Prediction of drug dissolution profiles from tablets using NIR diffuse reflectance spectroscopy: a rapid and nondestructive method

A comparison between dissolution profiles obtained by using a dissolution apparatus (conventional method) and the NIR diffuse reflectance spectra of a series of clonazepam-containing batches is reported. Ten different formulations with fixed amount of clonazepam and varying proportions of excipients were analyzed at seven dissolution times and three different media. The percentages of dissolution of each sample were correlated with the NIR spectra of three tablets of each batch, through a multivariate analysis using the PLS regression algorithm. The squared correlation coefficients for the plots of percentages of dissolution from the equipment laboratory (dissolution apparatus and HPLC determination) versus the predicted values, in the leave-one-out cross-validation, varied from 0.80 to 0.92, indicating that the NIR diffuse reflectance spectroscopy method is an alternative, nondestructive tool for measurement of drug dissolution from tablets.     

Prediction of tablets disintegration times using near-infrared diffuse reflectance spectroscopy as a nondestructive method

The goals of this study are to user near-infrared reflectance (NIR) spectroscopy to measure the disintegration time of a series of tablets compacted at different compressional forces, calibrate NIR data vs. laboratory equipment data, develop a model equation, validate the model, and test the model's predictive ability. Seven theophylline tablet formulations of the same composition but with different disintegration time values (0.224, 1.141, 2.797, 5.492, 9.397, 16.8, and 30.092 min) were prepared along with five placebo tablet formulations with different disintegration times. Laboratory disintegration time was compared to near-infrared diffuse reflectance data. Linear regression, quadratic, cubic, and partial least square techniques were used to determine the relationship between disintegration time and near-infrared spectra. The results demonstrated that an increase in disintegration time produced an increase in near-infrared absorbance. Series of model equations, which depended on the mathematical technique used for regression, were developed from the calibration of disintegration time using laboratory equipment vs. the near-infrared diffuse reflectance for each formulation. The results of NIR disintegration time were similar to laboratory tests. The near-infrared diffuse reflectance spectroscopy method is an alternative nondestructive method for measurement of disintegration time of tablets.     

Prediction of tablet hardness and porosity using near-infrared diffuse reflectance spectroscopy as a nondestructive method

The main objective of this research is to use the near-infrared diffuse reflectance method to evaluate and quantify the effects of hardness and porosity on the near-infrared spectras of tablets. To develop a model equation, validate the model and test the model predictive ability. Seven theophylline tablet formulations of the same composition but with seven different hardness values (3, 6, 8, 10, 12, 15, and 17 kp) were prepared. Another seven theophylline tablets formulation with seven different porosity values (57.4, 50.3, 41.9, 40.3, 39.9, 37.3, and 35.1%) were prepared. Five placebo tablets formulation with different hardness and porosity values were also prepared. Laboratory hardness and porosity values were compared to near-infrared diffuse reflectance data. Linear regression, quadratic, cubic and partial least square techniques were used to determine the relationship between hardness, porosity and the near-infrared spectras. The results demonstrated that an increase in tablet hardness and a decrease in tablets porosity produced an increase in near-infrared absorbance. Series of model equations depending on the mathematical technique used for regression were developed from the calibration of hardness and porosity data using laboratory equipment vs. the near-infrared diffuse reflectance for each formulations. The results of near-infrared hardness and porosity predictions were very similar to laboratory hardness and porosity tests. The near-infrared diffuse reflectance spectroscopy method is an alternative nondestructive method for measurement of hardness and porosity of tablets.     

Prediction of Tablet Hardness and Porosity Using Near‐Infrared Diffuse Reflectance Spectroscopy as a Nondestructive Method

The main objective of this research is to use the near‐infrared diffuse reflectance method to evaluate and quantify the effects of hardness and porosity on the near‐infrared spectras of tablets. To develop a model equation, validate the model and test the model predictive ability. Seven theophylline tablet formulations of the same composition but with seven different hardness values (3 kp, 6, 8, 10, 12, 15, and 17 kp) were prepared. Another seven theophylline tablets formulation with seven different porosity values (57.4, 50.3, 41.9, 40.3, 39.9, 37.3, and 35.1%) were prepared. Five placebo tablets formulation with different hardness and porosity values were also prepared. Laboratory hardness and porosity values were compared to near‐infrared diffuse reflectance data. Linear regression, quadratic, cubic and partial least square techniques were used to determine the relationship between hardness, porosity and the near‐infrared spectras. The results demonstrated that an increase in tablet hardness and a decrease in tablets porosity produced an increase in near‐infrared absorbance. Series of model equations depending on the mathematical technique used for regression were developed from the calibration of hardness and porosity data using laboratory equipment vs. the near‐infrared diffuse reflectance for each formulations. The results of near‐infrared hardness and porosity predictions were very similar to laboratory hardness and porosity tests. The near‐infrared diffuse reflectance spectroscopy method is an alternative nondestructive method for measurement of hardness and porosity of tablets.     

