Determination of water in ferrous lactate by near infrared reflectance spectroscopy with a fibre-optic probe

Near infrared diffuse reflectance spectroscopy with a fibre-optic probe was used to determine the water content in ferrous lactate dihydrate. Spectra were recorded by immersing the probe in a beaker containing the ferrous lactate sample. Spectral data were processed by using two different multivariate calibration procedures, viz. stepwise multiple linear regression (SMLR) and partial least-squares regression (PLSR). The results provided by the two calibration procedures were similar and departed by less than 1.5% from the values obtained by Karl Fischer titration.     

Moisture determination in hygroscopic drug substances by near infrared spectroscopy

The moisture level in a hygroscopic drug substance was successfully determined by near infrared spectroscopy using coulometric Karl Fischer titration as the reference method. The importance of sample handling and proper application of the reference technique are stressed for this difficult sample type. Samples were prepared with moisture levels from 0.5 to 11.4% (w/w) and reflectance spectra were collected over the spectral range 1100–2500 nm. Calibration models were built using partial least squares (PLS) regression analysis. Optimum models were found by choosing proper spectral ranges and number of PLS factors. The best calibration models were built using first derivative spectra, a spectral range of 1850–1936 nm and 5 PLS factors. The corresponding standard error of prediction was 0.11% (w/w) water.     

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.     

Determination of moisture content of lyophilized allergen vaccines by NIR spectroscopy

Moisture content is an important parameter for lyophilized vaccines. Currently, Karl Fischer titration is widely used for moisture determination in routine analysis. However, this method is time-consuming, sample destructive and requires environment polluting reagents, as well as the results rely on the random samplings. In this study, near infrared spectroscopy was used as a fast, non-invasive and non-destructive method to determine the moisture content in lyophilized allergy vaccines. Five different vaccine products were investigated, which contained water in the range of 0.17-1.51% (w/w, KF). Different data pre-treatments, wavelength selection and partial least squares regression were applied to construct calibration models. Multi-products model and product-specific models were obtained, which show the possibility of NIR as a rapid method to discriminate whether moisture content fit into the specifications of a pharmaceutical company.     

卡氏滴定法测定地奥心血康胶囊中的水分

目的提供一种中药制荆新的水分测定方法。方法采用卡氏(Karl Fischer)滴定法并与甲苯法作比较。结果卡氏滴定法的平均回收率为101．2％．两种方法测定的数据基本一致。结论卡氏滴定法测定地奥心血康胶囊中的水分简便、准确。     

Applying spectral peak area analysis in near-infrared spectroscopy moisture assays

Spectral peak area analysis has in this study been shown to be a viable method in near-infrared spectroscopy (NIRS) moisture assays. The study also shows that the required number of calibration samples can be minimized, and the method is, therefore, especially suitable for moisture assays in early formulation development and in-situ process monitoring. Diffuse NIRS was utilized in the development of moisture assays for the model compounds polyvinylpyrrolidone and hydroxypropyl-beta-cyclodextrin and also for a lyophilized formulation. Reference data were obtained using coulometric Karl Fischer titration. The NIRS measurements were performed through the bottoms of the sample vials using either a Fourier Transform-Near-Infrared (FT-NIR) spectrometer fitted with a diffuse reflectance probe or a dispersive single beam spectrometer. The ratios of the peak areas of a water peak at 5200 cm(-1) and a reference peak were evaluated using linear regression analysis. The spectral peak area analysis method was compared with a conventional partial least squares regression method. The moisture assays were verified using independent test sets. The investigated moisture range was 0-22% for the samples of PVP, 0-8.5% for the samples of hydroxypropyl-beta-cyclodextrin and 0.5-8.5% for the samples of the lyophilized formulation. The results of the spectral peak area analysis and the conventional partial least squares regression were similar, but the peak area method was more robust and could also make accurate predictions for lyophilized PVP samples, although the calibration set consisted of non-lyophilized samples. The peak area method required fewer calibration samples than the conventional partial least squares regression method.     

