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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.

Objectives. Design of Experiments (DOE) is a powerful tool for identifying important formulation factors and process parameters in drug design and manufacturing, to ensure certain product specifications. This study aimed at manufacturing curcumin-loaded polycaprolactone nanoparticles (CURC-PCL NP), and used DOE in order to understand how formulation and process variables impact the drug delivery system’s characteristics. Polymeric nanoparticles are a suitable approach for incorporating hydrophobic drugs such as curcumin, in order to maximize the numerous beneficial effects, and to minimize the side effects and shortcomings such as low water-solubility and bioavailability. Material and methods. The CURC-PCL NP were prepared by the solvent displacement method. The effects of various formulation and process variables on the nanoparticles’ characteristics were investigated by employing a fractional factorial design with 19 runs. Outcomes. Regression equations were generated to predict the impact of changing variables on particle size, size distribution, zeta potential, drug content and entrapment efficiency. The statistical analysis indicated that the chosen model was robust, reliable and assured good experimental control. Conclusions. Overall, this study shows that DOE is useful in achieving the desirable goals in polymeric nanoparticle development, in the shortest time possible and with a reduced number of experiments.

In recent years, the development of solid cosmetics, as part of sustainable cosmetics strategy, is generating increasing interest. In addition, novel approaches such as Quality by Design concept allowed the development of high-quality products together with a decrease in waste generation. The present study aimed the development of freeze-dried mouthwashes containing Cetraria islandica extract using the Quality by Design approach. Based on the results of preliminary experiments, a factorial design with three factors that varied on two levels was developed. As factors, the filler type (sorbitol or mannitol) was chosen as the qualitative factor and the two quantitative factors were: the filler ratio set from 3 to 5% and polymer (methylcellulose) ratio from 0 to 0.5%. After the preparation and the complete characterization of the formulations generated through the experimental design, the effect of the formulation variables on the lyophilized mouthwashes and the interactions between formulation factors were investigated. Finally, an optimal formulation with appropriate mechanical properties that ensure easy manipulation and no material loss when extracted from the package and fast reconstitution was generated.

Winery industry by-products have a great reuse potential in the pharmaceutical and cosmetic fields due to their bioactive compounds. This study investigates the phytochemical profile and the bioactivity of Vitis vinifera variety Fetească neagră tendrils extract (TE) and leaves extract (LE), intended to be used in oral hygiene products recommended in periodontal disease. The evaluation of the phenolic content was performed by colorimetric analysis. Liquid chromatography coupled with mass spectrometry was used to determine the chemical profile of the two extracts obtained from V. vinifera. Moreover, the antioxidant activity of the extracts was determined by spectrophotometric methods, as well as on human gingival fibroblasts (HGF) cell line. The cytocompatibility and cytoprotective effect against nicotine-induced cytotoxicity were tested, as well as the anti-inflammatory and antimicrobial effects. The TE showed higher total polyphenolic content, rich in rutin, compared to the leaves extract that displayed important amounts of isoquercitrin. The antioxidant effect was confirmed by both non-cellular and cellular tests. The cytocompatibility of the extracts was confirmed at a wide range of concentrations. The cytoprotective effect was demonstrated in HGF exposed to cytotoxic doses of nicotine, 300 &micro, g/mL of both tested extracts decreased nicotine toxicity by approximately 20%. When challenged with E. coli polysaccharides, in HGF cells co-exposed to TE and LE, a reduction in the release of proinflammatory cytokines (IL-8, IL-6 and IL-1&beta, ) was observed. The extracts were both able to reduce the levels of reactive oxygen species and inflammatory cytokines, and had notable antimicrobial effects on pathogenic bacteria associated with periodontitis.

The aim of this work was to develop and validate a NIR method for the quantification of three active ingredients from powder blends. Calibration set formulations were selected based on a D-optimal experimental design with three factors (ibuprofen, paracetamol, caffeine) and five variation levels (80–90–100–110–120%). NIR spectra were recorded in transmittance mode using a rotating sample configuration. Prior to model development the effect of spectral pre-processing was assessed by evaluating its impact over the transfer of orthogonality from concentration space to spectral space. NIR method was validated on the full calibration range with external prediction sets, using the accuracy profile approach. Robustness testing results showed that the accuracy of predictions for the analyte found in lower concentrations (caffeine) was influenced by relative humidity, while paracetamol/ibuprofen predictions were robust to all factors. Redefinition of interfering factor variation level was beneficial to reduce the bias in caffeine content predictions. Also, alternative solutions are provided for ensuring robustness and successful routine use.

