in the Measured Surface Conclusions Acknowledgements
Article
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Raman spectroscopy is a noninvasive, nondestructive tool for capturing multiplexed biochemical information across diverse molecular species including proteins, lipids, DNA, and mineralizations. Based on light scattering from molecules, cells, and tissues, it is possible to detect molecular fingerprints and discriminate between subtly different members of each biochemical class. Raman spectroscopy is ideal for detecting perturbations from the expected molecular structure such as those occurring during senescence and the modification of long-lived proteins by metabolic intermediates as we age. Here, we describe the sample preparation, data acquisition, signal processing, data analysis and interpretation involved in using Raman spectroscopy for detecting age-related protein modifications in complex biological tissues.
Article
Modern drug laws require that a seized sample be characterized for both the illegal substances present and the quantity of each of those substances. The goal of this work was to develop a common approach to model development based on Raman spectroscopic analysis followed by partial least squares (PLS) regression that would allow us to obtain quantitative information from simulated street-drug samples. Each drug sample contained one drug surrogate—either isoxsuprine, norephedrine, benzocaine, or lidocaine—and up to 3 different cutting agents. All spectra were acquired on a homebuilt Raman instrument equipped with a rotating sample holder. The same steps were employed for developing separate models for each drug surrogate, including spectral preprocessing by Savitsky-Golay smoothing, differentiation, mean-centering, and autoscaling. PLS models were developed using 2 latent variables that yielded root mean square errors of calibration (RMSEC) values in the 3% range and root mean square error of prediction (RMSEP) values in the 4% range.
Article
In-line monitoring of solid-state properties in crystallization processes is of great significance in controlling the quality of crystalline active pharmaceutical ingredients. In this work, the solvent-mediated phase transformation of anhydrous to dihydrated carbamazepine in ethanol−water mixtures was studied using an in-line Raman immersion probe. The solute concentration profile was measured by off-line sampling. The transformation experiments were conducted with different operation parameters in terms of solvent composition and temperature. The transformation rate depends on both solvent composition and temperature. The mechanism of the transition was interpreted with the two-step polymorphic form transformation mechanism. It was observed that the crystallization of the stable form was the rate-controlling step. The influence of the operation parameters on the transformation rate can be interpreted as the effects of solvent and supersaturation on the crystallization kinetics. Another interpretation is proposed by correlating the deviation of the water activity from the equilibrium value to the rate of phase transformation. It was observed that the correlation of the water activity deviation and the phase transformation rate was independent of solvent composition and temperature.
Article
Raman microscopy is used to investigate the spectral features of selected compounds known to be involved in the development of the eye disease age-related macular degeneration (AMD). Diagnostic features were identified in synthetic samples of these compounds and in a biological matrix. The study demonstrates the potential of Raman microscopy for the development of diagnostic markers of the onset of AMD. Copyright © 2008 John Wiley & Sons, Ltd.
Chapter
Introduction Ionization Apparatus, Mechanisms, and General Performance Drug Analysis in Biological Matrices using DESI and DART High-Throughput Analysis Chemical Imaging and Profiling Future Perspectives References
Article
The laser excitation wavelength is an important parameter in obtaining Raman spectra from drugs-of-abuse. This article compares the effect of near infrared wavelengths, 785 nm, using both benchtop and portable instrumentation and benchtop 1064 nm on the Raman spectra of seized drugs-of-abuse, including cocaine hydrochloride, cocaine freebase (crack), methylenedioxymethamphetamine (‘ecstasy’), amphetamine, diamorphine (heroin) and cannabis. The significant benefit of using 1064 nm for the interrogation of this type of sample is highlighted. Copyright © 2009 John Wiley & Sons, Ltd.
