Search

Pharmaceutical product development guided by Quality by Design (QbD) is based on a complete understanding of the critical process parameters (CPPs) that are important for achieving the desired product critical quality attributes (CQAs). The effect of process settings, such as the screw speed, the throughput, the barrel temperature, and the screw configuration, is a well-known factor in the setup of pharmaceutical hot melt extrusion (HME) processes. A CPP that has not yet been extensively researched is the type of cross-section geometry of the screw elements. Typically, pharmaceutical extruders have double-flighted screw cross-sections, with some elements having a single- or triple-flighted element section. The exception is a NANO16 extruder from Leistritz, with all screw elements having a triple-flighted screw geometry. We investigated the process setup and scale-up to a double-flighted extruder experimentally and in silico via a digital twin. Two formulations were processed on a NANO16 extruder and virtually transferred to a ZSE18 double-flighted co-rotating twin-screw extruder. Detailed smoothed particle hydrodynamics simulations of all screw elements available from both extruders were performed, and their efficiency in conveying, pressure build-up, and power consumption were studied. Reduced-order 1D HME simulations, which were carried out to investigate the process space and scalability of both extruders, were experimentally validated.

Following our study on the impact of hot melt extrusion (HME) process conditions on the product quality, we expanded our investigation to assessing the effect of scale-up on the product quality. To this end, we studied the influence of process settings and different scale-up variants on the active pharmaceutical ingredient (API) degradation in a pilot plant scale extruder. Six scale-up variants were investigated and none of them could replicate the product quality from the original process setup on a lab-scale extruder. By analyzing several process-dependent and -independent variables and cross referencing them to the experiments in the lab-scale extruder, we identified certain patterns. The results of the reduced order mechanistic 1D HME simulation of various process states made it possible to establish a correlation between the achieved API degradation and the local melt temperature and the exposure time in specific zones along the screw configuration. Since the same melt temperature and exposure time correlations were also valid for the lab scale-extruder, such an approach could be used in the future to predict the product quality as a function of processing conditions fully in silico prior to the first extrusion trials., Graphical abstract Unlabelled Image

The goal of our study was to develop a rational in silico scale-up and process transfer approach for hot melt extrusion processes occurring in the pharmaceutical and other industries. To that end, we performed high-fidelity simulations of individual twin-screw extruder elements via the Lagrangian-based Smoothed Particle Hydrodynamics (SPH) method. To parametrize a mechanistic 1D hot-melt extrusion (HME) model, the data generated by the SPH simulations was used together with the material properties. Two co-rotating twin-screw extruder setups were compared: the Coperion ZSK18 and the Leistritz MIC27 extruders. The pressure and power characteristics of the two extruders with different screw elements and geometries were obtained and compared. The impact of the HME process parameters (throughput, screw speed and barrel temperature) on the filling degree, melt temperature, axial specific mechanical energy consumption (SMEC) and residence time distribution in the two extruders was established. The torque and SMEC values obtained in silico were then compared to experiments to ensure that the 1D HME simulations were set up correctly. Next, scale-up methods from the literature were evaluated, yielding an unsatisfactory set of process parameters that might lead to material degradation. Finally, a rational scale-up approach was proposed. Based on this novel method alternative parameter settings on the MIC27 extruder were established, assuring equivalent thermo-mechanical load on the product compared to the process using the ZSK18 extruder.

