Chemometric and derivative methods as flexible spectrophotometric approaches for dissolution and assaying tests in multicomponent tablets

Two derivative spectrophotometric (ratio derivative spectra and algorithm bivariate calibration) and a chemometric methods (partial least squares, PLS) are proposed for the simultaneous determination of binary mixtures in tablet analysis and dissolutions tests, without prior separation. These approaches are successfully applied to quantify trimethoprim (TMP) combined with sulfamethoxazole (SMX) or sulfamethazine (SMZ) or sulfafurazole (SFZ) using the information in the absorption spectra of appropriate solutions. Beer's law was obeyed in the concentration range of 0.98-17.5 microg/ml for TMP, 0.95-17.2 microg/ml for SMX, 1.16-17.5 microg/ml for SMZ and 0.97-17.4 microg/ml for SFZ. The first derivative (1D) bivariate algorithm method involves the use of four calibration curves: two for each compound at two different wavelengths, selected by Kaiser's method. Similarly, the first derivative ratio spectrophotometry employs the linear relationship between the ratio spectra of the analytes and the concentration range. The results were compared with those obtained by PLS multivariate calibration. The calibration models from PLS were pre-treated by orthogonal signal correction and evaluated by cross-validation using the 'SIMCA-P 9' software. Synthetic mixtures of TMP and sulfonamides were used in five different sets for the validity of the calibrations. Mean recoveries for derivative ratio, derivative bivariate and PLS methods were found to be between 99.7% and 102.0% for TMP, 99.4% and 100.2% for SMX, 99.3% and 101.0% for SMZ and 98.1% and 102.3% for SFZ. The calibrations of the three methods were successfully applied to the assaying and dissolution of placebo and commercial tablets without any prior separation. More than 85% of TMP, SMX and SMZ were dissolved within 15 min. For SFZ, only 85% of the compound was dissolved after 60 min. In this study, the three spectrophotometric methods can be satisfactorily used for the quantitative analysis and for dissolution tests of multicomponent dosage forms.     

近红外漫反射光谱法同时测定复方甲氧那明胶囊中四个主成分含量

目的 同时测定复方甲氧那明中四个主成分含量。方法 通过近红外漫反射光谱法，采用偏最小二乘法，并选择一阶导数光谱及对其他因子进行了优化，建立了数学模型，对实际样品的四个主成分含量进行了测定，同时以高效液相分析法作为参照比较。结果 48个样品经内部交叉验证，相关系数分别达到了0．9949、0．9997、0．9991、0．9985。结论 本法可有效地同时检测四组分含量，快速、简便、结果准确。     

Near infrared spectroscopy of magnesium stearate hydrates and multivariate calibration of pseudopolymorph composition

Samples of magnesium stearate monohydrate and dihydrate were used to prepare standard mixtures of known pseudopolymorphic composition. Near infrared spectra (NIR) of the standard mixtures were measured to develop multivariate calibration models for the pseudopolymorphic composition of magnesium stearate by partial least squares (PLS) regression. Magnesium stearate hydrate compositions of the standard mixtures were compared against the hydrate composition based on thermogravimetric analysis (TGA). The mixture compositions determined from TGA mass loss on drying (LOD) measurements were found to be inaccurate. PLS regression was applied to the TGA thermograms of the standard mixtures to generate more accurate reference values, and this model was then applied to a set of validation samples. Application of the NIR PLS model to the validation sample set resulted in precise estimates of sample pseudopolymorphic composition when compared to the TGA PLS reference values. The NIR PLS model was found to be more sensitive than TGA LOD to small quantities of hydrates, and the TGA PLS model was also found to be more sensitive that TGA LOD. The results demonstrate the challenges and opportunities that arise when rapid, nondestructive spectroscopic methods depend on insensitive or inaccurate reference methods for development of multivariate calibration models.     