Article
Coatings are of great significance for pharmaceutical solid dosage forms. They fulfil a number of functions and are often necessary to control drug delivery, to mask bitter taste, or to protect the active pharmaceutical ingredient from detrimental environmental factors. The process of self-coating by melt crystallization of a suitable binary mixture eliminates the need for an additional process step in the manufacture of a solid drug. Self-coating relies upon the physical and spatial separation of individual components in a melt during solidification. This paper focuses on the use of confocal Raman microscopy as a nondestructive technique for quantifying the spatial distribution of the components in self-coated pastilles manufactured from the binary system ibuprofen/carnauba wax. Pastilles are produced from the melt. Raman spectroscopy allows the direct analysis of concentration profiles across the surface of the pastille. Here, the samples are cleaved and the cleaved surface is investigated in order to establish the distribution of the components in the interior of the solid. A univariate calibration model was developed and statistically validated with standard mixtures of ibuprofen and carnauba wax. Different regression models (linear or polynomial, using different significant peaks for the respective compounds) were assessed and a linear model was found to be adequate to determine the concentration gradient in the pastilles.
Article
This paper gives a summary of this special issue on ‘Pharmaceutical Applications of Raman Spectroscopy’. It summarizes the papers collected and introduces the possible applications of classical Raman spectroscopy (macro and micro) and surface-enhanced Raman spectroscopy to the identification of pharmacologically active substances, their qualitative and quantitative analysis, characterization of crystalline forms and structure determination. Copyright © 2004 John Wiley & Sons, Ltd.
Article
The rapid identification for drugs-of-abuse in airports is of critical importance. In this study we demonstrate the viability of Raman spectroscopy for the rapid identification of illicit substances in their containers in an airport environment. Raman spectra of drugs-of-abuse in situ were collected using portable Raman spectrometers; this technique offers distinct advantages to government agencies, first responders and forensic scientists working in the security field. We have demonstrated that the spectrometers are able to collect the spectra of suspect powders, including cocaine HCl and d-amphetamine sulphate with unknown constituents rapidly and with a high degree of discrimination. Copyright
Article
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Raman spectroscopy with far-red excitation has been used to study seized, tableted samples of MDMA (N-methyl-3,4-methylenedioxyamphetamine) and related compounds (MDA, MDEA, MBDB, 2C-B and amphetamine sulfate), as well as pure standards of these drugs. We have found that by using far-red (785 nm) excitation the level of fluorescence background even in untreated seized samples is sufficiently low that there is little difficulty in obtaining good quality data with moderate 2 min data accumulation times. The spectra can be used to distinguish between even chemically-similar substances, such as the geometrical isomers MDEA and MBDB, and between different polymorphic/hydrated forms of the same drug. Moreover, these differences can be found even in directly recorded spectra of seized samples which have been bulked with other materials, giving a rapid and non-destructive method for drug identification. The spectra can be processed to give unambiguous identification of both drug and excipients (even when more than one compound has been used as the bulking agent) and the relative intensities of drug and excipient bands can be used for quantitative or at least semi-quantitative analysis. Finally, the simple nature of the measurements lends itself to automatic sample handling so that sample throughputs of 20 samples per hour can be achieved with no real difficulty.
Article
Full-text available
Raman spectroscopy with far-red excitation has been investigated as a simple and rapid technique for composition profiling of seized ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine) tablets. The spectra obtained are rich in vibrational bands and allow the active drug and excipient used to bulk the tablets to be identified. Relative band heights can be used to determine drug/excipient ratios and the degree of hydration of the drug while the fact that 50 tablets per hour can be analysed allows large numbers of spectra to be recorded. The ability of Raman spectroscopy to distinguish between ecstasy tablets on the basis of their chemical composition is illustrated here by a sample set of 400 tablets taken from a large seizure of > 50,000 tablets that were found in eight large bags. The tablets are all similar in appearance and carry the same logo. Conventional analysis by GC-MS showed they contained MDMA. Initial Raman studies of samples from each of the eight bags showed that despite some tablet-to-tablet variation within each bag the contents could be classified on the basis of the excipients used. The tablets in five of the bags were sorbitol-based, two were cellulose-based and one bag contained tablets with a glucose excipient. More extensive analysis of 50 tablets from each of a representative series of sample bags have distribution profiles that showed the contents of each bag were approximately normally distributed about a mean value, rather than being mixtures of several discrete types. Two of the sorbitol-containing sample sets were indistinguishable while a third was similar but not identical to these, in that it contained the same excipient and MDMA with the same degree of hydration but had a slightly different MDMA/sorbitol ratio. The cellulose-based samples were badly manufactured and showed considerable tablet-to-tablet variation in their drug/excipient ratio while the glucose-based tablets had a tight distribution in their drug/excipient ratios. The degree of hydration in the MDMA feedstocks used to manufacture the cellulose-, glucose- and sorbitol-based tablets were all different from each other. This study, because it centres on a single seizure of physically similar tablets with the same active drug, highlights the fact that simple physical descriptions coupled with active drug content do not in themselves fully characterize the nature of the seized materials. There is considerable variation in the composition of the tablets within this single seizure and the fact that this variation can be detected from Raman spectra demonstrates that the potential benefits of obtaining highly detailed spectra can indeed translate into information that is not readily available from other methods but would be useful for tracing of drug distribution networks.
