Real-Time Cone-Growth Model for Determination of Pharmaceutical Powder Flow Properties.

The flow properties of pellets or granules are crucial for further processing drug dosage forms. Optimal compression or filling of multiparticulate dosage forms into capsules is influenced by forces between discrete particles, which could be partially characterized by flow properties. Several techniques have been developed to examine flowability, including static and dynamic methods applying empirical studies and up-to-date chaos theory; however, the newest methods seem only to be powerful with the supplementation of empirical principles. Our experiments try to refine both the technique of analysis and the methods, by finding new, alternative ways. Our approach to the flowability measurements was to set up a dynamic time-dependent model that combined empirical observations and chaos theory on a geometrical basis, thus finding new characteristics regarding the flow properties of pellets and granules that could be relevant for drug developers. Our findings indicate that sphericity and particle size are the most significant factors influencing the flowability of pharmaceutical multiparticular preparations. Furthermore, this study confirms that integrating chaos theory and empirical observations in a time-dependent dynamic model provides a comprehensive understanding of particle flow behavior, pivotal for optimizing manufacturing processes.

Influence of barium sulfate X-ray imaging contrast material on properties of floating drug delivery tablets.

The objective of the study was to reveal the influence of necessarily added barium sulfate (BaSO4) X-ray contrast material on floating drug delivery tablets. Based on literature survey, a chosen floating tablet composition was determined containing HPMC and carbopol 943P as matrix polymers. One-factor factorial design with five levels was created for evaluation of BaSO4 (X1) effects on experimental parameters of tablets including: floating lag time, total floating time, swelling-, erosion-, dissolution-, release kinetics parameters and X-ray detected volume changes of tablets. Applied concentrations of BaSO4 were between 0 and 20.0% resulting in remarkable alteration of experimental parameters related especially to flotation. Drastic deterioration of floating lag time and total floating time could be observed above 15.0% BaSO4. Furthermore, BaSO4 showed to increase the integrity of tablet matrix by reducing eroding properties. A novel evaluation of dissolutions from floating drug delivery systems was introduced, which could assess the quantity of drug dissolved from dosage form in floating state. In the cases of tablets containing 20.0% BaSO4, only the 40% of total API amount could be dissolved in floating state. In vitro fine resolution X-ray CT imagings were performed to study the volume change and the voxel distributions as a function of HU attenuations by histogram analysis of the images. X-ray detected relative volume change results did not show significant difference between samples. After 24h, all tablets containing BaSO4 could be segmented, which highlighted the fact that enough BaSO4 remained in the tablets for their identification.

Influence of different types of low substituted hydroxypropyl cellulose on tableting, disintegration, and floating behaviour of floating drug delivery systems.

The object of the present study is to evaluate the effect of application of low-substituted hydroxypropyl cellulose (L-HPC) 11 and B1 as excipients promoting floating in gastroretentive tablets. Directly compressed tablets were formed based on experimental design. Face-centred central composite design was applied with two factors and 3 levels, where amount of sodium alginate (X 1) and L-HPC (X2 ) were the numerical factors. Applied types of L-HPCs and their 1:1 mixture were included in a categorical factor (X 3). Studied parameters were floating lag time, floating time, floating force, swelling behaviour of tablets and dissolution of paracetamol, which was used as a model active substance. Due to their physical character, L-HPCs had different water uptake and flowability. Lower flowability and lower water uptake was observed after 60 min at L-HPC 11 compared to L-HPC B1. Shorter floating times were detected at L-HPC 11 and L-HPC mixtures with 0.5% content of sodium alginate, whereas alginate was the only significant factor. Evaluating results of drug release and swelling studies on floating tablets revealed correlation, which can serve to help to understand the mechanism of action of L-HPCs in the field development of gastroretentive dosage forms.

Preformulation studies and optimization of sodium alginate based floating drug delivery system for eradication of Helicobacter pylori.

The aim of this study was to design a local, floating, mucoadhesive drug delivery system containing metronidazole for Helicobacter pylori eradication. Face-centered central composite design (with three factors, in three levels) was used for evaluation and optimization of in vitro floating and dissolution studies. Sodium alginate (X1), low substituted hydroxypropyl cellulose (L-HPC B1, X2) and sodium bicarbonate (X3) concentrations were the independent variables in the development of effervescent floating tablets. All tablets showed acceptable physicochemical properties. Statistical analysis revealed that tablets with 5.00% sodium alginate, 38.63% L-HPC B1 and 8.45% sodium bicarbonate content showed promising in vitro floating and dissolution properties for further examinations. Optimized floating tablets expressed remarkable floating force. Their in vitro dissolution studies were compared with two commercially available non-floating metronidazole products and then microbiologically detected dissolution, ex vivo detachment force, rheological mucoadhesion studies and compatibility studies were carried out. Remarkable similarity (f1, f2) between in vitro spectrophotometrically and microbiologically detected dissolutions was found. Studies revealed significant ex vivo mucoadhesion of optimized tablets, which was considerably increased by L-HPC. In vivo X-ray CT studies of optimized tablets showed 8h gastroretention in rats represented by an animation prepared by special CT technique.

Technological and biopharmaceutical optimization of nystatin release from a multiparticulate based bioadhesive drug delivery system.

