Zoran Lavrič

Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature

Recently trans-resveratrol (trans-RSV) has received great attention due to its prophylactic and therapeutic properties. Its limited bioavailability provides compelling evidence of the need for more suitable formulations in order to attain better clinical effectiveness. Some physicochemical properties of trans-RSV are still unknown or research findings are contradictory. Therefore, this paper presents newly determined trans-RSV solubility and stability at various pH and temperatures, and the importance of such data for the studies of novel trans-RSV-loaded nanofibers. In acidic pH trans-RSV was stable, whereas its degradation started to increase exponentially above pH 6.8. Consequently, it is worthwhile to note that special consideration has to be dedicated to long dissolution testing or biological assays on cell lines in order to obtain relevant data. Measurements were done by validated UV/VIS spectroscopy, HPLC, and newly developed UPLC methods. Specificity was confirmed for HPLC and UPLC method, whereas UV/VIS spectroscopy resulted in false higher trans-RSV concentrations in conditions under which it was not stable (alkaline pH, light, increased temperature). The study is of interest because it draws attention to the importance of careful selected experimental conditions, their influence on the trans-RSV stability and the implications this has for formulation development, storage, and maintenance of therapeutic doses.

Electrospun polycaprolactone nanofibers as a potential oromucosal delivery system for poorly water-soluble drugs

The number of poorly water-soluble drug candidates is rapidly increasing; this represents a major challenge for the pharmaceutical industry. As a consequence, novel formulation approaches are required. Furthermore, if such a drug candidate is intended for the therapy of a specific group of the population, such as geriatric or pediatric, the formulation challenge is even greater, with the need to produce a dosage form that is acceptable for specific patients. Therefore, the goal of our study was to explore electrospun polycaprolactone (PCL) nanofibers as a novel nanodelivery system adopted for the oromucosal administration of poorly water-soluble drugs. The nanofibers were evaluated in comparison with polymer films loaded with ibuprofen or carvedilol as the model drugs. Scanning electron microscopy revealed that the amount of incorporated drug affects the diameter and the morphology of the nanofibers. The average fiber diameter increased with a higher drug loading, whereas the morphology of the nanofibers was noticeably changed in the case of nanofibers with 50% and 60% ibuprofen. The incorporation of drugs into the electrospun PCL nanofibers was observed to reduce their crystallinity. Based on the morphology of the nanofibers and the films, and the differential scanning calorimetry results obtained in this study, it can be assumed that the drugs incorporated into the nanofibers were partially molecularly dispersed in the PCL matrix and partially in the form of dispersed nanocrystals. The incorporation of both model drugs into the PCL nanofibers significantly improved their dissolution rates. The PCL nanofibers released almost 100% of the incorporated ibuprofen in 4h, whereas only up to 77% of the incorporated carvedilol was released during the same time period, indicating the influence of the drugs properties, such as molecular weight and solubility, on its release from the PCL matrix. The obtained results clearly demonstrated the advantages of the new nanodelivery system compared to the drug-loaded polymer films that were used as the reference formulation. As a result, electrospinning was shown to be a very promising nanotechnology-based approach to the formulation of poorly water-soluble drugs in order to enhance their dissolution. In addition, the great potential of the produced drug-loaded PCL nanofiber mats for subsequent formulation as oromucosal drug delivery systems for children and the elderly was confirmed.

Application of 14N NQR to the Study of Piroxicam Polymorphism

A study was conducted to test the capability of the (14)N nuclear quadrupole resonance (NQR) method to discriminate qualitatively and quantitatively among different forms of piroxicam. Samples of commercial piroxicam form I and its monohydrate were obtained on the local market. Additionally, samples of form I and II were prepared by recrystallization in 1,2-dichloroethane and ethanol, respectively. DSC and FT-IR were employed as reference methods. A (14)N NQR spectrometer was used to measure samples of different forms and mixtures of piroxicam at 2587 and 3439  kHz. DSC and FT-IR clearly confirmed differences between the different piroxicam forms. Measurements of (14)N NQR signals of different forms of piroxicam at 2587  kHz detected only spectral peaks of form I. The dependence of (14)N NQR signal intensity on the concentration of form I in mixtures with the monohydrate showed a clear linear relationship at both measured frequencies, though the scattering of data was greater at 3439  kHz due to the lower S/N ratio. The (14)N NQR method has the potential to become an additional and important spectroscopic tool in the study of solid-state forms, not only of pure active pharmaceutical ingredients or excipients, but also of their mixtures. This ability lends the method to a possible successful utilization at different levels of pharmaceutical manufacturing and product quality control.

Spherical agglomerates of lactose with enhanced mechanical properties

The aim of this study was to prepare spherical agglomerates of lactose and to evaluate their physicochemical properties, flow properties, particle friability and compaction properties, and to compare them to commercially available types of lactose for direct compression (spray-dried, granulated and anhydrous β-lactose). Porous spherical agglomerates of α-lactose monohydrate with radially arranged prism-like primary particles were prepared exhibiting a high specific surface area. All types of lactose analysed had passable or better flow properties, except for anhydrous β-lactose, which had poor flowability. Particle friability was more pronounced in larger granulated lactose particles; however, particle structure was retained in all samples analysed. The mechanical properties of spherical agglomerates of lactose, in terms of compressibility, established with Walker analysis, and compactibility, established with a compactibility profile, were found to be superior to any commercially available types of lactose. Higher compactibility of spherical agglomerates of lactose is ascribed to significantly higher particle surface area due to a unique internal structure with higher susceptibility to fragmentation.

