3D printing of tablets by photopolymerization and selective laser sintering: development and process optimisation

Cilj ove doktorske disertacije je bio razvoj i optimizacija formulacija i procesa 3D štampe u izradi tabletapostupcima fotopolimerizacije i selektivnog laserskog sinterovanja primenom naprednih alata za analizupodataka.Primenom dve različite veštačke neuronske mreže ispitan je uticaj faktora formulacije na kritičnekarakteristike kvaliteta tableta dobijenih LCD (engl. liquid-crystal display) 3D štampom. Izvršena jeoptimizacija fotopolimerizacione štampe i predviđanje produženog oslobađanja aktivne supstance kaociljne karakteristike kvaliteta LCD 3D tableta. Sličnost između eksperimentalno dobijenih i neuronskommrežom predviđenih profila oslobađanja je pokazana analizom faktora sličnosti (f2=52,15). Na osnovuovih rezultata zaključeno je da je adekvatna neuronska mreža u stanju da pruži razumevanje odnosaulaznih-izlaznih parametara fotopolimerizacione 3D štampe, a samim tim i da pruži bolji uvid u uticajekscipijenasa i procesnih parametara na karakteristike LCD 3D tableta.Na osnovu apsorpcionih karakteristika ispitivanih formulacija izvršena je optimizacija LCD štampača.Na ovaj način vreme štampe tableta je značajno smanjeno i postignuto je značajno brže oslobađanjeaktivne supstance.U trećoj fazi istraživanja je ispitana tehnologija selektivnog laserskog sinterovanje (SLS) u izradi tableta.Najpre je izvršena adaptacija konvencionalnog štampača čime je omogućeno štampanje sa manjimkoličinama materijala. Primenom modela stabla odluke ispitana je korelacija između faktora formulacije,gustine energije prilikom sinterovanja i printabilnosti. Na osnovu razvijenog stabla odluke, čija je tačnostiznosila 80%, najvažniji faktori koji su uticali na printabilnost su sadržaj krospovidona i gustina energije.Takođe, ova faza istraživanja je pokazala da je optimizacijom formulacije i parametara procesa, mogućeizraditi SLS tablete makroporozne strukture sa potpunim oslobađanjem aktivne supstance za manje od30 min.Ostvareni rezultati pružaju saznanja o primeni dve tehnologije 3D štampe u izradi tableta i daju značajanuvid u uticaj procesnih parametara i faktora formulacije na karakteristike dobijenih tableta.The aim of this doctoral dissertation was the development and optimization of formulations and processof 3D printing in the production of tablets by photopolymerization and selective laser sintering usingadvanced data analysis tools.The influence of formulation factors on the critical quality attributes of tablets obtained by LCD (liquid-crystal display) 3D printing was evaluated using two different artificial neural networks. Optimizationof photopolymerization printing and prediction of extended drug release as a target quality attribute ofLCD 3D tablets was performed. The similarity between the experimentally obtained and the neuralnetwork predicted release profiles was demonstrated by the similarity factor analysis (f2=52.15). It wasconcluded that an adequate neural network is able to provide an understanding of the ratio of input-outputparameters of photopolymerization 3D printing, and therefore to provide a better insight into theinfluence of excipients and process parameters on the characteristics of LCD 3D tablets.Based on the absorption characteristics of the examined formulations, the LCD printer was optimized.In this way, the printing time was significantly reduced and a significantly faster drug release wasachieved.In the third phase of the research, SLS technology in the production of tablets was evaluated. First, theadaptation of the conventional printer was carried out, which enabled printing with smaller amounts ofmaterial. By applying the decision tree model, the correlation between formulation factors, energydensity during sintering, and printability was evaluated. Based on the developed decision tree, theaccuracy of which was 80%, the most important factors that influenced the printability werecrospovidone content and energy density. Also, this phase of the research showed that by optimizing theformulation and process parameters, it is possible to produce SLS tablets with a macroporous structurewith complete drug release in less than 30 minutes.The obtained results provide knowledge about the application of two 3D printing technologies in theproduction of tablets and provide significant insight into the influence of process parameters andformulation factors on the characteristics of the obtained tablets