Formulation considerations of a new drug delivery system include controlling the site of release of the active ingredient, maintaining drug level for a suitable time and decreasing dosage frequency. In research and development practice, these therapeutic benefits can be attained by selecting suitable active ingredients and optimizing procedure parameters, determining the composition of the medicine, and dissolution properties. The aim of our study was to design a pharmaceutical preparation with increased local therapeutic effect in the therapy of gastrointestinal candidiasis. The polyene antibiotic nystatin may be an optimal choice for active agent, incorporated in a bioadhesive multiparticulate system. Choosing the proper excipients in the proper dosage form and ensuring prolonged residence time may further improve the optimal treatment. Using an experimental design, the micropellets were prepared with 5% nystatin content, taking the factors average pellet size (~200 to ~800 µm) and the amount of applied carbomer and hydroxyethylcellulose (0-5%) into consideration. Dissolution of the active ingredient was detected by UV spectrophotometric and microbiological assay. The bioadhesive character of the multiparticulate dosage form was examined by ex vivo wash-off test. The only factor which significantly influenced the examined parameters was average pellet size. The proportion of applied bioadhesive excipients had significance mostly in interactions with average pellet size. Eventually, optimized drug release (5-10 min mean dissolution time, 50-55% bioadhesion retention) could be achieved with 550 µm pellet size, containing carbomer and hydroxyethylcellulose in 85:15 ratio.

[Optimalization of biocompatible artificial tears containing povidone-iodine according to pharmaceutical technological and microbiological aspects]. / PVP-J tartalmú biokompatibilis mukönnyek gyógyszertechnológiai es mikrobiológiai optimalizálása.

Microbiological preservatives play a great role in the preparation of artificial tears because they protect the eyes from further microorganisms and the preparation from contamination. In this contribution we are summarizing our experimental results given by pharmaceutical and microbiological optimalization of artificial tears. The incidental adaptability of povidone-iodine (PVP-I) as a preservative in artificial tears was examined compared to usually used materials. Some artificial tears (Oculogutta carbomerae and Oculogutta viscosa) were prepared according to the Formulae Normales Edition VII., others were isotonisated and buffered containing 3.0% and 3.5% povidonum as active substance. The analysed samples as a preservative instead of generally used agents contained 0.10%, 0.05% and 0.01% PVP-I. Reference preparations were dispensed using microbiological preservatives (Cetrimidum, Thiomersalum solutum 0.1%, Benzalconium chloratum solutum 10%). Pharmaceutical (pH, viscosity, freezing-point depression, refraction, surface-tension) and microbiological (breeding on aerobe and anaerobe bacteriological culture medium) trials were made to determine the qualitative property and adaptability of analysed preparations in which we also studied the stability and the microbiological changes after opening them. According to our experimental results we can establish that the PVP-I is suitable as microbiological preservative in the examined preparations.

Pharmacotechnological pitfalls of priming--possible source of microembolization during open heart surgery.

OBJECTIVES: Besides low mortality and morbidity rates in cardiac surgery, the associated cognitive dysfunction is the focus of interest. One possible reason is microembolisation. METHODS AND RESULTS: The authors analysed the crystallogenesis in the calcium-containing prime, inspired by their observation that the fluid sometimes becomes turbid during the priming process. Lactated Ringer-based prime solutions were tested, adding mannitol, NaHCO(3), and heparin. The oxygenator was ventilated with compressed medical air. Samples were taken for dynamic light scattering particulate level analysis. The priming was furthermore modelled in the laboratory by mixing the components and then ventilating the mixture through with compressed air. Turbid solutions from the operating room contained 100-6500 nm crystals, while clear solutions contained 20-473 nm particles. In the model, continuous pH measurement showed pH 6.4-7.4 after blending the solutions, which then elevated the pH to 7.5-8.0 after ventilation with concomitant turbidity. The pH of the prime can be stabilized by the addition of ascorbic acid (1-2 mg/ml) and, also, the turbidity may be prevented. CONCLUSION: Ventilating the lactated Ringer-based calcium-containing primes after blending is not advisible because of alkalization and crystallogenesis. Ascorbic acid stabilizes the pH and prevents crystallogenesis in the prime. Pre-bypass filtration is recommended.

[Novel possibilities of development and therapeutical application of liposomes]. / Liposzómák fejlesztésének és gyógyszerterápiás alkalmazásának újabb lehetoségei.

Properties and possibilities of application of liposomal drug delivery systems are summarized in this review. Technological and biopharmeceutical criteria that have to be taken into consideration in the course of development of biocompatible liposomes are discussed. The manner and possibilities of active and passive targeting are shown according to the literary data and special liposome-based drug delivery systems responsible for pathologic or arteficial stimuli are introduced.

Investigation on drug dissolution and particle characteristics of pellets related to manufacturing process variables of high-shear granulation.

There is a growing interest for multiparticulate solid dosage forms such as pellets, because of their several advantages over tablets during drug therapy. It is essential to investigate the drug dissolution process which can be influenced by the composition and manufacturing process technology, too. This study was performed applying experimental design in order to evaluate the effects of independent process variables during high-shear pelletisation, taking the impeller speed (x1) and granulation binder flow rate (x2) as factors into consideration. Theophylline containing pellet formulation was prepared using a matrix consisted of ethylcellulose, microcrystalline cellulose and lactose. Dissolution profiles were modeled by the Weibull function to evaluate the power of process variables. Both process variables were powerful to influence the particle agglomeration. A linear regression was found between the particle size and the diffuse reflectance values after the Kubelka-Munk transformation. Differences in the diffuse reflectance spectra of pellet samples related to particle size offer a fast instrumental method for the in-process control.

[Particle size determination using the method of dynamic light scattering]. / Részecskeméret-meghatározás a dinamikus fényszóródás módszerével.

Realising the lacks of the classic methods of particle size determination a new method was needed to be developed which became suitable for measurements in the nano range as well. The principle of this method was discovered more than 20 years ago but manufacturers are still able to insert novelties by developing and refining the technique of - dynamic light scattering. Importance of multiparticular systems increases in pharmaceutical technology. It is necessary to apply this new method to investigate them.