Application of machine-learning algorithms for better understanding of tableting properties of lactose co-processed with lipid excipients

Co-processing (CP) provides superior properties to excipients and has become a reliable option to facilitated formulation and manufacturing of variety of solid dosage forms. Development of directly compressible formulations with high doses of poorly flowing/compressible active pharmaceutical ingredients, such as paracetamol, remains a great challenge for the pharmaceutical industry due to the lack of understanding of the interplay between the formulation properties, process of compaction, and stages of tablets’ detachment and ejection. The aim of this study was to analyze the influence of the compression load, excipients’ co-processing and the addition of paracetamol on the obtained tablets’ tensile strength and the specific parameters of the tableting process, such as (net) compression work, elastic recovery, detachment, and ejection work, as well as the ejection force. Two types of neural networks were used to analyze the data: classification (Kohonen network) and regression networks (multilayer perceptron and radial basis function), to build prediction models and identify the variables that are predominantly affecting the tableting process and the obtained tablets’ tensile strength. It has been demonstrated that sophisticated data-mining methods are necessary to interpret complex phenomena regarding the effect of co-processing on tableting properties of directly compressible excipients

High efficiency disperse dryer - an innovative process for drying of solutions, suspensions and pastes in a fluidized bed of inert particles

In this paper, an innovative fluidized bed dryer with inert particles is presented. The system can be used for drying of solutions, suspensions and pastes in order to obtain a powdered product. The experiments were performed in a pilot-scale dryer with a cylindrical column 0.215 m in diameter and 1.2 mm height, with glass spheres as inert particles. The material used for drying was CuSO4 solution. The effects of operating conditions on the dryer throughput and product quality were investigated. Main performance criteria, i.e. specific water evaporation rate, specific heat consumption and specific air consumption, were quantified. Nearly isothermal conditions were found due to thorough mixing of the particles. The energy efficiency of the dryer was also assessed. Simple heat and mass balances predicted the dryer performance quite well

Sušenje mulja iz procesa prečišćavanja otpadnih voda u fluidizovanom sloju inertnih čestica

Waste water treatment sludge is generated in increasing quantities, as the amount of treated municipal and industrial waste water increases. Also, the requirements concerning the conditions of sludge storage/landfill or reuse are growing. Due to these reasons, new solutions regarding sludge treatment, management and utilization are needed [1]. The benefits of drying waste water treatment sludge can be seen in several aspects: the dried sludge can be stored for longer periods of time and further used as an organic fertilizer, it can be a source of useful (active) microorganisms that can be reused in waste water treatment. Drying also enables incineration or co-incineration of sludge. Sludge drying process reduces mass and volume of the product, making its storage, transport, packaging and retail easier [2-4].ušenjem mulja iz procesa prečišćavanja otpadnih voda mogu se dobiti dva glavna upotrebljiva proizvoda: osušeni mulj može se skladištiti i koristiti kao organsko đubrivo, a može sadržati i aktivne (žive) mikroorganizme koji se ponovo mogu koristiti u tretmanu otpadnih voda. Sušenje suspenzija i pasta u fluidizovanom sloju inertnih čestica predstavlja atraktivnu alternativu ostalim postupcima sušenja u pogledu osnovnih kriterijuma za ocenu efikasnosti kao što su specifični kapacitet isparavanja, specifični utrošak toplote i specifični utrošak vazduha. Visoka efikasnost sušenja je rezultat velikih kontaktnih površina i velikih temperaturnih razlika između ulaznog i izlaznog toka vazduha za sušenje. Intenzivno mešanje inertnih čestica tokom agregativne fluidizacije obezbeđuje približno jednaku temperaturu u celoj zapremini sloja te ne postoji rizik od lokalnog pregrevanja. U radu su prikazani rezultati ispitivanja sušenja mulja na pilot postrojenju za sušenje suspenzija i pasta nominalnog kapaciteta isparavanja do20 kgH2O/h, čiji je centralni deo cilindrična kolona prečnika 215 mm sa fluidizovanim slojem staklenih sfera. Ispitivan je uticaj operativnih uslova na performanse sistema za sušenje i na kvalitet praškastog osušenog aktivnog mulja. Glavni cilj je da se odrede optimalne temperature sušenja mulja pri kojima bi korisni mikroorganizmu u mulju ostali aktivni (živi), a pri kojim aktivni mulj može da se koristi kao oragansko đubrivo. Izvršena je analiza efikasnosti sušenja sa stanovišta kapaciteta isparavanja i potrošnje vazduha u cilju boljeg sagledavanja performansi sistema za sušenje. Jednostavni bilansi mase i toplote adekvatno predviđaju radni režim sistema za sušenje u fluidizovanom sloju inertnog materijala

Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation

1. INTRODUCTION Co-processing has emerged as a suitable approach to meet the increasing demands for excipients with improved tableting performance. Apart from the most commonly used energy-consuming co-processing methods (e.g. spray-drying and wet granulation), melt granulation as a solvent-free and more environmentally friendly technique has recently gained more attention [1]. The aim of the present study was to investigate the influence of meltable binder particle size and compaction parameters on dilution capacity and compaction behaviour of lactose-based coprocessed excipients. 2. MATERIALS AND METHODS 2.1. Materials Paracetamol (Acros Organics, Belgium) was used as the model drug. Lactose monohydrate (Carlo Erba Reagents, Italy) was used as filler and glyceryl palmitostearate (Precirol® ATO 5 Gattefossé S.A.S, France) as meltable binder. 2.2. Preparation of co-processed excipients Co-processed excipients were prepared by in situ melt granulation in Mycrolab fluid bed processor (OYSTAR Hüttlin, Germany). Precirol® particles (15%) from the 125–180 μm (≈ 150 μm) or 600–710 μm sieve fraction (≈ 655 μm) were used for granulation of lactose (85%). The inlet air flow rate was 30 m3/h, and product temperature during agglomeration was 65 °C. 2.3. Particle size and shape analysis Granule size distribution was evaluated by sieve analysis, and median particle diameter (d50) was calculated by linear interpolation of the cumulative percentage frequency curve. Granule shape was examined by 2D scanned image (4800 dpi resolution) analysis using ImageJ software. The aspect ratio (AR) and circularity (C) were calculated for granule shape evaluation. 2.3. Determination of the Carr index The bulk and tapped (1250 taps) densities of coprocessed excipients and their mixtures with 30, 40 or 50% paracetamol were determined using tap density tester STAV 2003 (J. Engelsmann AG, Germany), and Carr index was calculated. 2.4. Dynamic compaction analysis Co-processed excipients and their mixtures with paracetamol were compressed on a single punch instrumented tablet press (GTP D series, Gamlen Tableting Ltd, UK). Compacts (100 mg) were compressed under compression load of 200 kg (≈ 70 MPa) or 500 kg (≈ 173MPa), and compression speed of 60 or 120 mm/min. 6 mm flat faced punches were used. The obtained force-displacement curves were used to calculate: net work of compression (NW), detachment stress (DS), ejection stress (ES). Tablet crushing force was determined using tablet hardness tester Erweka TBH 125D (Erweka GmbH, Germany), and the values obtained were used to calculate tensile strength (TS). Elastic recovery (24 h after compression) was calculated, as well. 2.4. Experimental Design In order to investigate the influence of binder particle size, paracetamol content and compression speed on the abovementioned compaction properties, compacts were prepared, at compression load of 500 kg, according to 23 full factorial design. 3. RESULTS AND DISCUSSION 3.1. Particle size and shape Larger initial binder particle size led to formation of larger and more spherical granules (Table 1). 147 Table 1. The size and shape of the co-processed excipients’ particles. Binder PS (μm) d50 AR C 150 564.9 1.33 0.81 655 846.2 1.14 0.86 3.2. Flowability The Carr index values obtained indicated considerably better flowability of the coprocessed excipient prepared by using larger binder particles (P655) in comparison with the excipient prepared with smaller binder particles (P150). This might be ascribed to more spherical and larger particles of P655. However, the addition of paracetamol led to an increase in Carr index values and less pronounced differences between two excipients (Fig. 1). Figure 1. The influence of paracetamol loading on flowability of co-processed excipients. 3.3. Compaction behaviour The results obtained revealed better mechanical properties of P150 in comparison with P655 compacts, irrespective of the compression pressure applied. The addition of paracetamol, as the model API with poor compaction properties, led to decrease in tensile strength of the compacts prepared with both excipients, and paracetamol content showed statistically significant influence on TS (p < 0.0001). Acceptable tensile strength (> 1 MPa) could be achieved for compacts with 30% paracetamol compressed at higher compression pressure (≈ 173 MPa). Paracetamol content, compression speed and interaction between binder particle size and paracetamol content were found to significantly affect NW. The influence of binder particle size was more pronounced at higher paracetamol content, with lower NW observed in the case of P655. Higher compression speed led to higher NW. Relatively low values of detachment and ejection stress (< 3.5 MPa) indicate good antiadhesive and lubricating properties of the investigated excipients. Lower values of both parameters were observed in the case of P655 which could be related to different agglomeration mechanisms involved. Besides binder particle size, compression speed and paracetamol content were found to significantly influence these properties. Elastic recovery values of the investigated samples ranged between 12 and 28%. In the case of both excipients, higher elastic recovery values were obtained at higher compression pressure. ER values of the compacts prepared at higher compression pressure were significantly affected by compression speed and interactions of the investigated variables. 4. CONCLUSION The results obtained show that meltable binder particle size affects granule size and shape, and consequently may influence flowability and compaction behaviour of the co-processed excipients. Interactions between binder particle size and compaction variables were also found to affect compaction properties of the investigated excipients.Pharma Sciences of Tomorrow Ljubljana, Slovenia, 15 th -17 th September, 202