Quantitative determination of diclofenac sodium in solid dosage forms by FT-Raman spectroscopy

The FT-Raman quantification of diclofenac sodium in tablets and capsules was performed with the help of the partial least squares (PLS), principal component regression (PCR) and counter-propagation artificial neural networks (CP-ANN) methods. For the analysed tablets, calibration models were built using unnormalised spectra and spectra normalised by the intensity of a selected band of an internal standard. Different pre-processing methods were applied for the capsules. To compare the predictive ability of the models, the relative standard errors of prediction (RSEP) were calculated. The 5 x 5 CP-ANN and PLS methods gave models of comparable quality, which were usually more efficient than the PCR ones. The RSEP error values for the tablets were in the range of 2.4-3.8% for the calibration and 2.6-3.5% for the validation data sets and for the three procedures applied. For capsules, the RSEP errors were in the range of 0.8-1.9% and 1.4-1.7% for the calibration and validation samples, respectively. Five commercial products containing 25, 50 or 75 mg of diclofenac sodium per tablet/capsule were quantified. Concentrations found from the Raman data analysis agree with the results of the reference analysis and correlate strongly with the declared values with the recovery of 99.5-101.3%, 99.7-102.0% and 99.9-101.2% for the PLS, PCR and CP-ANN methods, respectively. The proposed procedure can be a fast and convenient alternative to the standard pharmacopoeial methods of diclofenac sodium quantification in solid dosage forms.     

Quantitative solid-state analysis of three solid forms of ranitidine hydrochloride in ternary mixtures using Raman spectroscopy and X-ray powder diffraction

The aim of the study was to develop a reliable quantification procedure for mixtures of three solid forms of ranitidine hydrochloride using X-ray powder diffraction (XRPD) and Raman spectroscopy combined with multivariate analysis. The effect of mixing methods of the calibration samples on the calibration model quality was also investigated. Thirteen ternary samples of form 1, form 2 and the amorphous form of ranitidine hydrochloride were prepared in triplicate to build a calibration model. The ternary samples were prepared by three mixing methods (a) manual mixing (MM) and ball mill mixing (BM) using two (b) 5 mm (BM5) or (c) 12 mm (BM12) balls for 1 min. The samples were analyzed with XRPD and Raman spectroscopy. Principal component analysis (PCA) was used to study the effect of mixing method, while partial least squares (PLS) regression was used to build the quantification models. PCA score plots showed that, in general, BM12 resulted in the narrowest sample clustering indicating better sample homogeneity. In the quantification models, the number of PLS factors was determined using cross-validation and the models were validated using independent test samples with known concentrations. Multiplicative scattering correction (MSC) without scaling gave the best PLS regression model for XPRD, and standard normal variate (SNV) transformation with centering gave the best model for Raman spectroscopy. Using PLS regression, the root mean square error of prediction (RMSEP) values of the best models were 5.0–6.9% for XRPD and 2.5–4.5% for Raman spectroscopy. XRPD and Raman spectroscopy in combination with PLS regression can be used to quantify the amount of single components in ternary mixtures of ranitidine hydrochloride solid forms. Raman spectroscopy gave better PLS regression models than XRPD, allowing a more accurate quantification.     

Quantitative analysis of diclofenac sodium powder via near-infrared spectroscopy combined with artificial neural network

A method for quantitative analysis of diclofenac sodium powder on the basis of near-infrared (NIR) spectroscopy is investigated by using of orthogonal projection to latent structures (O-PLS) combined with artificial neural network (ANN). 148 batches of different concentrations diclofenac sodium samples were divided into three groups: 80 training samples, 46 validation samples and 22 test samples. The average concentration of diclofenac sodium was 27.80%, and the concentration range of all the samples was 15.01–40.55%. O-PLS method was applied to remove systematic orthogonal variation from original NIR spectra of diclofenac sodium samples, and the filtered signal was used to establish ANN model. In this model, the concentration of diclofenac sodium was determined. The degree of approximation was employed as selective criterion of the optimum network parameters. In order to compare with O-PLS–ANN model, principal component artificial neural network (PC-ANN) model and calibration models that use different preprocessing methods (first derivative, standard normal variate (SNV) and multiplicative scatter correction (MSC)) of the original spectra were also designed. In addition, partial least squares regression (PLS) models were also established to compare with ANN models. Experimental results show that O-PLS–ANN model is the best.     

