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The use of near infrared (NIR) spectroscopy to predict the concentration of two active pharmaceutical ingredients (APIs), paracetamol and caffeine, in intact tablets, has been evaluated in this study. A partial least squares (PLS) regression model was developed using spectral data obtained on a calibration set consisting of 28 formulations containing 80, 90, 100, 110 and 120% of each API. Regression models were developed for each API, both using un-processed spectral data as well as after applying various spectra pre-processing methods. Cross-validation was used to select best calibration model. The selected model was validated in terms of precision, trueness, accuracy and linearity in a concentration ranging from 90 to 110% of the targeted APIs concentration. The applicability of the method was tested on tablets containing 300 mg paracetamol and 30 mg caffeine as targeted composition, and the API content predicted by the proposed NIR-chemometric method was not statistically different from the one obtained by HPLC method, used as a reference method. Thus, the method presented in the current paper is a step forward towards the implementation NIR as useful tool for monitoring the manufacturing process of fixed-dose combination tablets with paracetamol and caffeine.

The purpose of this research was to apply near-infrared (NIR) spectroscopy in combination with chemometrics to predict particle size and flow characteristics of a meloxicam powder blends for tableting. In order to develop calibration models for particle size (mean particle size, poly-dispersion index), and flow properties (angle of repose and time of flow) prediction, the NIR reflection spectra of different meloxicam powder blends prepared according to an experimental design were analyzed using different preprocessing methods by partial last-square (PLS) regression followed by leaveone-out cross-validation. Very good prediction ability was found for mean particle size, poly-dispersion index, angle of repose, and time of flow in models in whose development no preprocessing spectrum was applied. Also, a good prediction was found preprocessing spectrum such smoothing - moving average for particle size characteristics, and unit vector normalization for powder flow properties. Therefore, NIR-chemometric methods developed in this work can be useful for the prediction of the granulometric properties and parameters related to the flowability of the meloxicam powder blends and may be used as process analytical technology (PAT) tools for process control during meloxicam tablets manufacturing.

Objectives. The aim of this study was to optimize the formulation of certain immediate release foaming vaginal tablets, with fast vaginal disintegration (part I), fallowing their time stability (part II). Material and methods. Modde optimizing software and a Box-Bhenken experimental design was used to establish an optimal formula that would provide maximum “in vitro” behaviour advantages, including stability during preservation; and the improvement of the foaming effect. There were prepared 15 formulations of foaming vaginal tablets in order to choose the optimal formula. Outcomes. The main factor, with influence over all the studied parameters, is the percentage of the effervescent mixture in the formulation. The excess of citric acid has a main role in the assurance of local pH; in the improvement of the flowing properties of the powder mixtures before compression; and in the improvement of the effervescent process, having, on the other hand, an effect of decreasing the stability of tablets and increasing their humidity adsorption. Sodium lauryl sulphate, at the chosen concentration levels (0.5-1.5%), did not influence the dependent variables, it only produced a stronger resistance of the foam. The optimal formula of a foaming vaginal tablet with an optimal stability during preservation must contain 0.5% sodium lauryl sulphate, while the effervescent mixture must contain a percentage of 24% excess of citric acid, and it must represent 44% of the total amount of excipients. Conclusions. The experimental determinations of the optimal formula were close to the theoretical values predicted by the program, this certifying the validity of the optimization and the conclusion draw after analysis the experimental design.

Objectives. The aim of this study was to develop and validate a NIR-chemometric method for direct quantification of loratadine in powder blends for tableting and tablets, without any sample preparation. Material and methods. Calibration samples were prepared according to an experimental design with 1 variable and 5 level, containing from 8 to 12 mg loratadine/tablet. Outcomes. For the powder blends, the model generated with the use of spectral range 9,000-4,000 cm-1 and FD+SNV pre-treatment method had the best results, considering the number of PLS factors 9, R2 = 0.984 and RMSECV = 0.267%. For the tablets, the model using the spectral range 11,100-7,128 cm-1 and mMN pre-treatment method had the best results, considering the number of PLS factors 10, R2 = 0.985 and RMSECV = 0.170 mg. Using these calibration models, the method was fully validated according to the ICH guidance. For both powder blends and tablets, the best accuracy was obtained at the concentration level of 10 mg/tablet and the relative bias had values between 0.05% and 1.98% respectively -0.360% and 0.618%. Conclusions. The NIR-chemometric method has good reproducibility and satisfactory accuracy and linearity profiles, indicating that this method could be used for direct determination of loratadine in powder blends for tableting and tablets, without any sample preparation.

