Study of polymorphism in drugs using spectroscopic techniques coupled with chemometric methods

Orientador: Ronei Jesus PoppiTese (doutorado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: O estudo do fenômeno de polimorfismo em fármacos é muito importante na indústria farmacêutica. Dessa forma, tem sido extensivamente investigado, devido ao seu impacto sobre a qualidade e eficácia das formulações farmacêuticas. Neste trabalho, três novas metodologias para o controle de qualidade de polimorfismo em fármacos foram propostas. O desenvolvimento, desses métodos, visa tomar as análises de controle de qualidade na indústria farmacêutica mais prática, rápida e sem a necessidade de consumo de reagentes com alto grau de toxicidade. Na primeira metodologia foi proposta a caracterização da composição polimórfica do fármaco Piroxicam em formulações farmacêuticas utilizando cartas de controle multivariadas baseada no cálculo do sinal analítico líquido e da espectroscopia na região do infravermelho próximo. Nesse caso, foi possível a identificação da presença das diferentes formas polimórficas nas formulações farmacêuticas. Em uma segunda metodologia, no qual também foi utilizado o fármaco Piroxicam, procurou-se realizar a quantificação e a distribuição de duas formas polimórficas através da espectroscopia de imagem na região do infravermelho próximo aliado ao método quimiométrico PLS. Os resultados mostraram que para ambos os modelos desenvolvidos os valores de RMSEP (%(m/m)) estão abaixo de 4%. Também foi possível obter a informação da distribuição espacial dos diferentes polimorfos nas formulações farmacêuticas. Na última metodologia utilizou-se da espectroscopia Raman e das cartas de controle multivariadas para identificação no fármaco Carbamazepina de adulteração em excipiente, transformação de formas polimórficas por humidade e detecção de diferentes formas polimórficas. Foi possível identificar a presença e a transformação dos diferentes polimórficos presentes, além da sua correta identificaçãoAbstract: The study of the polymorphism phenomenon in drugs is very important in the pharmaceutical industry. Thus, it has been extensively investigated because of its impact on the pharmaceutical formulations quality and effectiveness. In this work, three new methods for quality control of polymorphism in drugs were proposed. The development of these methods, aims to make the analysis of quality control in the pharmaceutical industry more practical, faster and without the need of reagent consumptions with a high degree of toxicity. In the first method it was proposed the characterization of Piroxican polymorphic composition in pharmaceutical formulations using multivariate control charts based on the calculation of the net analytical signal and the near infrared spectroscopy. In that case, it was possible to identify the presence of different polymorphic forms of the drug in the pharmaceutical formulations. In a second method, in which it was also used Piroxicam, there was an attempt to carry out the quantification and distribution of two polymorphic forms through the near-infrared imaging spectroscopy technique and PLS chemometric method. The results showed that for both models developed the RMSEP values (% (m / m)) are below 4%. It was also possible to distinguish the information from local and global distributions of different polymorphics in pharmaceutical formulations. In the last method it was used Raman spectroscopy and multivariate control charts to identify adulteration in excipients, polymorphic forms change by humidity and the detection of different polymorphic forms in the Carbamazepine drugDoutoradoQuimica AnaliticaDoutor em Ciência

Utilization of net analyte signal for validation of models of multivariate calibration by using figure of merit and chart control