The present work aimed to develop near-infrared (NIR) methods for the in-line monitoring of the powder blending process and off-line prediction of paliperidone tablets quality attributes. The powder blending monitoring method was developed for a Y-shaped mixing equipment, with the spectrometer attached to the filling port and remotely controlled, assuring that the NIR sensor was covered in powder every time spectra were recorded. The method was calibrated by using a set of five different formulations corresponding to a paliperidone content ranging from 60 to 140% of the expected product content. Based on the recorded data, a Partial Least Squares method has been developed taking into account the domain between 1350 and 1550nm of the 1st Savitzky-Golay derivatised spectra, with a low root mean square error of cross-validation of 6.7, offering a real time overview of the homogenisation process. The second part of the study was focused on the calibration and validation of NIR methods for the prediction of paliperidone content and resistance to crushing (hardness) of tablets. Both calibration strategies involved using samples with five levels of variation, 80 to 120% of the target drug concentration and hardness, respectively. The methods were validated by using three level datasets, 90 to 110% of the property of interest. The obtained results were promising, with measured vs. predicted recoveries of over 97.2% for paliperidone content and over 96.3% for tensile strength, values well within the tolerance limits. The in-line blending monitoring allowed a good process overview, enabling the establishment of the process end point, while the noninvasive assay of the tablets quality attributes granted an adequate end product.

The aim of the present study was to evaluate the funtion of fenugreek seed mucilage (FSM) as potential matrix forming agent for orodispersible pharmaceutical lyophilisates. The FSM was isolated and characterized. FSM colloidal dispersions were prepared and the rheological evaluation was performed. Oral lyophilisates (OLs) with different FSM concentrations, containing meloxicam as model drug were prepared by freeze drying method. The OLs were characterized and compared to gelatin containing tablets, prepared under the same conditions.The FSM dispersions revealed shear thinning flow type. Based on colloidal dispersions' rheological properties, five FSM concentrations were taken forward to the lyophilization step. Completely dry and elegant tablets were obtained. Texture analysis indicated highly porous structures, confirmed by SEM analysis, which explain the fast disintegration properties. All the prepared tablets disintegrated in less than 47 s. The disintegration process was prolonged by the increase in FSM content, due to the high viscosity the polymer creates in aqueous media. FSM tablets presented longer disintegration times, as compared to gelatin tablets, but also higher crushing strength. Considering the fast disintegration and the high crushing strength, FSM is a good candidate as matrix forming agent for fast disintegrating dosage forms or other freeze-dried preparations. Keywords: Meloxicam, Oral lyophilisates, Matrix forming agent, Galactomannan, Lyophilization

Sonia Iurian, Luana Turdean, Ioan Tomuta Department of Pharmaceutical Technology and Biopharmacy, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania Abstract: This study focuses on the development of a drug product based on a risk assessment-based approach, within the quality by design paradigm. A prolonged release system was proposed for paliperidone (Pal) delivery, containing Kollidon® SR as an insoluble matrix agent and hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), or sodium carboxymethyl cellulose as a hydrophilic polymer. The experimental part was preceded by the identification of potential sources of variability through Ishikawa diagrams, and failure mode and effects analysis was used to deliver the critical process parameters that were further optimized by design of experiments. A D-optimal design was used to investigate the effects of Kollidon SR ratio (X1), the type of hydrophilic polymer (X2), and the percentage of hydrophilic polymer (X3) on the percentages of dissolved Pal over 24 h (Y1–Y9). Effects expressed as regression coefficients and response surfaces were generated, along with a design space for the preparation of a target formulation in an experimental area with low error risk. The optimal formulation contained 27.62% Kollidon SR and 8.73% HPMC and achieved the prolonged release of Pal, with low burst effect, at ratios that were very close to the ones predicted by the model. Thus, the parameters with the highest impact on the final product quality were studied, and safe ranges were established for their variations. Finally, a risk mitigation and control strategy was proposed to assure the quality of the system, by constant process monitoring. Keywords: pharmaceutical development, quality by design, failure mode effects analysis, Ishikawa diagram, fish-bone diagram, hydrophilic matrix

The objectives of this work were to develop meloxicam based amorphous solid dispersion through electrospinning technique and evaluate the effect of the polymeric matrix on the physicochemical properties of the fibers and the downstream processing ability to orodispersible dosage forms. Drug – polymer interactions formed between Eudragit E and meloxicam, confirmed through Raman and 1HNMR spectra, enabled the development of fibers from ethanol, thus allowing an increased production rate compared to PVPk30 where a DMF:THF solvent system was suitable. Microflux dissolution-permeation studies showed a significantly higher diffusion from amorphous solid dispersions compared to crystalline meloxicam. The flux through the membrane was influenced by the polymers only under basic conditions, where the precipitation of Eudragit E limited the complete resolubilization of the active ingredient. This phenomenon was not observed during large volume conventional dissolution testing. The effect of formulation on long term stability could not be highlighted as all products were stable up to 15 months, stored in closed holders at 25 °C ± 2 °C and 50%RH ± 10%. The increased surface area of fibers enabled tablet preparation with low pressures due to favorable bonding between particles during compression. PVPk30 formulation presented higher tabletability and compactability, as higher tensile strength compacts could be prepared. Eudragit E formulation had lower detachment and ejection stress, suggesting a lower sticking tendency during tableting. The presence of HPsCD in PVPk30 formulation offered improved morphological features of the fibers, however no significant effect was observed on dissolution, permeation or mechanical properties. Downstream processing was guided by polymer mechanical properties and solubility, thus PVPk30 fibers could be delivered in the form of orodispersible webs and conventional tablets, whereas Eudragit E fibers as orodispersible tablets.