Use of Near-Infrared for Quantitative Measurement of Viscosity and Concentration of Active Ingredient in Pharmaceutical Gel

Near infrared (NIR) spectroscopy is gaining worldwide interest as an analytical tool for quality control of raw materials, intermediate products, and final dosage forms. This technique can be used without sample preparation, therefore, avoiding the need for reagents and solvents. Quantitative NIR analyses involve calibration by sophisticated mathematical techniques that have been used extensively since the advent of microcomputing and chemometrics. The main objective of this investigation was to use transmission near-Infrared spectroscopy to measure the potency of an active ingredient in a topical gel preparation. A second objective was to evaluate the effect of gel viscosity on the NIR reflectance spectra. Four gel formulations with different ibuprofen concentrations were used for quantitative determination of the active ingredient, and five gel formulations with different viscosity values were used for the evaluation of the effect of viscosity change on the near-infrared reflectance spectra. The laboratory ibuprofen quantitative determination was compared to near-infrared transmission data using linear, quadratic, cubic and partial least square techniques to determine the relationship between ultraviolet (UV) determination and near-infrared spectra. For viscosity, the laboratory data were compared to near-infrared diffuse reflectance data using the same techniques used to determine the relationship between Brookfield viscometer determination and near-infrared spectra. The results demonstrated that an increase in ibuprofen concentration and viscosity produced an increase in near–infrared absorbance. Series of model equations were developed from the calibration of laboratory vs. the near-infrared data for each formulation. The near-infrared spectroscopy method is an alternative method that does not require sample pretreatment for quantitative measurement of active ingredient and viscosity of pharmaceutical gel.     

Use of near-infrared for quantitative measurement of viscosity and concentration of active ingredient in pharmaceutical gel

Near infrared (NIR) spectroscopy is gaining worldwide interest as an analytical tool for quality control of raw materials, intermediate products, and final dosage forms. This technique can be used without sample preparation, therefore, avoiding the need for reagents and solvents. Quantitative NIR analyses involve calibration by sophisticated mathematical techniques that have been used extensively since the advent of microcomputing and chemometrics. The main objective of this investigation was to use transmission near-Infrared spectroscopy to measure the potency of an active ingredient in a topical gel preparation. A second objective was to evaluate the effect of gel viscosity on the NIR reflectance spectra. Four gel formulations with different ibuprofen concentrations were used for quantitative determination of the active ingredient, and five gel formulations with different viscosity values were used for the evaluation of the effect of viscosity change on the near-infrared reflectance spectra. The laboratory ibuprofen quantitative determination was compared to near-infrared transmission data using linear, quadratic, cubic and partial least square techniques to determine the relationship between ultraviolet (UV) determination and near-infrared spectra. For viscosity, the laboratory data were compared to near-infrared diffuse reflectance data using the same techniques used to determine the relationship between Brookfield viscometer determination and near-infrared spectra. The results demonstrated that an increase in ibuprofen concentration and viscosity produced an increase in near-infrared absorbance. Series of model equations were developed from the calibration of laboratory vs. the near-infrared data for each formulation. The near-infrared spectroscopy method is an alternative method that does not require sample pretreatment for quantitative measurement of active ingredient and viscosity of pharmaceutical gel.     

Moisture assay of an antifungal by near-infrared diffuse reflectance spectroscopy

Near-infrared (NIR) diffuse reflectance spectroscopy was employed in the method development and validation of a moisture assay for the novel antifungal caspofungin acetate. Spectra were obtained over the entire spectral region available (950-1650 nm) using an InGaAs photodiode array detector equipped with a diffuse reflectance probe. No sample pre-treatment was required and the analysis time was less than 1 min. Primary reference data were obtained using a Karl Fischer (KF) titration (coulometric, volumetric or both). The investigated range of water content was 2.6-9.9% (w/w) with a standard error of prediction (SEP) of 0.2%. The predictive capabilities of the partial least-squares (PLS) regression calibration model used in the moisture assay were verified using independent test sets. The NIR predicted values of the developed method were equivalent to the reference method sets and the prediction error was equivalent to the reference method error. These results reveal that the predictive model constructed by means of a PLS regression is valid, rugged and could be used to determine moisture levels on-line in caspofungin acetate drug substance.     

