Frederico Luis Felipe Soares

Evaluation of analytical tools and multivariate methods for quantification of co-former crystals in ibuprofen-nicotinamide co-crystals.

Co-crystals are multicomponent substances designed by the addition of two or more different molecules in a same crystallographic pattern, in which it differs from the crystallographic motif of its co-formers. The addition of highly soluble molecules, like nicotinamide, in the crystallographic pattern of ibuprofen enhances its solubility more than 7.5 times, improving the properties of this widely used drug. Several analytical solid state techniques are used to characterize the ibuprofen-nicotinamide co-crystal, being the most used: mid-infrared (ATR-FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRPD) and Raman spectroscopy. These analytical solid state techniques were evaluated to quantify a mixture of ibuprofen-nicotinamide co-crystal and its co-formers in order to develop a calibration model to evaluate the co-crystal purity after its synthesis. Raman spectroscopy showed better result than all other techniques with a combination of multivariate calibration tools, presenting lower values of calibration and prediction errors. The partial least squares regression model gave a mean error lower than 5% for all components presented in the mixture. DSC and mid-infrared spectroscopy proved to be insufficient for quantification of the ternary mixture. XRPD presented good results for quantification of the co-formers, ibuprofen and nicotinamide, but fair results for the co-crystal. This is the first report of quantification of ibuprofen-nicotinamide co-crystal, among its co-formers. The quantification is of great importance to determine the yield of the co-crystallization reactions and the purity of the product obtained.

Determination of acetylsalicylic acid in commercial tablets by SERS using silver nanoparticle-coated filter paper

In this work, filter paper was used as a low cost substrate for silver nanoparticles in order to perform the detection and quantification of acetylsalicylic acid by SERS in a commercial tablet. The reaction conditions were 150mM of ammonium hydroxide, 50mM of silver nitrate, 500mM of glucose, 12min of the reaction time, 45°C temperature, pretreatment with ammonium hydroxide and quantitative filter paper (1-2μm). The average size of silver nanoparticles deposited on the paper substrate was 180nm. Adsorption time of acetylsalicylic acid on the surface of the silver-coated filter paper was studied and an adsorption time of 80min was used to build the analytical curve. It was possible to obtain a calibration curve with good precision with a coefficient of determination of 0.933. The method proposed in this work was capable to quantify acetylsalicylic acid in commercial tablets, at low concentration levels, with relative error of 2.06% compared to the HPLC. The preparation of filter paper coated with silver nanoparticles using Tollens reagent presents several advantages such as low cost of synthesis, support and reagents; minimum amount of residuals, which are easily treated, despite the SERS spectroscopy presenting fast analysis, with low sample preparation and low amount of reactants as in HPLC analysis.

In-line monitoring of cocrystallization process and quantification of carbamazepine-nicotinamide cocrystal using Raman spectroscopy and chemometric tools

A cocrystallization process may involve several molecular species, which are generally solid under ambient conditions. Thus, accurate monitoring of different components that might appear during the reaction is necessary, as well as quantification of the final product. This work reports for the first time the synthesis of carbamazepine-nicotinamide cocrystal in aqueous media with a full conversion. The reactions were monitored by Raman spectroscopy coupled with Multivariate Curve Resolution - Alternating Least Squares, and the quantification of the final product among its coformers was performed using Raman spectroscopy and Partial Least Squares regression. The slurry reaction was made in four different conditions: room temperature, 40°C, 60°C and 80°C. The slurry reaction at 80°C enabled a full conversion of initial substrates into the cocrystal form, using water as solvent for a greener method. The employment of MCR-ALS coupled with Raman spectroscopy enabled to observe the main steps of the reactions, such as drug dissolution, nucleation and crystallization of the cocrystal. The PLS models gave mean errors of cross validation around 2.0 (% wt/wt), and errors of validation between 2.5 and 8.2 (% wt/wt) for all components. These were good results since the spectra of cocrystals and the physical mixture of the coformers present some similar peaks.

