Investigation of design space for freeze-drying injectable ibuprofen using response surface methodology

This study explores the use of a statistical model to build a design space for freeze-drying two formulations with ibuprofen. A 2 × 3 factorial experimental design was used to evaluate independent variables (filling volume and annealing time) and responses as residual moisture content, specific surface area and reconstitution time. A statistical model and response surface plots were generated to define the interactions among the selected variables. The models constructed for both formulations suggest that 1 ml of filled volume and no annealing should be used to achieve optimal residual moisture content, specific surface area and reconstitution time. The proposed models were validated with additional experiments, in which the responses observed were mainly in close agreement with the predicted ones. Additionally, the established models demonstrate the reliability of the evaluation procedure in predicting the selected responses

Solubilization of ibuprofen for freeze dried parenteral dosage forms

Ibuprofen, a weakly acidic non-steroidal anti-inflammatory drug having poor aqueous solubility, is a challenging drug for the development of pharmaceutical formulations, resulting in numerous research attempts focusing on improvement of its solubility and consequently bioavailability. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution. Solubility of ibuprofen was modified by various excipients suitable for parenteral application. Drug interactions with selected excipients in the final product/lyophilisate were studied by a combined use of XRPD, DSC, Raman and ssNMR. Analyses of lyophilized samples showed solubility enhancement of ibuprofen and in situ formation of an ibuprofen salt with the alkaline excipients used

Development and process optimization of freeze dried powder with ibuprofen for parenteral application

Protivnetna nesteroidna zdravila (NSAID) so široko uveljavljena skupina zdravil predvsem za peroralno aplikacijo, medtem ko jih je za parenteralno uporabo na tržišču zelo malo. Parenteralne oblike so primernejše predvsem za bolnike s težavami prebavnega trakta in z oteženim požiranjem peroralno apliciranih trdnih farmacevtskih oblik (FO) ter v primerih postoperativnih indikacij, kjer je zahtevano hitro analgetično, protivnetno in antipiretično delovanje. V eksperimentalnem delu doktorske disertacije smo kot modelno učinkovino uporabili ibuprofen (IBP) kot predstavnika široko uporabljene slabo topne zdravilne učinkovine (ZU), ki jo uvrščamo v skupino NSAID. Na seznamu zdravil, ki so odobrena s strani Ameriške agencije za hrano in zdravila (FDA), je le ena parenteralna oblika z IBP s koncentracijo > 10 mg/ml, kar je vsekakor posledica fizikalno-kemijskih lastnosti molekule, predvsem slabe vodotopnosti (< 1 mg/ml), ki poleg visokega odmerka (peroralno maks. 800 mg dnevno) predstavlja velik izziv za razvoj farmacevtske oblike z IBP. Številne objave opisujejo različne tehnike za izboljšanje topnosti predvsem za trdne peroralne FO, medtem ko je za paranteralne oblike to področje slabše raziskano. Eksperimentalno delo v doktorski disertaciji smo razdelili na dva dela. V prvem delu smo največ pozornosti namenili razvoju parenteralnega liofiliziranega izdelka z IBP, ki bo povečal topnost ZU ter hkrati omogočal izotoničnost končno pripravljene raztopine, ki nastane po raztapljanju liofilizata z vodo za injekcije (VZI). Pri tem smo se osredotočili na vrednotenje raztopine pred liofilizacijo za definiranje ključnih procesnih parametrov ter na izbor pomožnih snovi. V nadaljevanju smo predstavili pristop k optimizaciji energetsko in časovno potratnega liofilizacijskega procesa. Vpliv formulacijskih in procesnih parametrov na ključne lastnosti končnega izdelka smo vrednotili z multivariantno analizo podatkov (z metodo odzivnih površin) ter določili optimalno kombinacijo formulacijskega in procesnega parametra. V drugem delu doktorskega dela smo ovrednotili uporabnost procesne analizne tehnologije (PAT), in sicer bližnje infrardeče (NIR) in ramanske spektroskopije za merjenje ključnih karakteristik liofilizata, kot so vsebnost vode (RMC), specifična površina (SSA) in rekonstitucijski čas (RT). Pri obdelavi obsežnih podatkov smo si pomagali z multivariantno analizo podatkov (MVA), in sicer z metodo glavnih komponent (PCA) in regresijo delnih najmanjših kvadratov (PLS). Doktorsko delo predstavljajo uvodno poglavje in tri poglavja z raziskovalnimi rezultati v obliki člankov, ki smo jih objavili ali poslali v objavo v priznane znanstvene publikacije.Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for oral, while there are just a few for parenteral administration on the market. Parenteral forms are preferred in cases of postoperative indications, where rapid analgesic, anti-inflammatory and antipyretic action is required especially in patients with gastrointestinal problems and in patients with swallowing difficulties. Ibuprofen (IBP), which is classified in the NSAID group and is a representative of the widely used poorly soluble active pharmaceutical ingredient (API), was used in the experimental part of the doctoral thesis. US Food and Drug Administration (FDA) approved only one parenteral form with IBP with a concentration > 10 mg/mL, which is certainly due to the physicochemical properties of the molecule, especially poor water solubility (< 1 mg/mL), which in addition to the high dose (max. 800 mg daily) presents a great challenge to formulating dosage form with IBP. Numerous publications describe various techniques for IBP solubilization for solid dosage forms, while for parenteral forms solubility enchancment is less researched. The work of the doctoral thesis was divided into two parts. Firstly, the main focus was to develop a parenteral lyophilized product with enhanced solubility of IBP and isotonicity of the finally prepared solution after dissolving the lyophilisate with water for injections (WFI). We focused on the evaluation of the solution before lyophilization to define key process parameters and on the selection of excipients. Furtermore, as lyophilization is energy and time consuming technological process, its optimization was investigated. The influence of formulation and process parameters on the critical attributes of the final product was evaluated by multivariate data analysis (using the response surface method) and the optimal combination of formulation and process parameters was determined accordingly. In the second part of this thesis, the applicability of process analysis technology (PAT), namely near- infrared (NIR) and Raman spectroscopy for evaluation of critical attributes of the lyophilisate such as residual moisture content (RMC), specific surface area (SSA) and reconstitution time (RT) was evaluated. Multivariate data analysis (MVA), namely the principal components method (PCA) and partial least squares regression (PLS) were used for evaluation of the collected process data. The doctoral thesis consists of introduction part and three research papers that already are or will be published in recognised scientific journals