Article
Near-infrared (785 mn) excitation was used to obtain Raman spectra from a series of 33 solid mixtures containing cocaine, caffeine and glucose (9.8-80.6% by weight cocaine), which were then analysed using chemometric methods, Principal component analysis of the data was employed to ascertain what factors influenced the spectral variation across the concentration range. It was found that 98% of the spectral variation was accounted for by three principal components. Analysis of the score and loadings plots for these components showed that the samples can be clearly classified on the basis of cocaine concentration. Discrimination on the basis of caffeine and glucose concentrations was also possible. Quantitative calibration models were generated using partial least-squares algorithms which predicted the concentration of cocaine in the solid mixtures containing caffeine and glucose from the Raman spectrum with a root mean standard error of prediction (RMSEP) of 4.1%, Caffeine and glucose concentrations were estimated with RMSEPs of 5.2 and 6.6%, respectively, These measurements demonstrate the feasibility of using near-IR Raman spectroscopy for rapid quantitative characterization of illegal narcotics. Copyright (C) 2000 John Wiley & Sons, Ltd.
Article
The pharmaceutical industry uses successfully both FTNIR and Raman microscopy to produce chemical images of solid dosage forms, typically in troubleshooting roles. However, due to the chemical composition of the formulations,it is not always possible to describe the entire chemical formulation by using a single spectroscopic method. As Raman and NIR spectroscopies are complementary in nature, their combined usage offers the opportunity to describe heterogeneous mixtures in more detail. A novel sample referencing approach has been developed that allows data to be acquired from exactly the same area of the sample using both Raman and FT-NIR microscopies. The optimum images for the components are then overlaid, which gives rise to a combined chemical image that visually describes the entire formulation. We have named this approach chemical image fusion (CIF). CIF has been applied to two examples. The first shows how a simple formulation was used to validate the CIF approach. In the second, CIF allowed an entire formulation to be visualized and the cause of tabletting problems determined. CIF provides increased confidence in the results generated by each individual technique and offers a more powerful method for the evaluation of pharmaceutical formulations.
Article
FT-Raman spectroscopy based on band intensity or band area measurements was used for the quantitative determination of ciprofloxacin in pharmaceutical solid dosage forms. Univariate calibration was used for quantitative analysis. Bands observed at 1708, 1624, 1548, 1493, 1273, 1253, 1238, 1024, 805, 787, 752, 718, 665, and 638 cm-1 were used. Calibration curves were linear in the concentration range of 3-100% w/w with correlation coefficients of 0.99-0.996 and 0.991-0.9993 for band intensity and band area measurements, respectively. Precision ranged from 0-11 and 0.4-12% relative standard deviation (RSD) (n = 3) for band intensity and band area measurements, respectively, and results were in good agreement with the results obtained by the current United States Pharmacopoeia (USP 24) and National Formulary (NF 19) method. Multivariate calibration was also used for quantitative analysis. Multiple linear regression using the intensities of the 1545 and 1272 cm-1 bands gave results in accordance with those obtained by the current United States Pharmacopoeia (USP 24) and National Formulary (NF 19) method. As measurement takes just 30 s using the analytical readout from a single band, the proposed method can be used to replace tedious and time-consuming methods.
