Ivacaftor pharmacokinetics and lymphatic transport after enteral administration in rats.

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

Change in Magnetic Anisotropy at the Surface and in the Bulk of FINEMET Induced by Swift Heavy Ion Irradiation.

57Fe transmission and conversion electron Mössbauer spectroscopy as well as XRD were used to study the effect of swift heavy ion irradiation on stress-annealed FINEMET samples with a composition of Fe73.5Si13.5Nb3B9Cu1. The XRD of the samples indicated changes neither in the crystal structure nor in the texture of irradiated ribbons as compared to those of non-irradiated ones. However, changes in the magnetic anisotropy both in the bulk as well as at the surface of the FINEMET alloy ribbons irradiated by 160 MeV 132Xe ions with a fluence of 1013 ion cm-2 were revealed via the decrease in relative areas of the second and fifth lines of the magnetic sextets in the corresponding Mössbauer spectra. The irradiation-induced change in the magnetic anisotropy in the bulk was found to be similar or somewhat higher than that at the surface. The results are discussed in terms of the defects produced by irradiation and corresponding changes in the orientation of spins depending on the direction of the stress generated around these defects.

On the Formation of Nanocrystalline Grains in Metallic Glasses by Means of In-Situ Nuclear Forward Scattering of Synchrotron Radiation.

Application of the so-called nuclear forward scattering (NFS) of synchrotron radiation is presented for the study of crystallization of metallic glasses. In this process, nanocrystalline alloys are formed. Using NFS, the transformation process can be directly observed during in-situ temperature experiments not only from the structural point of view, i.e., formation of nanocrystalline grains, but one can also observe evolution of the corresponding hyperfine interactions. In doing so, we have revealed the influence of external magnetic field on the crystallization process. The applied magnetic field is not only responsible for an increase of hyperfine magnetic fields within the newly formed nanograins but also the corresponding components in the NFS time spectra are better identified via occurrence of quantum beats with higher frequencies. In order to distinguish between these two effects, simulated and experimental NFS time spectra obtained during in-situ temperature measurements with and without external magnetic field are compared.

Analysis of the origins of content non-uniformity in high-shear wet granulation.

In this study, the origins of granule content non-uniformity in the high-shear wet granulation of a model two-component pharmaceutical blend were investigated. Using acetaminophen as the active pharmaceutical ingredient (API) and microcrystalline cellulose as the excipient, the distribution of the API across the granule size classes was measured for a range of conditions that differed in the duration of the initial dry mixing stage, the overall composition of the blend and the wet massing time. The coarse granule fractions were found to be systematically sub-potent, while the fines were enriched in the API. The extent of content non-uniformity was found to be dependent on two factors - powder segregation during dry mixing and redistribution of the API between the granule size fractions during the wet massing phase. The latter was demonstrated in an experiment where the excipient was pre-granulated, the API was added later and wet massed. The content non-uniformity in this case was comparable to that obtained when both components were present in the granulator from the beginning. With increasing wet massing time, the extent of content non-uniformity decreased, indicating that longer wet massing times might be a solution for systems with a natural tendency for component segregation.

Dissolution and disintegration kinetics of high-active pharmaceutical granules produced at laboratory and manufacturing scale.

The effect of process scale-up from 4 to 400-L high-shear granulator on the release kinetics of the active ingredient from pharmaceutical granules has been investigated. The dissolution and disintegration rates of the granules were measured simultaneously by the combination of UV/vis spectroscopy and static light scattering. The granule batches were found to consist of sub-populations with qualitatively different dissolution behavior: "weaker" granules that disintegrated during dissolution, and "stronger" granules that retained their size and from which the active ingredient was gradually leached. The existence of these sub-populations was attributed to non-uniform distribution of normal and shear forces that prevail in granulators of different size. This hypothesis was confirmed by preparing granules at increasing values of the Froude number at the 4-L scale, and observing a transition from the break-up dissolution mode to the leaching dissolution mode with increasing granule densification. The simultaneous observation of solute concentration and particle size distribution during granules dissolution proved to be a useful tool for the understanding of dissolution mechanisms and for identifying non-uniformities of process conditions that can occur during scale-up.