Estimation of the transition temperature for an enantiotropic polymorphic system from the transformation kinetics monitored using Raman spectroscopy

Polymorphism is a frequently encountered phenomenon in organic materials and is particularly important for pharmaceuticals. For enantiotropically related polymorphs, one important property of the polymorphic pair is the thermodynamic transition temperature. The transition temperature is sometimes difficult to determine experimentally due to the rapid transformation between the two polymorphic forms in solution. Due to its relatively rapid spectral acquisition rate, as well as the possibility of in-line monitoring, Raman spectroscopy is ideally suited to monitoring the kinetics of transformation between different solid-state forms. In this study, it was demonstrated that the transition temperature could be estimated from polymorphic transformation profiles obtained from real-time in situ Raman data. Using this method, the estimated transition temperature for flufenamic acid was in good agreement with the previously published value. These results suggest that Raman spectroscopy may be a useful method to determine transition temperatures in systems not amenable to other methods.     

Detection of Lipitor counterfeits: a comparison of NIR and Raman spectroscopy in combination with chemometrics

Research has been carried on the feasibility of near infrared (NIR) and Raman spectroscopy as rapid screening methods to discriminate between genuine and counterfeits of the cholesterol-lowering medicine Lipitor. Classification, based on partial least squares discriminant analysis (PLS-DA) models, appears to be successful for both spectroscopic techniques, irrespective of whether atorvastatine or lovastatine has been used as the active pharmaceutical ingredient (API). The discriminative power of the NIR model, in particular, largely relies on the spectral differences of the tablet matrix. This is due to the relative large sample volume that is probed with NIR and the strong spectroscopic activity of the excipients. PLS-DA models based on NIR or Raman spectra can also be applied to distinguish between atorvastatine and lovastatine as the API used in the counterfeits tested in this study. A disadvantage of Raman microscopy for this type of analysis is that it is primarily a surface technique. As a consequence spectra of the coating and the tablet core might differ. Besides, spectra may change with the position of the laser in case the sample is inhomogeneous. However, the robustness of the PLS-DA models turned out to be sufficiently large to allow a reliable discrimination. Principal component analysis (PCA) of the spectra revealed that the conditions, at which tablets have been stored, affect the NIR data. This effect is attributed to the adsorption of water from the atmosphere after unpacking from the blister. It implies that storage conditions should be taken into account when the NIR technique is used for discriminating purposes. However, in this study both models based on NIR spectra and Raman data enabled reliable discrimination between genuine and counterfeited Lipitor tablets, regardless of their storage conditions.     

Characterization of melt extruded and conventional Isoptin formulations using Raman chemical imaging and chemometrics

Isoptin SR-E (Meltrex(?)) extruded tablets were assumed in a recent paper to be prepared with a composition different from a conventional (Isoptin SR) formulation. This study reveals, however, using Raman mapping and chemometric evaluation, that in fact the same composition, comprising Na alginate as polymer matrix, is used in both products. It means that only the difference in the manufacturing technology causes the reported sustained release of verapamil hydrochloride even in ethanol containing dissolution media. The products are compared based on the obtained Raman chemical images, which allowed concluding in a new structure-based explanation for the differences in the dissolution profiles in the presence of ethanol. It is also shown that extrusion technology influences the dissolution profile effectively, even in the cases when solid solution is formed only partially.     

The detection of flunitrazepam in beverages using portable Raman spectroscopy

Portable Raman spectroscopy has been used for the detection of the date‐rape drug flunitrazepam in spiked beverages that may be involved in cases of drug‐facilitated sexual assault. Solutions of flunitrazepam with different concentrations were prepared in water and for each beverage type. Although some bands attributable to the beverage matrix are present, they did not interfere with the identification of the drug. Definitive evidence for contamination of the spiked drink concerned can be acquired within 10 s. The data can be acquired in situ and sample extraction and/or preparation steps are unnecessary. The ability of portable Raman spectrometers to interrogate spiked alcoholic beverages with flunitrazepam has been demonstrated. Copyright © 2016 John Wiley & Sons, Ltd.     