Žižula (Ziziphus jujuba Mill.) je mediteranska voćna vrsta koja svojim ukrasnim i oblikovnim karakteristikama upotpunjuje pejsažnu sliku urbanog prostora grada Skradina. Na području Skradina ova kultura je posađena u sklopu kućnih vrtova i samostalnih voćnjaka. Danas na području grada Skradina kuća s vrtom sve više poprima gradska obilježja i udaljava se od tradicionalnog seoskog vrta. Tradicija uzgoja žižule je prvenstveno u gospodarske svrhe (radi ploda), premda je poznato da se zbog izuzetne ljekovitosti od žižule mogu još koristiti listovi i kora. Cilj rada bila je valorizacija utilitarnih i ukrasnih vrtova te voćnjaka (sveukupno 36) na području grada Skradina u kojima je posađena žižula. Kroz anketno istraživanje u uzorku od 50 ispitanika s područja grada Skradina istražili su se stavovi i percepcije o ukrasnim karakteristikama, primjeni, održavanju i ulozi žižule u gospodarstvu Skradina. Terenskim istraživanjima je utvrđeno da su za krajobrazno uređenje i oblikovanje vrtova s žižulom najveće ocijene postigli ukrasni vrtovi u sklopu stambenog objekta. U pogledu zastupljenosti (pojavnosti) u vrtovima na ovom području prevladavaju utilitarne vrste. Najveći broj stabala žižule zabilježen je u voćnjacima bez stambenog objekta. Izvrsne ocijene su dodijeljene stablima žižule u okviru voćnjaka u sklopu stambenog objekta i utilitarnim vrtovima u sklopu stambenog objekta. Rezultati anketnog istraživanja pokazuju da je vegetativnim organima ove voćke u pogledu uresnosti dodijeljena ocjena izvrstan kao i njenoj ulozi u krajobraznoj slikovitosti. Ocjenjivači atraktivnijim smatraju primjenu žižule u vrtovima nego na javnim krajobraznim površinama i parkovima. Smatraju da ova kultura treba postati i skradinski brend., Jujube (Ziziphus jujuba Mill.) is a Mediterranean fruit species that with its ornamental and design characteristics completes the landscape image of the urban space of the town of Skradin. In the area of Skradin this species has been planted in family house gardens and independent orchards. Nowadays family houses in the territory of the town of Skradin have been increasingly assuming urban features and departing from the traditional rural garden. The tradition of jujube cultivation is primarily for sale (for its fruit), although it is known that its leaves and bark can also be used because of their extremely beneficial medicinal properties. The specific objective of the paper was valorisation of utilitarian and decorative gardens and orchards (a total of 36) in the territory of the town of Skradin in which jujube had been planted. A survey research using the sample of 50 respondents from the territory of the town of Skradin explored attitudes and perceptions about ornamental characteristics, application, maintenance and the role of jujube in the economy of Skradin. According to field research findings, it was determined that ornamental gardens adjacent to a residential facility were given the highest grades for landscape architecture and garden design using jujube. According to prevalence in the gardens, utilitarian species prevail in this area. The highest number of jujube trees was recorded in orchards without an adjacent residential facility. Excellent grades were given to jujube trees in orchards adjacent to a residential facility and utilitarian gardens with an adjacent residential facility. According to survey research findings, vegetative organs of this fruit were given excellent grades in terms of ornamental features and its role in landscape picturesqueness. The evaluators deemed jujube tree more attractive in gardens rather than in public landscape spaces and parks. They believe that this species needs to become a Skradinian brand.

In product development, it is crucial to choose the appropriate drug manufacturing route accurately and timely and to ensure that the technique selected is suitable for achieving the desired product quality. Guided by the QbD principles, the pharmaceutical industry is currently transitioning from batch to continuous manufacturing. In this context, process understanding and prediction are becoming even more important. With regard to hot melt extrusion, the process setup, optimization and scale-up in early stages of product development are particularly challenging due to poor process understanding, complex product-process relationship and a small amount of premix available for extensive experimental studies. Hence, automated, quick and reliable process setup and scale-up requires simulation tools that are accurate enough to capture the process and determine the product-process relationships. To this end, the effect of process settings on the degradation of the active pharmaceutical ingredient (API) in a lab-scale Leistritz ZSE12 extruder was investigated. As part of the presented study, the limitations of traditional process analysis using integral process values were investigated, together with the potential that simulations may have in predicting the process performance and the product quality. The results of our investigation indicate that the average melt temperatures and the exposure times in specific zones along the screw configuration correlate well with the API degradation values and can be used as potent process design criteria to simplify the process development., Graphical abstract Unlabelled Image

This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-of-the-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation. The predicted optimal process setup can be validated quickly in the pilot plant. Lastly, a transfer of the process to any GMP-certified manufacturing site can be performed in silico for any extruder based on our validated computational framework. In summary, the proposed workflow massively reduces the risk in product and process development and shortens the drug-to-market time for enabling formulations.

To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV&ndash, Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time.

Complex flow patterns in twin-screw extruder (TSE) elements lead to a variability in residence times in the equipment. Changes in the Residence Time Distribution (RTD) depend on the processing conditions and can have a major impact on the product quality. While the RTDs of entire TSE processes can easily be determined via experiment, local RTDs (LRTDs) in sections of fully filled zones are difficult to measure experimentally. In this work, we propose an alternative in-silico method based on Smoothed Particle Hydrodynamics (SPH). We simulated five geometrically different screw elements and investigated how their local RTDs varied with the screw speed, throughput and screw length. Furthermore, in-silico tracer experiments provided insights into the underlying flow mechanisms and the resulting RTDs. Good agreement with experimental results confirms the validity of our approach.