酚咖片中对乙酰氨基酚和咖啡因的近红外漫反射光谱法测定

建立了近红外漫反射光谱法测定酚咖片中对乙酰氨基酚和咖啡因的含量.以HPLC法所得结果作参比,采用偏最小二乘(PLS)回归法建立了一阶导数光谱与两组分含量间的定量校正模型.并从光谱范围、导数光谱及PLS主因子阶数对模型进行了优化.     

Simultaneous spectrophotometric determination of paracetamol, phenylephrine and chlropheniramine in pharmaceuticals using chemometric approaches

Background and the purpose of the study

The linear multivariate calibration models such as principal components regression (PCR) and partial least squares regressions (PLS1 and PLS2) due to the mathematical simplicity and physical or chemical interpretability are sufficient and generally preferred method for analysis of multicomponent drugs. In this study, simultaneous determination of paracetamol, phenylephrine and chlorpheniramine in pharmaceuticals using chemometric methods and UV spectrophotometry is reported as a simple alternative technique.

Material and methods

Principal components regression (PCR) and partial least squares regressions (PLS1 and PLS2) were used for chemometric analyses of data obtained from the spectra of paracetamol, phenylephrine and chlorpheniramine between wavelengths of 200 to 400 nm at several concentrations within their linear ranges. The analytical performance of these chemometric methods were characterized by relative prediction errors and recoveries (%) and compared with each other.

Results

PCR, PLS1 and PLS2 were successfully applied to a tablet formulation, with no interference from excipients as indicated by the recovery. However, the PLS1 shows better results due to its flexibility and mathematical principals.

Conclusion

The proposed methods are simple and rapid requiring no separation step, and can be easily used as an alternative in the quality control of drugs.     

Application of two chemometric methods for the determination of imipramine, amitriptyline and perphenazine in content uniformity and drug dissolution studies

Double-divisor spectra derivative and partial least squares methods were developed for content uniformity and dissolution tests in binary or ternary mixtures. The simultaneous determinations of perphenazine (PER) combined with amitriptyline hydrochloride (AMI) and/or imipramine hydrochloride (IMI) have been accomplished using the information of the absorption spectra of appropriate solutions. The double-divisor method is based on the use of the first derivative of the ratio spectrum obtained by dividing the absorption spectrum of the ternary mixture PER-AMI-IMI by a standard spectrum resulted from the addition of two of the three analytes in equal concentrations. The concentration of each component is then determined from their respective calibration graphs established by measuring the ratio derivative analytical signal at a specific wavelength. In this method, the linear determination ranges were of 3.65-18.24 microg/mL for PER, 4.32-21.60 microg/mL for AMI, and 4.83-24.19 microg/mL for IMI. The results were compared with those obtained by partial least squares multivariate calibration (PLS) method pre-treated by a wavelet compression-orthogonal signal correction (W-OSC) filter in zero-order derivative spectra. The calibration model was evaluated by internal validation (cross-validation) and by external validation over synthetic mixtures, content uniformity and dissolution tests. According to the dissolution profile test more than 95% of the three substances were dissolved within 10 min. The results from both techniques were statistically compared with each other and can be satisfactorily used for quantitative analysis and dissolution tests of multicomponent tablets.     

Stability‐indicating chemometric methods for the determination of pyritinol dihydrochloride

Three multivariate calibration methods, including classical least square with nonzero intercept (CLS), principal component regression (PCR) and partial least square (PLS), have been used for the determination of pyritinol dihydrochloride in the presence of its degradation product. The CLS, PCR and PLS techniques are useful in spectral analysis because the simultaneous inclusion of many spectral wavelengths instead of the single wavelength used in derivative spectrophotometry has greatly improved the precision and predictive abilities of these multivariate calibrations. A training set was constructed for the mixture and the best model was used for the prediction of the concentration of the selected drug. The proposed procedures were applied successfully in the determination of pyritinol dihydrochloride in laboratory‐prepared mixtures and in commercial preparations. Pyritinol dihydrochloride was analysed with mean accuracies 99.99 ± 0.905, 99.91 ± 0.966 and 99.92 ± 0.962 using the CLS, PCR and PLS methods respectively. The validity of the proposed methods was assessed using the standard addition technique. The proposed procedures were found to be rapid and simple and required no preliminary separation. They can therefore be used for the routine analysis of pyritinol dihydrochloride in quality‐control laboratories. Copyright © 2009 John Wiley & Sons, Ltd.     