3D printing of tablets by photopolymerization and selective laser sintering: development and process optimisation

Cilj ove doktorske disertacije je bio razvoj i optimizacija formulacija i procesa 3D štampe u izradi tableta postupcima fotopolimerizacije i selektivnog laserskog sinterovanja primenom naprednih alata za analizu podataka. Primenom dve različite veštačke neuronske mreže ispitan je uticaj faktora formulacije na kritične karakteristike kvaliteta tableta dobijenih LCD (engl. liquid-crystal display) 3D štampom. Izvršena je optimizacija fotopolimerizacione štampe i predviđanje produženog oslobađanja aktivne supstance kao ciljne karakteristike kvaliteta LCD 3D tableta. Sličnost između eksperimentalno dobijenih i neuronskom mrežom predviđenih profila oslobađanja je pokazana analizom faktora sličnosti (f2=52,15). Na osnovu ovih rezultata zaključeno je da je adekvatna neuronska mreža u stanju da pruži razumevanje odnosa ulaznih-izlaznih parametara fotopolimerizacione 3D štampe, a samim tim i da pruži bolji uvid u uticaj ekscipijenasa i procesnih parametara na karakteristike LCD 3D tableta. Na osnovu apsorpcionih karakteristika ispitivanih formulacija izvršena je optimizacija LCD štampača. Na ovaj način vreme štampe tableta je značajno smanjeno i postignuto je značajno brže oslobađanje aktivne supstance. U trećoj fazi istraživanja je ispitana tehnologija selektivnog laserskog sinterovanje (SLS) u izradi tableta. Najpre je izvršena adaptacija konvencionalnog štampača čime je omogućeno štampanje sa manjim količinama materijala. Primenom modela stabla odluke ispitana je korelacija između faktora formulacije, gustine energije prilikom sinterovanja i printabilnosti. Na osnovu razvijenog stabla odluke, čija je tačnost iznosila 80%, najvažniji faktori koji su uticali na printabilnost su sadržaj krospovidona i gustina energije. Takođe, ova faza istraživanja je pokazala da je optimizacijom formulacije i parametara procesa, moguće izraditi SLS tablete makroporozne strukture sa potpunim oslobađanjem aktivne supstance za manje od 30 min. Ostvareni rezultati pružaju saznanja o primeni dve tehnologije 3D štampe u izradi tableta i daju značajan uvid u uticaj procesnih parametara i faktora formulacije na karakteristike dobijenih tableta.The aim of this doctoral dissertation was the development and optimization of formulations and process of 3D printing in the production of tablets by photopolymerization and selective laser sintering using advanced data analysis tools. The influence of formulation factors on the critical quality attributes of tablets obtained by LCD (liquid- crystal display) 3D printing was evaluated using two different artificial neural networks. Optimization of photopolymerization printing and prediction of extended drug release as a target quality attribute of LCD 3D tablets was performed. The similarity between the experimentally obtained and the neural network predicted release profiles was demonstrated by the similarity factor analysis (f2=52.15). It was concluded that an adequate neural network is able to provide an understanding of the ratio of input-output parameters of photopolymerization 3D printing, and therefore to provide a better insight into the influence of excipients and process parameters on the characteristics of LCD 3D tablets. Based on the absorption characteristics of the examined formulations, the LCD printer was optimized. In this way, the printing time was significantly reduced and a significantly faster drug release was achieved. In the third phase of the research, SLS technology in the production of tablets was evaluated. First, the adaptation of the conventional printer was carried out, which enabled printing with smaller amounts of material. By applying the decision tree model, the correlation between formulation factors, energy density during sintering, and printability was evaluated. Based on the developed decision tree, the accuracy of which was 80%, the most important factors that influenced the printability were crospovidone content and energy density. Also, this phase of the research showed that by optimizing the formulation and process parameters, it is possible to produce SLS tablets with a macroporous structure with complete drug release in less than 30 minutes. The obtained results provide knowledge about the application of two 3D printing technologies in the production of tablets and provide significant insight into the influence of process parameters and formulation factors on the characteristics of the obtained tablets

