Formulation and characterization of desloratadine mini-tablets obtained by photopolimerization 3D printing technique

3D štampa lekova, kao aditivna tehnologija, predstavlja jednostavnu i ekonomski prihvatljivu alternativu konvencionalnim metodama, pružajući mogućnost dobijanja inovativnih farmaceutskih oblika i prilagođavanje terapije individualnim potrebama pacijenata (1). Cilj istraživanja bio je da se formulišu i izrade mini tablete desloratadinа (DSL) primenom 3D tehnike digitalne obrade svetlosti (engl. Digital light processing, DLP) mehanizmom nanošenja materijala “sloj po sloj”. Mini tablete DSL (10%, m/m) odabrane su kao farmaceutski oblik leka koji je pogodan za primenu u pedijatrijskoj populaciji, pre svega sa aspekta fleksibilnosti doziranja. Pripremljena je formulacija sa 1% fotoinicijatora i 10% vode, dok su polietilenglikol-diakrilat i polietilenglikol 400 bili prisutni u masenom odnosu 1:1. Kreirani 3D modeli (4,00 × 3,00 mm) uspešno su odštampani primenom WanhaoD8 štampača. Dobijene su žuto-narandžaste mini tablete uniformnog oblika, debljine i mase (4,16 ± 0,06 × 2,24 ± 0,04 mm; 42,61 ± 1,15 mg). Nepotpuna ekstrakcija DSL iz unakrsno umreženog polimernog matriksa rezultovala je relativno niskim sadržajem lekovite supstance u mini tabletama u odnosu na teorijski sadržaj (72,14 ± 1,04%) (2). Prilikom ispitivanja brzine rastvaranja, nakon 45 min oslobođeno je 50,29 ± 0,14% DSL u 0,1M hlorovodoničnoj kiselini, kao medijumu, uz postizanje platoa nakon 4 sata (81,19 ± 0,63%). Rezultati DSC analize pokazali su da je došlo do amorfizacije lekovite supstance, dok je posmatranjem poprečnih preseka odštampanih mini tableta pod polarizacionim svetlosnim mikroskopom uočeno prisustvo slojevite strukture. DLP tehnika 3D štampe lekova ima potencijal da obezbedi brzu izradu mini tableta odgovarajućih fizičko-hemijskih karakteristika, uz mogućnost postizanja modifikovanog oslobađanja lekovite supstance.3D printing as an additive technology represents a simple and economically acceptable alternative to conventional methods and offers the possibility of obtaining innovative dosage forms and individualizing therapy according to the specific needs of patients. (1). The aim of the research was to formulate and manufacture desloratadine mini-tablets (DSL) using digital light processing (DLP) 3D technique based on a successive layering mechanism. Mini-tablets of DSL (10%,w/w) were selected as a dosage form suitable for the pediatric population, particularly because of its flexible dosing. The formulation was prepared with 1% photoinitiator and 10% water, while poly(ethylene glycol) diacrylate and poly(ethylene glycol) 400 were present in a mass ratio of 1:1. The created 3D models (4.00×3.00 mm) were successfully printed using WanhaoD8 printer. Yellow-orange mini- tablets with uniform shape, thickness and mass (4.16±0.06×2.24±0.04 mm; 42.61±1.15 mg) were produced. Incomplete extraction of DSL from the cross-linked polymer matrix resulted in a relatively low content of the drug in the mini-tablets compared to the theoretical content (72.14±1.04%) (2). The dissolution test showed that 50.29±0.14% of DSL was released after 45 minutes in 0.1M hydrochloric acid medium and reached a plateau after 4 hours (81.19±0.63%). The results of DSC analysis showed amorphisation of the drug, while observation of the cross-sections of printed mini- tablets under a polarizing microscope indicated the presence of a layered structure. The DLP technique has the potential to ensure the rapid production of mini-tablets with suitable physicochemical properties and to enable modified release of the drug.Treći naučni simpozijum Saveza farmaceutskih udruženja Srbije sa međunarodnim učešćem „Lekovi za specifične populacije pacijenata: inovacijama ka unapređenju zdravstvenih ishoda“, Niš, Srbija, 26. oktobar 2023