Article
Citation Anthony G. Severdia and Kevin Siek, "Fourier Transform Raman Spectroscopy for Identification and Differentiation Between Dosage Strengths of an Active Drug in White Opaque Hard Gelatin Capsules," Appl. Spectrosc. 56, 545-548 (2002) http://www.opticsinfobase.org/as/abstract.cfm?URI=as-56-4-545
Article
In this study, near-infrared (NIR) transmittance and Raman spectroscopy chemometric calibrations of the active substance content of a pharmaceutical tablet were developed using partial least-squares regression (PLS). Although the active substance contained the strongly Raman active C≡N functional group, the best results were obtained with NIR transmittance, which highlights the difference between (microscopic) surface sampling and whole tablet diffuse transmittance sampling. The tablets exist in four dosages with only two different concentrations of active substance (5 mg (5.6% w/w), and 10, 15, and 20 mg (8.0% w/w) active substance per tablet). A calibration on all four dosages resulted in a prediction error expressed as the root mean squared error of cross-validation (RMSECV) of 0.30% w/w for the NIR transmittance calibration. The corresponding error when using Raman spectra was 0.56% w/w. Specially prepared calibration batches covering the range 85-115% of the nominal content for each dosage were added to the first sample set, and NIR transmittance calibrations on this set - containing coated as well as uncoated tablets - gave a further reduction in prediction errors to 0.21-0.289% w/w. This corresponds to relative prediction errors (RMSECV/ynom) of 2.6-3.7%. This is a reasonably low error when compared to the error of the chromatographic reference method, which was estimated to 3.5%.
Book
Many scientists have a passing familiarity with Raman spectroscopy and those of us who have tried using it, say 15 years ago, to identify chemical groups were probably disappointed. At the time, a long recording time and poor signal/noise ratios did not inspire strong recommendations for chemical analysis. This was disappointing because there was always a deep-seated feeling that here was a technique that could be capable of detailed chemical analysis, indeed chemical imaging. How things have changed! The more widespread use of infrared lasers, CCD detectors and signal processing using powerful PCs have all reduced the recording times from around one hour to about 30 seconds. The general convenience of the technique is bringing it to the attention of a wider audience of chemists and materials scientists. This volume by McCreery is another in the excellent Wiley series of monographs on Analytical Chemistry. These have provided a very high standard, indeed a `flagship' of authority and quality in this broad area. The treatment given here will capture the attention of both the novice who wants to find out how Raman spectroscopy works, and the expert practitioner who requires some original sources of information. It will be very useful to all researchers who use, or wish to use, the Raman technique. The introductory sections really do highlight the differences to be expected between modern Raman techniques and the `rival' techniques of near infrared (NIR) and Fourier transform infrared (FTIR) spectroscopies. The treatment is a no-nonsense, pragmatic approach, with comparable spectra for the techniques, warts and all! Later sections then go on to give a rigorous analysis of signal levels, signal/noise ratios and practical details of the lasers, detectors and software that are best suited to specific needs and applications. There are several extensions of Raman spectroscopy that have been made possible by improved software and instrumentation in recent years, but probably the ability to form images is the one that will capture a large share of devotees. In conclusion, McCreery gives a very well balanced and authoritative account of Raman microscopy in all its different variants. He repeats this very effectively for its application via fibre-optic probes, and the examples that he has selected are clear, simple and useful. The section on surface enhanced Raman spectroscopy (SERS) is a model of clarity and one that I will use in future lectures. I can recommend this volume without hesitation. P J Dobson
Article
Raman spectroscopy offers the potential for the identification of illegal narcotics in seconds by inelastic scattering of light from molecular vibrations. In this study cocaine, heroin, and MDMA were analyzed using near-IR (785 nm excitation) micro-Raman spectroscopy. Narcotics were dispersed in solid dilutants of different concentrations by weight. The dilutants investigated were foodstuffs (flour, baby milk formula), sugars (glucose, lactose, maltose, mannitol), and inorganic materials (Talc powder, NaHCO3, MgSO4 ?7H2O). In most cases it was possible to detect the presence of drugs at levels down to ~10% by weight. The detection sensitivity of the Raman technique was found to be dependent on a number of factors such as the scattering cross-sections of drug and dilutant, fluorescence of matrix or drug, complexity of dilutant Raman spectrum, and spectrometer resolution. Raman spectra from a series of 20 mixtures of cocaine and glucose (0–100% by weight cocaine) were collected and analyzed using multivariate analysis methods. An accurate prediction model was generated using a Partial Least Squares (PLS) algorithm that can predict the concentration of cocaine in solid glucose from a single Raman spectrum with a root mean standard error of prediction of 2.3%.
