Balázs Farkas

Melt‐Blown and Electrospun Drug‐Loaded Polymer Fiber Mats for Dissolution Enhancement: A Comparative Study

Melt blowing (MB) was investigated to prepare a fast dissolving fibrous drug-loaded solid dispersion and compared with solvent-based electrospinning (SES) and melt electrospinning (MES). As a conventional solvent-free technique coupled with melt extrusion and using a high-speed gas stream, MB can provide high-quality micro- and nanofibers at industrial throughput levels. Carvedilol, a weak-base model drug with poor water solubility, was processed using a common composition optimized for the fiber spinning and blowing methods based on a hydrophilic vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) and PEG 3000 plasticizer. Scanning electron microscopy combined with fiber diameter analysis showed diameter distributions characteristic to each prepared fibrous fabrics (the mean value increased toward SES<MB<MES). Differential scanning calorimetry and X-ray diffraction studies revealed that the incorporated drug was in amorphous form regardless the preparation method. The HPLC studies demonstrated that all of the materials produced by the different techniques passed the regulatory purity requirements. The fibers exhibited ultrafast drug release tested under neutral pH conditions; the melt-blown sample dissolved within 2 min owing to its large specific surface area. The presented results confirm the applicability of MB as a novel formulation technique for polymer-based drug delivery systems.

Detailed stability investigation of amorphous solid dispersions prepared by single-needle and high speed electrospinning.

In this research the long-term stability (one year) of amorphous solid dispersions (ASDs) prepared by high speed electrospinning was investigated at 25 °C/60% relative humidity (RH) (closed conditions) and 40 °C/75% RH (open conditions). Single needle electrospinning and film casting were applied as reference technologies. Itraconazole (ITR) was used as the model API in 40% concentration and the ASDs consisted of either one of the following polymers as a comparison: polyvinylpyrrolidone-vinyl acetate 6:4 copolymer (no hydrogen bonds between API and polymer) and hydroxypropyl methylcellulose (possible hydrogen bonds between oxo or tertiary nitrogen function of API and hydroxyl moiety of polymer). DSC, XRPD and dissolution characteristics of samples at 0, 3 and 12 months were investigated. In addition, Raman maps of certain electrospun ASDs were assessed to investigate crystallinity. A new chemometric method, based on Multivariate Curve Resolution-Alternating Least Squares algorithm, was developed to calculate the spectrum of amorphous ITR in the matrices and to determine the crystalline/amorphous ratio of aged samples. As it was expected ITR in single needle electrospun SDs was totally amorphous at the beginning, in addition hydroxypropyl methylcellulose could keep ITR in this form at 40 °C/75% RH up to one year due to the hydrogen bonds and high glass transition temperature of the SD. In polyvinylpyrrolidone-vinyl acetate matrix ITR remained amorphous at 25 °C/60% RH throughout one year. Materials prepared by scaled-up, high throughput version of electrospinning, which is compatible with pharmaceutical industry, also gained the same quality. Therefore these ASDs are industrially applicable and with an appropriate downstream process it would be possible to bring them to the market.

AC and DC electrospinning of hydroxypropylmethylcellulose with polyethylene oxides as secondary polymer for improved drug dissolution

Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.1% or less enabled the production of high quality HPMC-based fibrous mats without altering its physicochemical properties remarkably. Increasing concentrations of higher molecular weight PEOs led to the thickening of fibers from submicronic diameters to several microns of thickness. ACES fibers loaded with the poorly water-soluble model drug spironolactone were several times thinner than drug-loaded fibers prepared with DCES in spite of the higher feeding rates applied. The amorphous HPMC-based fibers with large surface area enhanced the dissolution of spironolactone significantly, the presence of small amounts of PEO did not affect the dissolution rate. The presented results confirm the diverse applicability of ACES, a novel technique to prepare fibrous drug delivery systems.

The effect of formulation additives on in vitro dissolution-absorption profile and in vivo bioavailability of telmisartan from brand and generic formulations

Abstract In this study, brand and four generic formulations of telmisartan, an antihypertensive drug, were used in in vitro simultaneous dissolution‐absorption, investigating the effect of different formulation additives on dissolution and on absorption through an artificial membrane. The in vitro test was found to be sensitive enough to show even small differences between brand and generic formulations caused by the use of different excipients. By only changing the type of filler from sorbitol to mannitol in the formulation, the flux through the membrane was reduced by approximately 10%. Changing the salt forming agent as well resulted in approximately 20% of flux reduction compared to the brand formulation. This significant difference was clearly shown in the published in vivo results as well. The use of additional lactose monohydrate in the formulation also leads to approximately 10% reduction in flux. The results show that by changing excipients, the dissolution of telmisartan was not altered significantly, but the flux through the membrane was found to be significantly changed. These results pointed out the limitations of traditional USP dissolution tests and emphasized the importance of simultaneously measuring dissolution and absorption, which allows the complex effect of formulation excipients on both processes to be measured. Moreover, the in vivo predictive power of the simultaneous dissolution‐absorption test was demonstrated by comparing the in vitro fluxes to in vivo bioequivalence study results. Graphical abstract Figure. No caption available.