Prediction of Dissolution Profiles From Process Parameters,Formulation, and Spectroscopic Measurements

This study utilized multiple modeling approaches to predict immediate release tablet dissolution profiles of 2 model drugs: theophylline and carbamazepine. Two sets of designs of experiments were applied based on individual drug characteristics to build in adequate dissolution variability. The tablets were scanned using a near-infrared (NIR) spectrometer and then subjected to in vitro dissolution test at critical time points. Because of the inherent difference in dissolution profiles, a hierarchical modeling approach was applied for theophylline data, whereas global models were constructed from carbamazepine data. The partial least squares models were trained using 3 predictor sets including (1) formulation, material, and process variables, (2) NIR spectra, and (3) a combination of both. The dependent variables of the models were the dissolution profiles, which were presented either as parameters of Weibull fitting curves or raw data. The comparison among the predictive models revealed that the incorporation of NIR spectral information in calibration reduced prediction error in the carbamazepine case but undermined the performance of theophylline models. It suggests that the modeling strategy for dissolution prediction of pharmaceutical tablets should not be universal but on a case-by-case basis.     

近红外光谱快速检测痰咳净散中咖啡因的含量

目的:研究光纤近红外漫反射光谱快速检测痰咳净散中咖啡因的方法。方法:按照处方自制了34批痰咳净散实验室样品,收集了31批痰咳净散工业化生产样品。以高效液相色谱法的分析值作为参考,运用偏最小二乘法建立近红外光谱与咖啡因参考含量的校正模型;进一步用马氏距离法建立定性模型鉴别不同阴性样品和不同厂家的样品。结果:定量模型校正集的R2为0.975,RMSECV为0.239%(w/w);预测集样品的R2为0.926,RMSEP为0.128%(w/w),平均(最大)相对误差为1.0%(3.2%);t-检验结果表明,近红外光谱预测的咖啡因含量与参考含量无显著性差异;还能正确鉴别痰咳净散和各种阴性样品,并能提示不同生产工艺的样品。结论:近红外光谱方法可用于痰咳净散中咖啡因的快速检测,同时为其生产过程的在线分析打下了坚实的基础。     

利用NIR技术建立异烟肼片一致性比对模型的研究

目的应用近红外漫反射技术建立异烟肼片一致性检验模型快检方法。方法收集异烟肼片的近红外漫反射光谱,运用OPUS软件建立一致性检验模型,采用三台仪器对模型进行交叉验证,并用其它厂家生产的异烟肼片进行验证。结果模型通过仪器交叉验证,也能区分出其它厂生产的异烟肼,利用该一致性检验模型能无损伤、快速、准确地判断异烟肼片的真伪。结论该方法建立的模型操作简单、快速有效,能作为异烟肼片真伪鉴别的快速筛选方法。     

Chemoinformetrical evaluation of dissolution property of indomethacin tablets by near-infrared spectroscopy

PURPOSE: The purpose of this study was to use near-infrared spectrometry (NIR) with chemoinformetrics to predict the change of dissolution properties in indomethacin (IMC) tablets during the manufacturing process. A comparative evaluation of the dissolution properties of the tablets was performed by the diffused reflectance (DRNIR) and transmittance (TNIR) NIR spectroscopic methods. METHODS: Various kinds of IMC tablets (200 mg) were obtained from a powder (20 mg of IMC, 18 mg of microcrystalline cellulose, 160 mg of lactose, and 2 mg of magnesium stearate) under various compression pressures (60-398 MPa). Dissolution tests were performed in phosphate buffer, and the time required for 75% dissolution (T75) and mean dissolution time (MDT) were calculated. DRNIR and TNIR spectra were recorded, and the both NIR spectra used to establish a calibration model for predicting the dissolution properties by principal component regression analysis (PCR). RESULTS: The T75 and MDT increased as the compression pressure increased, since tablet porosity decreased with increasing pressure. Intensity of the DRNIR spectra of the compressed tablets decreased as the compression pressure increased. However, the intensity of TNIR spectra increased along with the pressure. The calibration models used to evaluate the dissolution properties of tablets were established by using PCR based on both DRNIR and TNIR spectra of the tablets. The multiple correlation coefficients of the relationship between the actual and predictive T75 by the DRNIR and TNIR methods were 0.831 and 0.962, respectively. CONCLUSION: It is possible to predict the dissolution properties of pharmaceutical preparations using both DRNIR and TNIR chemoinformetric methods. The TNIR method was more accurate for predictions of the dissolution behavior of tablets than the DRNIR method.     

