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.     

Determination of film-coated tablet parameters by near-infrared spectroscopy

Near-infrared (near-IR) spectroscopy was used in the determination of three parameters of theophylline tablets film-coated with ethylcellulose. Spectra of individual intact tablets were collected on two near-IR spectrometers: a grating-based spectrometer, and an acousto-optic tunable filter spectrometer. Calibrations were developed for the prediction of the time to 50% dissolution (t_50%) of theophylline for tablets of varying coat thickness, for the determination of the thickness of the ethylcellulose coat applied, and for the prediction of the hardness of coated tablets. Principal component analysis was performed on the spectra prior to calibration development. The standard errors of calibration (SEC) and prediction (SEP) for determination of dissolution rates were 2.8 and 6.6 min, respectively. The SEC for the coating thickness calibration was 0.0002 inches, with an SEP of 0.00024 inches, and the SEC and SEP for the determination of tablet hardness were 0.54 and 0.62 kilopons, respectively.     

Nondestructive prediction of oren extract powder,a herbal medicine,in suppositories by chemometric near-infrared spectroscopy

Near-infrared (NIR) spectroscopy combined with chemometrics has been utilized in predictions of natural medicine content without destroying samples. Suppositories (oren powdered extract content 0, 0.5, 1.0, 2.5, 10, 12.5, and 15%) were produced by mixing oren powdered extract with macrogol mixture consisting of 1 part macrogol 1500 and 2.5 parts macrogol 4000 at 54°C, and pouring the melt mixture into a plastic container. NIR spectra of the 10 prepared samples were recorded 10 times, and a total of 100 spectra were randomly divided into two data sets, one for calibration and the other for validation. The calibration model for the oren content of the suppository was calculated based on NIR spectra using a partial least-squares regression analysis after pre-treatment (smoothing and the multiplicative scatter correction). The relationship between the actual and predicted values for calibration and validation models had a straight line with correlation coefficients of 0.9936 and 0.9898, respectively. The regression vector result of the calibration model indicates that the peaks at 6945, 5747, and 5160 cm⁻¹ in the regression vector were consistent with those in oren powder extracts. NIR spectroscopy combined with chemometrics offers promise as a method of predicting the oren powder content in suppositories without destroying the samples.     

Bioequivalence testing of a new tablet formulation of generic fluoxetine.

The pharmacokinetics and relative bioavailability of fluoxetine capsules (reference) and tablets (test) were compared in 24 healthy subjects of both sexes after a single 20 mg oral dose of fluoxetine (as a hydrochloride salt). A randomized, crossover design with a 2-week wash-out period between each dose was applied. Serum samples, obtained before dosing and at various appropriate time points up to 192 hours, were analyzed for fluoxetine and norfluoxetine content by a simple, accurate and precise HPLC method. ANOVA, power analysis, 90% confidence intervals (CI), and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters. The tolerability of the preparations was good. The respective point estimates of the ratios of the geometric means of log-Cmax and log-AUC(0-infinity) of fluoxetine were 0.912 and 0.935 with 90% of 0.838-0.992 and 0.857-1.020. The corresponding point estimates of norfluoxetine were 0.952 (90% CI = 0.843-1.075) and 0.904 (90% CI = 0.807-1.013), respectively. Since both 90% CI for the AUC(0-infinity). and Cmax geometric mean ratios of fluoxetine and norfluoxetine were included in the 80% to 125% interval proposed by the FDA the test drug (fluoxetine tablets) was considered bioequivalent to the reference one (Prozac capsules) according both to the rate and extent of absorption.     

Nondestructive measurements of the compact strength and the particle-size distribution after milling of roller compacted powders by near-infrared spectroscopy

Compact strength and the particle-size distribution of milled roller compacted compacts were correlated to the slope of the best-fit line through near-infrared spectra for samples prepared under different roll speeds and feed rates. The above correlations were found to hold for compacts prepared from microcrystalline cellulose powder as well as from a typical direct compression pharmaceutical powder blend containing tolmetin sodium dihydrate, microcrystalline cellulose, and dicalcium phosphate dihydrate. Near-infrared spectra were also collected real time for the compacts prepared from the tolmetin powder blend. The real-time slope values for the spectra showed good agreement with the off-line data. The strength of compacts was determined using three-point beam bending method and the particle-size distribution of the milled compacts was determined using sieve analysis. The results suggest that the real-time values of the slope of the best-fit line through the near-infrared spectrum offers a robust, yet simple and fast quality control tool to monitor/control manufacturing and scale-up processes involving dry granulation by roller compaction.     