Leachate quality assessment of protected water bodies in Serbia and Croatia

Modern agricultural production can not be imagined without the use of pesticides and, if their use is improper, it could lead to continuous introduction of pesticide residues to different environmental media. Water pollution which originates from agricultural activities is a common problem in both observed countries, Serbia and Croatia. The paper provides evaluation of leachate water quality of protected water bodies, Tompojevački ritovi, Croatia, and Lake Zobnatica, Serbia, with the results of detected pesticide residues and other relevant organic micropollutants

Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers

Powder bed fusion–laser beam (PBF-LB) three-dimensional (3D) printing: Influence of laser hatching distance on the properties of zolpidem tartrate tablets

Laser sintering, known as powder bed fusion–laser beam (PBF-LB), offers promising potential for the fabrication of patient-specific drugs. The aim of this study was to provide an insight into the PBF-LB process with regard to the process parameters, in particular the laser hatching distance, and its influence on the properties of zolpidem tartrate (ZT) tablets. PHARMACOAT® 603 was used as the polymer, while Candurin® Gold Sheen and AEROSIL® 200 were added to facilitate 3D printing. The particle size distribution of the powder blend showed that the layer height should be set to 100 µm, while the laser hatching distance was varied in five different steps (50, 100, 150, 200 and 250 µm), keeping the temperature and laser scanning speed constant. Increasing the laser hatching distance and decreasing the laser energy input led to a decrease in the colour intensity, mass, density and hardness of the ZT tablets, while the disintegration and dissolution rate were faster due to the more fragile bonds between the particles. The laser hatching distance also influenced the ZT dosage, indicating the importance of this process parameter in the production of presonalized drugs. The absence of drug-polymer interactions and the amorphization of the ZT were confirmed

3D tehnika digitalne obrade svetlosti (DLP) primenjena u izradi dvoslojnih tableta: koncept kombinovane polipilule

Ever since 3D printing was introduced to the field of pharmacy, it has caused a paradigm shift from the manufacturing of large-scale to small batches of medicines tailored accordingly to the specific needs of patients. This study aimed to formulate and fabricate two-layered 3D tablets using the digital light processing (DLP) technique. Hydrochlorothiazide (HHT,5%,w/w) and warfarin sodium (WS,5%,w/w) were selected as model drugs. The printing process was initiated with 0.1% of photoinitiator, at a constant ratio of poly(ethylene glycol)diacrylate and poly(ethylene glycol) 400, 1:1, with the addition of water (10%,w/w). Single-layered tablets of 8.00 mm diameter and 1.50 mm thickness, containing HHT and WS respectively, were successfully printed, as well as combined two-layered 3D tablets, with each of the active substances in separate layers. Dissolution tests of single-layered tablets showed immediate, but incomplete release of WS (81.47±1.47%, after 45min), and prolonged and complete release of HHT (98.17±3.11%, after 8h), while significantly slower and incomplete release of both drugs from the combined two-layered 3D tablets was observed. The absence of drug-polymer interaction and presence of a layered cross-sectional tablet structure were confirmed. DLP technique enables simple and rapid fabrication of combined two-layered 3D tablets, while further optimization of formulation factors is necessary to achieve complete drug release.Uvođenje tehnologije 3D štampe u oblasti farmacije uslovilo je razvoj fundamentalnih promena, pri čemu serijska proizvodnja velikih šarži pretenduje da bude zamenjena malim serijama lekova prilagođenih prema specifičnim potrebama pacijenata. Cilj istraživanja bio je da se formulišu i izrade dvoslojne tablete primenom tehnike digitalne obrade svetlosti (DLP). Hidrohlortiazid (HHT, 5%, m/m) i varfarin-natrijum (WS, 5%, m/m) odabrani su kao model lekovite supstance. Proces štampanja sproveden je u prisustvu 0,1% fotoinicijatora, pri konstantnom masenom odnosu poli(etilen glikol)diakrilata i poli(etilen glikola) 400, 1:1, uz dodatak 10% vode. Jednoslojne 3D tablete prečnika 8,00 mm i debljine 1,50 mm, koje sadrže HHT, odnosno WS, kao i kombinovane dvoslojne 3D tablete, sa svakom od aktivnih supstanci u posebnom sloju, uspešno su odštampane. Prilikom ispitivanja brzine rastvaranja lekovite supstance iz jednoslojnih tableta, došlo je do trenutnog (81,47±1,47%, nakon 45 min), ali nepotpunog oslobađanja WS, i produženog i potpunog oslobađanja HHT (98,17±3,11%, nakon 8 h), dok je iz kombinovanih tableta zapaženo znatno sporije i nepotpuno oslobađanje obe lekovite supstance. Potvrđeno je odsustvo interakcija i prisustvo slojevite strukture. DLP tehnika pruža mogućnost jednostavne i brze izrade kombinovanih tableta, pri čemu je dalja optimizacija formulacionih faktora neophodna u cilju postizanja potpunog oslobađanja lekovite supstance