A comparison of reflectance and transmittance near-infrared spectroscopic techniques in determining drug content in intact tablets

Drug contents of intact tablets were determined using non-destructive near infrared (NIR) reflectance and transmittance spectroscopic techniques. Tablets were compressed from blends of Avicel PH-101 and 0.5% w/w magnesium stearate with varying concentrations of anhydrous theophylline (0, 1, 2, 5, 10, 20 and 40% w/w). Ten tablets from each drug content batch were randomly selected for spectral analysis. Both reflectance and transmittance NIR spectra were obtained from these intact tablets. Actual drug contents of the tablets were then ascertained using a UV-spectrophotometer at 268 nm. Multiple linear regression (MLR) models at 1116 nm and partial least squares (PLS) calibration models were generated from the second derivative spectral data of the tablets in order to predict drug contents of intact tablets. Both the reflectance and the transmittance techniques were able to predict the drug contents in intact tablets over a wide range. However, a comparison of the results of the study indicated that the lowest percent errors of prediction were provided by the PLS calibration models generated from spectral data obtained using the transmittance technique.     

Example for a new alternative application of NIR spectroscopy in the parallel determination of active ingredients and an excipient in powders and tablets

Near infrared reflectance (NIR) spectroscopy was used to determine paracetamol, caffeine and lactose based excipient content of powders for direct compression and in intact tablet formulations as well. The nominal concentrations of the active moiety was different in each sample set, and calibration was carried out by multiple linear regression calculations from the reflectance spectral data. The results obtained with NIR spectroscopy were comparable with those obtained with high-performance liquid chromatography (HPLC) used as reference method. The non-destructive NIR method applied is thus suitable for the alternative quantitative determination of paracetamol, caffeine and additionally the excipient in intact tablets and have the advantage over HPLC of being rapid and can be simply carried out without sample preparation and without the use of any reagent.     

Near-Infrared Spectroscopy as a Nondestructive Alternative to Conventional Tablet Hardness Testing

Purpose. Near-infrared reflectance Spectroscopy (NIRS) was used to evaluate and quantify the effect of compression force on the NIR spectra of tablets. Methods. Flat, white tablets with no orientation (scoring, etc.) were manufactured on a Stokes Rotary Tablet Press. NIRS was used to predict tablet hardness on the following four formulations and one placebo matrix: hydrochlorothiazide (HCTZ) 15% and 20% in a placebo matrix (microcrystalline cellulose and magnesium stearate), and chlorpheniramine maleate (CTM) 2% and 6% in a placebo matrix. Five or six levels of tablet hardness from 2 to 12 kg were used for each formulation. Laboratory hardness data was compared to NIR reflectance data using a NIRSystems Rapid Content Analyzer^®. Multiple linear regression and partial least squares regression techniques were used to determine the relationship between tablet hardness and NIRS spectra. Results. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIRS spectra. A series of equations was developed by calibrating tablet hardness data against NIR reflectance response for each formulation. The results of NIRS hardness prediction were at least as precise as the laboratory hardness test (SE = 0.32). Conclusions. A NIRS method is presented which has the potential as an alternative to conventional hardness testing of tablets.     

近红外漫反射光谱法鉴别不同厂家的甲硝唑片

建立了快速、有效鉴别不同厂家生产的甲硝唑片的方法.直接采集样品的近红外漫反射光谱,并进行褶合变换-可视化指纹图谱-相似系数分析,根据相似系数即可鉴别不同厂家的样品.     

近红外光谱法对不同厂家磷霉素钙片快速鉴别及区分

目的运用近红外（near-infrared,NIR）漫反射光谱法快速鉴别及区分不同厂家的磷霉素钙片,鉴别假劣药品,保障人民用药安全有效。方法通过收集A厂家生产的18个批次的样本以及其他厂家生产的多批样本,扫描其近红外光谱,运用布鲁克公司的OPUS软件,建立A厂家生产的磷霉素钙片的一致性检验模型,并对模型进行优化以及用其他厂家的样本来验证所建最优模型。结果建立的模型可以显著快速鉴别和区分不同厂家的磷霉素钙片。结论所建立的方法快速、简便、有效,可应用于药品的快速检验。     

Development of a method for the determination of caffeine anhydrate in various designed intact tablets [correction of tables] by near-infrared spectroscopy: a comparison between reflectance and transmittance technique