Crystalline phase transition of ezetimibe in final product, after packing, promoted by the humidity of excipients: Monitoring and quantification by Raman spectroscopy

Ezetimibe (EZT), in its anhydrous form, is a drug used for cholesterol and lipids reduction in blood plasma. The presence of EZT monohydrate in commercial tablets can change the solubility rate of the API, decreasing its activity. The objective of this work was to verify if the humidity present in the excipients could promote the phase transition from EZT anhydrous to hydrate. Initially the stability of the pure anhydrous form was monitored by Raman, at room temperature (23°C) and relative humidity (75%). The MCR-ALS method showed that almost all EZT changed to hydrated form in 30 min. Then tablets of ezetimibe in the presence of its excipients were prepared and vacuum packed using a polyethylene film. Such tablet was monitored by Raman spectroscopy for 24h in order to quantify the mixture of the crystalline forms. A multivariate calibration model using Raman spectroscopy and Partial Least Square (PLS) regression was built, with validation and cross validation errors around 0.6% (wt/wt), for both crystalline forms, and R(2) higher than 0.96. The PLS model was used to quantify the crystalline mixture of ezetimibe in the monitored tablet, after 24h more than 70% of ezetimibe changed to the hydrated form.

Determination of B-complex vitamins in pharmaceutical formulations by surface-enhanced Raman spectroscopy

The aim of this work was to quantify B-complex vitamins in pharmaceutical samples by surface enhanced Raman spectroscopy technique using gold colloid substrate. Synthesis of gold nanoparticles was performed according to an adapted Turkevich method. Initial essays were able to suggest the orientation of molecules on gold nanoparticles surface. Central Composite design was performed to obtain the highest SERS signal for nicotinamide and riboflavin. The evaluated parameters in the experimental design were volume of AuNPs, concentration of vitamins and sodium chloride concentration. The best condition for nicotinamide was NaCl 2.3×10-3molL-1 and 700μL of AuNPs colloid and this same condition showed to be adequate to quantify thiamine. The experimental design for riboflavin shows the best condition at NaCl 1.15×10-2molL-1 and 2.8mL of AuNPs colloid. It was possible to quantify thiamine and nicotinamide in presence of others vitamins and excipients in two solid multivitamin formulations using the standard addition procedure. The standard addition curve presented a R2 higher than 0.96 for both nicotinamide and thiamine, at orders of magnitude 10-7 and 10-8molL-1, respectively. The nicotinamide content in a cosmetic gel sample was also quantified by direct analysis presenting R2 0.98. The t-student test presented no significant difference regarding HPLC method. Despite the experimental design performed for riboflavin, it was not possible its quantification in the commercial samples.

Characterization of Gasoline by Raman Spectroscopy with Chemometric Analysis

ABSTRACT A rapid Raman spectroscopy protocol is reported to classify gasoline according to its distributor and to identify and quantify common adulterants. Gasoline from three distributors was collected from 19 stations in São Paulo, Brazil. Principal component analysis (PCA) showed specific clusters for each distributor, and partial least squares discriminant analysis (PLS-DA) correctly identified the origin of the samples. To evaluate the technique for the identification and quantification of the adulterants, authentic samples from each distributor were fortified at levels from 2.5 up to 25.0% (v/v) using ethanol, methanol, toluene, and turpentine to obtain 120 altered samples. PCA showed clear separation among the samples with the adulterants and PLS-DA precisely identified the adulterants (478 in 480 predictions by cross-validation), irrespective of the distributor and the concentration. One classification model was used to characterize all distributors. To quantify the adulterants, 36 multivariate calibration models were constructed using partial least squares (PLS), interval PLS, and PLS genetic algorithm for each distributor and for each adulterant. Cross-validation errors of less than 5.0% were obtained for all adulterants regardless of the distributor. Raman spectroscopy and multivariate analysis were shown to be powerful for rapid and inexpensive for the characterization of gasoline origin and the identification and quantification of common adulterants.