Technological Aspects of the Electrical-Discharge Machining of Small-Diameter Holes in a High-Density Ceramic. Part 1

Results are presented from a study of the effect of the technological regimes used in electrical-discharge machining on the accuracy of small-diameters holes formed in parts made of a high-density ceramic. It is established that increases in the frequency and duration of the pulses in the electrical-discharge machining of holes in an oxide-carbide ceramic increase the diameter of the holes, deviations in their shape, and the diameter and height of the cone at the bottom of the holes. It was determined that it is necessary to optimize the electrical-discharge machining of small-diameter holes in high-density ceramics.

Experimental Investigation of Tool Breakage in Micro Drilling of EN AW-5083 Aluminium

Nowadays micro hole drilling is more and more applied machining operation. Because of less than 1 millimeter diameter, and of the relatively high thrust force, micro drills are more easily break than conventional ones. In this paper the experiences of micro drilling tests are summarize in order to demonstrate that measuring thrust force is efficient way to recognize the tool breakage. In order to evaluate the micro drill breakage monitoring method the authors carried out experimental measurements varying the cutting conditions, too.

Investigation of machinability of iron based metal matrix composite (MMC) powder metallurgy parts

One of the advantages of powder metallurgy technology is that we may produce the final geometry of the required part saving considerable time and cost. However there are several applications that require parts need additional machining for example when the product contains threads, cross bore or slots. In these cases cutting of the hard and porous material may causes difficulties in manufacturing. The aim of the introduced research is the experimental investigation of the machinability of the iron based MMC powder metallurgy parts, determining the favourable composition of the powder and advantageous process parameters regarding the properties of the machinability. The research try to answer to the challenge of the poorly defined expression: machinability, and after defining the features and methods of the evaluation we develop advises for the proper technology parameters.

Performance analysis of a novel oil-free rotary compressor

A novel rotating piston-type compressor is presented. The conventional rolling piston architecture was redesigned to allow oil-free operation. The spring activated vane was replaced by a directly driven swinging vane to provide constant contact to the rotating piston. The model of the compressor was implemented in the AMESim simulation platform. Experiments were conducted on prototypes and the data were evaluated based on the simulation results. Directly unobservable geometric dimensions were estimated by adjusting the mathematical model parameters to the measured thermodynamic state variables with the use of a multi-parametric genetic algorithm. The simple genetic algorithm proved fast and adequate solutions. According to the collected results, the oil-free rotating piston architecture is significantly more sensitive to the sealing clearances compared to the conventional oil lubricated rolling piston compressors. Therefore, the theoretically estimated performance can only be achieved with extremely small manufacturing tolerances, which has to be maintained during the operation.

Homogenization of Amorphous Solid Dispersions Prepared by Electrospinning in Low-Dose Tablet Formulation

Low-dose tablet formulations were produced with excellent homogeneity based on drug-loaded electrospun fibers prepared by single-needle as well as scaled-up electrospinning (SNES and HSES). Carvedilol (CAR), a BCS II class compound, served as the model drug while poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was adopted as the fiber-forming polymer. Scanning electron microscopy (SEM) imaging was used to study the morphology of HSES and SNES samples. Different homogenization techniques were compared to maximize homogeneity: mixing in plastic bags and in a high-shear granulator resulting in low-shear mixing (LSM) and high-shear mixing (HSM). Drug content and homogeneity of the tablets were measured by UV-Vis spectrometry, the results revealed acceptably low-dose fluctuations especially with formulations homogenized with HSM. Sieve analysis was used on the final LSM and HSM powder mixtures in order to elucidate the observed differences between tablet homogeneity. Tablets containing drug-loaded electrospun fibers were also studied by Raman mapping demonstrating evenly distributed CAR within the corpus.

The Influence of the Machining Parameters on the Quality of the Holes Made by μEDM in Electrically Conductive Alumina-Oxide

The micro electrical discharge machining is a novel technology applicable for the production of geometries which cannot be made by any other technologies assuming the material is electrically conductive. The machining of electrically conductive ceramics becomes possible by this way. Hole machining into these materials has high importance, however the machining parameters for the efficient and acceptable quality manufacturing are still not well discovered. In this paper authors introduce the experiments focused on learning some most important relationship between the composition of the ceramics and the machining efficiency.