Why should the pharmaceutical industry claim for the implementation of second-order chemometric models-A critical review.

Today, pharmaceutical products are submitted to a large number of analytical tests, planned to either ensure or construct their quality. The official methods of analysis used to perform these determinations are very different in nature, but almost all demand the intensive use of reagents and manpower as major drawbacks. Thus, analytical development is continuously evolving to find fast and smart approaches. First-order chemometric models are well-known in the pharmaceutical industry, and are extensively used in many fields. Such is the impact of chemometric models that regulatory agencies include them in guidelines and compendia. However, the mention or practical application of higher-order models in the pharmaceutical industry is rather scarce. Herein, we try to bring a brief introduction to chemometric models and useful literature references, focusing on higher-order chemometric models (HOCM) applied to reduce manpower, reagent consumption, and time of analysis, without sacrificing accuracy or precision, while gaining selectivity and sensitivity. The advantages and drawbacks of HOCM are also discussed, and the comparison to first-order chemometric models is also analyzed. Along the work, HOCM are evidenced as a powerful tool for the pharmaceutical industry; moreover, its implementation is shown during several steps of production, such as identification, purity test and assay, and other applications as homogeneity of API distribution, Process Analytical Technology (PAT), Quality by Design (QbD) or natural product fingerprinting. Among these topics, qualitative and quantitative applications were covered. Experimental approaches of chemometrics coupled to several analytical techniques such as UV-vis, fluorescence and vibrational spectroscopies (NIR, MIR and Raman), and other techniques as hyphenated-chromatography and electrochemical techniques applied to production and analysis are discussed throughout this work.

Development and validation of a green method for dissolution monitoring of pharmaceutical combinations. Meloxican and pridinol.

The development of a chemometric method for monitoring the pharmaceutical dissolution, under green analytical chemistry principles, was reported. Meloxicam (MEL) and pridinol (PRI) were employed as a combination model. Multivariate curve resolution with alternating least squares (MCR-ALS) was proposed to resolve UV spectra of the analytes during pharmaceutical dissolution. Empowering UV-vis spectrophotometry, which is considered an economical, ecological and fast technique, but poor in terms of selectivity. The developed method was validated in accordance to ICH guidelines, fulfilling acceptance criteria for linearity (r > 0.99 in the ranges 3.5-19.6 mg L-1 and 0.81-5.41 mg L-1 for MEL and PRI, respectively), accuracy (96.3% and 100.6% recoveries for MEL and PRI respectively), and precision (RSD < 10%) were evaluated using an independent validation set. Using a commercial sample, the method's accuracy was evaluated against HPLC analysis. Dissolution profiles were obtained using both methods. A point-to-point comparison with Moore and Flanner's factors (f1 and f2) were calculated. Specificity was evaluated by spectral correlation (R2>0.950). Additionally, the developed method works on-line and forgoes organic solvents and dilutions, lending itself to automation.

Pharmaceutical impurities and degradation products: uses and applications of NMR techniques.

Current standards and regulations demand the pharmaceutical industry not only to produce highly pure drug substances, but to achieve a thorough understanding of the impurities accompanying their manufactured drug substances and products. These challenges have become important goals of process chemistry and have steadily stimulated the search of impurities after accelerated or forced degradation procedures. As a result, impurity profiling is one of the most attractive, active and relevant fields of modern pharmaceutical analysis. This activity includes the identification, structural elucidation and quantitative determination of impurities and degradation products in bulk drugs and their pharmaceutical formulations. Nuclear magnetic resonance (NMR) spectroscopy has evolved into an irreplaceable approach for pharmaceutical quality assessment, currently playing a critical role in unequivocal structure identification as well as structural confirmation (qualitative detection), enabling the understanding of the underlying mechanisms of the formation of process and/or degradation impurities. NMR is able to provide qualitative information without the need of standards of the unknown compounds and multiple components can be quantified in a complex sample without previous separation. When coupled to separative techniques, the resulting hyphenated methodologies enhance the analytical power of this spectroscopy to previously unknown levels. As a result, and by enabling the implementation of rational decisions regarding the identity and level of impurities, NMR contributes to the goal of making better and safer medicines. Herein are discussed the applications of NMR spectroscopy and its hyphenated derivate techniques to the study of a wide range pharmaceutical impurities. Details on the advantages and disadvantages of the methodology and well as specific challenges with regards to the different analytical problems are also presented.

Method development and validation for the simultaneous determination of meloxicam and pridinol mesylate using RP-HPLC and its application in drug formulations.