Procena metoda za oblaganje višečestičnih supstrata topljenjem - oblaganje u pateni vs. oblaganje u bubnju

Hot-melt coating (HMC) is an alternative, solvent-free coating method generally used to modify substrate release rate and/or mask its unpleasant taste. The aim of this study was to assess two HMC methods (pan-coating and mortar-coating) by assaying functional properties of the coated material. The selected substrates included highly soluble sodium chloride (model substance) and caffeine (bitter drug), and the coating agent was glycerol distearate without/with the addition of liquid paraffin. Experiments with sodium chloride revealed that pan-coating yielded particles of more regular shape, while mortar-coating yielded samples of more uniform coating layer. The flowability of the coated material depended on the particle size. Sustained sodium chloride release was achieved for all mortar-coated and some pan-coated samples. The analysis of the results indicated mortar-coating as a preferable HMC method for caffeine coating. The resulting caffeine yield in the coated samples was high (99%), the material showed satisfactory mechanical properties and drug release from the coated particles was sustained. Overall, the obtained results suggest that both pan- and mortar-coating can be used to sustain the release of drugs with unpleasant taste, but mortar-coating can be considered as a more simple and practical method that can be potentially used in compounding pharmacies.Oblaganje topljenjem je alternativna metoda oblaganja, bez upotrebe rastvarača i uglavnom se koristi za modifikaciju brzine rastvaranja i/ili maskiranje neprijatnog ukusa supstrata. Cilj ovog rada je da se procene dve metode za oblaganje topljenjem (oblaganje u bubnju i oblaganje u pateni), ispitivanjem funkcionalnih karakteristika obloženog materijala. Izabrana su dva visoko rastvorljiva supstrata: natrijum-hlorid (model supstanca) i kofein (lekovita supstanca gorkog ukusa), a za oblaganje je korišćen glicerildistearat bez/sa dodatkom tečnog parafina. Eksperimenti sa natrijum-hloridom su pokazali da su oblaganjem u bubnju dobijene čestice pravilnijeg oblika, dok su oblaganjem u pateni dobijeni uzorci sa ujednačenijom oblogom. Protočnost obloženog materijala je zavisila od veličine čestica. Usporeno rastvaranje natrijumhlorida postignuto je kod svih uzoraka obloženih u pateni i kod nekih uzoraka obloženih u bubnju. Analiza rezultata je izdvojila oblaganje u pateni kao pogodniju metodu za oblaganje kofeina. Dobijeni prinos obloženih čestica kofeina je bio visok (99%), obloženi materijal je imao zadovoljavajuće mehaničke osobine i postignuta je usporena brzina rastvaranja kofeina. Sumarno, dobijeni rezultati su pokazali da se i oblaganje u bubnju i u pateni mogu koristiti za usporavanje rastvaranja lekovitih supstanci neprijatnog ukusa, no oblaganje u pateni predstavlja jednostavniju i praktičniju metodu koja se potencijalno može koristiti i u izradi magistralnih lekova