Analysis of lecithin-cholesterol mixtures using Raman spectroscopy

FT-Raman spectroscopy has been used to investigate interactions between lecithin and cholesterol. Raman spectra of lecithin show multiple peaks which can be classified into three regions: hydrophobic chain, interfacial, and headgroup regions. Binary lipid mixtures (1:1, w/w, lecithin:cholesterol) were prepared by physical mixing, granulation, coprecipitation, hydration and heating (65 degrees C), and heating (120 degrees C). Regardless of the preparation method, no changes in the spectra were observed in the hydrophobic region. A shift in the wavenumber of the choline methyl asymmetric stretching mode was observed when the samples were prepared by coprecipitation, hydration and heating (65 degrees C), and heating (120 degrees C). This may indicate a modification of phospholipids in the headgroup region in these samples. The difference in degrees of frequency shift (physical mixing approximately granulation相似文献   

Measurement of lactose crystallinity using Raman spectroscopy

Raman spectroscopy (RS) was used to determine the crystallinity of lactose (a commonly used carrier in dry powder inhaler (DPI) formulations). Samples of alpha-lactose monohydrate and amorphous lactose were prepared using ethanol precipitation and lyophilisation respectively. The anomeric forms were confirmed using DSC at a rate of 10 degrees C/min and heated to 250 degrees C. The Raman spectra of both alpha-lactose monohydrate and amorphous lactose were obtained. Distinguishable differences were seen between the two spectra including peak areas and intensities. Depolarisation ratios (rho) of each form were then determined to identify the crystallinity of the lactose carrier samples. At the prominent Raman bands 865 and 1082 cm-1, significant differences in rho values were observed for crystalline (0.80+/-0.07, 0.89+/-0.06 respectively) and amorphous samples (0.44+/-0.07, 0.51+/-0.10).     

Discrimination of legal and illegal Cannabis spp. according to European legislation using near infrared spectroscopy and chemometrics

Aerial parts containing cannabidiol can be purchased in a legal way but cannabis used as recreational drug is illegal in most European countries. Δ9‐tetrahydrocannabinol is one of the main cannabinoids responsible for the psychotropic effect. European Union countries and Switzerland authorize a concentration of THC of 0.2 % and 1.0 % w/w, respectively, for smoking products and industrial hemp. Public health inspectors and law enforcement officers need to check the legality of samples. Therefore there is a need for innovative approaches, allowing quality control of these products in an easy way and preferably on site. In many countries, cultivation of industrial hemp is permitted if the THC content does not exceed 0.2 % w/w. A portable equipment could be a useful measuring tool for farmers to check for the THC content at regular time. In this work, 189 samples were analysed with a benchtop and a handheld NIR device in order to create two classification methods according to European and Swiss laws. All samples were also analysed by GC‐FID to determine their THC concentration. Supervised analysis was applied in order to establish the best model. For the first classification, the accuracy was 91% for the test set with the benchtop data and 93 % for the test set with the handheld data. For the second classification, the accuracies were respectively 91 % and 95 %. The obtained models, hyphenating spectroscopic techniques and chemometrics, enable to discriminate legal and illegal cannabis samples according to European and Swiss laws.     

In-line reaction monitoring of entacapone synthesis by Raman spectroscopy and multivariate analysis

In-line Raman spectroscopy and multivariate analysis were used to monitor Knoevenagel condensation reaction, the final step in preparation of drug entacapone. By applying a fiber optical Raman probe immersed into a reaction vessel Raman spectra of the reaction mixture were recorded in situ during the entacapone synthesis in toluene, heptane and isobutyl acetate. Due to the complexity of the measured spectra, the obtained data were analyzed and interpreted by means of principal component analysis. It has been shown that progress of this reaction can be monitored in real-time and reaction end points can be determined in different solvents. The reaction was found to be the fastest in heptane due to the lower loss of the catalyst. For a comparison the reaction was independently monitored by off-line Raman spectroscopy and liquid chromatography which confirmed the results obtained in-line. The results presented here have shown that this in-line approach can be used as a fast, non destructive and reliable method to monitor the Knoevenagel reaction in real time. The knowledge gained in this study can further be exploited for the industrial process control.     

Assessment and prediction of tablet properties using transmission and backscattering Raman spectroscopy and transmission NIR spectroscopy

This study investigated whether Raman and Near Infrared (NIR) spectroscopy could predict tablet properties. Granules were produced on a continuous line by varying granulation parameters. Tableting process parameters were adjusted to obtain uniform tablet weight and thickness. Spectra were collected offline and tablet properties determined with traditional analyzing methods. Partial Least Squares (PLS) regression was used to correlate spectral information to tablet properties, but predictive models couldn't be established. Principal component analysis (PCA) was effectively used to distinguish theophylline concentrations and hydration levels and multiple linear regression (MLR) analysis allowed insight on how granulation parameters affect granule and tablet properties.     

Direct assay and shelf-life monitoring of aspirin tablets using Raman spectroscopy

A comparison was made between Raman and high-performance liquid chromatography (HPLC) analysis of aspirin tablets. The basis was an assay of aspirin content and the determination of salicylic acid produced by decomposition. Raman observations were performed directly on both intact and powdered tablet material. The limit of detection of HPLC with an ultraviolet detector is lower than that of the Raman measurement, but both are adequate for this application. The reproducibility of the Raman measurement is somewhat better than that of the HPLC measurement. Both methods were used in a degradation study in which samples were stored in a humid atmosphere for a maximum period of 8 weeks. Aside from somewhat higher salicylic acid responses from the HPLC method, which were attributed to hydrolysis during chromatography, results from the two methods were comparable. Direct Raman measurements are faster and do not require the use of solvents.     