新型口服固体速释制剂———口腔速崩片

目的：介绍目前口腔速崩片崩解剂的特性、制备工艺、特点,为国内口崩片的设计和制备提供参考及思路。方法：概述了近十几年来,国外选用的崩解剂和改善口感的方法及其应用概况。结果：通过对口崩片崩解剂特性的了解,为口崩制剂的处方设计提供依据,开阔思路。结论：对口崩制剂的深入研究有助于开发有价值的老年人和其他特殊病人用药。     

Process characterization of powder blending by near-infrared spectroscopy: blend end-points and beyond

The purpose of this paper is to utilize near-infrared (NIR) spectroscopy to characterize powder blending in-line. A multivariate model-based approach was used to determine end-point and variability at the end-point of blending processes. Two monitoring positions for NIR spectrometers were evaluated; one was located on the top of the Bin-blender and the other was on the rotation axis. A ternary powder mixture including acetaminophen (APAP, fine and coarse powder), lactose (LAC) and microcrystalline cellulose (MCC, Avicel 101 and 200) was used as a test system. A Plackett-Burman design of experiments (DOE) for different blending parameters and compositions was utilized to compare the robustness of end-point determination between the multivariate model-based algorithm and reference algorithms. The end-point determination algorithm, including root mean square from nominal value (RMSNV) and two-tailed Student's t-test, was developed based on PLS predicted concentrations of all three constituents. Mean and standard deviation of RMSNV after end-point were used to characterize blending variability at the end-point. The blending end-point and variability of two sensors were also compared. The multivariate model-based algorithm proved to be more robust on end-point determination compared to the reference algorithms. Blending behavior at the two sensor locations demonstrated a significant difference in terms of end-point and blending variability, indicating the advantage to employ process monitoring via NIR spectroscopy on more than one location on the Bin-blender.     

Determination of a novel bile acid sequestrant in rodent diet by near-infrared spectroscopy

DMP 504 is a high molecular weight polymer currently under development by The DuPont Merck Pharmaceutical Company as a novel bile acid sequestrant to lower serum cholesterol. To assess its safety, DMP 504 is incorporated into rodent diet for oral administration to rats and mice. An analytical method was developed to determine the accuracy and homogeneity of the blends. Since a physical separation or extraction of DMP 504 from the diet was not feasible, near-infrared spectroscopy (near-IR) was employed. The near-IR method provides accurate and precise results for blends containing 1.5–8.0% of DMP 504. Comparison of results at the 1.5% level with a cholate binding referee method is also presented. Both methods provided equivalent results for the 1.5% level.     

Developing a quality by design approach to model tablet dissolution testing: an industrial case study

Abstract

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.     

A process analytical technology approach based on near infrared spectroscopy: tablet hardness, content uniformity, and dissolution test measurements of intact tablets

Near infrared spectroscopy (NIRS) is a nondestructive analytical technique that enables simultaneous measurements of chemical composition (viz. the content in active pharmaceutical ingredient, API) and various physical properties (viz. tablet hardness and dissolution profile) in pharmaceutical tablets. In this work, partial least squares (PLS) calibration models and discriminant partial least squares (DPLS) classification models were constructed by using calibration sets consisting of laboratory samples alone. The laboratory samples were mixtures of the API and excipients that were pressed into tablets. API content, tablet hardness, and dissolution measurements of intact tablets were made by using three different calibration models that are fast--results can be obtained within a few seconds--, simple and robust--they involve minimal analyst intervention--, and clean--they use no toxic reagent and produce no toxic waste. Based on the results, the proposed NIR method is an effective alternative to current reference methods for the intended purpose. The advantages provided by NIR spectroscopy in this context confirm its potential for inclusion in process analytical technologies in the pharmaceutical industry.     

Measurement of potency and lipids in monensin fermentation broth by near-infrared spectroscopy

A transmission near-infrared (NIR) spectroscopic method for quantification of potency and lipids in monensin fermentation broth was developed and validated. Two multiple linear regression calibration curves were established for a set of 100 fermentation samples, correlating the appropriate absorption bands in the NIR spectrum to the laboratory reference methods; high-performance liquid chromatography for potency, and chloroform extraction for lipids. During method development, potency was found to be well correlated to NIR absorbances specific for monensin. While acceptable, correlation of NIR absorbances characteristic of oil to the chloroform lipid method was weaker due to a greater amount of relative variation in the lipid measurements. Following establishment of the optimal calibration curves, the NIR method for potency and lipids was validated for selectivity, accuracy, precision, and robustness. In order to investigate long-term drift in the measurement system, samples were tested both by the NIR and the reference methods over a 7-month period. The differences between results from the two measurements were calculated and statistically analyzed.     