Пренос масе у инверзно флуидизованом слоју

In this work, the coefficient of fluid-wall mass transfer in an inverse fluidized bed was determined using the adsorption method. The experiments were carried out in a column with a diameter of 45 mm with spherical and non-spherical particles of polypropylene and polyethylene with a diameter of 3.3-4.9 mm and a density of about 930 kg m-3. A diluted solution of methylene blue was used as a fluidization medium, which was adsorbed on part of the surface of the column on silica gel. The obtained results showed that the presence of particles during inverse fluidization does not contribute significantly to mass transfer compared to the influence of particles on transfer in conventional fluidized beds. Therefore, the pseudofluid concept was introduced into the analysis and an empirical correlation was performed to determine the mass transfer coefficient. The obtained results were compared with literature correlations for inverse and conventional fluidized beds.У овом раду је одређиван коефицијент преноса масе флуид-зид у инверзнофлуидизованом слоју применом адсорпционе методе. Експерименти су вршени у колони пречника 45 мм са сферичним и несферичним честицама полипропилена и полиетилена пречника 3.3-4.9 мм и густине око 930 кг м-3. Као флуидизациони медијум коришћен је разблажени раствор метиленски плавог који је адсорбован на делу површине колоне на силикагелу. Добијени резултати показали су да присуство честица при инверзној флуидизацији не доприноси значајно преносу масе у поређењу са утицајем честица на пренос масе у конвенционално флуидизованим слојевима. Због тога је у анализу уведен концепт псеудофлуида и изведена је емпиријска корелација за одређивање коефицијента преноса масе. Извршено је поређење добијених резултата са литературним корелацијама за инверзну и конвенционалну флуидизације

