Hot-Melt Extrusion-Based Fused Deposition Modeling 3D Printing of Atorvastatin Calcium Tablets: Impact of Shape and Infill Density on Printability and Performance.

The main objective of the current research was to investigate the effect of tablet shapes (heart-shaped and round tablets) and infill densities (50% and 100%) on the drug release profiles of 3D printed tablets prepared by hot-melt extrusion paired with fused deposition modeling techniques. Drug-loaded filaments of 1.5 mm and 2.5 mm diameters were extruded using a Process 11 mm hot-melt extruder employing atorvastatin calcium as a model drug and Kollicoat® IR, Kollidon® VA64, Kollidon® 12PF, and Kolliphor® P407 as hydrophilic polymers. Filaments of Kollicoat® IR in combination with Kollidon® VA64/Kollidon® 12PF has resulted in successful printing of immediate release tablets. The mechanical properties of drug-loaded filaments were evaluated using a 3-point bend test and stiffness test. The transformation of a crystalline drug to an amorphous form and the absence of drug-polymer interactions were confirmed by differential scanning calorimetry and Fourier transform infrared spectroscopy, respectively. The effect of infill density on drug release profiles was greater than that of tablet shape. The stability of 3D printed tablets was preserved even after storage under accelerated conditions (40 ± 2°C and 75 ± 5% RH) for 6 months. Thus, the 3D printing process of hot-melt extrusion paired with fused deposition modeling serves as an alternative manufacturing approach for developing patient-focused doses.

3D printing in personalized drug delivery: An overview of hot-melt extrusion-based fused deposition modeling.

Advancements in pharmaceutical technologies have led to the personalization of therapies over the last decade. Three-dimensional printing (3DP) is an emerging technique in the manufacturing of pharmaceutical dosage forms because of its potential to create complex and customized dosage forms according to the patient's needs. Among the various 3DP techniques based on different functioning mechanisms, fused deposition modeling (FDM) 3D printing is a versatile and widely used method with advantages such as precision of quantity and the ability to incorporate different fill densities. This method is also economical and easily produces complex designs. Hot-melt extrusion (HME) is an established technique in pharmaceutical manufacturing that is utilized in the development of filaments which are used as "ink roll" or feedstock material in FDM 3D printing. This review discusses the various stages involved in FDM 3D printing, including feedstock filament preparation using HME, digital dosage form designs, filament characterization, and various novel applications, and future perspectives.

Theophylline-nicotinamide pharmaceutical co-crystals generated using hot melt extrusion technology: Impact of polymeric carriers on processability.

The objective of the current study was to develop theophylline (TPH) nicotinamide (NAM) pharmaceutical co-crystals using the hot melt extrusion (HME) technology and evaluate the processability of the co-crystals using different polymeric carriers. A physical mixture of 1:1 M ratio of TPH and NAM was employed to prepare the co-crystals. Hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, and Kollidon® VA-64 (5% w/w) were investigated as polymeric carriers for the HME process. Solid-state characterization using differential scanning calorimetry showed two endothermal peaks, one at 126.4 °C indicating eutectic formation and another at 174 °C indicating the melting point of the co-crystal for all formulations, except the Kollidon® VA-64 extrudates, which showed a single peak at 174 °C. Fourier-transform infrared spectroscopy and powder X-ray diffraction studies revealed the formation of co-crystals. The feasibility to formulate the extrudates into solid dosage forms was assessed by formulating a tablet blend. The three-month stability studies showed no degradation at the accelerated stability conditions of 40 (±2) ° C and 75 (±5) % RH. Finally, the results demonstrated that the presence of mixing zones in screw configuration and extrusion temperature are critical processing parameters that influence co-crystal formation.

Coupling hot melt extrusion and fused deposition modeling: Critical properties for successful performance.

Interest in 3D printing for pharmaceutical applications has increased in recent years. Compared to other 3D printing techniques, hot melt extrusion (HME)-based fused deposition modeling (FDM) 3D printing has been the most extensively investigated for patient-focused dosage. HME technology can be coupled with FDM 3D printing as a continuous manufacturing process. However, the crucial pharmaceutical polymers, formulation and process parameters must be investigated to establish HME-coupled FDM 3D printing. These advancements will lead the way towards developing continuous drug delivery systems for personalized therapy. This brief overview classifies pharmaceutical additive manufacturing, Hot Melt Extrusion, and Fused Deposition Modeling 3D printing techniques with a focus on coupling HME and FDM 3D printing processes. It also provides insights on the critical material properties, process and equipment parameters and limitations of successful HME-coupled FDM systems.