PYROLYSIS OF WOOD BIOMASS

Cilj diplomskega dela je opisati in predstaviti proces pirolize lesa in se osredotočiti na proces pirolize, kjer se pridobi največ trdnega produkta – to je proces torefikacije lesa. V prvem delu diplomskega dela je predstavljena lesna biomasa in pomen posameznih sestavnih delov v lesu. Predstavljen in opisan je postopek pirolize ter vsi tipi pirolize s prevladujočimi produkti in značilnostmi. Diplomsko delo je osredotočeno na počasno pirolizo, ki jo imenujemo torefikacija, ker pri tem postopku dobimo največ trdnega produkta. Drugi del diplomske naloge zajema podrobne opise različnih tehnologij, uporabljenih pri postopku torefikacije lesne biomase, kjer dobimo kot produkt toreficirane pelete. Narejena je energetska primerjava energentov – lesa, toreficirane biomase, toreficiranih peletov in oglja. Primerjava vključuje energetske vrednosti in gostote pri značilni vrednosti vlage v materialu. Za primerjavo je bil izbran kotel na trdna goriva za ogrevanje poslovnega objekta. Kotel obratuje po principu pirolize lesa. Preračunana je primerjava porabe posameznih energentov ter ekonomska in energetska analiza, v smislu kurilnih vrednosti vseh energentov. Energenti, ki so bili izbrani za izgorevanje v kotlu na trdna goriva, so les, lesni peleti, toreficirani peleti in oglje.The purpose of this diploma thesis is to describe and introduce the process of pyrolysis of wood and focus on the process of pyrolysis, which is the one that produces the largest quantity of solid products – this is the process of wood torrefaction. The first part of the thesis introduces wood biomass and the importance of individual wood components. The thesis presents the process of pyrolysis and all types of pyrolysis with their main products and characteristics. The thesis is focused on the slow pyrolysis, called torrefaction, because it is the process in which the largest number of solid products is produced. The second part of the thesis involves detailed descriptions of various technologies, used in the process of wood biomass torrefaction, the product of which is torrefied pellets. I have made an energy comparison of energy products – wood, torrefied biomass, torrefied pellets and charcoal. The comparison includes energy values and densities at different moisture value in the material. The solid fuels boiler used to heat business premises has been chosen for the comparison. The boiler operates on the wood pyrolysis principle. The thesis includes use calculations of individual energy products, economic and energy analyses, within the meaning of heating value of all energy products. The energy products chosen for combustion in the solid fuels boilers are wood, wood pellets, torrefied pellets and charcoal