Article
Quantitative analysis of solid state composition is often used to ensure the safety and efficacy of drug substances or to establish and validate the control of the pharmaceutical production process. There are a number of common techniques that can be applied to quantify the phase composition and numerous different methods for each technique. Each quantitative option presents its own issues in ensuring accuracy and precision of the solid state method. The following article describes many of the common techniques that are used for quantitative phase analysis and many of the considerations that are necessary for the development of such methods.
Article
Two independent methods for determination of the effectively sampled mass per unit area are presented and compared. The first method combines directional-hemispherical transmittance and reflectance measurements. A three-flux approximation of the equation of radiative transfer is used, to separately determine the specific absorption and scattering coefficients of the powder material, which subsequently are used to determine the effective sample size. The second method uses a number of diffuse reflectance measurements on layers of controlled powder thickness in an empirical approach. The two methods are shown to agree well and thus confirm each other. From the determination of the effective sample size at each measured wavelength in the visible-NIR region for two different model powder materials, large differences was found, both between the two analyzed powders and between different wavelengths. As an example, the effective sample size ranges between 15 and 70 mg/cm(2) for microcrystalline cellulose and between 70 and 300 mg/cm(2) for film-coated pellets. However, the contribution to the spectral information obtained from a certain layer decreases rapidly with increasing distance from the powder surface. With both methods, the extent of contribution from various depths of a powder sample to the visible-NIR diffuse reflection signal is characterized. This information is valuable for validation of analytical applications of diffuse reflectance visible-NIR spectrometry.
Article
The ideal quality control method for pharmaceutical products should be capable of rapid nondestructive testing of intact tablets or capsules. Raman spectroscopy using near-infrared excitation is shown to be capable of obtaining useful spectral data directly from drug formulations in gel capsules and from the gel capsules inside blister packs. The Raman data collected from the capsules inside blister packs containing 0-100 mg of the active ingredient (bucindolol), when coupled with multivariate calibration, resulted in a calibration SEP of 3.36 mg. The largest source of error was found to be due to sample inhomogeneity. Even so, the method is shown to have significant potential as a rapid nondestructive quality control method for pharmaceutical samples.
Article
Laser Raman spectroscopy was used for the quantitative determination of aspirin in aspirin-maize starch tablets. A calibration curve was constructed from spectra obtained from tablets with known quantities of aspirin and starch. The calibration curve is given from the relationship: I(552)/I(478) = (W(aspirin)/W(starch)) x 4.21, where I(552) and I(478) are the relative Raman intensities for the 552 and 478 cm(-1) Raman shift, respectively. W(aspirin) and W(starch) represent the weight of aspirin and starch in a pellet.
Article
To establish if FT-Raman spectroscopy can be used to quantitate the degree of crystallinity in a model compound. Mixtures containing different proportions of amorphous and crystalline indomethacin were prepared. Using the peak intensity ratio 1698 cm(-1) (crystalline) to 1680 cm(-1) (amorphous), a correlation curve was prepared. This correlation curve was validated by testing further samples of known composition. Partially crystalline indomethacin was prepared by milling crystalline indomethacin. A linear correlation curve was obtained across the entire range of 0-100% crystallinity. Using this method, it was possible to detect down to either 1% amorphous or crystalline content. The largest errors were found to result from inhomogeneities in the mixing of the calibration and validation samples. The spectra of the mechanically processed samples were similar to the spectra of the calibration samples, and the degree of crystallinity could be estimated in these samples. FT-Raman spectroscopy is a potentially useful method to complement existing techniques for the quantitative determination of crystallinity.