Ispitivanje dinamike granulacije praškastih materijala u fluidizovanom sloju

In this paper, experimental investigation of the dynamics of the process of fluidized bed granulation was performed, in order to find optimal process conditions and binder concentration to achieve the desired granules development. The experiments were performed in batch system using corn flour as starting material. Ten experiments were performed in which sucrose solution of different concentrations (20, 30, 35 and 40 %) was used as binder. The temperature of the system was kept constant during the granulation process and amounted to 40-50°C. Samples were taken from the fluidized bed at time intervals of 3 min. The dynamics of granulation was examined by determining three different factors (bulk density, moisure content and particle size distribution) for each of the samples. It has been found that bulk density continuously decreases during the granulation process, while in the drying phase it remains constant. Particle size distribution has shown that the average diameter of the projected surface increases uniformly during the process. By comparing all of the three investigated factors, it was shown that the best quality of granules is achieved using 35 % sucrose solution .U ovom radu izvršeno je eksperimentalno ispitivanje procesa mokre granulacije u fluidizovanom sloju u cilju pronalaženja optimalnih uslova izvođenja procesa i sastava veziva kojim će se ostvariti željena dinamika razvoja granula. Ispitivanje je izvršeno u šaržnom sistemu, a korišćeno je kukuruzno brašno kao polazni materijal. Izvršeno je 10 eksperimenata u kojima je kao vezivno sredstvo korišćen rastvor saharoze različitih koncentracija: 20, 30, 35 i 40 %. Temperatura je održavana konstantnom tokom procesa granulacije i iznosila je 40-50C. Uzorci su iz sloja uzimani u jednakim vremenskim intervalima od 3 min. Dinamika granulacije ispitivana je određivanjem tri različita faktora (nasipne gustina, vlažnosti i raspodele veličine čestica) za svaki od uzoraka. Utvrđeno je da nasipna gustina kontinualno opada tokom izvođenja procesa granulacije, dok u fazi sušenja ostaje konstantna. Raspodela veličina čestica je pokazala da srednji prečnik projektovane površine ravnomerno raste tokom procesa. Poređenjem sva tri ispitivana faktora pokazano je da se najbolji kvalitet granula postiže korišćenjem 35 % rastvora saharoze kao vezivnog sredstva.Related to: [http://cer.ihtm.bg.ac.rs/handle/123456789/3293

Ispitivanje dinamike granulacije praškastih materijala u fluidizovanom sloju

In this paper, experimental investigation of the dynamics of the process of fluidized bed granulation was performed, in order to find optimal process conditions and binder concentration to achieve the desired granules development. The experiments were performed in batch system using corn flour as starting material. Ten experiments were performed in which sucrose solution of different concentrations (20, 30, 35 and 40 %) was used as binder. The temperature of the system was kept constant during the granulation process and amounted to 40-50°C. Samples were taken from the fluidized bed at time intervals of 3 min. The dynamics of granulation was examined by determining three different factors (bulk density, moisure content and particle size distribution) for each of the samples. It has been found that bulk density continuously decreases during the granulation process, while in the drying phase it remains constant. Particle size distribution has shown that the average diameter of the projected surface increases uniformly during the process. By comparing all of the three investigated factors, it was shown that the best quality of granules is achieved using 35 % sucrose solution .U ovom radu izvršeno je eksperimentalno ispitivanje procesa mokre granulacije u fluidizovanom sloju u cilju pronalaženja optimalnih uslova izvođenja procesa i sastava veziva kojim će se ostvariti željena dinamika razvoja granula. Ispitivanje je izvršeno u šaržnom sistemu, a korišćeno je kukuruzno brašno kao polazni materijal. Izvršeno je 10 eksperimenata u kojima je kao vezivno sredstvo korišćen rastvor saharoze različitih koncentracija: 20, 30, 35 i 40 %. Temperatura je održavana konstantnom tokom procesa granulacije i iznosila je 40-50C. Uzorci su iz sloja uzimani u jednakim vremenskim intervalima od 3 min. Dinamika granulacije ispitivana je određivanjem tri različita faktora (nasipne gustina, vlažnosti i raspodele veličine čestica) za svaki od uzoraka. Utvrđeno je da nasipna gustina kontinualno opada tokom izvođenja procesa granulacije, dok u fazi sušenja ostaje konstantna. Raspodela veličina čestica je pokazala da srednji prečnik projektovane površine ravnomerno raste tokom procesa. Poređenjem sva tri ispitivana faktora pokazano je da se najbolji kvalitet granula postiže korišćenjem 35 % rastvora saharoze kao vezivnog sredstva.Related to: [http://cer.ihtm.bg.ac.rs/handle/123456789/3293

Analogija prenosa količine kretanja, toplote i mase pri vertikalnom hidrauličkom transportu inertnih čestica