Study of microfiltration ceramic membrane filtration of whey proteins

Fizikalno-kemijska obdelava, kot je postopek mikrofiltracije (MF) in ultrafiltracije (UF) sirotke, povzroča reverzibilno in ireverzibilno mašenje por keramičnih membran kot tudi spremembe v strukturi in interakciji proteinov s številnimi komponentami sirotke ter površino membran. Slednje vodi do denaturacije in agregacije proteinov in ravno tako prispeva k mašenju membrane. Vrste in obseg proteinskih interakcij so odvisni od pogojev obdelave, sestave in ionske moči sirotke ter vrednosti pH. Obdelave, ki destabilizirajo strukturo sirotkinih proteinov in spodbujajo razvijanje proteinov, pospešijo interakcije med sirotkinimi proteini v raztopini in vodijo do različnih intramolekularnih ali intermolekularnih reakcij. Sirotka vsebuje različne komponente, kot so mikroorganizmi, encimi in proteini, zaradi katerih se njihove lastnosti s časom in z različnimi pogoji shranjevanja spreminjajo in vplivajo na medsebojne interakcije. Pomembno je bilo opredeliti fizikalno-kemijsko in mikrobiološko stabilnost sirotke, ki se je spremljala po preteku enega tedna, da se določi vpliv temperature in način shranjevanja sirotke pred pričetkom postopkov MF in UF. Namen testiranj MF in UF membran je bila je optimizacija procesov, s ciljem doseganja visoke prepustnosti za sirotkine proteine (predvsem laktoferina - LF) in zadrževanje mikroorganizmov ter drugih komponent sirotke, ki bi omejevale uporabo sirotke v nadaljnjih postopkih predelave. V eksperimentih smo opredelili najbolj učinkovit režim delovanja MF keramične membrane ter režim čiščenja le-teh, ki omogoča čim daljše delovanje filtracije brez zamašitve membran ter povrnitev polnega pretoka po zamašitvi. Ugotovili smo, da aktivnost encima laktoperoksidaze (LPO) hitro pada ne glede na shranjevanje sirotke. Protein LF je stabilen 8 dni v hladilniku, medtem ko na sobni temperaturi postopoma razpade. Z MF keramično membrano s premerom por 0,5 μm smo dosegli 51 % prepustnost LF v permeat pri tlaku 1 bar. Opazili smo, da je membrana učinkovito očiščena v treh korakih, in sicer s 0,4 % raztopino natrijevega hidroksida (NaOH), 0,3 % raztopino dušikove kisline (HNO3) in 0,5 % raztopino natrijeviega hipoklorida (NaOCl) pri temperaturi 60 °C in pri večji hitrosti črpalke kot je delovna ter pri tlaku povratnega toka 0,5 bar. UF keramična membrana s premerom por 0,05 μm je 100 % zadržala protein LF v retentatu.Physicochemical treatment, such as the process of microfiltration (MF) and whey ultrafiltration (UF), causes reversible and irreversible fouling of ceramic membrane pores, as well as changes in protein structure and interaction of proteins with many whey components and membrane surface. The latter leads to protein denaturation and aggregation and also contributes to membrane fouling. The types and extent of protein interactions depend on the processing conditions, the composition and ionic strength of the whey, and the pH value. Processes that destabilize the structure of whey proteins and promote the development of proteins, accelerate interactions between whey proteins in solution and lead to various intramolecular or intermolecular reactions. Whey consists of various components, such as microorganisms, enzymes and proteins, due to which, also taking into account different storage conditions, its characteristics change over time and can affect the interactions between them. It was important to determine the physicochemical and microbiological stability of whey monitored in a one-week period, to establish the effect of temperature, and how the whey was stored prior to the initiation of MF and UF procedures. The purpose of MF and UF membrane testing was to optimize processes, with the aim of achieving high permeability for whey proteins (especially lactoferrin - LF) and retention of microorganisms and other whey components, that would limit the use of whey in further processing operations. In the experiments, we determined the most efficient mode of operation of the MF ceramic membrane and the regime of cleaning them, which allows the filtration to last as long as possible without membrane fouling and restoring the full flow after fouling. We observed that the activity of the lactoperoxidaze (LPO) enzyme declines rapidly regardless of whey storage conditions. The LF protein is stable 8 days in the refrigerator, while gradually decomposing at room temperature. A MF ceramic membrane with a pore diameter of 0,5 μm achieved a 51 % permeability in permeate of LF at a pressure of 1 bar. We detected, that the membrane was effectively cleaned in three steps, with 0,4 % sodium hydroxide solution (NaOH), 0,3% nitric acid solution (HNO3) and 0,5 % sodium hypochlorite solution (NaOCl) at 60 °C and at a higher pump speed than the operating speed and at the pressure of reverse flow at 0,5 bars. An UF ceramic membrane with a pore diameter of 0,05 μm held the LF protein in retention