Orientador: Ronei Jesus PoppiDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de QuimicaResumo: Este trabalho teve como objetivo realizar a validação de modelos de calibração multivariada através do cálculo de figuras de mérito e de cartas de controle multivariadas do medicamento Nimesulida por meio do infravermelho próximo. Foram preparadas 69 amostras sintéticas contendo o princípio ativo (Nimesulida) na faixa 10,38-39,47% (m/m) em excipiente (lactose, povidona-KV29- 32, celulose 200, lauril sulfato de sódio, croscarmelose sódica e estereato de magnésio). Destas, 49 amostras foram utilizadas para a calibração e 20 para a validação as quais foram separadas através do algoritmo de Kennard-Stone.O tratamento utilizado nos espectros foi a correção do espalhamento multiplicativo. Na sequência, foram obtidos os seguintes valores para as figuras de mérito: limite de detecção (0,61), limite de quantificação (2,03), exatidão (RMESC 0,66 %(m/m), RMESCV 0,92 %(m/m), RMESP 1,05 %(m/m) de Nimesulida), seletividade média (0,0056), sensibilidade (0,0036), inverso da sensibilidade analítica (0,20 %(m/m)-1 de Nimesulida) e razão sinal ruído (181,11). Na segunda parte do trabalho foram utilizadas 113 amostras sintéticas para construção das cartas de controle multivariadas. Foram desenvolvidas três cartas de controle e calculado os limites de controle para cada carta. Os valores encontrados foram: - carta NAS (Superior = 6,54x10; Inferior = 5,25x10), carta interferente (7,45) e carta resíduo (2,38x10). Através dessas cartas de controle multivariadas foi possível identificar as amostras que estavam dentro e fora de controle. Obteve-se 64 amostras fora de controle e 20 amostras dentro de controle de acordo com o planejamento experimental realizado. Sendo assim, foi possível identificar, de forma qualitativa, as amostras de Nimesulida que estavam dentro e fora de controle. Portanto, a dissertação desenvolvida sugere um novo método analítico que pode ser usado para controle de qualidade em fármacos e para validação de modelos de calibração multivariada, pois os resultados obtidos, indicam que o modelo desenvolvido pode ser utilizado na indústria farmacêutica como uma alternativa ao método-padrãoAbstract: This study was mainly intended to elaborate the validation of multivariate calibration models based on the determination of figures of merit and multivariate control charts constructed with data from Nimesulide tablets upon near-infrared spectroscopy use. A total of 69 synthetic samples were prepared containing the active principle (Nimesulide) in the range of 10,38-39, 47% (m/m) in excipients (Cellulose,Sodium Lauryl Sulphate, Magnesium Stearate, Carmellose Sodium,Povidone and Lactose). It was used 49 samples for the calibration and 20 for the validation that were separated by the Kennard-Stone algorithm. It was used the multiplicative scatter correction on the spectra set. Then, the following values for figures of merit were calculated: limit of detection (0,61) , limit quantification (2,03) , accuracy (RMESC 0,66 %(m/m), RMESCV 0,92%(m/m), RMESP 1,05%(m/m) of Nimesulide), mean selectivity (0,0056), sensitivity (0,0036), inverse analytical sensitivity (0,20 %(m/m)- 1 of the Nimesulide) and signal-to-noise ration (181, 11). In the second application, 113 synthetic samples were used for the construction of multivariate control charts. Three control charts were designed and the control limits for each chart were calculated. The values found were: - chart NAS (upper = 6,54x10; below = 5,25x10), chart interferent (7,45) and chart residual (2,38x10). From these charts it was possible to identify the samples that were in and out of control. It was obtained 64 samples out of control and 20 samples in control, according to the experimental design. Therefore, it was possible to identify, in a qualitative way, the Nimisulide samples that were in control and the ones that were out of control. Hence it follows that, this research project suggests a new analytical method that can be used for quality control in drugs and also for the validation of multivariate calibration models. Thus, the results obtained indicate that this model can be used in pharmaceutical industries as an alternative to the standard procedureMestradoQuimica AnaliticaMestre em Químic

Monte Carlo simulation for the evaluation of measurement uncertainty of pharmaceutical certified reference materials

