Balázs Vajna

Comparison of electrospun and extruded Soluplus®-based solid dosage forms of improved dissolution.

Electrospinning (ES) and extrusion of a poorly water-soluble active pharmaceutical ingredient were used to improve its dissolution, which is a major challenge in the field of pharmaceutical technology. Spironolactone was applied as model drug and recently developed polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) was used as carrier matrix and solubilizer. ES of the polymer matrix from ethanol solution was optimized at first without spironolactone and then the cosolution of the drug and the carrier was used for forming electrospun fibers. It resulted in real solid solution due to its very efficient amorphization effect. On the contrary, a low amount of crystalline spironolactone appeared in the extrudates according to Raman microscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy-dispersive spectrometry (EDS). Raman microspectrometry had the lowest detection limit of spironolactone crystals compared with XRD and differential scanning calorimetry. Both ES and extrusion techniques resulted in significantly improved dissolution. Electrospun ultrafine fibers increased the dissolution more effectively, owing to the formed solid solution and huge surface. The developed continuous technologies demonstrate great potential to tackle the challenge of inadequate dissolution of poorly water-soluble drugs in several cases.

Solvent-free melt electrospinning for preparation of fast dissolving drug delivery system and comparison with solvent-based electrospun and melt extruded systems

The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery system with fast release of carvedilol (CAR), a drug with poor water solubility. To the authors knowledge, this is the first report for preparing drug-loaded melt electrospun fibers. Cationic methacrylate copolymer of Eudragit® E type was used as a fiber forming polymer matrix. For comparison, ethanol-based electrospinning and melt extrusion (EX) methods were used to produce samples that had the same composition as the melt electrospun system. According to the results of scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transformed infrared spectrometry investigations, amorphous solid nanodispersions/solutions of CAR in Eudragit® E matrix were obtained in all cases with 20 m/m % drug content. In vitro drug release in acidic media from the extrudates was significantly faster (5 min) than that from crystalline CAR. Moreover, ultrafast drug release was achieved from the solvent-free melt and ethanol-based electrospun samples because of their huge surface area and the soluble polymer matrix in the acidic media. These results demonstrate that solvent-free MES is a promising, novel technique for the production of drug delivery systems with enhanced dissolution because it can combine the advantages of EX (e.g., solvent-free, continuous process, and effective amorphization) and solvent-based electrospinning (huge product surface area).

Raman microscopic evaluation of technology dependent structural differences in tablets containing imipramine model drug

Raman imaging method was used to characterize the effect of different manufacturing technologies on properties of the produced tablets, such as compound distribution, polymorphism, strength, and estimated active pharmaceutical ingredient (API) content. The obtained chemical maps were evaluated based on their visual appearance and on the statistical properties of the component scores obtained by direct classical least squares (DCLS) modelling. It is demonstrated that changes in the distribution of the API and excipients can be detected with chemical imaging and these differences are in close relationship with the applied granulation method and with the mechanical properties of the analyzed tablet. It is also shown that the chemical images used for characterizing the component distribution can also be processed for obtaining a cautious estimation to the mass fractions of the components.

Redox- and pH-Responsive Cysteamine-Modified Poly(aspartic acid) Showing a Reversible Sol–Gel Transition

Synthesis and characterization of a pH- and redox-sensitive hydrogel of poly(aspartic acid) are reported. Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol-disulphide interconversion in the side chain of the polymers. Structural changes are confirmed by Raman microscopy and rheological measurements. Injectable aqueous solutions of thiolated poly(aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery. Reduction-facilitated release of an entrapped drug from disulphide cross-linked hydrogels is studied.

Characterization of melt extruded and conventional Isoptin formulations using Raman chemical imaging and chemometrics

Isoptin SR-E (Meltrex(®)) extruded tablets were assumed in a recent paper to be prepared with a composition different from a conventional (Isoptin SR) formulation. This study reveals, however, using Raman mapping and chemometric evaluation, that in fact the same composition, comprising Na alginate as polymer matrix, is used in both products. It means that only the difference in the manufacturing technology causes the reported sustained release of verapamil hydrochloride even in ethanol containing dissolution media. The products are compared based on the obtained Raman chemical images, which allowed concluding in a new structure-based explanation for the differences in the dissolution profiles in the presence of ethanol. It is also shown that extrusion technology influences the dissolution profile effectively, even in the cases when solid solution is formed only partially.

