Segregacija v vertikalnih cevnih povezavah z zaprtim dnom: obravnava procesa s postopkom numerične analize tokov in eksperimentalno potrditvijo modela : doktorska disertacija

Jaklič, Miha Tomaž (author), Srčič, Stanko (mentor), Kočevar, Klemen (co-mentor)

Gravitacijski transport po vertikalnih cevnih povezavah je osnoven in hkrati ključen proces transporta praškastih snovi v farmacevtski industriji. V primeru vertikalnih cevnih povezav z zaprtim dnom lahko protitočni izhajajoči zrak povzroči obsežno segregacijo, kar ima znaten vpliv na enakomernost vsebnosti in druge ključne biofarmacevtske lastnosti končnih farmacevtskih izdelkov. Napoved pojava in obsega segregacije že v fazi razvoja izdelka in vpeljava ustreznih ukrepov za preprečitev pojava segregacije je pomemben element pri razvoju izdelka z vgrajeno kakovostjo. Eksperimentalno analizo granularnega toka in segregacije farmacevtskih praškov smo izvedli na laboratorijskem modelu vertikalne cevne povezave. Uporabili smo materiale in zmesi, ki se dejansko uporabljajo v industrijskih procesih. Steklena prosojna cev je omogočila snemanje tokovnih struktur padajočih praškov, s slikovno analizo pa smo kvantificirali tokovne parametre. S postopno modifikacijo laboratorijskega modela smo proučevali tokovne strukture pri različnih pogojih izpusta: zaprta cev, odprta cev in izpust brez cevi. Za testiranje segregacije v cevi z zaprtim dnom smo razvili ventil za plastovito vzorčenje sedimenta, kar je omogočilo kvantifikacijo vertikalne segregacije enokomponentnih materialov ter dvo- in večkomponentnih zmesi. Numerično simulacijo granularnega toka smo izvedli po Euler-Eulerjevem pristopu. Za modeliranje smo uporabili program za numerično analizo tokov Fluent, kjer smo predpostavili, da je vsaka izmed simuliranih faz fluid: v našem primeru tako obravnavamo plin (izhajajoči zrak) ter na podlagi kinetične teorije granularnega modela eno oziroma dve granularni fazi. Zasnova simulacij je bila enaka eksperimentalnemu delu: simulirali smo granularni tok za vse tri pogoje izpusta, dodatno pa smo izvedli simulacijo segregacije binarne zmesi. Granularni tok v zaprti cevi je kompleksen, večfazen proces. Celotno nasutje praškov se zaradi permeacije zraka skozi njegovo porozno strukturo počasi spušča; bistveno hitrejši je redek granularni tok, ki nastane ob dispergiranju odcepljenih paketov s spodnje strani nasutja praškov. Še za dodaten red velikosti hitrejše pa je spuščanje praškov v cevi z odprtim dnom, kjer nasutje praškov zrak potisne skozi izpust cevi. Podobno hiter tok smo opazovali v poskusih brez cevi. Na granularnih tokovih smo opazili Plateau-Rayleighjevo in Rayleigh-Taylorjevo nestabilnost, kar kaže na podobnost obravnavanih granularnih tokov s tekočinami. Vrsta materiala vpliva na pretok zlasti v pogoju zaprte cevi, medtem ko je za pogoj odprte cevi ta vpliv manjši. Pri kvantificiranju segregacije enokomponentnih praškov smo ugotovili, da se z naraščajočo plastjo sedimenta velikost delcev postopno manjša, kar je posledica akumulacije majhnih delcev v zraku med padanjem praškov. Pri testih segregacije na binarnih zmeseh smo na eni strani identificirali segregacijsko stabilno kombinacijo laktoze sušene z razprševanjem in mikrokristalne celuloze, na drugi strani pa pokazali obsežno segregacijo pri kombinaciji laktoze sušene z razprševanjem in krospovidonom ter kombinaciji laktoze sušene z razprševanjem in kopovidonom. Na primeru ternarnih zmesi smo pokazali, da dodatek koloidnega silicijevega dioksida segregacijsko destabilizira sicer stabilno binarno zmes. Drugi primer ternarne zmesi – binarna zmes praškov z dodatkom tekoče komponente v vlogi veziva – je pokazal, da višanje deleža tekoče komponente bistveno zmanjša segregacijo zmesi. Na petkomponentni zmesi za direktno tabletiranje smo pokazali, da je uskladitev velikosti delcev učinkovine in glavnega polnila uspešen ukrep za zmanjšanja obsega segregacije na sprejemljivo raven. Izsledki numerične simulacije granularnega toka v odprti cevi se z eksperimentalnimi rezultati dobro ujemajo tako v tokovnih strukturah, kakor tudi v hitrostih pretoka. Podobno smo ugotovili za primer brez cevi. Pri cevi z zaprtim dnom pa je ujemanje slabše, ker se je granularni model fluida izkazal za šibkega pri napovedovanju realnega odcepljanja paketov praškov iz spodnje strani nasutja. Po drugi strani pa simulacija pokaže obstoj anularnega toka, ki ga z optičnim opazovanjem ne moremo ne potrditi ne ovreči. Pri simulaciji segregacije binarne zmesi praškov smo odkrili pričakovani trend vertikalne segregacije, dodatno pa smo s simulacijo pokazali še močno lateralno segregacijo. Eksperimentalna in simulacijska obravnava tokovnih struktur in segregacije sta komplementarni: eksperiment potrjuje simulacijo, hkrati pa simulacija dodaja vpogled v obravnavani proces z ločljivostjo, ki je eksperiment ne more doseči. Skupna uporaba obeh predstavlja ključ za detajlno razumevanje procesov in aplikacijo dognanj v realnih industrijskih procesih.