7 p. : il.O suplemento do Guia para a Expressão da Incerteza de Medição (GUM) publicado em 2008, o qual trata da propagação de distribuições, encoraja o uso do método de Monte Carlo (MC) para a estimativa de incerteza de medição. Este artigo descreve a aplicação deste método para estimativa da incerteza de medição do teor de ingredientes ativos farmacêuticos em dois novos materiais de referência certificados (MRC): metronidazol e captopril. Os resultados obtidos pelo método de Monte Carlo e pelo método tradicional (GUM) mostraram concordância considerando um valor crítico δ de 0,005 para metronidazol e 0,05 para captopril. Deste modo, o método de Monte Carlo validou os resultados obtidos pelo método tradicional (GUM) para a expressão do teor dos fármacos com no mínimo duas casas decimais._________________________________.ABSTRACT - The supplemental Guide to the Expression of Uncertainty Measurement (2008), which deals with the propagation of distributions, encourages the use of the Monte Carlo simulation (MCS) for estimating the uncertainty of measurands. This paper describes the application of this method to estimate the measurement uncertainty of active pharmaceutical ingredient (API) mass fractions of two certified reference materials (CRMs): metronidazole and captopril. The Monte Carlo results complied with the GUM results in terms of the critical value δ of 0.005 for metronidazole and 0.05 for captopril. Therefore, the Monte Carlo method validated the GUM through the expression of the API mass fraction with at least two decimal places

Quality control of the paracetamol drug by chemometrics and imaging spectroscopy in the near infrared region

5 p. : il.In this work, it was used imaging spectroscopy and chemometric tools for the development and analysis of paracetamol and excipients in pharmaceutical formulations. It was also built concentration maps to study the distribution of the drug in the tablets surface. Multivariate models based on PLS regression were developed for paracetamol and excipients concentrations prediction. For the construction of the models it was used 31 samples in the tablet form containing the active principle in a concentration range of 30.0–90.0% (w/w) and errors below to 5% were obtained for validation samples. Finally, the study of the distribution in the drug was performed through the distribution maps of concentration of active principle and excipients. The analysis of maps showed the complementarity between the active principle and excipients in the tablets. The region with a high concentration of a constituent must have, necessarily, absence or low concentration of the other one. Thus, an alternative method for the paracetamol drug quality monitoring is presented

Study of the similarity between distribution maps of concentration in near-infrared spectroscopy chemical imaging obtained by different multivariate calibration approaches

6 p. : il.Nowadays, near-infrared spectroscopy chemical imaging (NIR-CI) has been widely used in pharmaceutical analysis since it provides important surface information about the samples. In thiswork the information of NIR-CI at the pixel levelwas compared through calculation of the similarity between distribution maps of concentration obtained by differentmultivariate calibration approaches. The comparison was performed by using four different multivariate methods (MCR, MLR, CLS and PLS) in analysis of carbamazepine pharmaceutical formulations. For global determination, all models developed showed RMSEP below 1.9% (w/w) for active principal ingredient (API) and better than 4.6%(w/w) for excipients. Also, the distributionmaps obtained by PLS, CLS andMCR showed great similarity for all compounds of the formulation as well with concentrations in the tablets. However, comparing the distribution maps obtained by MLR with those from the other chemometric tools, a lower similaritywas observed. Thus, this fitted model does not ensure, by itself, that the images obtained are reliable or accurate. The paper also compares the distribution maps of concentrations obtained fromall constituents present in the pharmaceutical formulation with their respective micrographs

Characterization of sildenafil citrate tablets of different sources by near infrared chemical imaging and chemometric tools

In this paper the chemical imaging technique by near infrared spectroscopy was applied for characterization of drug formulations in tablets of sildenafil citrate of different sources. This work is original and has never been published because it was used the sildenafil citrate, including in the commercial one called "Viagra". In the first stage of the study, a chemometric method based on multivariate curve resolution was properly chosen for the development of the distribution map of concentrations of the active ingredient in tablets. In the second step, the normalized histograms of images from active ingredient were classified by hierarchical cluster analysis. Finally it was possible to recognize the patterns of homogeneity of images in sildenafil citrate tablet. This concept can be used to improve the knowledge of industrial products and processes, as well as, for characterization of counterfeit drugs