This study aims to develop and validate NIR-chemometric methods for quantifying the API (quetiapine) and two excipients in extended-release tablets without sample preparation. The calibration samples were prepared following an experimental design with three variables (quetiapine, HPMC and microcrystalline cellulose) and five levels (concentration 80-90-100-110-120% of API). The validation set included three concentration levels (90-100-110%). The best calibration algorithms have used the same pre-treatment method (SNV), and different factors: 7 PLS factors (R² -0,966 and RMSEP-6,84) for quetiapine, 8 PLS factors (R²-0,927 and RMSEP 6,84) for HPMC and 3 PLS factors (R²-0,983 and RMSEP-7,26) for microcrystalline cellulose. The methods were fully validated according to the ICH guidance using these calibration models. Regarding the trueness of the methods, the recovery was between 98.51 and 99.43 for quetiapine, between 98.61 and 100.85 for HPMC, and between 100.61 and 101.78 for microcrystalline cellulose. According to data obtained, the accuracy profile was ± 5 for quetiapine and HPMC, and ± 6 for microcrystalline cellulose. Linearity profile was also in establish intervals at accuracy and the R2 value was 0.983 for quetiapine, 0.948 for HPMC and 0.997 for microcrystalline cellulose. In conclusion, the developed NIR-chemometric methods have suitable reproducibility, accuracy, linearity and can be used for quantitative characterisation of extended-release tablets with quetiapine, with any sample preparation.

Objectives. The objective of this study was to investigate the possibility of developing metoprolol extended-release tablets by using hydroxypropyl methylcellulose (HPMC) in order to obtain the hydrophilic matrix and Eudragit NE 40D, Kollicoat SR 30D and Surelease E7 as binders during the granulation process. Material and methods. The extended-release tablets were prepared via fluid bed granulation of metoprolol powder using Eudragit NE 40D / Kollicoat SR 30D / Surelease E7 as binders, followed by compression. The influence of three formulation factors (the type of granulation polymers, the ratio of granulation polymers and the HPMC ratio) on the kinetic metoprolol tartrate release was investigated through a full factorial experimental design. Outcomes. The kinetic release of all 26 formulations was best fitted with Peppas model. According to n values of Peppas equation, the release mechanism of drug consists in water diffusion into the matrix, followed by matrix swelling and erosion. The results also indicated that the formulations containing an increased amount of Eudragit NE (10% or more) as binder in the granulation process presented a satisfactory release rate of metoprolol over 12 hours from the granules incorporated in the hydrophilic matrix. Conclusions. This study demonstrated the possibility of lowering of the burst effect from hydrophilic matrix extendedrelease dosage forms incorporating a freely soluble drug, by granulating the drug with a high amount of Eudragit NE 40D and processing the obtained granules in a hydrophilic matrix by tableting.

Objectives. The aim of this study was to evaluate the stability over time after storage under normal environmental thermo-hygrometric conditions of immediate release foaming vaginal tablets. Material and methods. 15 formulation of foaming vaginal tablets prepared according with a Box-Bhenken experimental design were packaged in tightly sealed bottles with anhydrous sodium sulphate as desiccant and stored in normal thermo-hygrometric conditions (temperature of 25°C, relative humidity 40-75%). Immediate after preparation, after 1 and 3 months the tablets pharmaceutical characteristics were analysed and modification over time evaluated. Outcomes. The formulation factors studied with experimental design have, in general, the same influence on tablets characteristics after 1 or 3 months storage as immediate after preparation After one month storage in normal thermohygrometric conditions, an increase of the tablets hardness and the foaming time was observed, and a decrease of the volume of the foam, the mass of carbon dioxide released by the foaming. These modifications are accentuated especially by an increased effervescent mixture ratio and not significantly influenced by the other formulation variables. The results obtained after three months storage show that the changes on the tablets characteristics become slower than in the first month. The tablets hardness reaches maximum values after one month, but also there are slower changes regarding the maximum volume of the foam, the resistance of the foam, or the mass of carbon dioxide released after foaming. Low modification was observed for the pH generated in the water, which has a fairly high stability over time, both at one month and after three months storage. Conclusions. Foaming vaginal tablets stored in normal thermo-hygrometric conditions, suffer a sudden modification of their characteristics during the first month of storage, a phenomenon that is due to both the humidity of the environment and the preparation conditions. This modification can be minimized by preparing and storing tablets in low humidity conditions (lower that 10%) or by preparation the formulations with a low effervescent mixture ratio (less than 25%).