Fabrication of Taste-Masked Donut-Shaped Tablets Via Fused Filament Fabrication 3D Printing Paired with Hot-Melt Extrusion Techniques.

The objective of this work was to develop taste-masked donut-shaped tablet formulations utilizing fused filament fabrication three-dimensional printing paired with hot-melt extrusion techniques. Caffeine citrate was used as the model drug for its bitter taste, and a 3-point bend test was performed to assess the printability of filaments. The stiffness constant was calculated to represent the printability by fitting the breaking distances and stress data into Hooke's law. The formulations without Eudragit E PO (F6) and with Eudragit E PO (F7) filaments exhibited the desired hardness with a "k" value of 48.30 ± 3.52 and 45.47 ± 3.51 g/mm3 (n = 10), respectively, and were successfully printed. The donut-shaped tablets were 3D printed with 10, 50, and 100% infill densities. In vitro dissolution studies were performed in simulated salivary fluid (pH 6.8, artificial saliva) to evaluate the taste-masking efficiency of the printed donuts. In the first minute, the concentrations of caffeine citrate observed in the dissolution media from all the printed donuts were less than the bitter threshold of caffeine citrate (0.25 mg/mL). Formulation F7, which contained Eudragit E PO copolymer, demonstrated better taste-masking efficiency than formulation F6. Furthermore, both formulations F6 and F7 demonstrated immediate drug release profiles in gastric medium (10% infill, > 80% release within 1 h). Taste-masked caffeine citrate formulations were successfully developed with donut shapes, which will enhance appeal in pediatric populations and increase compliance and patient acceptance of the dosage form.

Extended release pellets prepared by hot melt extrusion technique for abuse deterrent potential: Category-1 in-vitro evaluation.

The objective of the present study was to develop extended-release (ER) hot-melt extruded (HME) abuse-deterrent pellets of acetaminophen, a model drug, by utilizing high molecular weight polyethylene oxide (PEO) and gelling agents (xanthan gum, guar gum, and gellan gum). The HME pellets were evaluated for their abuse-deterrence (AD) potential by Category-1 laboratory in-vitro evaluation parameters, including particle size reduction (PSR), small volume extraction, dissolution, viscosity, syringeability, and injectability. Further, the pellets were investigated for resistance to physical (crushing) and thermal (oven and microwave) manipulation to evaluate the strength of the AD properties. Physical manipulation studies demonstrated that the pellets were intact, extremely hard, and resistant to PSR and manipulation to bypass ER properties. Dissolution of all intact and physically manipulated pellets led to complete drug release within 8 h, and resistance to dose-dumping in 40% ethanol was observed. The drug extraction was <50% in 10 mL of ingestible and non-ingestible solvents under static, agitation, and thermal manipulation conditions with an incubation time of 30 min. The PEO/xanthan gum-based formulation showed higher viscosity, syringe and injection forces, and lower syringeable volume in all manipulation conditions compared with plain PEO pellets. These findings supported the AD potential of PEO and xanthan gum pellets against intravenous abuse.

Polymer-Assisted Aripiprazole-Adipic Acid Cocrystals Produced by Hot Melt Extrusion Techniques.

Pharmaceutical cocrystals are a promising strategy to increase the solubility and dissolution rate of poorly soluble drugs. However, their manufacturing process requires a large quantity of solvents. The present study aimed to produce cocrystals by a solvent-free hot melt extrusion (HME) method to improve their solubility and dissolution rate. Aripiprazole (ARP) and adipic acid (ADP) were used as a weakly basic drug and acidic coformer, respectively. The processability of a plain ARP-ADP physical mixture (PM) compared with a PM with 5% Soluplus® (SOL) was investigated. Incorporating 5% SOL into the ARP-ADP blend reduced the processing torque and improved processability. The effects of temperature and screw speed on the formation of cocrystals were studied, and cocrystals were characterized by differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscopy, and hot-stage microscopy. FTIR spectra revealed noncovalent interaction between ARP and ADP, which was confirmed by NMR spectra. Similarly, PXRD data exhibited characteristic peaks confirming the formation of new crystalline material. Further, the results indicated that cocrystals demonstrated higher dissolution rates and improved compressibility, as well as enhanced flow characteristics compared with pure ARP, suggesting its suitability in the development of solid dosage forms.