Advanced flow cell design for in vitro release testing of mucoadhesive buccal films

Films for buccal application are a slowly emerging new platform for drug delivery. There remains a lack of analytical techniques for the determination of in vitro active pharmaceutical release. The aim here was to develop an alternative method to the commonly used United States Pharmacopoeia (USP) 2 method, based on the flow-through cell. This system extends the release time and enables more detailed sample discrimination according to formulation. It could be used as a tool for in vivo prediction of drug release rates from buccal film formulations. The flow cell contains two chambers separated by a membrane through which the released active pharmaceutical ingredient is measured. Vital system variables and their effects on the release rate of the model active pharmaceutical ingredient are presented for formulations based on sodium alginate polymer. The method reflects the differences between films and is shown to be discriminatory for evaluation of buccal formulations

Effect of Textural Properties and Presence of Co-Cation on NH3-SCR Activity of Cu-Exchanged ZSM-5

Comparative studies over micro-/mesoporous Cu-containing zeolites ZSM-5 prepared by top-down treatment involving NaOH, TPAOH or mixture of NaOH/TPAOH (tetrapropylammonium hydroxide) were conducted. The results of the catalytic data revealed the highest activity of the Cu-ZSM-5 catalyst both in the absence and presence of water vapor. The physico-chemical characterization (diffuse reflectance UV-Vis (DR UV-Vis), Fourier transform infrared (FT-IR) spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, temperature-programmed desorption of NOx (TPD-NOx), and microkinetic modeling) results indicated that the microporous structure of ZSM-5 effectively stabilized isolated Cu ion monomers. Besides the attempts targeted to the modification of the textural properties of the parent ZSM-5, in the next approach, we studied the effect of the co-presence of sodium and copper cations in the microporous H-ZSM-5. The presence of co-cation promoted the evolution of [Cu–O–Cu]2+ dimers that bind NOx strongly with the desorption energy barrier of least 80 kJ mol−1. Water presence in the gas phase significantly decreases the rate of ammonia oxidation, while the reaction rates and activation energies of NH3-SCR remain unaffected

Biorefining Twin Transition: Digitalisation for Bio-based Chemicals/Materials - Discovery, Design and Optimisation

The article discusses the production of platform chemicals from various biological sources, including glycerol, lignin, cellulose, bio-oils, and sea products. It presents the results of catalytic and downstream processes involved in the conversion of these biomass-derived feedstocks. The experimental approaches are complemented by numerical descriptions, ranging from density functional theory (DFT) calculations to kinetic modellingof the experimental data. This multi-scale modelling approach helps to understand the underlying mechanisms and optimize the production of platform chemicals from renewable resources