On-Line Moisture Detection for a Microwave Vacuum Dryer

A method has been developed to determine the moisture end point in a microwave vacuum dryer using near-infrared spectroscopy (NIR). Dryer studies were conducted in two T. K. Fielder microwave dryers, a Spectrum 65 and a Spectrum 1200. On-line spectra were collected using a NIRSystems Model 5000 Analyzer with a fiber-optic probe. The calibration equation uses absorbances measured at 1410, 1930, and 1630 nm. Moisture values determined online with this equation correlate to within 1% of the Karl Fischer results for samples below 6% moisture. The absolute SEP is 0.6% and the average residual is – 0.2%. At levels above 6% moisture, the NIR results do not correlate well with Karl Fischer but the moisture curve can be used to assess the homogeneity of the water in the granulation. The combination of qualitative and quantitative information makes it possible to monitor the drying process and to predict consistently the moisture end point in the microwave dryer.     

近红外光谱技术快速测定杞菊地黄丸的水分含量

目的应用近红外光谱技术建立一种杞菊地黄丸(浓缩丸)中水分含量的快速测定方法。方法以甲苯法测定的样品中水分的含量为真实值,运用近红外漫反射光谱技术采集96份杞菊地黄丸(浓缩丸)样品的近红外漫反射光谱,结合偏最小二乘法(PLS)建立水分含量的定量分析模型。结果所建水分校正模型的相关系数(R2)和内部交叉验证均方差(RMSECV)分别为0.988 09和0.0587;经外部验证,模型的预测相关系数(r2)和预测均方差(RMSEP)分别为0.9969和0.075 2。结论该方法操作简便,无污染,结果准确可靠,可用于杞菊地黄丸(浓缩丸)中水分含量的快速测定。     

In situ moisture determination of a cytotoxic compound during process optimization

A simple and safe prototype apparatus was designed and adapted for the in situ determination of the moisture content of a cytotoxic compound (9-fluorenylmethyl-protected doxorubicin-peptide conjugate, or Fm-DPC) by near-infrared absorbance spectroscopy during optimization of the chemical isolation procedure. The cytotoxic nature of the compound restricts one's ability to safely sample such drying processes for more traditional means of moisture determination for fear of hazardous solids dusting, hence in situ sampling approaches are of great importance. These concerns also exist for the process development laboratory, where despite the smaller scale of operations, the volume of experiments (hence cytotoxic samples) required to define a chemical process is often more significant. In this application, partial least squares regression was used with Karl Fischer volumetric titration analysis to generate a calibration model. Although pronounced differences in cake density were observed as a function of the buffer selected for the isolation process, the model still achieved a standard error of calibration of 0.63% w/w and a standard error of prediction of 0.99% (w/w). These results demonstrated the versatility of the prototype apparatus/data processing approach to model Fm-DPC drying under extremely variable conditions, as inherently expected during the investigational laboratory development of a chemical process.     

卡尔费休库仑滴定法测定注射用氢溴酸高乌甲素水分方法的探讨

目的研究并改进注射用氢溴酸高乌甲素卡尔费休氏库仑滴定法（KF库仑法）水分测定方法。方法采用样品溶解取样实验法取样,用KF库仑法测定注射用氢溴酸高乌甲素水分,并与传统样品称量取样实验法进行比较。结果样品溶解取样实验法与样品称量取样实验法水分测定结果存在较大差异,样品溶解取样实验法平均回收率为102．3％,RSD=2．37（n=6）。结论KF库仑法样品溶解取样实验法准确,简便,节省取样量,可以用于易吸潮药品的水分质量控制。     

Simultaneous determination of benzocaine and cetylpiridinium chloride in tablets by first-derivative spectrophotometric method

A new spectrophotometric method for the simultaneous determination of benzocaine and cetylpiridinium chloride in pharmaceutical tablets, which does not require any preliminary separation or treatment of the samples, is described. The quantitative determination of both drugs was carried out using the first derivative values measured at 231.40 and 310.00 nm for benzocaine and at 220.70 nm for cetylpiridinium chloride using the zero-crossing method. The calibration graphs were linear in the ranges from 10 to 25 mg/l of benzocaine and from 4 to 20 mg/l of cetylpiridinium chloride. The developed method was successfully applied for the assay of pharmaceutical tablets and proved to be simple, sensitive and selective. Thermogravimetric techniques, Karl Fischer and loss on drying were also used for a stoichiometric evaluation of the substances studied.     