The quantification of citral in lemongrass and lemon oils by near-infrared spectroscopy

Previous work has demonstrated the capability of near-infrared (NIR) spectroscopy to determine the cineole content (not less than 70% w/w) of eucalyptus oil with an accuracy comparable with that of the British Pharmacopoeia (BP) assay method. The aim of the present study was to determine if the same method was capable of quantifying other chemical constituents at similar levels in essential oils and also to ascertain if NIR spectroscopy can accurately quantify compounds present at much lower levels in essential oils. Lemongrass oil contains citral at concentrations of approximately 65-85% w/w, and lemon oil contains citral at a concentration of approximately 2-5% w/w. A total of 26 samples of pure lemongrass oil and 35 samples of pure lemon oil (both including samples that were "spiked" with citral to increase the calibration range) were scanned on the FOSS NIRSystems 6500 Rapid Content Sampler using a reflectance vessel as sample presentation method. The reference method for both types of oil was the BP monograph titration assay for the citral content of lemon oil and calibrations were constructed using these reference data. For the lemongrass oils, the mean accuracy was found to be 1.00% or less and the mean bias was 0.09% or less. For the lemon oils, the mean accuracy was found to be 4.28% or less and the mean bias was -0.71% or less. The NIR method developed was rapid, simple and non-destructive and may prove beneficial for the accurate determination of the citral content of lemongrass oils and for the approximate citral content of lemon oils.     

Gastroscopic and pharmacokinetic evaluation of a new pivmecillinam tablet

Summary Three different pivmecillinam preparations, a conventional 200 mg tablet (P tablet) and two new formulations containing respectively pivmecillinam 200 mg and 400 mg plus Avicel^? (microcrystalline cellulose) as a disintegrator (PA tablet), were compared in vitro and in a gastroscopic study in 8 healthy volunteers. Disintegration of the PA tablet was significantly more rapid both in vitro and in the stomach. Following disintegration, the content of the PA tablet was spread over a larger area of the gastric mucosa (1088 mm²) than was observed with the P tablets (408 mm²). Three of the 8 volunteers taking the P tablet developed hyperaemia, interstitial bleeding or erosions of the mucosa of the stomach. No such reactions were seen with the PA tablets. Serum concentrations of mecillinam following ingestion of pivmecillinam tablets were determined in three groups of subjects; fasting volunteers, both supine and ambulant, and in ambulant subjects who took the preparation with a light meal. There was a tendency for the new PA tablets to produce a higher peak serum level as well as greater bioavailability of mecillinam. Administration of the PA tablets with a meal significantly increased the peak serum level and total bioavailability of the drug. On the basis of our observations we recommend adoption of the new PA tablet, because of its quick passage through the oesophagus and its more rapid and complete disintegration in the stomach.     

Development and validation of a method for the analysis of a pharmaceutical preparation by near-infrared diffuse reflectance spectroscopy

A near-infrared (NIR) spectroscopic method based on the use of a fiber optical probe for the analysis of a commercially available pharmaceutical preparation is proposed. The analyte is identified by comparison with a second-derivative spectral library, using the correlation coefficient as the discriminating parameter. Once a sample has been positively identified, the active principle is quantified with partial least-squares (PLS) calibration. The proposed method was validated for use as a control method; to this end, the selectivity of the identification process, and the repeatability, intermediate precision, accuracy, linearity, and robustness of the active principle quantitation, were assessed.     

Mass-balanced blend uniformity analysis of pharmaceutical powders by at-line near-infrared spectroscopy with a fiber-optic probe

A near-infrared (NIR) fiber-optic probe was used at-line to study the blending dynamics of pharmaceutical powder blends on a mass-balanced basis. The probe with a flexible fiber-optic cable can be inserted directly into a 10-L bin blender to get quantitative readings. NIR calibration models were developed and validated for the probe based on a designed 50-sample calibration set. A model formulation containing acetaminophen, mannitol, Avicel, magnesium stearate and AcDiSol was used in the study. The blending study was conducted at 18 rpm for 20 min. NIR probe scans were performed at 1 min intervals and five different locations in the bin. Thief samples were collected and later analyzed by a bench-top NIR instrument to confirm the results from the probe. Complete blending profiles were constructed and compared based on the assay results from both instruments.     

Estimation of paracetamol and aceclofenac in tablet formulation by ratio spectra derivative spectroscopy

A new sensitive, simple, rapid and precise method for simultaneous estimation of paracetamol and aceclofenac in combined tablet dosage form has been developed. The method is based on ratio derivative spectrophotometry. The amplitude in first derivative of the ratio spectra at 256 nm and 268 nm (minima) were selected to determine paracetamol and aceclofenac in combined formulation. The method showed good linearity, accuracy and reproducibility. Results of analysis were validated statistically and by recovery studies.     