Evaluation of segregation of binary mixtures with spherical crystalized lactose

Segregacija zmesi je v farmacevtski industriji velik problem, za katerega ne poznamo preproste univerzalne rešitve. Najpomembnejši vpliv ima v procesu direktnega tabletiranja. Pri tem procesu izdelave trdnih farmacevtskih oblik uporabljamo zmesi zdravilne učinkovine in pomožnih snovi. Pripravljene zmesi so izpostavljene specifičnim mehanskim obremenitvam, ki povzročajo preurejanje delcev. Vsaka sprememba v lokalni sestavi zmesi direktno vpliva na enakomernost vsebnosti zdravilne učinkovine v posamezni odmerni enoti. Zato je vsakršno preurejanje delcev med procesom tabletiranja problematično in nezaželeno. Določene zmesi so bolj dovzetne za pojav segregacije, medtem ko so lahko druge povsem homogene, ob enakih okoljskih dejavnikih. Stopnje segregacije določene zmesi zaradi kompleksnosti sistema ne moremo vnaprej napovedati. V primeru, ko ne moremo zagotoviti zadostne robustnosti zmesi, moramo pred procesom stiskanja tablet izvesti dodatno procesno operacijo granulacije zmesi. Vsaka dodatna procesna stopnja pa predstavlja strošek in nevarnost za kontaminacijo izdelka. Zato si za izdelavo trdnih farmacevtskih oblik želimo postopek direktnega stiskanja tablet. V magistrski nalogi smo se lotili preučevanja lastnosti segregacije različnih laktoz. Primerjali smo komercialno dostopne laktoze z modificirano laktozo, ki smo jo pripravili na fakulteti. Vse laktoze, ki smo jih preučevali, so primerne za proces direktnega stiskanja tablet, saj izkazujejo dobre pretočne lastnosti in imajo primerno kompresibilnost ter kompaktibilnost. Komercialno dostopni laktozi sta bili Flowlac® 100 in Tabletose® 70. Modificirano laktozo pa smo pripravili s postopkom sferične kristalizacije po metodi dodatka netopila k raztopini. Ugotavljali smo vezavo modelne zdravilne učinkovine na površino laktoze in tvorbo urejenih zmesi. Pripravili smo zmesi treh različnih snovi z laktozami v dveh razmerjih in sicer z 12,5 % in 25 % zdravilne učinkovine. Z metodami nasutega stožca, vrtljivega bobna in sejanja na sitih smo preučevali stopnjo segregacije posamezne zmesi. Segregacija je pojem, ki nima količine, s katero bi jo lahko absolutno opisali. Rezultat vseh meritev je predstavljen v obliki primerjave med različnimi zmesmi. Iz dobljenih rezultatov smo ugotovili, da je sferično aglomerirana laktoza bistveno manj dovzetna za pojav segregacije od komercialno dostopnih. Zaradi svojih odličnih lastnosti predstavlja velik potencial za uporabo v proizvodnji trdnih farmacevtskih oblik.Segregation of mixtures is a major problem in pharmaceutical industry for which we do not possess a standard solution. It has the most significant impact in process of direct tableting. In this process raw mixtures of the active pharmaceutical ingredient and excipients are used. During the production the mixtures are exposed to different mechanical stresses, which cause segregation of particles. Every deviation in homogeneity of mixture leads to the difference in uniformity of content of a single dosage form. There are different types of mixtures, some are very delicate to handle and the others can retain their homogeneity even at more harsh conditions. Complexity of the system is the reason why we can not predict the level of segregation. Segregation data of mixtures is experimentally determined. There are situations in which we can not prepare mixtures that are robust enough. And we must add additional process of granulation before tableting. Every extra process is connected with higher cost of production and there exists a higher possibility of contamination of the product. This master thesis was devoted to examination of segregation properties of different types of lactose. We have compared commercially available lactoses with a modified lactose which we prepared at the faculty. All examined excipients are appropriate for the usage in the process of direct tableting, because they exhibit good compressibility, compactness and flowing properties. Commercially available lactoses which we examined were Tabletose® 70 and Flowlac® 100. Modified lactose has been prepared by spherical crystallisation with a method solvent, anti-solvent. We have examined the bond between the lactose and a model active pharmaceutical ingredient and possible forming of organised mixtures. We have prepared mixtures of various active pharmaceutical ingredients with lactoses with different content (12.5 % and 25 %) of the active pharmaceutical ingredient. We have used the cone forming method, rotating drum and moving of powders through the sieve to determine the level of segregation. Segregation could not be quantified because there is no measurable unit of segregation. Therefore the result of any measurement is a comparison between different mixtures. Results have shown that mixtures with the modified lactose are at least twice less subjected to segregation than mixtures with commercially available lactoses. Because of the excellent properties of the modified lactose there is a huge potential in its application in the process of direct tableting

Development of polymer buccal films for systemic administration of active pharmaceutical ingredients and discriminatory in vitro release method

Nenehen razvoj zdravil je ključen pri spopadanju z boleznimi sodobnega sveta. Majhen košček k temu razvoju predstavlja tudi doktorsko delo, v katerem smo sistematično predstavili področje bukalnih filmov in se poglobili v njihovo formuliranje. Filmi za bukalno aplikacijo so mukoadhezivne farmacevtske oblike, ki so namenjene sistemski ali lokalni dostavi ZU. Njihova lastnost je, da se oprimejo sluznice v ustih in tam sprostijo zdravilno učinkovino (ZU). Izdelava takšnih formulacij zahteva dodatna znanja, ki smo jih pridobili med razvojem bukalnih filmov. Razvoja filmov smo se lotili večplastno. Sprva smo poiskali primerne ZU za bukalno dostavo. Osredotočili smo se na ZU z nizko biološko uporabnostjo in z nizkimi odmerki. Določili smo prednosti filmov s temi ZU pred konvencionalnimi zdravili. Filme smo razvijali sistematično s pomočjo statističnih metod. Z namenom, da bi določili najbolj primerne procesne parametre in optimalno kvantitativno sestavo filma, smo si pomagali s pristopi načrtovanja eksperimentov. Predstavili in preizkusili smo različne metode za vrednotenje tankoslojnih filmov in potrdili skladna opažanja z drugimi raziskovalci o specifičnosti tovrstnih farmacevtskih oblik. Za njihovo vrednotenje je na voljo malo metod, ki bi dajale aplikativne rezultate. Naslovili smo izziv sproščanja ZU iz bukalnih filmov z razvojem lastne metode sproščanja ICRF (Innovative cell for release of films). To metodo smo podrobno ovrednotili in jo primerjali z drugimi sistemi, ki jih najpogosteje zasledimo v literaturi. Potrdili smo, da je dvostransko vrednotenje sproščanja ZU iz filmov primernejše od enostranskega, saj je bolj primerljivo z in vivo pogoji. Posvetili smo se formuliranju filmov z valasartanom in metoklopramidom. Filme smo pripravili z ZU v amorfni in kristalni obliki ter vrednotili njihove lastnosti. Med razvojem formulacij smo prepoznali pomembnost opazovanja videza filmov, saj ta vsebuje veliko informacij o njihovi kakovosti. Poseben izziv predstavlja vrednotenje abstraktnih pojavov, kot so pokanje filma med sušenjem, pojav kristalizacije ZU in ocena homogenosti filma. Vrednotenje teh lastnosti, smo preučevali z uporabo strojne analize slik z nevronsko mrežo. To je odprlo nove možnosti za preučevanje in kvantitativno vrednotenje bukalnih filmov. Področje bukalnih filmov je zaradi ozkega nabora primernih ZU med bolj zapostavljenimi raziskovalnimi področji. Zaradi številnih prednosti tega dostavnega sistema njihov razvoj še vedno vzbuja zanimanje med raziskovalci.Continuous development is the key to managing disease in the modern lifestyle. This doctoral thesis, in which we have systematically presented the field of buccal films and dealt with their formulation, also represents a small piece of this development. Buccal films are mucoadhesive pharmaceutical forms intended for systemic or local drug delivery. They are characterized by the fact that they adhere to the mucous membranes in the mouth and release the active ingredient there. The production of such formulations requires additional knowledge acquired in the development of buccal films. We approached the development of the films in different ways. First, we searched for suitable drugs for buccal administration. We focused on drugs with low bioavailability and low dosage. We determined the advantages of films containing these drugs over conventional drugs. We systematically developed the films using statistical methods. We used experimental design approaches to determine the most suitable process parameters and the optimal quantitative composition of the film. We presented and tested different methods for the evaluation of thin films, confirming consistent observations with other researchers about the specificity of such dosage forms. There are few methods for their evaluation that would provide applicable results. We have addressed the challenge of drug release from buccal films by developing our own innovative cell for release of films (ICRF) release method. We evaluated this method in detail and compared it with other systems. We confirmed that two-sided release of films is more suitable than one-sided release as it is more comparable to in vivo conditions. We addressed the formulation of films with valasartan and metoclopramide. We prepared films with the drug in amorphous and crystalline form and evaluated their properties. During the development of the formulations, we realized how important it is to observe the appearance of the films, as this contains a lot of information about their quality. A particular challenge is the evaluation of abstract phenomena such as the cracking of the film during drying, the phenomenon of drug crystallization and the evaluation of the homogeneity of the film. The evaluation of these properties was approached using machine image analysis with a neural network. This opened up new possibilities for the examination and quantitative evaluation of buccal films. The field of buccal films is one of the neglected areas of research, as the selection of suitable drugs is limited. Nevertheless, this direction of pharmaceutical development continues to attract the interest of researchers due to the many advantages of this delivery system