14N Nuclear Quadrupole Resonance Study of Piroxicam: Confirmation of New Polymorphic Form V

A new polymorphic crystal form of piroxicam was discovered while preparing crystalline samples of piroxicam for (14) N nuclear quadrupole resonance (NQR) analysis. The new crystal form, designated as V, was prepared by evaporative recrystallization from dichloromethane. Three known polymorphic forms (I, II, and III) were also prepared. Our aim was to apply (14) N NQR to characterize the new polymorphic form of piroxicam and compare the results with those of the other known polymorphic forms. Additional analytical methods used for characterization were X-ray powder diffraction (XRPD), thermal analysis, and vibrational spectroscopy. For the first time, a complete set of nine characteristic (14) N NQR frequencies was found for each prepared polymorph of piroxicam. The consistent set of measured frequencies and calculated characteristic quadrupole parameters found for the new polymorphic form V is a convincing evidence that we are dealing with a new form. The already known piroxicam polymorphic forms were characterized similarly. The XRPD results were in accordance with the conclusions of (14) N NQR analysis. The performed study clearly demonstrates a strong potential of (14) N NQR method to be applied as a highly discriminative spectroscopic analytical tool to characterize polymorphic forms.

14N Nuclear Quadrupole Resonance Study of Polymorphism in Famotidine

(14)N nuclear quadrupole resonance (NQR) in two known polymorphs of famotidine was measured. At room temperature, seven quadrupolar sets of transition frequencies (ν(+), ν(-), and ν(0)) corresponding to seven different nitrogen sites in the crystal structure of each of the two polymorphs were found. This confirms the expected ability of NQR to distinguish polymorph B from its analog A. NQR can also measure their ratio in a solid mixture and in the final dosage form, that is, a tablet. The NQR frequencies, line shapes, and tentative assignation to all seven molecular (14)N atoms were obtained. Unravelment of these two entangled NQR spectra presents a valuable contribution to the NQR database and enables studies of some possible correlations therein. Moreover, nondestructive (14)N NQR studies of commercial famotidine tablets can reveal some details of the drug fabrication process connected with compression.

Application of miscibility analysis and determination of Soluplus solubility map for development of carvedilol-loaded nanofibers

Electrospinning was used to produce carvedilol-loaded Soluplus polymer nanofibers using a systematic approach. Miscibility between drug and polymer was determined through calculation of the interaction parameter, χ, and the difference between the total solubility parameters, Δdt. A solubility map for Soluplus was obtained by examining different solvent systems, carrying out electrospinning, and characterizing the nanofibers formed. Miscibility studies showed that carvedilol and Soluplus can form a miscible system (χ=-2.3054; Δδt<7.0MPa1/2). Based on the Soluplus solubility map, acetone: chloroform (90:10; w/w) represents a suitable solvent system for electrospinning of carvedilol-loaded Soluplus nanofibers. Scanning electron microscopy of these nanofiber samples showed smooth surface morphology. The nanofibers had a regular cylindrical morphology. Beads appeared along the nanofibers more frequently in formulations with lower percentages of carvedilol. Differential scanning calorimetry showed no melting endothermic peak for carvedilol, which suggests its complete conversion from the crystalline to the amorphous form (at polymer: carvedilol 1:1). The infrared spectrum of the carvedilol-loaded Soluplus nanofibers showed no characteristic carvedilol peak at 3344.5cm-1, which suggests interactions between carvedilol and Soluplus. Dissolution studies of these nanofibers showed improved pure carvedilol dissolution properties, with >85% of the carvedilol released in the first 15min, versus 20% for pure carvedilol. The use of miscibility analysis and polymer solubility studies demonstrate great technological potential to tackle the challenge for inadequate dissolution of poorly water-soluble drugs.

Novel Spray Dried Glycerol 2-Phosphate Cross-Linked Chitosan Microparticulate Vaginal Delivery System—Development, Characterization and Cytotoxicity Studies

Chitosan microparticulate delivery systems containing clotrimazole were prepared by a spray drying technique using glycerol 2-phosphate as an ion cross-linker. The impact of a cross-linking ratio on microparticle characteristics was evaluated. Drug-free and drug-loaded unmodified or ion cross-linked chitosan microparticles were examined for the in vitro cytotoxicity in VK2/E6E7 human vaginal epithelial cells. The presence of glycerol 2-phosphate influenced drug loading and encapsulation efficacy in chitosan microparticles. By increasing the cross-linking ratio, the microparticles with lower diameter, moisture content and smoother surface were observed. Mucoadhesive studies displayed that all formulations possessed mucoadhesive properties. The in vitro release profile of clotrimazole was found to alter considerably by changing the glycerol 2-phosphate/chitosan ratio. Results from cytotoxicity studies showed occurrence of apoptotic cells in the presence of chitosan and ion cross-linked chitosan microparticles, followed by a loss of membrane potential suggesting that cell death might go through the mitochondrial apoptotic pathway.

Consolidation trend design based on Young's modulus of clarithromycin single crystals

The key aim of this study was to determine single mechanical properties of clarithromycin polymorphic forms in order to select some of them as more suitable for the tableting process. For this purpose, AFM single-point nanoindentation was used. The Youngs moduli of clarithromycin polymorphs were substantially different, which was consistent with the structural variations in their packing motifs. The presence of the adjacent layers, which can easily slide over each other due to the low energy barrier (the lowest Youngs modulus was 0.25 GPa) resulted in better bulk compressibility (the highest Heckel coefficient) of clarithromycin Form I. We also addressed the importance of tip geometry screening because the stress during the force mode often results in tip apex fracture. Even the initial manufacture of the diamond-coated tips can result in defects such as double-apex tips.