A simple and reliable reversed-phase high-perfomance liquid chromatographic method has been developed and validated for the simultaneous determination of meloxicam and pridinol mesylate in their synthetic mixtures and combined tablet formulations. Both drugs were separated on a 250 mm x 4.6mm C18 column packed with 5 microm particles. The mobile phase, optimized through an experimental design, was a 51:9:40 (v/v/v) mixture of methanol, isopropanol and 50mM potassium phosphate buffer (pH 5.9), pumped at a flow rate of 1.0 ml min(-1). UV detection was performed at 225 nm. The method was validated in the sample concentration ranges of 33.7-61.8 mg l(-1) for meloxicam and 8.8-16.8 mg l(-1) for pridinol mesylate, where it demonstrated good linearity with r=0.9989 and 0.9987 (n=15), respectively. The assay was shown to be repeatable at concentration levels of 70%, 100% and 130%, with relative standard deviation values of 1.09% and 0.82% for meloxicam and pridinol, respectively. For independent 100% level samples, the intra-day precision was 0.4% and 1.0% while the intermediate precision was 0.7% and 1.0% for the drugs. The method demonstrated to be robust, resisting to small deliberate changes in pH, flow rate and composition (organic:aqueous ratio) of the mobile phase. The LOD values were 0.22 and 0.20 mg l(-1), while the LOQ were 1.7 and 1.1 mg l(-1), for meloxicam and pridinol, respectively. The applicability of the method was demonstrated by determining the drug content of two commercial pharmaceutical formulations, where it exhibited good performance.

Alternative and improved method for the simultaneous determination of fexofenadine and pseudoephedrine in their combined tablet formulation.

An alternative method for the determination of fexofenadine (FEX) and pseudoephedrine (PSE) in their combined tablet formulation has been developed, employing the partial least squares (PLS) analysis of spectral data of the analytes in their pharmaceutical association. A full-factorially designed set of 16 synthetic samples was employed for calibration purposes. The calibration models were constructed with wavelengths selection, in the ultraviolet region, according to their predictive ability. These were validated internally by the leave-one-out procedure and externally, employing appropriate sets of validation samples. The described method was linear for both analytes, over the range 160.6-301.2 mg L(-1) for FEX (R(2)=0.9993) and between 325.6 and 610.5 mg L(-1) for PSE (R(2)=0.9992). It was accurate, exhibiting 99.8% and 99.9% drug recoveries for FEX and PSE, respectively (N=9), while in the intermediate precision experiment relative standard deviations were 1.4% for FEX and 1.2% for PSE. The contents of both analytes were assayed in commercial tablets employing this method and the results were compared with those furnished by HPLC, being in good statistical agreement. The method represents an improvement over the first derivative of spectral ratio (DSR) technique and allows high sample throughput with minimum reagent consumption and waste generation. The obtained results confirm that the method is highly suitable for its intended purpose.

PLS and first derivative of ratio spectra methods for determination of hydrochlorothiazide and propranolol hydrochloride in tablets.

Two new analytical methods have been developed as convenient and useful alternatives for simultaneous determination of hydrochlorothiazide (HCT) and propranolol hydrochloride (PRO) in pharmaceutical formulations. The methods are based on the first derivative of ratio spectra (DRS) and on partial least squares (PLS) analysis of the ultraviolet absorption spectra of the samples in the 250-350-nm region. The methods were calibrated between 8.7 and 16.0 mg L(-1) for HCT and between 14.0 and 51.5 mg L(-1) for PRO. An asymmetric full-factorial design and wavelength selection (277-294 nm for HCT and 297-319 for PRO) were used for the PLS method and signal intensities at 276 and 322 nm were used in the DRS method for HCT and PRO, respectively. Performance characteristics of the analytical methods were evaluated by use of validation samples and both methods showed to be accurate and precise, furnishing near quantitative analyte recoveries (100.4 and 99.3% for HCT and PRO by use of PLS) and relative standard deviations below 2%. For PLS the lower limits of quantification were 0.37 and 0.66 mg L(-1) for HCT and PRO, respectively, whereas for DRS they were 1.15 and 3.05 mg L(-1) for HCT and PRO, respectively. The methods were used for quantification of HCT and PRO in synthetic mixtures and in two commercial tablet preparations containing different proportions of the analytes. The results of the drug content assay and the tablet dissolution test were in statistical agreement (p < 0.05) with those furnished by the official procedures of the USP 29. Preparation of dissolution profiles of the combined tablet formulations was also performed with the aid of the proposed methods. The methods are easy to apply, use relatively simple equipment, require minimum sample pre-treatment, enable high sample throughput, and generate less solvent waste than other procedures.

Application of a chemometric method for simultaneous determination of acetaminophen and diclofenac in content-uniformity and drug-dissolution studies.

A new, repeatable, and rapid method has been developed for resolution of binary mixtures of acetaminophen and diclofenac with minimum sample pretreatment and without separation of the analytes. The method, based on the PLS1 processing of absorbance data in the UV region, was successfully used for quantification of the drug content of three tablet preparations. The results obtained were in good agreement with HPLC recovery data. The method also enabled determination of drug-dissolution profiles of these commercial tablets, by simultaneous determination of both analytes during the dissolution test.