Oral dosage forms with carvedilol fabricated by selective laser sintering (SLS) 3D printing technique

1. INTRODUCTION When it comes to pharmacy, 3D printing has gained immense popularity in recent years due to its revolutionary use in printing drugs tailored to individual patient needs [1,2]. Selective laser sintering (SLS) is an industrial 3D printing technique which uses a powder bed to build up the 3D object thanks to a laser which binds the powder particles together. Advantages of SLS technique include the fact that it is a solvent-free process and offers relatively fast production. Until today, a limited number of studies investigating the production of drug dosage forms using SLS have been reported [2,3]. 2. MATERIALS AND METHODS 2.1. Materials Carvedilol (CRV) was used as a model substance in this study and it was donated by Hemofarm (Vršac, Serbia). The following excipients used to obtain 3D printing tablets: polyvinyl alcohol (PVA, Merck), mannitol (Parteck® M, Merck), Ludipress® (coprocessed excipient consisting of 93% lactose monohydrate, 3.5% crospovidone (Kollidon® CL) and 3.5% povidone K30 (Kollidon® 30), BASF), talc (Merck) and candurin (Candurin® Gold Sheen, Merck). 2.2. Preparation of formulations The compositions of the formulations are shown in Table 1. Table 1. Composition of the formulations Material Formulation 1 Formulation 2 CRV 10% 10% PVA 55% 55% Parteck® M 30% / Ludipress® / 30% Talc 2% 2% Candurin® Gold Sheen 3% 3% Powder for 3D printing was obtained by mixing all the components of the formulation and sifting through a sieve with a diameter of 180 μm. 2.3. 3D printing of oral dosage forms A cylindrical 3D models of the printed tablets (8.00 mm diameter and 2.00 mm thickness) were designed with Autodesk Fusion 360 software version 2.0.8809 (Autodesk Inc, San Rafael, CA, USA), exported as a stereolithography file (.stl) and printed with Sintratec Kit 3D printer (Sintratec AG, Switzerland). The printing parameters were controlled using Sintratec 3D printer software. After a series of variations in temperature and laser speed, the optimal values of these parameters used in the 3D printing process were established and shown in Table 2. Table 2. SLS 3D printing process parameters Surface Temperature ( ◦C) Chamber Temperature ( ◦C) Laser speed (mm/s) Hatch space 80 ºC 70 ºC 60 250 μm 2.4. Mechanical properties of 3D tablets Tablets (n = 10) were weighed on a Sartorius BP 210 D analytical balance (Sartorius, Goettingen, Germany) and measured (diameter and thickness) using a digital caliper (Vogel, Kevelaer, Germany). 2.5. Powder X-ray diffraction analysis (PXRD) PXRD analysis was performed to assess whether the laser induced amorphization of any of the compounds, especially amorphization of poorly soluble CRV. Samples were collected using a Philips PW-1050 (Philips, The Netherlands) diffractometer, operated at 40 kV and 30 mA, using Ni-filtered Cu Kα radiation. 2.6. Dissolution and Drug Release Analysis Dissolution testing was performed under nonsink conditions using mini paddle apparatus (Erweka DT 600, Germany) with a paddle rotation speed of 50 rpm for 8 h, in 100 ml of phosphate buffer (pH 6.8). The amount of dissolved CRV was determined by HPLC method using Dionex Ultimate 3000 (Thermo Scientific, USA) HPLC system. 3. RESULTS AND DISCUSSION 3.1. 3D printing process It was shown that SLS printer was able to fabricate 3D tablets with CRV, as well as that success of the printing process depended on the used printing parameters. 3.2. Mechanical properties of 3D tablets The dimensions of the obtained 3D tablets were in accordance with the defined values of the created 3D models (F1: 8.10 ± 0.08 mm diameter and 2.10 ± 0.13 mm thickness, F2: 8.13 ± 0.09 mm diameter and 2.10 ± 0.12 mm thickness). Significant variations in tablet weight between formulations were not observed (m1=0.146 ± 0.04; m2=0.136 ± 0.03). 3.3. Powder X-ray diffraction analysis (PXRD) Figure 1. The X-ray powder diffraction of F1 and F2. 3.4. Dissolution and Drug Release Analysis Figure 2. Dissolution profiles of 3D printing tablets 4. CONCLUSION SLA represents a new chapter in 3D printing of solid oral dosage forms and in individualized therapy in particular. By adjusting the formulation and process parameters, it was possible to produce SLS tablets with coamorphous CRV and PVA as a main polymer. Complete drug release was achieved under non sink conditions after 8 hours in phosphate buffer. The tailoring of drug release might be achieved by varying formulation factors as well as process parameters, although it could be governed by the composition of the whole formulation.9th BBBB International Conference on Pharmaceutical Sciences Pharma Sciences of Tomorrow Ljubljana, Slovenia, 15th-17th September, 202