Off-line and on-line measurements of drug-loaded hot-melt extruded films using Raman spectroscopy

The objective of this study was to investigate the use of Raman spectroscopy for the quantitative and qualitative analysis of an active ingredient in hot-melt extruded film formulations. Clotrimazole and ketoprofen were used as the active pharmaceutical ingredients (APIs) in the subject formulations. Films were prepared with contents varying from 1 to 20% of the respective API. Raman spectroscopy was used to quantify these APIs, both off-line and on-line. The spectral data were also used to ascertain the physical status of these APIs in the formulations. For off-line analysis, the films were cut into small rectangles, and the amount of the API was measured using a fiber optic probe equipped with a non-contact optic (NCO). For on-line analysis, real-time measurements were accomplished by fixing the probe over the extruded film for continuous data collection. Raman spectroscopy can be a convenient alternative to HPLC and other techniques currently employed for the quantification of the API in these formulations. Because Raman is also sensitive to changes in crystallinity, employment of the technique provided additional information to deduce the crystalline status of the API. The results reported in this paper suggest the suitability of Raman for PAT applications because of the on-line capability.     

Determination of the crushing strength of intact tablets using Raman spectroscopy

In the present study, the Raman spectroscopy technique was used as a non-invasive, rapid analytical method for measuring the crushing strength of tablets. The compressed tablets were individually detected, using Raman spectroscopy, and the respective crushing strength values were measured, using a tablet hardness tester as a reference method. The tablets were compressed from a granule mass containing theophylline anhydrate as an active substance. For measuring the crushing strength of the tablets, Raman spectra were recorded from the tablets. Partial least squares (PLS) regression models were constructed to obtain information from the spectra. The correlation between measured and predicted crushing strength values for the tablets was shown to be very favorable. With Raman spectroscopy, shifting of the baseline was observed as the crushing strengths of tablets (and the smoothness of the tablet surface) were increased. Consequently, correlation between the crushing strength data on the present tablets and Raman spectra was observed. Multiple scanning electron (SEM) and non-contact laser profilometry (LP) micrographs from the surfaces of the tablets were taken to describe the surfaces and applied as supportive information for the proposed spectroscopy approach. In conclusion, Raman spectroscopy is a promising alternative for established off-line/at-line tablet-testing methods for some tablet formulations.     

In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy

Process-induced transformations are very important to control during pharmaceutical manufacturing because they may change the properties of the active pharmaceutical ingredient in the drug product, compromising therapeutic efficacy. One process that may facilitate a process-induced transformation is high-shear wet granulation. In this study, the feasibility of Raman spectroscopy for in-line monitoring of the transformation of theophylline anhydrous to theophylline monohydrate during high-shear wet granulation has been evaluated. The midpoint of conversion occurred 3 min after the binder solution was added. The effects of several processing parameters were also examined, including mixing speed and monohydrate seeding. Mixing speed had the greatest effect on the transformation, where an increase in mixing speed shortened the onset time and increased the rate of transformation. In contrast, seeding with monohydrate or changing the way in which the binder was incorporated into the granules did not affect the transformation profile. The transformation kinetics observed during wet granulation were compared with those generated by a simple model describing the solvent-mediated transformation of theophylline in solution. In conclusion, these studies show that Raman spectroscopy can be used for in-line monitoring of solid-state transformations during wet granulation. In addition, for this particular compound, a simple solvent-mediated transformation model has been shown to be useful for estimating the time scale for hydrate formation during high-shear wet granulation.     

A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies

Near-infrared spectroscopy (NIRS) is a fast and non-destructive analytical method. Associated with chemometrics, it becomes a powerful tool for the pharmaceutical industry. Indeed, NIRS is suitable for analysis of solid, liquid and biotechnological pharmaceutical forms. Moreover, NIRS can be implemented during pharmaceutical development, in production for process monitoring or in quality control laboratories.This review focuses on chemometric techniques and pharmaceutical NIRS applications. The following topics are covered: qualitative analyses, quantitative methods and on-line applications. Theoretical and practical aspects are described with pharmaceutical examples of NIRS applications.     