Packaging for food delivery

Embalaža je produkt, ki ga srečamo skoraj na vsakem koraku. Izpolnjevati mora tako osnovne funkcije embalaže, to sta varovanje in zaščita izdelka, kot tudi mnogo drugih. Namen diplomskega dela je bil raziskati trg embalaž za dostavo hrane, podati njihove dobre in slabe lastnosti ter opisati vrste materialov, s ciljem, da se na koncu oblikuje lastna embalaža za pripravljeno hrano. Diplomsko delo je razdeljeno na dva delateoretični del, v katerem je podano nekaj splošnih dejstev o embalaži in materialih s poudarkom na embalaži, namenjeni dostavi na dom. V eksperimentalnem delu smo analizirali tri obstoječe embalaže za pakiranje pripravljene hrane, in sicer plastično embalažo iz polipropilena, ekspandiranega polistirena ter iz aluminija. Izvedli smo tudi spletno anketo, katere namen je bil ugotoviti, kateri material povzroča najmanj težav, kako funkcionalne so embalaže ter kako pomemben je videz in trajnostni vidik tovrstne embalaže. Rezultati ankete in analiza obstoječe embalaže so podali smernice za načrtovanje lastne embalaže. Nadalje je opisan postopek izdelave lastne embalaže v programu 3D modeliranje Blender. Novo razvita embalaža je izdelana iz silikona in polipropilena. Je preproste oblike, funkcionalna in omogoča preprosto rokovanje. Izdelana je iz reciklabilnih materialov in je namenjena večkratni uporabi.Packaging is a product we encounter in many aspects of everyday life. There are several basic functions every proper packaging needs to have, most notable of which are safety and protection of its content. The purpose of this paper is to examine various types of packaging used in home delivery of prepared food, outline their pros and cons and describe the types of materials used for its production. The ultimate goal of the research was to collect data in order to produce an own type of packaging that would be used to contain prepared food. This paper is divided into two parts. The first part deals with the theoretical aspect and gives insight into some general facts about packaging and materials, emphasizing on packaging used in home delivery of prepared food. The second, experimental part provides the analysis of three types of existing packaging that are used to contain prepared food: plastic (polypropylene) packaging, expanded polystyrene packaging and tin (aluminum) packaging. An online survey was also conducted. The respondents were asked to answer which of the mentioned materials cause the least difficulties, which ones serve the functionality of the packaging the best and how important the appearance and lifespan of the packaging are to them. The results of the survey and the analysis of the existing packaging samples helped develop the design for the production of our own piece of packaging. Furthermore, the process of production, using 3D computer program Blender, is described. The new type of packaging is made from silicon and polypropylene. It is of simple shape, highly functional and easy to handle. The packaging is made of recyclable materials and is designed for multiple uses

Investigation of design space for freeze-drying injectable ibuprofen using response surface methodology

This study explores the use of a statistical model to build a design space for freeze-drying two formulations with ibuprofen. A 2 × 3 factorial experimental design was used to evaluate independent variables (filling volume and annealing time) and responses as residual moisture content, specific surface area and reconstitution time. A statistical model and response surface plots were generated to define the interactions among the selected variables. The models constructed for both formulations suggest that 1 mL of filled volume and no annealing should be used to achieve optimal residual moisture content, specific surface area and reconstitution time. The proposed models were validated with additional experiments, in which the responses observed were mainly in close agreement with the predicted ones. Additionally, the established models demonstrate the reliability of the evaluation procedure in predicting the selected responses

Solubilization of ibuprofen for freeze dried parenteral dosage forms

Ibuprofen, a weakly acidic non-steroidal anti-inflammatory drug having poor aqueous solubility, is a challenging drug for the development of pharmaceutical formulations, resulting in numerous research attempts focusing on improvement of its solubility and consequently bioavailability. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution. Solubility of ibuprofen was modified by various excipients suitable for parenteral application. Drug interactions with selected excipients in the final product/lyophilisate were studied by a combined use of XRPD, DSC, Raman and ss-NMR. Analyses of lyophilized samples showed solubility enhancement of ibuprofen and in situ formation of an ibuprofen salt with the alkaline excipients used