Understanding the Effect of Energy Density and Formulation Factors on the Printability and Characteristics of SLS Irbesartan Tablets-Application of the Decision Tree Model

Selective laser sintering (SLS) is a rapid prototyping technique for the production of three-dimensional objects through selectively sintering powder-based layer materials. The aim of the study was to investigate the effect of energy density (ED) and formulation factors on the printability and characteristics of SLS irbesartan tablets. The correlation between formulation factors, ED, and printability was obtained using a decision tree model with an accuracy of 80%. FT-IR results revealed that there was no interaction between irbesartan and the applied excipients. DSC results indicated that irbesartan was present in an amorphous form in printed tablets. ED had a significant influence on tablets' physical, mechanical, and morphological characteristics. Adding lactose mon-ohydrate enabled faster drug release while reducing the possibility for printing with different laser speeds. However, formulations with crospovidone were printable with a wider range of laser speeds. The adjustment of formulation and process parameters enabled the production of SLS tablets with hydroxypropyl methylcellulose with complete release in less than 30 min. The results suggest that a decision tree could be a useful tool for predicting the printability of pharmaceutical formulations. Tailoring the characteristics of SLS irbesartan tablets by ED is possible; however, it needs to be governed by the composition of the whole formulation

Optimization and prediction of ibuprofen release from 3D DLP printlets using artificial neural networks

The aim of this work was to investigate eects of the formulation factors on tablet printability as well as to optimize and predict extended drug release from cross-linked polymeric ibuprofen printlets using an artificial neural network (ANN). Printlets were printed using digital light processing (DLP) technology from formulations containing polyethylene glycol diacrylate, polyethylene glycol, and water in concentrations according to D-optimal mixture design and 0.1% w/w riboflavin and 5% w/w ibuprofen. It was observed that with higher water content longer exposure time was required for successful printing. For understanding the eects of excipients and printing parameters on drug dissolution rate in DLP printlets two dierent neural networks were developed with using two commercially available softwares. After comparison of experimental and predicted values of in vitro dissolution at the corresponding time points for optimized formulation, the R2 experimental vs. predicted value was 0.9811 (neural network 1) and 0.9960 (neural network 2). According to dierence f1 and similarity factor f2 (f1 = 14.30 and f2 = 52.15) neural network 1 with supervised multilayer perceptron, backpropagation algorithm, and linear activation function gave a similar dissolution profile to obtained experimental results, indicating that adequate ANN is able to set out an input–output relationship in DLP printing of pharmaceutics

3D printing of tablets by photopolymerization and selective laser sintering: development and process optimisation