Orodispersible tablets (ODTs) emerged as dosage forms recommended for special groups of patients like pediatrics or geriatrics, due to their multiple advantages. Among their critical quality attributes, palatability determines patient acceptance, with high impact on treatment efficacy. The aim of this study was to develop an instrumental method to assess in vivo disintegration time and palatability of ODTs. The formulation factors that can influence palatability were refined through an experimental design. The most important ones were taken forward and a calibration set was prepared for multivariate calibration model development. The ODTs were tested for their pharmaceutical properties, texture profile, followed by in vivo disintegration and palatability characteristics assessed by a panel of 16 healthy volunteers. Acceptability was correlated to high palatability scores, sweet taste and long disintegration time and negatively correlated to with the bitter taste and a voluminous residue. Results revealed the importance of choosing the right type of filler or filler ratio for the oral disintegration time and associated mouth feel. The calibration set included formulations with different ratios of mannitol and microcrystalline cellulose as fillers. Regression models were built by correlating the texture profiles to the in vivo evaluation parameters. The model performance was good on both external prediction set formulations and on marketed ODTs, with good predictive capacity (Q2 > 0.7) for most of the subjective ODTs characteristics: in vivo disintegration time, residual volume and palatability.

The aim of the present study was to establish the best experimental conditions that lead to the extracts richest in polyphenolic compounds obtained from pomace and canes of Vitis vinifera. In this regard, a D-Optimal design of experiments (DoE) method was applied to investigate the extraction process parameters from each of three materials: red pomace (RP), white pomace (WP) and canes (C). The input variables were the extraction temperature and the ethanol ratio and as response, the total polyphenols content (TPC) was determined. A design space was generated for each of the plant materials and the most concentrated polyphenol extracts were obtained using 50% ethanol at a temperature of 80 &deg, C. Further, the phenolic profiles of the concentrated extracts were detected by LC/MS/MS and the results showed that WP extract was richer in polyphenolic compounds, both flavonoid and phenolic acids, followed by the RP and C extracts. The antioxidant assays revealed that WP and RP extracts exhibited a higher antioxidant activity which correlated to the high content of polyphenols. These findings revealed that RP, WP and C, currently considered agricultural wastes from winery, may be valorized as an important source of natural antioxidants.

The aim of this study was to formulate and prepare compression-coated tablets for colonic release (CR-tablets), and to evaluate the bioavailability of ketoprofen following the administration of a single dose from mini-tablets with immediate release (IR-tablets) compared to CR-tablets. CR-tablets were prepared based on time-controlled hydroxypropylmethylcellulose K100M inner compression-coating and pH-sensitive Eudragit® L 30D-55 outer film-coating. The clinical bioavailability study consisted of two periods, in which two formulations were administered to 6 volunteers, according to a randomized cross-over design. The apparent cumulative absorption amount of ketoprofen was estimated by plasma profile deconvolution. CR-tablets were able to delay ketoprofen’s release. Compared to IR-tablets used as reference, for the CR-tablets the maximum plasma concentration (Cmax) was lower (4920.33±1626.71 ng/mL vs. 9549.50±2156.12 ng/mL for IR-tablets) and the time needed to reach Cmax (tmax) was 5.33±1.63 h for CR-tablets vs. 1.33±0.88 h for IR-tablets. In vitro-in vivo comparison of the apparent cumulative absorption amount of ketoprofen showed similar values for the two formulations. Therefore, the obtained pharmacokinetic parameters and the in vitro-in vivo comparison demonstrated the reliability of the developed pharmaceutical system and the fact that it is able to avoid the release of ketoprofen in the first part of the digestive tract.

The aim of this study was to develop oral lyophilisates with improved meloxicam (MEL) dissolution, optimizing each step of the preparation by design of experiments. First, meloxicam nanosuspensions were prepared by high-pressure homogenization (HPH), using PVP, Poloxamer or PEG as stabilizers and were subjected to freeze-drying using mannitol as cryoprotectant. The effects of the stabilizers and cryoprotectant were assessed and an optimal formulation was generated within the Design Space where the particle sizes and the PDIs are at their lowest values. The optimal formulation was used at the preparation of oral lyophilisates. Sodium alginate (SA) and croscarmellose sodium (CCS) were tested as matrix forming agents and three different freezing regimes were applied. The formulation was optimized, choosing the polymer that yielded both high mechanical strength and fast MEL dissolution. Poloxamer led to particle size reduction down to 10.27% of the initial size, meaning 477.6±7.5nm, with a slight increase during freeze-drying process. PEG showed lower nanonizing capacity during HPH, but freeze-drying produced further diminution of the particle size. Since Poloxamer provided advanced size reduction while preserving MEL crystallinity, it was used for the optimized formulation containing 1% Poloxamer and 5% mannitol added before freeze-drying. SA showed good structural properties when compared to CCS and allowed fast MEL dissolution at low ratios. The optimal formulation contained 1.157% of SA was subjected to thermal treatment during freeze-drying. It disintegrated in 3.33s and released 77.14% of the MEL after 2min. The quality by design (QbD) approach for the development of pharmaceutical products ensured high quality of the dosage form and good understanding of the preparation process.