Article
To compare the physical state of a drug in a liquid with a polymeric matrix. Solid solutions of ibuprofen in polyvinylpyrrolidone were obtained from the hot melt extrusion technique. In order to investigate the physicochemical stability, content, and homogeneity of the formulation, the tablets produced by a subsequent calendering step were examined using confocal Raman spectroscopy. In addition, a dimeric vinylpyrrolidone was synthesized and used to compare the physical state of embedding in a polymeric matrix with a physical solution of the active in a solvent, i.e. the dimeric vinylpyrrolidone. The spatial resolution of confocal Raman spectroscopy was used to image the drug distribution in the final form. Confocal Raman spectroscopy has been successfully used to determine the state of ibuprofen in a solid matrix showing equivalence to a physical solution. Moreover, the physicochemical stability of the formulation under stress conditions and content, as well as homogeneity of drug distribution in the formulation matrix, has been examined with the same method, proving the efficiency of the approach. Confocal Raman spectroscopy offers a new approach for the analytical assessment of solid dispersions both covering the physical state as well as the distribution of the drug via its spatial resolution. Moreover, it is a promising tool for observing changes in a formulation due to physicochemical processes, e.g. recrystallisation and at the same time for locating the area where changes occur. Therefore, it may contribute to standard analytical methods to evaluate content and homogeneity.
Article
This study examined the effects of polymeric components on the physical state of chlorhexidine within bioadhesive, semisolid formulations using Raman spectroscopy. Semisolid formulations were prepared in which chlorhexidine base (CHX, 5%w/w, particle size <63 microm) was dispersed in aqueous (phosphate-buffered saline, pH 6.8) polymer matrices consisting of one or more polymeric components, namely HEC (3%w/w), PVP (3%), and PC (PC, 3%). Raman spectra were recorded using 785-nm excitation and were typically accumulated for 360 s. The Raman spectra were dominated by the presence of CHX. The spectra of CHX in HEC and in HEC/PVP gels were indistinguishable from that for solid CHX as a result of the insolubility of CHX in these formulations. However, in systems containing PC and CHX, there was a shift in the strongest band from 1564 cm(-1) to 1608 cm(-1), which may be accredited to protonation of the basic CHX by the numerous carboxylic acidic groups on PC. Identical shifts in the band positions were observed when this protonation was modeled using ethanoic acid, supporting the view that there was a simple acid base reaction between PC and CHX. However, there were notable differences in the relative intensities of the peaks from these samples, with the spectrum of CHX in the PC matrix displaying properties intermediate between those of CHX dissolved in ethanoic acid and solid CHX diacetate. This may be accredited to the limited solubility of the CHX-PC ion pair. In matrices containing HEC and PC, no peak was observed at 1564 cm(-1), whereas the intensity of the peak at 1608 cm(-1) was increased. Therefore, in these formulations CHX was completely converted to the di-cation as a result of the synergistic effects of PC (which protonated CHX) and HEC (which solubilized the di-cation). In the absence of either HEC or PC, complete protonation was not achieved. It is suggested that this enhancement of solubility of H(2)CHX(2+) may be due to hydrogen bonding, given the hydroxylated nature of HEC. In conclusion, this study has shown the applicability of Raman spectroscopy for both the analysis of opaque, semisolid formulations and, additionally, for the examination of the state of therapeutic agents within such matrices. In particular, using Raman spectroscopy, it was uniquely possible to identify the roles of various polymeric components on both the ionization and solubilization of CHX within aqueous semisolid systems.
Article
The physical characterization of pharmaceutical solids is an integral aspect of the drug development process. This review summarizes the use of solid-state spectroscopy techniques used in the physical characterization of the active pharmaceutical ingredient, excipients, physical mixtures, and the final dosage form. A brief introduction to infrared, Raman, and solid-state NMR experimental techniques are described as well as a more thorough description of qualitative and quantitative applications. The use of solid-state imaging techniques such as IR, Raman, and TOF-SIMS is also introduced to the reader.
Article
A procedure for quantitative determination of acetylsalicylic acid and acetaminophen in pharmaceuticals by PLS (partial least squares) and PCR (principal component regression) treatment of FT (Fourier transform)-Raman spectroscopic data is proposed. The proposed method was tested on powdered samples. Three chemometric models were built: the first, for samples consisting of an active substance diluted by lactose, starch and talc; the second, in which a simple inorganic salt was applied as an internal standard and additions were not taken into account; and the third, in which a model was constructed for a commercial pharmaceutical, where all constituents of the tablet were known. By utilising selected spectral ranges and by changing the chemometric conditions it is possible to carry out fast and precise analysis of the active component content in medicines on the basis of the simplified chemometric models. The proposed method was tested on five commercial tablets. The results were compared with data obtained by intensity ratio and pharmacopoeial methods. To appraise the quality of the models, the relative standard error of predictions (RSEPs) were calculated for calibration and prediction data sets. These were 0.7-2.0% and 0.8-2.3%, respectively, for the different PLS models. Application of these models to the Raman spectra of commercial tablets containing acetylsalicylic acid gave RSEP values of 1.3-2.0% and a mean accuracy of 1.2-1.7% with a standard deviation of 0.6-1.2%.