Anti-theft device staining on banknotes detected by mass spectrometry imaging

We describe the identification and limits of detection of ink staining by mass spectrometry imaging (MSI), as used in anti-theft devices (ATDs). Such ink staining is applied to banknotes during automated teller machine (ATM) explosions. Desorption electrospray ionization (DESI) coupled with high-resolution and high-accuracy orbitrap mass spectrometry (MS) and a moving stage device were applied to obtain 2D molecular images of the major dyes used for staining, that is, 1-methylaminoanthraquinone (MAAQ), rhodamine B (RB) and rhodamine 6G (R6G). MAAQ could not be detected because of its inefficient desorption by DESI from the banknote cellulose surface. By contrast, ATD staining on banknotes is perceptible by the human naked eye only at concentrations higher than 0.2μgcm(-2), whereas both RB and R6G at concentrations 200 times lower (as low as 0.001μgcm(-2)) could be easily detected and imaged by DESI-MSI, with selective and specific identification of each analyte and their spatial distribution on samples from suspects. This technique is non-destructive, and no sample preparation is required, which ensures sample preservation for further forensic investigations.We describe the identification and limits of detection of ink staining by mass spectrometry imaging (MSI), as used in anti-theft devices (ATDs). Such ink staining is applied to banknotes during automated teller machine (ATM) explosions. Desorption electro2602226CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR23038.006844/2014-4

Evaluation study of different glass electrodes by an interlaboratory comparison for determining the pH of fuel ethanol

6 p. : il.This work evaluated different combined glass electrodes by means of an interlaboratory comparison in order to determine the pH of fuel ethanol. Four electrodes with different reference electrode systems (Ag/AgCl or Pt/redox pair), liquid junctions (single or double) and internal filling solutions (aqueous KCl or ethanolic LiCl) were used in comparison with the Orion Ross Sure-flow® N◦ 8172 BN electrode, a specific electrode advised by the ASTM D6423 standard. Three fuel ethanol samples with different water contents (0.1, 0.6 and 6.8%, w/w) were analyzed by nine laboratories. The results showed that all the electrodes with aqueous KCl filling solution and single liquid junction, including the Orion® electrode, presented equivalent results. The sole electrode with ethanolic LiCl filling solution showed pH results lower than the other electrodes, whereas the sole electrode with double liquid junction, showed pH results slightly higher than those with similar filling solution containing single liquid junction. On the other hand, only the latter two electrodes presented acceptable repeatability limit values. The results indicate a need to revise the ASTM D6423 standard with the purpose of enlarging the number of electrodes that can be used to measure the pH of ethanol fuel, as well as support the harmonization of the different regional standards used to measure the pH of fuel ethano

Development Studies of a New Metronidazole Certified Reference Material

10 p. : il.Este artigo apresenta os resultados dos estudos realizados com o candidato a material de referência certificado (MRC) de metronidazol, primeiro MRC deste fármaco disponibilizado no mercado e segundo MRC de fármacos brasileiro. Os estudos incluem a determinação dos teores de impurezas orgânicas, inorgânicas e voláteis, validação do método analítico de cromatografia líquida de alta eficiência (CLAE), estudos de estabilidade em condições de transporte e estocagem, estudo de homogeneidade, determinação do teor de metronidazol por balanço de massa, confirmação deste valor por calorimetria exploratória diferencial (DSC) e cálculo de incertezas de medição. ____________________________________________________________________________________.This paper presents the results of the studies carried out with the candidate certified reference material (CRM) of metronidazole, first CRM of this active pharmaceutical ingredient (API) available on the market and second Brazilian CRM of an API. The investigation includes the determination of organic impurities, inorganic impurities and volatiles, validation of the HPLC‑DAD method, stability studies under transport and storage conditions, homogeneity testing, calculation of metronidazole content by mass balance, confirmation of the certified value by differential scanning calorimetry (DSC), and estimation of measurement uncertainties