In-line monitoring of granule moisture in fluidized-bed dryers using microwave resonance technology

This is the first report on in-line moisture measurement of pharmaceutical products by microwave resonance technology. In order to meet the FDA’s PAT approach, a microwave resonance sensor appropriate for pharmaceutical use was developed and implemented into two different fluidized-bed dryers. The novel sensor enables a continuous moisture measurement independent from the product density. Hence, for the first time precise real time determination of the moisture in pharmaceutical granules becomes possible. The qualification of the newly developed sensor was performed by drying placebo granules under experimental conditions and the validation using drug loaded granules under real process conditions. The results of the investigations show good correlations between water content of the granules determined by the microwave resonance sensor and both reference methods, loss on drying by infrared light exposure and Karl Fischer titration. Furthermore, a considerable time saving in the drying process was achieved through monitoring the residual water content continuously by microwave resonance technology instead of the formerly used discontinuous methods.     

Thermal stability studies of 5‐fluorouracil using diffuse reflectance infrared spectroscopy

5‐Fluorouracil is one of the oldest chemotherapy drugs and it has been in use for decades. It is an active medicine against several types of cancer and effectively blocks the replication of DNA viruses. The present study assessed the potential of diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy to determine the thermal stability of 5‐fluorouracil. Infrared spectra of the drug before and after exposure to thermal radiation at different temperatures were collected in diffuse reflectance mode using a Fourier transform infrared (FTIR) spectrophotometer. Differential scanning calorimetry (DSC) and X‐ray diffraction (XRD) analysis were carried out simultaneously to confirm and support the results of infrared spectroscopy. The DRIFT spectra reveal that the drug shows good thermal stability up to 275 °C and undergoes complete thermal breakdown at about 285 °C. The results of DSC and XRD analysis also give the same information, which support the implementation of diffuse reflectance infrared spectroscopy for the determination of thermal stability of 5‐fluorouracil. Copyright © 2009 John Wiley & Sons, Ltd.     

近红外光谱法测定不同厂家天麻胶囊中的水分

目的应用近红外光谱技术建立天麻胶囊中水分定量快速测定的检测方法。方法通过对天麻胶囊的近红外光谱应用OPUS软件进行分析处理,建立水分定量测定模块,验证样品的数据基本符合。结果该方法能准确、快速测定天麻胶囊的水分,相对误差小于3%。结论该方法简便,快速,准确,重现性好,且不破坏样品,能应用于药品监督工作中对药品中水分的快速检测。     

Determination and differentiation of surface and bound water in drug substances by near infrared spectroscopy

Near infrared spectroscopy (NIRS) was utilized to determine the water content during the drying of a drug substance with Karl Fisher titration as the reference measurement. NIRS calibration models were built with Partial Least Squares (PLS) regression based on spectral region of 1822-1948 nm for samples with 1-40% (w/w) water from five batches. A standard error of prediction (SEP) of 1.85% (w/w) was obtained from validation of the model with additional batches. A second NIRS calibration model using PLS was constructed in the region of 1-10% (w/w) water with samples from the same five calibration batches. This calibration model improved the accuracy of the prediction in the critical region around the end point of drying and provided a standard error of prediction 0.42% (w/w). In addition, direct spectral analyses with Principal Component Analysis (PCA) and peak ratios were applied to distinguish between surface (unbound) water and bound water incorporated into the crystal lattice of the drug substance. Direct spectral analysis indicated the existence of significant numerical and graphical differences between samples containing both surface and bound water, and those containing bound water only. Applying this method to monitor an actual drying process with the graphical assistance of spectral analysis, the drying process can be controlled, and the end point of drying clearly determined to ensure the desired hydrate form of the product. This study has demonstrated the in-line monitoring capability of NIRS to differentiate the surface and bound water simultaneously in addition to the determination of the water level.     

