Rok Šibanc

Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam.

The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion-diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200-900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate, and thus possibly enhance fast onset of therapeutic drug effect.

Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate

In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)solubility. Here we focus on solubility parameters as a tool for predicting the solubility of a drug in certain carriers. Solubility parameters were determined in two different ways: solely by using calculation methods, and by experimental approaches. Six different calculation methods were applied in order to calculate the solubility parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calculation models for salts are still not defined. Therefore, the extended Hansen’s approach and inverse gas chromatography (IGC) were used for evaluating of solubility parameters for ibuprofen lysinate. The obtained values of the total solubility parameter did not differ much between the two methods: by the extended Hansen’s approach it was δt = 31.15 MPa0.5 and with IGC it was δt = 35.17 MPa0.5. However, the values of partial solubility parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behaviour of a salt in the presence of various solvents.

Deformation properties of pharmaceutical excipients determined using an in-die and out-die method

This study investigated deformation mechanisms of some commonly used pharmaceutical fillers, such as microcrystalline cellulose, lactose, dicalcium phosphate, isomalt and cornstarch, using a combination of the in-die and out-die method with the Heckel and Walker models. The tableting mixtures contained of 98.5% (w/w) filler, the rest consisted of dry binder and an antiadhesive agent. Our results showed that plasticity and elasticity may be considered independent deformation properties as highly plastic materials (microcrystalline cellulose, cornstarch) also exhibited high elasticity. Particular emphasis was placed on explaining the differences observed between the in-die and out-die method-comparison revealed that the differences are a consequence of the materials elastic properties. Larger error of in-die results can be expected for more elastic materials, and thus in-die Heckel should be used with some considerations. In contrast, the Walker model was found to be more robust and smaller differences were observed between the two methods. We consider the most correct results to have been obtained by the out-die approach, which excludes the elastic properties of the material evaluated. An excellent correlation between elastic determination at the single-particle level and multiple-particle scale was demonstrated, suggesting a great potential of nanoscale determination of a materials mechanical properties for better elucidation of deformation mechanisms.

Comparative study of the uniformity of coating thickness of pellets coated with a conventional Wurster chamber and a swirl generator-equipped Wurster chamber.

This study evaluated the performance of two bottom-spray coaters and the effect of pellet-size variability on coating uniformity. A conventional Wurster chamber was used for the first group of trials, and a Wurster chamber with a novel swirl-flow generator design was used for the second. The results confirmed that when using a conventional Wurster coating chamber, pellets with a smaller diameter receive significantly less coating material compared to those with larger diameters. The swirl generator-equipped Wurster chamber achieved close to uniform coating thickness regardless of pellet size. The ratio (MS) of the mass of dye deposited in the coating layer to pellet surface area indicates that coating was much more evenly distributed using the swirl-flow coater. Coating thickness was also analyzed using SEM micrographs and the results were in close agreement with the MS factor values. Inter-particle coating mass variation was also lower in case of swirl-flow coater. The results of this study show that a swirl-flow coater is suitable for coating particles of variable size. They also showed an improvement in coating process yield when using the swirl-flow coater.

Design and evaluation of a specific, bi-phase extended release system based on differently coated mini-tablets

Mini-tablets are gaining great attention as systems capable of being formulated into multiple unit systems providing a specific drug release pattern. Within the presented research a combined, multiple-unit system, based on different coated matrix mini-tablets, has been developed in order to achieve 24-h specific sigmoid extended release of the model drug paliperidone. The mini-tablets were based on different amounts of polyvinyl acetate/polyvinyl pyrolidone mixture as the matrix former, providing extended release, and two different types of pH-dependent, acrylic polymer coatings, providing delay in release onset, and thus achieving the required specific sigmoid release pattern imposed by the original drug on the market. The selected formulation proved to be consistent with pharmacopoeial requirements. It was also in vitro similar (f2) to the original drug and the theoretical linear release profile, as well as robust and reproducible regarding in vitro release in different fasted gastro-intestinal conditions. This is proof of concept that 24-h, specific, and almost linear release profile of drugs with high solubility can be achieved by employing technology of coated matrix mini-tablets.