Wall-to-bed momentum, heat and mass transfer in the vertical liquid-solids flow, as well as in the single phase flow, were studied. The aim of this investigation was to establish the analogy among those phenomena. Also, effect of particle concentration on momentum, heat and mass transfer was studied. The experiments in hydraulic transport were performed in 25.4 mm I.D. cooper tube equipped with a steam jacket, using spherical glass particles of 1.94 mm in diameter and water as a transport fluid. The segment of the transport tube used for mass transfer measurements had internal coating made of benzoic acid. In the hydraulic transport two characteristic flow regimes were observed: turbulent and parallel particle flow regime. The transition between two characteristic regimes (Y* = 0), occurs at a critical voidage ε ≈ 0.85. The vertical two-phase flow was con­sidered as the pseudofluid, and modified mixture-wall friction coefficient (fw) and modified mixture Reynolds number (Rem) were introduced for system characterization. Experimental data show that the wall-to-bed momentum, heat and mass transfer coefficients, in vertical flow of pseudofluid, for the turbulent regime are significantly higher than in parallel regime. Wall-to-bed, mass and heat transfer coefficients in hydraulic transport of particles were much higher than in single-phase flow for lower Reynolds numbers (Re LT 15000), while for high Reynolds numbers (Re > 15000), there was not significant difference. The experimental data for wall-to-bed momentum, heat and mass transfer in vertical flow of pseudofluid in parallel particle flow regime, verify analogy among these three phenomena.U ovom radu prikazani su rezultati eksperimentalnih ispitivanja prenosa količine kretanja, toplote i mase zid-fluid u vertikalnom hidrauličkom transportu inertnih čestica i pri strujanju fluida u cevi istog prečnika. Eksperimentalna ispitivanja vršena su istovremenim merenjem potrebnih parametara za definisanje navedenih prenosa. Cilj ovih ispitivanja bio je određivanje koeficijenata prenosa pri vertikalnom hidrauličkom transportu inertnih čestica i uspostavljanje analogije tri prenosa. Eksperimentalni sistem predstavljala je vertikalna transportna cev prečnika 25,4 mm snabdevena omotačem za zagrevanje parom, kao i segmentom transportne cevi prepariranim rastopom benzoeve kiseline. Kao fluid korišćena je voda, a vršen je transport staklenih sfernih čestica prečnika 1,94 mm. U rezultatima su prikazani dobijeni koeficijenti trenja, prelaza toplote i prelaza mase. Korišćenjem koncepta pseudofluida, pokazano je postojanje analogije prenosa količine kretanja, toplote i mase u transportnoj cevi za paralelni režim strujanja

Functionality and Palatability of Yogurt Produced Using Beetroot Pomace Flour Granulated with Lactic Acid Bacteria

Following the idea of sustainability in food production, a yogurt premix based on beetroot (Beta vulgaris) pomace flour (BPF) was developed. BPF was granulated with lactose solution containing lactic acid bacteria (LAB) by a fluidized bed. Particle size increased ~30%. A decrease in Carr Index from 21.5 to 14.98 and Hausner ratio from 1.27 to 1.18 confirmed improved flowability of granulated BPF, whereas a decrease in water activity implied better storability. Yogurts were produced weekly from neat starters and granulated BPF (3% w/w) that were stored for up to one month (4 °C). High viability of Streptococcus thermophilus was observed. Less pronounced syneresis, higher inhibition of colon cancer cell viability (13.0–24.5%), and anti-Escherichia activity were ascribed to BPF yogurts or their supernatants (i.e., extracted whey). Acceptable palatability for humans and dogs was demonstrated. A survey revealed positive consumers’ attitudes toward the granulated BPF as a premix for yogurts amended to humans and dogs. For the first time, BPF granulated with LAB was used as a premix for a fermented beverage. An initial step in the conceptualization of a novel DIY (do it yourself) formula for obtaining a fresh yogurt fortified with natural dietary fiber and antioxidants has been accomplished