Monitoring of mannitol phase behavior during freeze-drying using non-invasive Raman spectroscopy

In this study, the feasibility of using Raman spectroscopy as a fast, non-invasive, non-destructive technique to monitor crystallization and polymorphic transformations during freeze-drying is assessed using mannitol as the model compound. In-line process monitoring was achieved by interfacing a Raman spectrometer with a fiber-optically coupled, long-working-distance probe to a freeze-drier. By analyzing the process data using principal component analysis, it was possible to extract valuable information pertaining to ice and mannitol crystallization points, the polymorphic form of mannitol, and dehydration of the mannitol hydrate. In conclusion, Raman spectroscopy is a potentially useful technique to monitor physical changes during freeze-drying.     

琥珀酸美托洛尔的合成工艺改进

目的 优化琥珀酸美托洛尔的合成路线.方法 以4-(2-甲氧基乙基)苯酚和环氧氯丙烷为原料在相转移催化剂四丁基溴化铵催化下,先得到1-(2,3-环氧丙氧基)-4-(2-甲氧基乙基)-苯;再与异丙胺在催化剂AlCl3的作用下反应,得到美托洛尔;最后将美托洛尔与琥珀酸的饱和乙醇溶液反应即得琥珀酸美托洛尔.结果 目标化合物琥珀酸美托洛尔的结构经核磁共振氢谱(1 H-NMR)和电喷雾质谱法(ESI-MS)确证,高效液相色谱法测定纯度为99.01%,总收率为51.8%.结论 本实验工艺简单,反应时间短,收率较高,产品纯度好,而且在较大程度上降低了环境污染,绿色环保.     

Raman spectroscopy of protein pharmaceuticals

Recent advances in optical and spectroscopic technologies have enabled a plethora of Raman spectrometers that are suitable for studies of protein pharmaceuticals. Highly sensitive Raman spectrometers have overcome the handicap of the fundamentally weak Raman effect that hampered their applications to protein pharmaceuticals in the past. These Raman spectrometers can now routinely measure protein therapeutics at the low concentration of 1 mg/mL, which is on par with other spectroscopic methods such as CD, fluorescence and FTIR spectroscopies. In this article, various Raman techniques that can be used for protein pharmaceutical studies are reviewed. Novel Raman marker of proteins discovered from fundamental studies of protein complexes are examined along with established Raman spectra and structure correlations. Examples of Raman spectroscopic studies of protein pharmaceuticals are demonstrated. Future applications of Raman spectroscopy to protein pharmaceuticals are discussed.     

Diagnostic applications of Raman spectroscopy

Raman spectroscopy has been widely used in various fields of science. It has been successfully utilized to qualitatively and quantitatively determine the molecular compositions of solid, liquid, and gaseous samples. This review focuses on the diagnostic applications of Raman spectroscopy in the past 5 years, with specific emphasis on transplant allograft rejection and cancer detections. First we introduce the principle of Raman spectroscopy and associated surface enhancement techniques. Various recent biomedical and clinical applications of Raman spectroscopy are then reviewed in detail. Finally, we present the experimental and analytical techniques required to implement Raman spectroscopy in a laboratory. FROM THE CLINICAL EDITOR: This review focuses on evolving diagnostic applications of Raman spectroscopy with special emphasis on transplant allograft rejection and cancer detection.     

Real‐time monitoring of tritium gas reactions using Raman spectroscopy

The utility of Raman spectroscopy for noninvasive, real‐time monitoring of a range of tritium gas labeling reactions has been investigated, using deuterium gas as a model in most cases. Reaction types include organoiridium‐catalyzed heteroatom‐directed exchange (HDE), olefin hydrogenation and catalytic aryl dehalogenation. Five examples of HDE reactions with several different substrate types were monitored by observation of Raman vibrational bands sensitive to the isotopic substitutions. Changes in peak intensities and/or frequencies associated with the course of labeling are clearly observable at concentrations and reaction scales typical of tritium gas reactions. Similarly, Raman bands sensitive to the chemical changes that occur during catalytic deuterogenation of an olefin and to catalytic deuterium–bromine exchange of an aryl bromide were successfully monitored. This methodology can provide unprecedented real‐time information, otherwise difficult to obtain, over the course of such reactions. Copyright © 2004 John Wiley & Sons, Ltd.     

Determination of hydrate transition temperature using transformation kinetics obtained by Raman spectroscopy

The thermodynamic transition temperature is a key parameter to ascertain when assessing the properties of a crystalline hydrate. The transition temperature is sometimes difficult to determine experimentally due to rapid transformation between the two crystal forms in solution. In this study, a new approach for determining the transition temperature is presented, utilizing the temperature dependence of the transformation kinetics in aqueous slurries, as determined using in-line Raman spectroscopy. The transition temperatures of several hydrate forming compounds, namely theophylline, carbamazepine and caffeine, are presented. In general, good correlations with literature values were found. This method was found to be a simple, fast and reliable approach for the determination of crystal hydrate transition temperatures in aqueous environments.