Dissolution and assaying of multicomponent tablets by chemometric methods using computer-aided spectrophotometer

Dissolution of three component tablets containing paracetamol (APAP), propyphenazone (PP), and caffeine (CAF) was carried out by USP paddle method. Three chemometric methods; inverse least square (ILS), principal component regression (PCR) and partial least squares (PLS) were applied to simultaneous assay of APAP, PP and CAF in tablets. The PCR, PLS and ILS methods were applied to simultaneous dissolution APAP, PP and CAF in tablets using a double beam UV-Vis spectrophotometer without any chemical separation and any graphical treatment of the overlapping spectra of three drugs. Twenty two mixture solutions in different concentrations were prepared in simulated gastric juice (SGJ, USP) for the chemometric calibrations as training set. The absorbance data matrix was obtained by measuring the absorbance at 14 wavelength points (from 222.5 to 292.5 nm) with the intervals of 5 nm (Deltalambda=5 nm) in the spectral region between 200 and 310 nm. Training set and absorbance data were used for the calibrations of chemometric methods. The developed calibrations were tested for the previously prepared solutions of mixture of three drugs for the validation of the assay method. The chemometric calculations were performed by using the 'MAPLE VRSQUO; software. The results of three chemometric methods were statistically compared with each other. These chemometric calibrations were successfully applied to the content uniformity and dissolution of the multicomponent tablets without any separation procedure. The synthetic mixtures of three drugs were used for the validity of the calibrations. Means recoveries (percent) and relative standard deviation of PLS, PCR and ILS methods were found to be 100.1+/-0.6, 101.4+/-1.6 and 100.1+/-0.6 for APAP; 100.9+/-3.2, 102.0+/-3.3 and 100.9+/-3.2 for PP; 99.9+/-3.5, 101.6+/-3.3 and 99.9+/-3.2 for CAF, respectively. Dissolution profiles of three component tablets were performed. More than 95% of drugs were dissolved within 15 min. All of the three-chemometric methods in this study can be satisfactorily used for the quantitative analysis and for dissolutions test of multicomponent dosage form.     

Stability‐indicating chemometric methods for the determination of tazarotene

Two multivariate calibration methods—principal component regression (PCR) and partial least square (PLS)—have been used to determine tazarotene in the presence of its degradation products. Both methods are useful in spectral analysis because of the simultaneous inclusion of many spectral wavelengths instead of the single wavelength used in derivative spectrophotometry. A great improvement in the precision and predictive abilities of these multivariate calibrations was observed. A calibration set was constructed for the mixture and the best model was used to predict the concentration of the selected drug. The proposed methods were applied successfully in the determination of tazarotene in laboratory‐prepared mixtures and in commercial preparations. Tazarotene was analyzed with mean accuracies of 100.006 ± 0.695 and 100.007 ± 0.690 using the PCR and PLS methods, respectively. The validity of the proposed methods was assessed using the standard addition technique. The proposed methods were found to be rapid, simple and required no preliminary separation. They can therefore be used for the routine analysis of tazarotene in quality‐control laboratories. Copyright © 2010 John Wiley & Sons, Ltd.     