Cilj ove doktorske disertacije je bio razvoj i optimizacija formulacija i procesa 3D štampe u izradi tableta postupcima fotopolimerizacije i selektivnog laserskog sinterovanja primenom naprednih alata za analizu podataka. Primenom dve različite veštačke neuronske mreže ispitan je uticaj faktora formulacije na kritične karakteristike kvaliteta tableta dobijenih LCD (engl. liquid-crystal display) 3D štampom. Izvršena je optimizacija fotopolimerizacione štampe i predviđanje produženog oslobađanja aktivne supstance kao ciljne karakteristike kvaliteta LCD 3D tableta. Sličnost između eksperimentalno dobijenih i neuronskom mrežom predviđenih profila oslobađanja je pokazana analizom faktora sličnosti (f2=52,15). Na osnovu ovih rezultata zaključeno je da je adekvatna neuronska mreža u stanju da pruži razumevanje odnosa ulaznih-izlaznih parametara fotopolimerizacione 3D štampe, a samim tim i da pruži bolji uvid u uticaj ekscipijenasa i procesnih parametara na karakteristike LCD 3D tableta. Na osnovu apsorpcionih karakteristika ispitivanih formulacija izvršena je optimizacija LCD štampača. Na ovaj način vreme štampe tableta je značajno smanjeno i postignuto je značajno brže oslobađanje aktivne supstance. U trećoj fazi istraživanja je ispitana tehnologija selektivnog laserskog sinterovanje (SLS) u izradi tableta. Najpre je izvršena adaptacija konvencionalnog štampača čime je omogućeno štampanje sa manjim količinama materijala. Primenom modela stabla odluke ispitana je korelacija između faktora formulacije, gustine energije prilikom sinterovanja i printabilnosti. Na osnovu razvijenog stabla odluke, čija je tačnost iznosila 80%, najvažniji faktori koji su uticali na printabilnost su sadržaj krospovidona i gustina energije. Takođe, ova faza istraživanja je pokazala da je optimizacijom formulacije i parametara procesa, moguće izraditi SLS tablete makroporozne strukture sa potpunim oslobađanjem aktivne supstance za manje od 30 min. Ostvareni rezultati pružaju saznanja o primeni dve tehnologije 3D štampe u izradi tableta i daju značajan uvid u uticaj procesnih parametara i faktora formulacije na karakteristike dobijenih tableta.The aim of this doctoral dissertation was the development and optimization of formulations and process of 3D printing in the production of tablets by photopolymerization and selective laser sintering using advanced data analysis tools. The influence of formulation factors on the critical quality attributes of tablets obtained by LCD (liquid- crystal display) 3D printing was evaluated using two different artificial neural networks. Optimization of photopolymerization printing and prediction of extended drug release as a target quality attribute of LCD 3D tablets was performed. The similarity between the experimentally obtained and the neural network predicted release profiles was demonstrated by the similarity factor analysis (f2=52.15). It was concluded that an adequate neural network is able to provide an understanding of the ratio of input-output parameters of photopolymerization 3D printing, and therefore to provide a better insight into the influence of excipients and process parameters on the characteristics of LCD 3D tablets. Based on the absorption characteristics of the examined formulations, the LCD printer was optimized. In this way, the printing time was significantly reduced and a significantly faster drug release was achieved. In the third phase of the research, SLS technology in the production of tablets was evaluated. First, the adaptation of the conventional printer was carried out, which enabled printing with smaller amounts of material. By applying the decision tree model, the correlation between formulation factors, energy density during sintering, and printability was evaluated. Based on the developed decision tree, the accuracy of which was 80%, the most important factors that influenced the printability were crospovidone content and energy density. Also, this phase of the research showed that by optimizing the formulation and process parameters, it is possible to produce SLS tablets with a macroporous structure with complete drug release in less than 30 minutes. The obtained results provide knowledge about the application of two 3D printing technologies in the production of tablets and provide significant insight into the influence of process parameters and formulation factors on the characteristics of the obtained tablets

Evaluation of exposure time and visible light irradiation in LCD 3D printing of ibuprofen extended release tablets

Liquid crystal display (LCD) 3D printing technology is one of the three currently available photocuring three-dimensional printing technologies. LCD 3D printers usually use wavelengths in the ultraviolent (UV) range. However, recently introduced light-emitting diodes (LED) projectors enable visible light-induced photopolymerization, which would have an advantage in terms of safety in drug production. The aim of this work was to investigate the feasibility of printing ibuprofen extended release tablets under visible light irradiation and to evaluate characteristics of printed tablets. Influences of exposure time and wavelengths (UV versus visible light) on characteristics of tablets were evaluated. Tablets were printed using 405 nm and 450 nm LED light. Visible light enabled significantly faster printing as well as better dimensions accuracy of printed tablets. It was noticed that printing under 450 nm LED resulted in slightly softer tablets compared to tablets printing with 405 nm LED. Extended ibuprofen release was obtained from all formulations. Exposure time did not have influence on drug release in formulations with low water content. However, in a formulation with higher water content, the exposure time had a pronounced effect on drug release (in eight hours of testing, differences were from 27% to 95%). Wavelength affected the release rate of ibuprofen. Tablets prepared using 450 nm LEDs released ibuprofen faster than tablets prepared with 405 nm LEDs. The main mechanism of ibuprofen release was diffusion, regardless of exposure time and wavelength. Characteristics of obtained tablets indicate that further optimization of this process is necessary, but this new printing process approach opens the possibility for novel wavelength consideration in order to obtain the safe printing process of tablets

Tailoring amlodipine release from 3D printed tablets: Influence of infill patterns and wall thickness