Due to its meshless nature, the smoothed particle hydrodynamics method (SPH) provides high potential for the simulation of free-surface flows and mixing in complex geometries. We used SPH to analyze the flow inside five typical screw elements of corotating twin-screw extruders, two conveying elements, two kneading elements and a mixing element. Our results show conveying capabilities, pressure generation and power input for various operation states, completely and partially filled. We conducted a detailed mixing analysis based on tracer particles, which yielded the time evolution of the intensity of segregation for different tracers. From that, we determined exponential mixing rates, which describe the relative decrease of the intensity of segregation per screw revolution and characterize the mixing performance in different operation states. This provides valuable input information for simplified models of extruders, which are relevant to industrial applications and can significantly contribute to the efficient design, optimization and scale-up of extruders. © 2017 American Institute of Chemical Engineers AIChE J, 63: 2451–2463, 2017

The shape and form of twin-screw extruder elements determine the physical conditions under which the material is processed. In this work, we investigated the pressure build-up, power consumption, dissipation and distributive mixing behavior of fully filled extruder elements via Smoothed Particle Hydrodynamics simulations, covering a wide range of conveying, kneading and mixing elements used in the ZSE12, ZSE18 and ZSE27 pharma extrusion equipment series. As a result, a comprehensive parameter catalogue of characteristic values was computed. These parameters allow studying the pressure build-up, power consumption and mixing behavior for all elements under various operating conditions. Additionally, we show novel process maps which support optimizing the length of a process zone. Properly used, the catalogue can assist a rational selection of screw elements during process design and transfer.

Previously, we introduced a one-step nano-extrusion (NANEX) process for transferring aqueous nano-suspensions into solid formulations directly in the liquid phase. Nano-suspensions were fed into molten polymers via a side-feeding device and excess water was eliminated via devolatilization. However, the drug content in nano-suspensions is restricted to 30 % (w/w), and obtaining sufficiently high drug loadings in the final formulation requires the processing of high water amounts and thus a fundamental process understanding. To this end, we investigated four polymers with different physicochemical characteristics (Kollidon(®) VA64, Eudragit(®) E PO, HPMCAS and PEG 20000) in terms of their maximum water uptake/removal capacity. Process parameters as throughput and screw speed were adapted and their effect on the mean residence time and filling degree was studied. Additionally, one-dimensional discretization modeling was performed to examine the complex interactions between the screw geometry and the process parameters during water addition/removal. It was established that polymers with a certain water miscibility/solubility can be manufactured via NANEX. Long residence times of the molten polymer in the extruder and low filling degrees in the degassing zone favored the addition/removal of significant amounts of water. The residual moisture content in the final extrudates was comparable to that of extrudates manufactured without water.

Članak govori o gradu Čakovcu na koji, kao i na mnoge druge gradove, utječu okolnosti naglog razvoja turizma i sve oštrija konkurencija na turističkom tržištu. Kako bi Čakovec postao privlačna destinacija za posjetitelje, ljudi koji njime upravljaju trebaju pažljivo oblikovati njegov identitet i turističku ponudu koja će najbolje odgovarati njegovom atrakcijskom sustavu. Time se stvaraju uvjeti za započinjanje procesa uspostave odnosa sa svima onima kojima bi ponuđena koncepcija na neki način mogla biti zanimljiva ili korisna. Odnosi s javnošću, kao jedna od komunikacijskih funkcija, predstavljaju važnu aktivnost u tom procesu i stoga im treba posvetiti potrebnu pažnju. Pomoću odnosa s javnošću Grad bi trebao na prihvatljiv način komunicirati sa svojim okruženjem. Takva bi komunikacija treba biti uvjerljiva i jasna, s karakterističnim obraćanjem i prilagođena komunikacijskim kanalima koji se koriste. Rad se temelji na analizi stručne literature, a korištena je i metoda intervjua. Naime, da bi se poduprla ponuđena gledišta, proveden je razgovor s djelatnikom za odnose s javnošću u gradskoj u Upravi grada Čakovca.