Primena fotopolimerizacione tehnike 3D štampe lekova u izradi dvoslojnih tableta

In recent years, introduction of modern technologies, such as 3D printing, has opened a new chapter and caused a paradigm shift from manufacturing of large-scale to small batches of medicines tailored accordingly to the specific needs of patients (1). The aim of this study was to formulate and fabricate two-layered tablets using digital light processing (DLP) technique, which utilizes light irradiation to create solid objects from photoreactive liquid resin in a layer-by-layer manner. Hydrochlorothiazide (HHT, 5%,w/w) and warfarin sodium (VRN, 5%,w/w) were selected as model drugs, commonly used together in the treatment of cardiovascular diseases. 3D printing process was initiated with 0.10% of photoinitiator, at a constant ratio of poly(ethylene glycol)diacrylate and poly(ethylene glycol) 400, 1:1, with the addition of water (10%,w/w). 3D tablets, with each of the active substances in a separate layer, 8.00 mm in diameter and 1.50 mm thick, as well as combined two-layered tablets with HHT and VRN in individual layers, were successfully printed with Wanhao D8 printer. Dissolution test results showed immediate, but incomplete release of VRN (81.47 ± 1.47%, after 45 min) from individual layers, while the release of HHT was prolonged and complete (98.17 ± 3.11%, after 8 h). Significantly slower and incomplete release of VRN and HHT from combined tablets was observed. The absence of interactions and the presence of a layered structure were confirmed. DLP technique has a potential to provide fast fabrication of combined tablets, while further optimization of formulation factors is necessary in order to achieve complete drug release.Poslednjih godina, uvođenjem savremenih tehnologija, poput 3D štampe, otvorilo se novo poglavlje u načinu proizvodnje lekova i uslovilo razvoj fundamentalnih promena, pri čemu serijska proizvodnja velikih šarži pretenduje da bude zamenjena malim serijama lekova prilagođenih specifičnim potrebama pacijenata (1). Cilj ovog istraživanja bio je da se formulišu i izrade dvoslojne tablete primenom tehnike digitalne obrade svetlosti (DLP) koja omogućava dobijanje objekata mehanizmom nanošenja materijala “sloj po sloj” iz tečne fotopolimerizacione smole pod uticajem svetlosti. Hidrohlortiazid (HHT, 5%, m/m) i varfarin-natrijum (VRN, 5%, m/m) odabrani su kao model lekovite supstance, koje se obično primenjuju zajedno u lečenju kardiovaskularnih bolesti. Proces 3D štampanja sproveden je u prisustvu 0,10% fotoinicijatora, pri konstantnom masenom odnosu poli(etilen glikol)diakrilata i poli(etilen glikola) 400, 1:1, uz dodatak 10% vode. 3D tablete, sa svakom od aktivnih supstanci u posebnom sloju, prečnika 8,00 mm i debljine 1,50 mm, kao i kombinovane dvoslojne tablete sa HHT i VRN u pojedinačnim slojevima, uspešno su odštampane u Wanhao D8 štampaču. Prilikom ispitivanja brzine rastvaranja lekovite supstance iz pojedinačnih slojeva, došlo je do trenutnog (81,47 ± 1,47% nakon 45 min), ali nepotpunog oslobađanja VRN, dok je HHT u potpunosti oslobođen, prateći kinetiku produženog oslobađanja (98,17 ± 3,11%, nakon 8 h). Zapaženo je znatno sporije i nepotpuno oslobađanje VRN i HHT iz kombinovanih dvoslojnih tableta, nakon 8 h. Potvrđeno je odsustvo interakcija i prisustvo slojevite strukture. DLP tehnika ima potencijal da obezbedi brzu izradu kombinovanih tableta, pri čemu je neophodna dalja optimizacija formulacionih faktora u cilju postizanja potpunog oslobađanja lekovite supstance.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Selective laser sintering (SLS) 3D printing process: Influence of model design on the properties of zolpidem tartrate tablets