Catalytic cracking of biomass-derived hydrocarbon tars or model compounds to form biobased benzene, toluene, and xylene isomer mixtures

The gasification of biomass is one of the most prominent technologies for the conversion of the raw material feedstock to polymers, useful chemical substances, and energy. The main engineering challenge during the processing of wastes is the presence of tars in gaseous reaction products, which could make this operation methodology unsuccessfully due to the blockage of separating particle filters, fuel line flow, and substantial transfer losses. Catalytic hydrocarbon cracking appears to be a promising developing approach for their optimal removal. However, it is still highly desirable to enhance the catalysts’ activity kinetics, selectivity, stability, resistance to (ir)­reversible coke deposition, and regeneration solutions. The purpose of this Review is to provide a comparative systematic evaluation of the various natural, synthetic, and hybrid ways to convert the model molecular compounds into benzene, toluene, xylene, (poly)­aromatics, syngas, and others. The recent scientific progress, including calcite, dolomite, lime, magnesite, olivine, char, nonmetallic activated carbons, supported alkali, noble, and transition metals, and (metal-promoted) zeolites, is presented. A special concentrated attention is paid to effectiveness, related to hydrogenation, peculiar pore structure, and formulations’ suitable acidity. The role of catalysis is described, recommendations for prospective catalyzed mechanisms are provided, and future technical feasibility is discussed as well

Mechanistic reaction micro-kinetics-based structure–activity relationships for palmitic acid hydrodeoxygenation over ▫NiMoSx/Al2O3NiMoS_x/Al_2O_3▫ catalysts

The kinetics of palmitic acid hydro-deoxygenation over sulfided NiMo/γ-Al$_2$O$_3$ have been described, including the gas–liquid–solid mass transport/surface chemistry in a magnetically-stirred batch reactor via temperature (225–275 °C), hydrogen pressure (30–70 bar) and catalyst loading (0.1–0.4 g) variation. Intermediates, the hexadecanol and palmityl palmitate, have been probed for a deeper physical understanding of mechanisms. Rates were used to show the impact of the continuum H$_2$ thermodynamic phenomena, availability and coverages on the selectivity among the direct hydrogenation, hydrogenolysis and decarbonylation reactions through the role of H$^•$ formation dependent and independent changes. The system was reduced to 11 catalytic transformation steps, including 8 different molecular species, present in medium. Sequence is simulated to happen on the calculated functional number of active site structures, the activity of which was averaged, while the activation of H$_2$ was supposed to initiate independently. The results of model integrate parameters, such as energies, constants and performance. Process was highly temperature-related, while H$_2$ presence expressed linearly. Phases were characterized with temperature-programmed desorption analysis, coupled with mass spectrometry (TPD–MS) technique, transmission- (TEM), scanning electron microscopy (SEM), X-ray powder diffraction (XRD)