• Language: Slovenian
• Keywords: farmacevtska industrija, praški, gravitacijski transport, granularni tok, vertikalne cevne povezave z zaprtim dnom, segregacija, farmacevtski preparati, kvaliteta, numerična simulacija, modeliranje, disertacije
• Work type: Doctoral dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [M. Jaklič]
• Year: 2016
• Number of pages: 149 str.
• PID: 20.500.12556/RUL-143756
• UDC: 661.12(043.3)
• COBISS.SI-ID: 283043584
• Publication date in RUL: 11.01.2023

Secondary language

• Language: English
• Title: Segregation of powders in vertical pipes with closed outlet: computational fluid dynamics simulation and experimental model validation

Abstract

Gravity driven flow of granular material in vertical pipes is simple and widespread means of bulk powder transport in pharmaceutical industry. Vertical pipes with closed outlet promote segregation of falling powders by counter-flow of displaced air which results in inadequate content uniformity of the tablet constituents and can influence biopharmaceutical properties of the finished dosage forms. Segregation prediction and its quantification in the early stages of product development enable the implementation of adequate counter measures for its prevention on full scale manufacture as an integral part of Quality by Design paradigm. Experimental evaluation of powder flow and segregation was performed on laboratory scale model of vertical pipe. Materials and powder mixtures which are actually used in manufacturing processes were tested. Laboratory model was made from transparent glass, which enabled video recording of the falling powders and subsequent extraction of flow parameters by means of image analysis. Evaluation of powder flow was performed on three pipe outlet conditions: closed outlet, open outlet and condition without the pipe. Segregation of materials was tested on vertical pipe with closed outlet, where stratified sampling of materials was accomplished by specially designed sampling valve which enabled vertically stratified sampling of settled powders. Computational fluid dynamics (CFD) simulation of powder flow was performed with Euler-Euler approach using Fluent CFD software. The kinetic theory of granular flow was applied for simulation of granular flow. Simulation of segregation was performed with two granular phases. The design of simulation runs was identical to the design of performed experiments: granular flow in vertical pipe with all three pipe outlet conditions as well as segregation of binary mixture were simulated. Powder flow in vertical pipe with closed outlet is a complex process where two simultaneous flow regimes co-exist: one is a slow, dense moving powder bed flow, which descends due to air permeation trough porous material and the second is by order of magnitude faster dilute granular flow, which occurs due to detachment of powder packets from the bottom part of the powder bed and its full dispersion in air. Powder flow in vertical pipes with open outlet is once again by order of magnitude faster where the dense granular flow is not hindered by the trapped air. In experiments without the pipe, powder flow was similar to the open outlet condition. Granular flows exhibited Plateau-Rayleigh and Rayleigh-Taylor instabilities, which confirms fluid-like behaviour. Material type influences flow in pipe with closed outlet, whereas in the open outlet condition the material influence is less distinct. Segregation based on particle size was confirmed on single-component powders where particle size decreases with increasing sediment layer. Observed phenomenon is caused by accumulation of powder fines in air and their slow sedimentation. Segregation tests of binary mixtures identified a combination of spray dried lactose and icrocrystalline cellulose which proved to be resistant to segregation. On the other hand a substantial segregation of powder mixtures containing spray dried lactose/crospovidone and spray dried lactose/copovidone was observed. Ternary mixtures containing fumed silica proved to be prone to segregation compared to mixture without the fumed silica. Ternary mixtures containing fluid component in function of binder demonstrated reduced segregation. In a five-component mixture for direct compression the active pharmaceutical ingredient particle size was matched to that of the main filler, which resulted in reduction of segregation. CFD simulation of granular flow in vertical pipe with open outlet was in good agreement with experimental data in terms of flow structures and flow rates; similar was established for case without the pipe. However the simulation fit in pipes with closed outlet was weaker. Its major drawback was the inability to simulate powder packets detachment from the powder bed. On the other hand a typical annular flow regime was simulated, which cannot be confirmed nor rejected by optical observation. CFD simulation of binary granular mixture (three fluids model) has shown an expected trend of vertical segregation. In addition the simulation revealed a strong lateral segregation pattern. The experimental and simulation approach to characterization of flow structure and segregation are complementary: experiment verifies the simulation and simulation enables a detailed insight into the process with unrivalled resolution. Joint use of both approaches is a key to thorough understanding of processes and enables application of findings in real industrial environment.