Pinacidil,a new vasodilator: Pharmacokinetics and pharmacodynamics of a new retarded release tablet in essential hypertension

In an open study increasing doses of a retarded tablet formulation of pinacidil were given twice daily for four weeks to 9 patients with untreated essential hypertension (WHO I-II). In all patients a decrease in diastolic blood pressure to below 100 mmHg, or a fall exceeding 15 mmHg, was obtained 2 h after tablet intake (p less than 0.02), but in only two patients was the effect maintained after 10 hours (n.s.). At a mean serum concentration of 100 ng/ml 2 h after pinacidil 30 mg, the mean blood pressure had decreased by 14 and 12.7 mmHg in the supine and erect positions, respectively (p less than 0.05). In contrast, mean blood pressure 10 h after the same dose was unchanged, when the mean serum concentration was 47.5 ng/ml. No change in heart rate was observed. Pharmacokinetic and pharmacodynamic investigations showed a tendency towards a more gradual and longer lasting antihypertensive effect and serum concentration-time curve after the retarded tablet than the previous tablet. Pinacidil 40 mg in the retarded tablet reduced mean blood pressure and increased heart rate for at least 8 h. There was a linear correlation between the serum concentration and the change in mean blood pressure, and between the changes in mean blood pressure and in heart rate. There was no indication of tachyphylaxis. A serum level of 50 ng/ml of pinacidil appeared to be the minimal effective concentration. The side effect consisted of fluid retention, and the body weight increased by 1.0 kg (p less than 0.05); four patients complained of oedema.(ABSTRACT TRUNCATED AT 250 WORDS)     

近红外光谱分析法鉴别感觉神经和运动神经

目的 探讨近红外光谱(NIRS)分析法在鉴别周围神经运动束和感觉束的可行性.方法 采集离体Beagle犬面神经的颞支、颧支、颊支、下颌缘支(均为运动神经)和颈丛皮神经(感觉神经)的漫反射近红外光谱,通过聚类分析法进行归类鉴别.结果 面神经和颈丛皮神经的一、二阶导数光谱较为相近,不能直观进行鉴别;经聚类分析可以将两者归为两类,达到直观鉴别的目的,准确率90.0%.结论 运动神经束和感觉神经束可以经NLRS技术结合聚类分析法快速区分.     

基于近红外光谱法的阿托伐他汀钙片质量一致性评价及含量快速测定

目的：建立近红外光谱法对阿托伐他汀钙片进行质量一致性评价及有效含量的快速测定。方法：采用便携式近红外光谱仪,采集23批阿托伐他汀钙片样品的漫反射近红外光谱数据,使用主成分分析（principal component analysis,PCA）建立不同批次阿托伐他汀钙片样品的质量一致性评价模型。使用不同光谱预处理方法对原始光谱进行光谱预处理,采用组合区间偏最小二乘（synergy interval partial least squares,SiPLS）算法对建模波数区间进行优化,并以高效液相色谱（high performance liquid chromatography,HPLC）法为参考方法,建立阿托伐他汀钙片的近红外定量分析模型。结果：使用不同批次阿托伐他汀钙片的光谱信息建立的PCA模型分类效果良好。对不同的光谱预处理方法进行比较,得到光程散射校正（multiplicative scattering correction,MSC）为最佳光谱预处理方法。当全光谱划分为30个区间时,选择3个子区间进行组合可得到最佳建模波数范围。校正模型的交叉验证均方根误差（root mean square error of cross-validation,RMSECV）为1.230 2,交叉验证相关系数（correlation coefficient of cross-validation,R_CV）为0.914 6,预测模型的预测均方根误差（root mean square error of prediction,RMSEP）为1.676 4,预测相关系数（correlation coefficient of the prediction,R_P）为0.964 2。结论：该研究建立的定性和定量方法准确、可靠,可以快速进行阿托伐他汀钙片的质量一致性评价及含量测定。     

Extended multiplicative signal correction and spectral interference subtraction: new preprocessing methods for near infrared spectroscopy.

Near infrared (NIR) spectroscopy spectra can be converted mathematically to precise quantitative information of chemical and physical nature by multivariate calibration. This makes NIR analysis useful for a variety of "difficult" sample types (powders, slurries), more or less without any sample preparation. The paper emphasizes the importance of using prior knowledge for spectral preprocessing of spectral data prior to the linear multivariate calibration modelling. Two new preprocessing methods are presented: extended multiplicative signal correction (EMSC) for elimination of uncontrollable path length or scattering effects, and spectral interference subtraction (SIS) for elimination of known spectral interferences. Determination of toluene in mixtures with benzene and xylene from NIR spectra with gross simulated light scattering effects is used for illustration.