Article
Eighty-five solid samples consisting of illegal narcotics diluted with several different materials were analyzed by near-infrared (785 nm excitation) Raman spectroscopy. Principal Component Analysis (PCA) was employed to classify the samples according to narcotic type. The best sample discrimination was obtained by using the first derivative of the Raman spectra. Furthermore, restricting the spectral variables for PCA to 2 or 3% of the original spectral data according to the most intense peaks in the Raman spectrum of the pure narcotic resulted in a rapid discrimination method for classifying samples according to narcotic type. This method allows for the easy discrimination between cocaine, heroin, and MDMA mixtures even when the Raman spectra are complex or very similar. This approach of restricting the spectral variables also decreases the computational time by a factor of 30 (compared to the complete spectrum), making the methodology attractive for rapid automatic classification and identification of suspect materials.
Article
Mannitol is a polymorphic excipient which is usually used in pharmaceutical products as the beta form, although other polymorphs (alpha and delta) are common contaminants. Binary mixtures containing beta and delta mannitol were prepared to quantify the concentration of the beta form using FT-Raman spectroscopy. Spectral regions characteristic of each form were selected and peak intensity ratios of beta peaks to delta peaks were calculated. Using these ratios, a correlation curve was established which was then validated by analysing further samples of known composition. The results indicate that levels down to 2% beta could be quantified using this novel, non-destructive approach. Potential errors associated with quantitative studies using FT-Raman spectroscopy were also researched. The principal source of variability arose from inhomogeneities on mixing of the samples; a significant reduction of these errors was observed by reducing and controlling the particle size range. The results show that FT-Raman spectroscopy can be used to rapidly and accurately quantitate polymorphic mixtures.
Article
FT-IR and Raman spectroscopic methods are suggested for identification of orthorhombic (form II) and monoclinic (form I) paracetamol and for their quantitative determination in mixes. The intensity ratio of the 836 cm(-1) FT-IR band (attributed to the presence of both forms) to the 806 cm(-1) monoclinic band plotted against the inverse monoclinic molar fraction (X) yields a straight line: I(836)/I(806)=0.515/X+0.700, r=0.9965 for eight calibration points on the regression line. Similarly, the area under the 454 cm(-1) band in FT-Raman spectra (which is attributed to both forms) over the area under the 465 cm(-1) band of monoclinic form is inversely related to its molar fraction (X): A(454)/A(465)=0.482/X-0.324, r=0.9954 for eight calibration points. Precision (RSD%) was <5% for both methods. Linear regression analysis between content and intensity of characteristic XRD reflections for four different samples gave r=0.9964 at 4.62 A and r=0.9894 at 3.70 A, for form II. For the content of form I, r=0.9596 at 3.37 A. The limit of detection for monoclinic form was estimated to be 0.012 mole fraction for both methods.
Article
This study was performed to develop a fast and reliable analytical method for the quantitative determination of diltiazem hydrochloride in tablets. HPLC is currently the preferred method, but is time consuming due to extensive sample preparation. FT-Raman spectroscopy was used to quantitatively analyse diltiazem hydrochloride in commercially available tablets (Tildiem) and in experimental tablets prepared at lab-scale. The percentage of diltiazem hydrochloride in each tablet was determined by calculating-after vector normalisation-the total peak area of the spectral band between 1625 and 1560 cm(-1). No spectral interference from tablet excipients was seen at this spectral band. After FT-Raman spectroscopy the same samples were analyzed based on the HPLC method described in the USP XXIV. The drug dosage per tablet obtained from the vibrational spectroscopy method correlated well with the results obtained using HPLC analysis for both the commercial tablets (HPLC: 63.57+/-0.13 mg; Raman: 63.28+/-0.26 mg (n=50)) and the experimental tablets (HPLC: 181.02+/-0.25 mg; Raman: 181.22+/-0.35 mg (n=50)). FT-Raman is a reliable alternative for the HPLC method to quantify the amount of diltiazem hydrochloride in tablets. The spectroscopic method is faster because it eliminates sample pre-treatment. Furthermore the FT-Raman method has an additional advantage of not requiring solvents.