Three-dimensional printing (3DP) is an innovative additive manufacturing technology in the field of pharmaceuticals that has the potential to provide small batches of patient-tailored medicines (Wang et al., 2021). One of the newest and most advanced 3DP techniques is selective laser sintering (SLS), a one-step manufacturing process that uses a laser to selectively sinter powder particles into layers and create a 3D structure of a solid dosage form. Depending on the 3D design of the object, the laser is focused to draw specific patterns on the surface of the powder. Once the first layer is sintered, a fresh layer of powder is sprinkled on top so that a new layer can be sintered (Allahham et al., 2020). The aim of this study was to formulate and investigate the influence of the model design on the properties of zolpidem tartrate (ZT) tablets produced by the SLS 3DP process.14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202

Digital light processing 3D printing of Hydrochlorothiazide with modified release

Additive manufacturing also known as 3D printing gains more attention in scientific research due to its great advantages in simple and fast producing custom-designed products. 3D models created with computer-aided design (CAD) are presented to the printers and with different techniques, printing layer-by-layer desired products are made. Most used techniques in additive manufacturing are fused deposition modeling (FDM), material and ink jetting, sintering and vat polymerization techniques. Stereolithography (SLA) and digital light processing (DLP) are the most frequently used techniques in vat polymerization due to their advantages. In DLP technique, a digital micromirror is used for gradually exposing and solidifying a layer of liquid photopolymer solution following a layer-by-layer mechanism (Adamov et al., 2022; Zhu et al., 2020). Nowadays additive manufacturing finds its place in medicine by producing medical devices, implants, prostheses and medical equipment. 3D printing has enormous potential in personalized medicine as a result of different possibilities in production of dosage forms with desired shapes that contain one or more active compounds that can have different release profiles. 3D printing helps in overcoming the problem with permeability and solubility of some drugs and enables using drugs from different BCS classes.14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202

3D printing of carvedilol oral dosage forms using selective laser sintering technique

The adjustment of the dose according to the individual needs of the patient is a unique advantage of 3D printing technology, which is of particular importance for the pediatric and geriatric population, due to the diverse needs and characteristics of these groups of patients (Kotta et al., 2018). Selective laser sintering (SLS) is one of the newest 3D printing techniques that uses powder materials, where the powder particles are connected under the influence of laser beams. The main disadvantage of SLS 3D printing is the high process temperature, which can lead to the degradation of active substances. On the other hand, this technique has many advantages, such as high resolution, the possibility of powder recycling and the absence of pre- processing (Fina et al., 2018; Thakkar et al., 2021).14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202