Péter L. Sóti

Polymer-free and polyvinylpirrolidone-based electrospun solid dosage forms for drug dissolution enhancement

Fast-release nano- and microfibres of lipophilic spironolactone were prepared in a continuous manner by electrostatic spinning, in which the application of polyvinylpyrrolidone K90 as matrix polymer enabled formation of solid solutions. However, instead of the anticipated immediate drug release, temporary precipitation was observed. The polyvinylpyrrolidone web gelled immediately after wetting, hindering drug diffusion and aiding the crystallisation of the solvated amorphous spironolactone. These local supersaturations could be successfully avoided by using hydroxypropyl-β-cyclodextrin. The dependence of fibre diameter and dissolution rate on the complexing agent-polymer ratio was also studied. A small addition of hydroxypropyl-β-cyclodextrin proved enough for a dramatic release rate enhancement even in the case of high drug loaded formulations. Transmission Raman spectroscopy, differential scanning calorimetry and X-ray powder diffraction showed that the drug was totally amorphised during processing in all formulations. Polymer-free hydroxypropyl-β-cyclodextrin fibres containing spironolactone were also electrospun from an ethanolic solution, which is a new way of dissolution improvement in the case of poorly water-soluble drugs. This novel approach ensured nearly total drug release in a minute, making the system a suitable age-appropriate orally dissolving formulation.

Plasticized Drug‐Loaded Melt Electrospun Polymer Mats: Characterization, Thermal Degradation, and Release Kinetics

Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent-based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water-soluble and thermal-sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution studies revealed ultrafast drug dissolution of the fibrous samples. According to the HPLC impurity tests, the reduced stability of CAR under conditions applied without plasticizer could be avoided using plasticizers, whereas storage tests also indicated the importance of optimizing the process parameters during MES.

Comparison of spray drying, electroblowing and electrospinning for preparation of Eudragit E and itraconazole solid dispersions

Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospinning (electroblowing; EB) were used to prepare solid dispersions of itraconazole and Eudragit E. Samples with the same API/polymer ratios were prepared in order to make the three technologies comparable. The structure and morphology of solid dispersions were identified by scanning electron microscopy and solid phase analytical methods such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman chemical mapping. Moreover, the residual organic solvents of the solid products were determined by static headspace-gas chromatography/mass spectroscopy measurements and the wettability of samples was characterized by contact angle measurement. The pharmaceutical performance of the three dispersion type, evaluated by dissolution tests, proved to be very similar. According to XRPD and DSC analyses, made after the production, all the solid dispersions were free of any API crystal clusters but about 10 wt% drug crystallinity was observed after three months of storage in the case of the SD samples in contrast to the samples produced by ES and EB in which the polymer matrix preserved the API in amorphous state.

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.

Predicting final product properties of melt extruded solid dispersions from process parameters using Raman spectrometry.

Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity and glass-transition temperature in the case of melt-extruded pharmaceutical products. Tight correlation was shown between the results obtained by confocal Raman mapping and transmission Raman spectrometry, a PAT-compatible potential in-line analytical tool. Immediate-release spironolactone-Eudragit E solid dispersions were the model system, owing to the achievable amorphization and the heat-sensitivity of the drug compound. The deep investigation of the relationship between process parameters, residual drug crystallinity and degradation was performed using statistical tools and a factorial experimental design defining 54 different circumstances for the preparation of solid dispersions. From the examined factors, drug content (10, 20 and 30%), temperature (110, 130 and 150°C) and residence time (2.75, 11.00 and 24.75min) were found to have significant and considerable effect. By forming physically stable homogeneous dispersions, the originally very slow dissolution of the lipophilic and poorly water-soluble spironolactone was reasonably improved, making 3minute release possible in acidic medium.

Electrospun polylactic acid and polyvinyl alcohol fibers as efficient and stable nanomaterials for immobilization of lipases.

Electrospinning was applied to create easy-to-handle and high-surface-area membranes from continuous nanofibers of polyvinyl alcohol (PVA) or polylactic acid (PLA). Lipase PS from Burkholderia cepacia and Lipase B from Candida antarctica (CaLB) could be immobilized effectively by adsorption onto the fibrous material as well as by entrapment within the electrospun nanofibers. The biocatalytic performance of the resulting membrane biocatalysts was evaluated in the kinetic resolution of racemic 1-phenylethanol (rac-1) and 1-phenylethyl acetate (rac-2). Fine dispersion of the enzymes in the polymer matrix and large surface area of the nanofibers resulted in an enormous increase in the activity of the membrane biocatalyst compared to the non-immobilized crude powder forms of the lipases. PLA as fiber-forming polymer for lipase immobilization performed better than PVA in all aspects. Recycling studies with the various forms of electrospun membrane biocatalysts in ten cycles of the acylation and hydrolysis reactions indicated excellent stability of this forms of immobilized lipases. PLA-entrapped lipases could preserve lipase activity and enantiomer selectivity much better than the PVA-entrapped forms. The electrospun membrane forms of CaLB showed high mechanical stability in the repeated acylations and hydrolyses than commercial forms of CaLB immobilized on polyacrylamide beads (Novozyme 435 and IMMCALB-T2-150).