Article
Ranitidine hydrochloride exists as two polymorphs, forms I and II, both of which are used to manufacture commercial tablets. Raman spectroscopy can be used to differentiate the two forms but univariate methods of quantitative analysis of one polymorph as an impurity in the other lack sensitivity. We have applied principal components analysis (PCA) of Raman spectra to binary mixtures of the two polymorphs and to binary mixtures prepared by adding one polymorph to powdered tablets of the other. Based on absorption measurements of seven spectral regions, it was found that >97% of the spectral variation was accounted for by three principal components. Quantitative calibration models generated by multiple linear regression predicted a detection limit and quantitation limit for either forms I or II in mixtures of the two of 0.6 and 1.8%, respectively. This study demonstrates that PCA of Raman spectroscopic data provides a sensitive method for the quantitative analysis of polymorphic impurities of drugs in commercial tablets with a quantitation limit of less than 2%.
Article
Three different Raman microspectroscopic imaging methodologies using a single experimental configuration are compared; namely, point and line mapping, as representatives of serial imaging approaches, and direct or wide-field Raman imaging employing liquid-crystalline tunable filters are surveyed. Raman imaging data acquired with equivalent low-power 514.5-nm laser excitation and a cooled CCD camera are analyzed with respect to acquisition times, image quality, spatial resolution, intensity profiles along spatial coordinates, and spectral signal-to-noise ratios (SNRs). Point and line mapping techniques provide similar SNRs and reconstructed Raman images at spatial resolutions of approximately 1.1 microm. In contrast, higher spatial resolution is obtained by direct, global imaging (approximately 313 nm), allowing subtle morphological features on test samples to be resolved.
Article
Fourier transform (FT) Raman spectroscopy based on band intensity or band area measurements was used for the quantitative determination of acyclovir in pharmaceutical solid dosage forms through their poly(vinyl chloride) blister package. Univariate calibration using the bands observed at 1690, 1630, 1574, 1482, 1181, 578, and 508 cm(-1) was found to be sufficient for the analysis. Calibration curves were linear, the correlation coefficients being 0.997-0.9993 and 0.996-0.9991 for band intensity and band area measurements, respectively. Results obtained compare well, as indicated by the t-test, with those obtained by the current United States Pharmacopoeia (USP 24) and National Formulary (NF 19) method. Precision ranged from 0.7-4.5 and 0.4-4.0% RSD (n = 3) for band intensity and band area measurements, respectively. The developed nondestructive FT-Raman method is rapid, simple, and can be used for the on-line, real-time monitoring of acyclovir formulation production lines.
Article
Here we report the results of the largest study yet carried out on composition profiling of seized "ecstasy" tablets by Raman spectroscopy. Approximately 1500 tablets from different seizures in N. Ireland were analysed and even though practically all the tablets contained MDMA as active constituent, there were very significant differences in their Raman spectra, which were due to variations in both the nature and concentration of the excipients used and/or the degree of hydration of the MDMA. The ratios of the peak heights of the prominent drug bands at 810 cm(-1) and 716 cm(-1) (which vary with hydration state of the drug), and the drug band at 810 cm(-1) against the largest clearly discernible excipient band in the spectrum were measured for all the samples. It was found that there was sufficient variation in composition in the general sample population to make any matches between batches of tablets taken from different seizures significant, rather than the result of random chance. Despite the large number of different batches of tablets examined in this study, only two examples of indistinguishable sets of tablets were found and in only one of these had the two batches of tablets been seized at different times. Finally, the fact that there are many examples of batches of tablets (particularly in different batches taken from single seizures) in which the differences between each set are sufficiently small that they appear to arise only from random variations within a standard manufacturing method implies that, with more extensive data, it may be possible to recognize the "signature" of tablets prepared by major manufacturers.
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