Simultaneous determination of Fe(II) and Fe(III) in pharmaceutical formulations with chromogenic mixed reagent by using principal component artificial neural network and multivariate calibration

The use of chemometric approaches for the simultaneous determination of Fe(II) and Fe(III) ions has been explored by means of a two component reagent. Mixed reagents of 1,10-phenanthroline and thiocyanate were used as a selective chromogenic system for speciation of Fe(II) and Fe(III). Although the complexes of Fe(II) and Fe(III) with mixed reagent show a spectral overlap, they have been simultaneously determined with chemometric approaches, such as principal component artificial neural network (PC-ANN), principal component regression (PCR) and partial least squares (PLS). A set of synthetic mixtures of Fe(II) and Fe(III) was evaluated and the results obtained by the applications of these chemometric approaches were discussed and compared. It was found that the PC-ANN and PLS methods afforded better precision relatively than its of PCR. PC-ANN and PLS methods were also applied satisfactorily in determination of Fe(II) and Fe(III) in pharmaceutical samples.     

High-Throughput NIR-Chemometric Method for Meloxicam Assay from Powder Blends for Tableting

A near infrared (NIR) method able to directly quantify the active content in pharmaceutical powder blends used for manufacturing meloxicam tablets, without any sample preparation, was developed and fully validated. To develop calibration models for the assay of meloxicam in powder blends for tableting, the NIR reflectance spectra of different meloxicam powder blends prepared according to a calibration protocol was analysed using different preprocessing methods by partial last-square regression (PLS) and principal component regression (PCR).The best calibration model was found when partial last-square regression (PLS) was used as regression algorithm in association with Smoothing-Savitsky as pre-processing spectrum method. The trueness, precision (repeatability and intermediate precision), accuracy, linearity and range of application of the developed NIR method were validated according to the International Conference of Harmonization (ICH) and Medicine European Agency (EMA) guidelines and found to be fit for its intended purpose.     

Simultaneous determination of metformin hydrochloride and pioglitazone hydrochloride in binary mixture and in their ternary mixture with pioglitazone acid degradate using spectrophotometric and chemometric methods

In this work two well known oral hypoglycemic drugs that are administered in combination for patients with type‐II diabetes were simultaneously determined. Several spectrophotometric methods were developed and validated for the determination of metformin hydrochloride (MET), pioglitazone hydrochloride (PIO) and pioglitazone acid degradate (PIO Deg). Derivative, ratio derivative, isosbestic and chemometric‐assisted spectrophotometric methods were developed. The first derivative (D₁) method was used for the determination of MET in the range of 5–30 µg.mL^?1 and PIO in the range of 10–90 µg.mL^?1 by measuring the peak amplitude at 247 nm and 280 nm, respectively. The concentration of PIO was calculated directly at 268 nm. The first derivative of ratio spectra (DD₁) method used the peak amplitudes at 238 nm and 248.6 nm for the determination of MET in the range of 5–30 µg.mL^?1. In the isosbestic point method (ISO), the total mixture concentration was calculated by measuring the absorbance at 254.6 nm. Classical least squares (CLS), principal component regression (PCR) and partial least squares (PLS‐2) were used for the quantitative determination of MET, PIO and PIO Deg. The methods developed have the advantage of simultaneous determination of the cited components without any pre‐treatment. Resolution and quantitative determination of PIO degradate with a minimum concentration of 3 µg.mL^?1 in drug samples was done. The proposed methods were successfully used to determine each drug and the acid degradate in a laboratory‐prepared mixture and pharmaceutical preparations. The results were statistically compared using one‐way analysis of variance (ANOVA). The methods developed were satisfactorily applied to the analysis of the two drugs in pharmaceutical formulations. Copyright © 2009 John Wiley & Sons, Ltd.     

Validated stability-indicating methods for determination of cilostazol in the presence of its degradation products according to the ICH guidelines