Using near-infrared (NIR) spectroscopy, an assay method which is not affected by such elements of tablet design as thickness, shape, embossing and scored line was developed. Tablets containing caffeine anhydrate were prepared by direct compression at various compression force levels using different shaped punches. NIR spectra were obtained from these intact tablets using the reflectance and transmittance techniques. A reference assay was performed by high-performance liquid chromatography (HPLC). Calibration models were generated by the partial least-squares (PLS) regression. Changes in the tablet thickness, shape, embossing and scored line caused NIR spectral changes in different ways, depending on the technique used. As a result, noticeable errors in drug content prediction occurred using calibration models generated according to the conventional method. On the other hand, when the various tablet design elements which caused the NIR spectral changes were included in the model, the prediction of the drug content in the tablets was scarcely affected by those elements when using either of the techniques. A comparison of these techniques resulted in higher predictability under the tablet design variations using the transmittance technique with preferable linearity and accuracy. This is probably attributed to the transmittance spectra which sensitively reflect the differences in tablet thickness or shape as a result of obtaining information inside the tablets.     

Use of Near-Infrared Spectroscopy to Evaluate an Active in a Film Coated Tablet

Purpose. To provide a method to rapidly screen tablets in the development of new coating technology. Methods. Near-Infrared (NIR) reflectance spectroscopy was used to quantitatively analyze tablets which were composed of a drug active encasing an active drug core. Diffuse reflectance NIR scans of 240 individual tablets over the range of 1100–2500 nm were obtained. High Performance Liquid Chromatography (HPLC) was used as the reference method. Results. Both qualitative, Principal Component Analysis, and quantitative results showed a strong agreement between the NIR and HPLC methods. The NIR analysis was non-invasive and allowed subsequent testing of the tablets. The contents of the drug active contained in a drug coating was determined to ± 4% of the target value using NIR analysis. Over 400 samples were analyzed in less than a month utilizing this technique which allowed the optimization of a new coating technology. Conclusions. NIR analysis allowed the evaluation of the efficiency of a new drug film coating manufacturing process more quickly and inexpensively. Because the Near-Infrared method was non-invasive the tablets were available for further analysis unlike the chromatography method.     

近红外漫反射光谱法快速检测维C银翘片中的对乙酰氨基酚

目的:应用近红外漫反射光谱法对维C银翘片中的对乙酰氨基酚进行快速定量分析。方法:采集样品的近红外漫反射光谱数据,采用偏最小二乘法（PLS）建立光谱数据和样品中对乙酰氨基酚含量的相关模型,应用所建模型对未知样品进行预测。结果:应用对乙酰氨基酚定量分析模型,以731个维C银翘片样品为校正集,浓度范围为186～476mg·g^-1,366个样品用于外部验证,浓度范围为191～409mg·g^-1,校正集交叉检验均方差（RMSECV）为12.3,相关系数R²=92.52;预测集外部检验均方差（RMSEP）为14.2,相关系数R²=86.86。结论:方法快速、准确,可用于维C银翘片中维C银翘片中对乙酰氨基酚的快速检测。     

Application of Monte Carlo Simulation‐Based Photon Migration for Enhanced Understanding of Near‐Infrared (NIR) Diffuse Reflectance. Part I: Depth of Penetration in Pharmaceutical Materials

This is the first of a series of articles applying Monte Carlo simulation‐based photon migration to enhance understanding of near‐infrared (NIR) diffuse reflectance in pharmaceutical analysis. This article aims to enhance mechanistic understanding on the interaction between NIR light and pharmaceutical materials, specifically focusing on the physical effects on NIR absorbance and depth of penetration profiles. Variations of particle size of lactose powder and density of a model tablet were used here as examples to represent the physical effects. An NIR chemical imaging system was used to measure the light‐interrogated area and the depth of penetration. Absorption and reduced scattering coefficients of powder and tablet samples, determined by spatially resolved spectroscopy, were combined with Monte Carlo simulation‐based photon migration to illustrate the mechanism of NIR light interaction with pharmaceutical materials. The empirically measured data and simulated results were consistent with one another and demonstrated a relationship between the physical effects of pharmaceutical samples and NIR absorbance/depth of penetration. The absorption coefficients and reduced scattering coefficients were discovered to be the dominant factors in the NIR absorbance profile and depth of penetration characteristics, respectively. The enhanced understanding of the roles of absorption and scattering in NIR diffuse reflectance is expected to provide useful insights for efficient multivariate calibration, unique spectroscopic pretreatments, and depth‐resolved NIR chemical imaging. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2399–2412, 2010