The aim of this study was to investigate the impact of infill patterns on the drug release of 3D-printed tablets and the possibility of tailoring drug release through the use of excipients. Furthermore, the influence of wall thickness was evaluated. Amlodipine was used as a model drug, polyvinyl alcohol (PVA) as a polymer and excipients including sodium starch glycolate (SSG) and hydroxypropyl methyl cellulose (HPMC) HME 4 M were used. Four different formulations were prepared. Firstly, the substances were mixed and then extruded by hot melt extrusion to form filaments. The obtained filaments were used to print amlodipine tablets by fused deposition modeling (FDM) 3D-printing technique. Each formulation was printed in four different infill patterns: zigzag, cubic, trihexagon and concentric, while infill density remained constant (20%). The mechanical properties of the obtained filaments were also evaluated using three-point bend test. Amlodipine tablets were printed with varying wall thickness (1 mm, 2 mm and 3 mm) and varying infill patterns. With regard to the infill patterns, higher drug release was achieved with zigzag infill pattern. The simultaneous effect of excipients and infill patterns on amlodipine release has been described and modeled through self - organizing maps (SOMs), which visualize the effect of these variables. Self-organizing maps confirmed the fastest drug release when the zigzag pattern and SSG were used, but also showed that the presence of HPMC HME 4 M was not decisive for drug release rate. As for the wall thickness, higher drug release was achieved with decreasing wall thickness. The results indicated that proper selection of excipients and/or adjusting the infill pattern and wall thickness are ways of tailoring drug release in FDM 3D printing. This study draws the attention to the importance of adjusting the settings of the printer and the usage of excipients to produce release-tailored medications

Paracetamol extended release FDM 3D printlets: Evaluation of formulation variables on printability and drug release

Paracetamol printlets were prepared via hot-melt extrusion process and fused deposition modelling, using two types of backbone polymers. Polycaprolactone (PCL) and Polyethylene oxides (PEO) 100 K and 200 K were used, while Arabic gum was used as a plasticizer to facilitate the material flow and Gelucire® 44/14 as an enhancer of drug release. Different drug/polymer ratios were prepared. Extrusion temperature was adjusted according to the mixture/polymer types. It was possible to produce filaments with maximum of 60% w/w of drug. Mechanical properties of filaments were evaluated using three-point bend test, while obtained parameters were modelled using decision tree as a data mining method. Correlation between maximum displacement, maximum force and printability was obtained with accuracy of 84.85% and can be a useful tool for predicting printability of filaments. This study briefly demonstrated that backbone polymer in formulation plays crucial role in obtaining FDM printlets with desired properties. PEO-based filaments were more prone to be clogged in printcore, but their printlets showed much faster drug release. Drug release from all printlets was prolonged: from 50% in 8 h (PCL), to complete release in 4 h (PEO). Paracetamol release kinetics was guided by anomalous transport, attributed to the diffusion and erosion process

The evaluation of the effect of different superdisintegrants on the drug release from FDM 3D printed tablets through different applied strategies: In vitro-in silico assessment

Paracetamol-loaded tablets were printed by fused deposition modelling technique, using polyvinyl alcohol as a backbone polymer and Affinisol™ HPMC as a plasticizer in all formulations. Four different strategies were applied in order to accelerate the drug release from the tablets. First, different release enhancers were added: sodium starch glycolate, croscarmellose sodium, Kollidon CL and mannitol. Kollidon CL and mannitol showed the greatest influence on the drug dissolution rate. The second strategy included lowering the infill density, which did not make any significant changes in dissolution profiles, according to the calculated similarity factor. Then the best two release enhancers from the first strategy were combined (Kollidon CL and mannitol) and this proved to be the most effective in the drug release acceleration. The fourth strategy, increasing the percentage of the release enhancers in formulation, revealed the importance of their concentration limits. In summary, the drug release accelerated from 58% released after 5 h to reaching the plateau within 2 h. In silico physiologically-based biopharmaceutics modelling showed that formulations with mannitol and Kollidon CL, especially the formulation containing a combination of these release enhancers, can provide relatively fast drug release and extent of drug absorption that complies with an immediate release tablet