Sensitive and selective stability-indicating assay methods (SIAMs) are suggested for the determination of cilostazol (CIL) in the presence of its acid, alkaline and oxidative degradation products. Developing SIAMs is necessary to carry out any stability study. Stress testing of CIL was performed according to the International Conference on Harmonization (ICH) guidelines in order to validate the stability-indicating power of the analytical procedures. Stress testing showed that CIL underwent acid, alkaline and oxidative degradation; on the other hand, it showed stability towards photo- and thermal degradation. Two chromatographic SIAMs were developed, namely HPLC and HPTLC methods. The concentration range and the mean percentage recovery were 1.0-31.0 microg/ml and 99.96+/-0.46 and 0.6-14.0 microg/spot and 99.88+/-1.10 for HPLC and HPTLC methods, respectively. In addition, derivative spectrophotometric methods were developed in order to determine CIL in the presence of its acid degradation product; these were performed by using the third derivative spectra (3D) and the first derivative of the ratio spectra (1DD) methods. The linearity range and the mean percentage recovery were 2.0-34.0 microg/ml and 100.27+/-1.20 for the (3D) method, while they were 2.0-30.0 microg/ml and 99.94+/-1.18 for the (1DD) method. Also, two chemometric-assisted spectrophotometric methods, based on using partial least squares (PLS) and concentration residual augmented classical least squares method (CRACLS), for the determination of CIL were developed. Both methods were applied on zero order spectra of the mixtures of CIL and its acid degradation product, the mean percentage recovery was 100.03+/-1.09 and 99.91+/-1.27 for PLS and CRACLS, respectively. All methods were validated according to the International Conference on Harmonization (ICH) guidelines and applied on bulk powder and pharmaceutical formulations.     

Quantitative determination of diclofenac sodium and aminophylline in injection solutions by FT-Raman spectroscopy

The FT-Raman quantification of diclofenac sodium and aminophylline commercial injection solutions was performed. The efficiency of various spectra treatment procedures including classical univariate intensity ratio and multivariate partial least squares (PLS) and principal component regression (PCR) methods was compared. First, the calibration models were built using unnormalised spectra. Next, spectra normalised by the intensity of a selected band of CH₃CN added as an internal standard to the studied samples were utilised. To compare the predictive ability of the models constructed, the relative standard error of prediction (RSEP) was calculated. The errors found for multivariate calibrations were a few times smaller than those for the univariate ones. Usually, the most effective was the PLS method, for which RSEP values of the order of 1–2% for calibration and 2–3% for testing data sets were obtained.

Four commercial preparations of diclofenac sodium and one of aminophylline containing by weight, 2.4% of the active pharmaceutical ingredient (API) were quantified applying the developed models. Concentrations found from the Raman data analysis correlate with the declared values and the results of reference analyses. For the studied diclofenac sodium solutions they amount to 99.2–101.2% of the former and 101.2–102.4% of the latter quantities for the PLS models optimised for each medicine based on unnormalised spectra. These values for the aminophylline preparation were found to be 101.0 and 99.1%, respectively. It shows that the proposed procedure based on the chemometric treatment of FT-Raman spectra can be a fast and convenient alternative to the standard pharmacopoeial procedures of API quantification even in relatively diluted injection solutions.     

Content uniformity and dissolution tests of triplicate mixtures by a double divisor-ratio spectra derivative method

The use of a UV double divisor-ratio spectra derivative calibration for the simultaneous analysis of synthetic samples and commercial tablet preparations without prior separation is proposed. The method was successfully applied to quantify three ternary mixtures, chlorpheniramine maleate and caffeine combined with paracetamol or acetylsalicylic acid and a mixture of acetylsalicylic acid combined with paracetamol and caffeine, using the information in the absorption spectra of appropriate solutions. Beer's law was obeyed in the concentration range of 0.84-4.21 microg/ml for chlorpheniramine maleate, 1.60-15.96 microg/ml for caffeine, 2.0-20.0 microg/ml for acetylsalicylic acid and 1.58-15.93 microg/ml for paracetamol. The whole procedure was applied to synthetic mixtures of pure drugs as well as to commercial preparations (Algon) by using content uniformity and dissolution tests (USP 24) and was found to be precise and reproducible. According to the dissolution profile test more than 84% of paracetamol and caffeine were dissolved within 20 min. Acetylsalicylic acid dissolved more slowly, taking about 45-60 min to dissolve completely. A chemometric method partial least squares (PLS) and a HPLC method were also employed to evaluate the same mixtures. The results of the proposed method were in excellent agreement with those obtained from PLS and HPLC methods and can be satisfactorily used for routine analysis of multicomponent dosage forms.     

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.