Testing the performance of pure spectrum resolution from Raman hyperspectral images of differently manufactured pharmaceutical tablets.

Chemical imaging is a rapidly emerging analytical method in pharmaceutical technology. Due to the numerous chemometric solutions available, characterization of pharmaceutical samples with unknown components present has also become possible. This study compares the performance of current state-of-the-art curve resolution methods (multivariate curve resolution-alternating least squares, positive matrix factorization, simplex identification via split augmented Lagrangian and self-modelling mixture analysis) in the estimation of pure component spectra from Raman maps of differently manufactured pharmaceutical tablets. The batches of different technologies differ in the homogeneity level of the active ingredient, thus, the curve resolution methods are tested under different conditions. An empirical approach is shown to determine the number of components present in a sample. The chemometric algorithms are compared regarding the number of detected components, the quality of the resolved spectra and the accuracy of scores (spectral concentrations) compared to those calculated with classical least squares, using the true pure component (reference) spectra. It is demonstrated that using appropriate multivariate methods, Raman chemical imaging can be a useful tool in the non-invasive characterization of unknown (e.g. illegal or counterfeit) pharmaceutical products.

Characterization of drug-cyclodextrin formulations using Raman mapping and multivariate curve resolution.

Raman chemical imaging was used in the characterization of drug-excipient interactions between a drug and different types of cyclodextrins. Detailed analysis was carried out regarding the interactions between the active ingredient (API) and the cyclodextrins and the heterogeneity of the samples was studied using multivariate curve resolution-alternating least squares algorithm. The amount of recrystallized pure API was also estimated using the same curve resolution method. The Raman mapping results were validated via scanning electron microscopy-energy dispersive X-ray spectroscopy and X-ray powder diffraction. Raman mapping was found to be suitable to detect traces of pure crystalline API below the detection limit of X-ray powder diffraction.

Investigation of drug distribution in tablets using surface enhanced Raman chemical imaging.

This paper reports the first application of surface enhanced Raman chemical imaging on pharmaceutical tablets containing the active ingredient (API) in very low concentrations. Taking advantage of the extremely intensive Raman signals in the presence of silver colloids, image aquisition time was radically decreased. Moreover, the investigation of drug distribution below the detection limit of regular micro-Raman spectrometry was made feasible. The characteristics of different manufacturing technologies could be revealed at very low API concentrations by using chemometric methods for processing and evaluating the large number of varying spectra provided with this imaging method.

Challenges in Detecting Magnesium Stearate Distribution in Tablets

Magnesium stearate (MS) is the most commonly used lubricant in pharmaceutical industry. During blending, MS particles form a thin layer on the surfaces of the excipient and drug particles prohibiting the bonding from forming between the particles. This hydrophobic layer decreases the tensile strength of tablets and prevents water from penetrating into the tablet restraining the disintegration and dissolution of the tablets. Although overlubrication of the powder mass during MS blending is a well-known problem, the lubricant distribution in tablets has traditionally been challenging to measure. There is currently no adequate analytical method to investigate this phenomenon. In this study, the distribution of MS in microcrystalline cellulose (MCC) tablets was investigated using three different blending scales. The crushing strength of the tablets was used as a secondary response, as its decrease is known to result from the overlubrication. In addition, coating of the MCC particles by MS in intact tablets was detected using Raman microscopic mapping. MS blending was more efficient in larger scales. Raman imaging was successfully applied to characterize MS distribution in MCC tablets despite low concentration of MS. The Raman method can provide highly valuable visual information about the proceeding of the MS blending process. However, the measuring set-up has to be carefully planned to establish reliable and reproducible results.

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.