Integrated twin-screw wet granulation, continuous vibrational fluid drying and milling: A fully continuous powder to granule line.

Highly homogeneous low-dose (50 µg) tablets were produced incorporating perfectly free-flowing granules prepared by a fully integrated Continuous Manufacturing (CM) line. The adopted CM equipment consisted of a Twin-Screw Wet Granulator (TSWG), a Continuous Fluid Bed Dryer (CFBD) and a Continuous Sieving (CS) unit. Throughout the experiments a pre-blend of lactose-monohydrate and corn starch was gravimetrically dosed with 1 kg/h into the TSWG, where they were successfully granulated with the drug containing water-based PVPK30 solution. The wet mass was subsequently dried in the CFBD on a vibratory conveyor belt and finally sieved in the milling unit. Granule production efficiency was maximized by determining the minimal Liquid-to-Solid (L/S) ratio (0.11). Design of Experiments (DoE) were carried out in order to evaluate the influence of the drying process parameters of the CFBD on the Loss-on-Drying (LOD) results. The manufactured granules were compressed into tablets by an industrial tablet rotary press with excellent API homogeneity (RSD < 3%). Significant scale-up was realized with the CM line by increasing the throughput rate to 10 kg/h. The manufactured granules yielded very similar results to the previous small-scale granulation runs. API homogeneity was demonstrated (RSD < 2%) with Blend Uniformity Analysis (BUA). The efficiency of TSWG granulation was compared to High-Shear Granulation (HSG) with the same L/S ratio. The final results have demonstrated that both the liquid distribution and more importantly API homogeneity was better in case of the TSWG granulation (RSD 1.3% vs. 4.5%).

Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole.

Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.

Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions.

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

Rapid diagnostics of urinary iodine using a portable EDXRF spectrometer.

A method for urinary iodine diagnostics using a portable energy-dispersion X-ray fluorescent (EDXRF) spectrometer is proposed. The principle of the method consists in excitation of the sample atoms fluorescence by the energy spectrum intentionally formed from the spectrum of an X-ray tube using an optimized X-ray scheme. The optimization by the criterion of the minimum detection limit for L-series iodine fluorescence lines included the calculation of optimal atomic numbers for materials of a re-radiator and a filter, and their thicknesses, the collimation system parameters, and an X-ray tube voltage. Experimentally achieved detection limits were 45 and 75 µg/L by I-Lα and I-Lß lines, respectively, at the theoretically extreme value 30 µg/L. This sensitivity is found to be sufficient for urinary iodine diagnostics in the range from 50 to 200 µg/L. The results obtained from different patients have shown the satisfactory convergence for the iodine concentration determination by Lα and I-Lß fluorescence lines. The simple sample preparation procedure and comparably small sizes of the apparatus allows rapid researches directly in clinical settings.

PECULIARITIES OF THE CEREBELLUM NUCLEI IN AGED PERSONS.

The study of the clinical anatomy and functional features of the cortex, subcortical and conductive pathways of the cerebellum is necessary for clinicians for elaboration rational surgical approaches to these formations, for determination the localization of pathological processes associated with these formations. Cerebellar nucleus neurons are crucial to the olivo-cerebellar circuit as they provide the sole output of the entire cerebellum. The relationship between mobility and cognition in aging is well established, but the relationship between mobility and the structure and function of the aging brain is relatively unknown. In connection with the above, the purpose of our study was detection of the morphological characteristics of the cerebellum nuclei in aged persons. Study was performed on 48 specimens of the cerebellum from people (24 male and 24 female), who died at the age from 75 to 99 years due to diseases, which were not related to the central nervous system damaging. Formalin-fixed human hemispheres were dissected with the Ludwig and Klingler fiber dissection technique under x6 to x40 magnifications of binocular microscope Olympus BX41 (Japan). The morphological features of the human cerebellar nuclei were established. Namely, on the series of sections of the cerebellum in the horizontal, frontal and sagittal planes, as well as on the macro-microscopic preparations of the cerebellar nuclei location, their relative position, shape, linear dimensions, weight and volume were described. The features of macro-microscopic and histological structure of the nuclei of the cerebellum were made own classification of the gyri and teeth of the dentate nucleus of the cerebellum was offered. Macro-microscopic dissection of persons died after 75 years old show no significant variability of linear dimensions of cerebellar nuclei with their specific location and options. Simultaneously, reliable reducing of cellular density was detected for Purkinje, granule and basket neurons more pronounced in male for Purkinje cells.

PECULIARITIES OF CATENIN ACTIVITY IN THE EMBRYONAL TESTICULAR CARCINOMA.

The aim of the research was to study immunohistochemical peculiarities of catenin activity in the embryonal testicular carcinoma. Material is presented by 39 cases of embryonal testicular carcinoma for the period from 1993 to 2013. Macroscopic and histological investigation has been performed according to the WHO classification (2004). Immunohistochemical examination with monoclonal antibodies to Ki-67, ß-catenin and E-cadherin were performed. Embryonal carcinoma is presented 12.38% of all testicular germ cell tumors in our observations with median age of patients 30.85±1.16 years. Embryonic cancer of testis has been characterized histologicaly with combination of different areas of the structure: solid, forming a diffuse field, and acinar, tubular and papillary structures with different developed connective tissue background. Tumor cells are characterized by well-defined cytoplasm, polymorphic hyperchromatic nuclei with distinct nucleoli. Embryonic cancer is characterized pronounced reducing of membranous ß-catenin expression (that is usual localization of that protein) with uneven level of expression from weak till strong. Simultaneously nuclear positive immunoreactivity has been appeared in embryonic cancer in isolate and grouped cells of tumor. Correlation between Ki-67 and ß-catenin expression is 0.562, between E-cadherin and ß-catenin is 0.737. It was concluded that immunohistochemical catenin activity must be interpreted accurately in case of embryonal carcinoma of the testis as there is no clear evidence on prognostic importance of neoplastic behavior as it is in some other tumors.