近红外光谱法快速测定野菊花药材中水分及蒙花苷含量

目的 应用近红外光谱技术建立一种野菊花药材中水分及有效成分含量的快速分析方法。方法 采集45批野菊花药材的近红外光谱,分别用烘干法和HPLC测得药材中水分及蒙花苷含量值作为参考,运用偏最小二乘法(PLS)建立野菊花药材水分及蒙花苷的定量模型,并用未知样品进行验证。结果 野菊花药材水分和有效成分蒙花苷含量PLS模型得到的NIR预测值与实测值有较好的相关性,模型的交互验证误差均方根(RMSECV)分别为0.568和0.282;相关系数R2为0.976 1和0.955 1;RESP均控制在10%以内,完全符合中药生产过程实时分析的精度要求。结论 研究表明近红外光谱技术能够快速测定野菊花药材水分和蒙花苷含量,有助于药材入库的快速检验,节省人力物力。     

Determination of residual moisture in lyophilized protein pharmaceuticals using a rapid and non-invasive method: near infrared spectroscopy

This study examined the application of near-infrared (NIR) spectroscopy to analyze residual moisture in lyophilized protein pharmaceuticals sealed in glass vials. We demonstrated that NIR was able to determine residual moisture in five marketed and clinical products with the same precision as Karl Fischer titration. We further investigated how changes in product configuration and protein formulation affected NIR measurement accuracy using a lyophilized monoclonal antibody rhuMAb E25 containing 1% to 5% residual moisture. The results indicated that the lyophilized cake porosity and dimensions had no effect on NIR measurement when the cake height and diameter exceeded the NIR penetration depth. In addition, changing the buffer and surfactant concentrations in the formulation did not affect moisture determination by NIR. However, doubling or halving the concentration of a disaccharide, which was used as a lyoprotectant, caused significant deviation between the NIR and Karl Fischer data because the NIR absorbance of the disaccharide overlapped with the moisture signal. Furthermore, complete removal of the disaccharide resulted in alteration of the protein NIR spectra, suggesting that NIR may be used to evaluate solid-state protein structure. The disaccharide concentration must be kept constant in this formulation to obtain accurate moisture results by NIR.     

Near-Infrared Spectroscopic Determination of Residual Moisture in Lyophilized Sucrose Through Intact Glass Vials

A rapid, noninvasive, and nondestructive method for determining moisture in sealed freeze-drying vials is described. The method, based on near-infrared spectrometry, used a novel fiber-optic diffuse-reflectance probe to make remote reflectance measurements from 1100 to 2500 nm through the bottom of glass vials. The correlation of the method to results obtained by Karl Fischer analysis was good (r ² = 0.97). The moisture content of sucrose, a common cryoprotectant, was determined with an error of 0.27% using a single sample scan.     

Influence of physical factors on the accuracy of calibration models for NIR spectroscopy

The quality of pharmaceutical drugs is strongly influenced by a number of physical and chemical factors that require careful control during the production process in order to ensure that the end-product will meet the specifications. Near infrared spectroscopy has proved effective for monitoring changes in such factors and is currently the most widely used technique for controlling drug manufacturing processes. In this work, the authors determined an active pharmaceutical ingredient (API) throughout its production process. The influence of particle size, galenic form, compaction pressure and coating thickness on NIR spectra was evaluated with a view to developing effective methodologies for constructing simple, accurate calibration methods affording API quantization at different stages of a drug production process. All calibration models were constructed from data for laboratory samples alone and NIR calibration models for determining the API determination by using product weights as reference values. The proposed models were validated by application to samples obtained at three stages of a drug manufacturing process and comparison of the predicted values with HPLC reference values. The RSEP values thus obtained never exceeded 1.5%.     

近红外光谱技术对女贞子进行快速检测方法的研究

目的:通过近红外光谱技术建立女贞子的快速检测鉴别真伪及产地的方法。方法:利用近红外漫反射光谱技术,按中国药典2015年版一部相关标准,以女贞子中水分及特女贞苷含量为参考值,建立女贞子中水分及特女贞苷定量模型,对女贞子进行快速含量测定;建立女贞子一致性检验模型,进行快速真伪鉴定及产地鉴别。结果:建立女贞子中特女贞苷含量与女贞子水分校正模型校正集的相关系数分别为95.15%,97.3%,校正集的内部交叉验证均方差(RMSECV)分别为0.364,0.161;预测值与实测值相差较小,能较准确地测定女贞子中特女贞苷的含量与女贞子水分。建立对女贞子定性鉴别的一致性检验模型能较准确判别女贞子的产地。结论:利用近红外光谱对女贞子中特女贞苷与女贞子水分进行定量,不同产地进行定性的方法快速、简便、预测结果准确,可成为女贞子的快速检验方法。