Effect of pH, Ionic Strength and Agitation Rate on Dissolution Behaviour of 3D-Printed Tablets, Tablets Prepared from Ground Hot-Melt Extruded Filaments and Physical Mixtures.

With the current focus on 3D-printing technologies, it is essential to understand the processes involved in such printing methods and approaches to minimize the variability in dissolution behaviour to achieve better quality control outcomes. For this purpose, two formulations of theophylline tablets were prepared using hydroxypropyl cellulose (HPC) and ethyl cellulose (EC). Among the two types of tablets, three different methods (physical mixture (PM), hot-melt extrusion (HME) and 3D-printing fused deposition modelling (FDM)) were applied and their dissolution behaviours were studied under various conditions using a biodissolution tester. This was carried out at pH values of 1.2, 2.2, 5.8, 6.8, 7.2 and 7.5, mimicking the medium in the gastrointestinal tract. Dissolution tests under two dipping rates (10 dpm and 20 dpm) and two ionic strengths (0.2 M and 0.4 M) were conducted to mimic fed and fasting conditions. The dissolution efficiency (DE%), release rate, similarity factor (f2) and difference factor (f1) were calculated. When comparing the DE%, the formulation containing EC showed less sensitivity to changes in the dipping rate and ionic strength compared to the HPC formulation. As for the manufacturing method, 3D-printing FDM could improve the robustness of the dissolution behaviour of both formulations to dipping rate changes. However, for ionic strength changes, the effect of the manufacturing method was dependent on the formulation composition. For example, the 3D-printed tablets of the HPC formulation were more sensitive to changes in ionic strength compared to the EC-containing formulation. The release mechanism also changed after the thermal process, where n values in the Korsmeyer-Peppas model were much higher in the printing and HME methods compared to the PM. Based on the formulation composition, the 3D-printing method could be a good candidate method for tablets with a robust dissolution behaviour in the GI tract. Compared to HPC polymers, using hydrophobic EC polymers in printable formulations can result in a more robust dissolution behaviour in fed and fasting states.

An Insight into the Impact of Thermal Process on Dissolution Profile and Physical Characteristics of Theophylline Tablets Made through 3D Printing Compared to Conventional Methods.

The dissolution profile is of great importance in drug delivery and is affected by the manufacturing method. Thus, it is important to study the influence of the thermal process on drug release in emerging technologies such as 3D printing-fused deposition modeling (FDM). For this purpose, the characteristics of 3D printed tablets were compared to those of tablets prepared by other thermal methods such as hot-melt extrusion (HME) and non-thermal methods such as physical mixture (PM). Theophylline was used as a drug model and blends of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) were used as a matrix former. The solid state of the drug in all formulations was investigated by differential scanning calorimetry, X-ray powder diffraction, and Fourier-transformed infrared spectroscopy. All studied tablets had the same weight and surface area/volume (SA/V). Dissolution data showed that, for some formulations, printed tablets interestingly had a faster release profile despite having the highest hardness values (>550 N) compared to HME and PM tablets. Porosity investigations showed that 100% infill printed tablets had the highest porosity (~20%) compared to HME (<10%) and PM tablets (≤11%). True density records were the lowest in printed tablets (~1.22 g/m3) compared to tablets made from both HME and PM methods (~1.26 g/m3), reflecting the possible increase in polymer specific volume while printing. This increase in the volume of polymer network may accelerate water and drug diffusion from/within the matrix. Thus, it is a misconception that the 3D printing process will always retard drug release based on increased tablet hardness. Hardness, porosity, density, solid-state of the drug, SA/V, weight, and formulation components are all factors contributing to the release profile where the total balance can either slow down or accelerate the release profile.

Solubility Study of Acetylsalicylic Acid in Ethanol + Water Mixtures: Measurement, Mathematical Modeling, and Stability Discussion.

Solubility determination of poorly water-soluble drugs is pivotal for formulation scientists when they want to develop a liquid formulation. Performing such a test with different ratios of cosolvents with water is time-consuming and costly. The scarcity of solubility data for poorly water-soluble drugs increases the importance of developing correlation and prediction equations for these mixtures. Therefore, the aim of the current research is to determine the solubility of acetylsalicylic acid in binary mixtures of ethanol+water at 25 and 37°C. Acetylsalicylic acid is non-stable in aqueous solutions and readily hydrolyze to salicylic acid. So, the solubility of acetylsalicylic acid is measured in ethanolic mixtures by HPLC to follow the concentration of produced salicylic acid as well. Moreover, the solubility of acetylsalicylic acid is modeled using different cosolvency equations. The measured solubility data were also predicted using PC-SAFT EOS model. DSC results ruled out any changes in the polymorphic form of acetylsalicylic acid after the solubility test, whereas XRPD results showed some changes in crystallinity of the precipitated acetylsalicylic acid after the solubility test. Fitting the solubility data to the different cosolvency models showed that the mean relative deviation percentage for the Jouyban-Acree model was less than 10.0% showing that this equation is able to obtain accurate solubility data for acetylsalicylic acid in mixtures of ethanol and water. Also, the predicted data with an average mean relative deviation percentage (MRD%) of less than 29.65% show the capability of the PC-SAFT model for predicting solubility data. A brief comparison of the solubilities of structurally related solutes to acetylsalicylic acid was also provided.

Liqui-Mass Technology as a Novel Tool to Produce Sustained Release Liqui-Tablet Made from Liqui-Pellets.

The Liqui-Mass technology (also known as Liqui-Pellet technology) has shown promising results in terms of enhancing the drug release rate of water insoluble drugs in a simplistic approach. However, there is no current study on sustained-release formulation using the Liqui-Mass technology. In this study, an attempt was made to produce a sustained-release Liqui-Tablet for the first time using a matrix-based approach. The non-volatile co-solvent used in the investigation included Tween 80, Tween 20 and Kolliphor EL. The production of sustained-release propranolol hydrochloride Liqui-Tablet was successful, and data from the saturation solubility test and dissolution test did not show much difference among the mentioned non-volatile co-solvent. The best Liqui-Tablet formulation took 24 h for drug release to reach at around 100%. There seemed to be a synergistic retarding drug release effect when a non-volatile co-solvent and Eudragit RS PO were used together. The increase of Eudragit RS PO concentration increased the retardant effect. Kinetic drug release analysis suggests that the best formulation followed the Higuchi model. The flowability of pre-compressed Liqui-Tablet pellets had no issues and its size distribution was narrow. Liqui-Tablet was generally robust and most formulations passed the friability test. The study revealed that Liqui-Mass technology can be employed to sustain drug release.

A comprehensive overview of extended release oral dosage forms manufactured through hot melt extrusion and its combination with 3D printing.

Oral dosage formulations are considered to be the most convenient pharmaceutical dosage forms for almost all ages because of their simplicity and non-invasive administration compared to other dosage forms. To improve therapeutic efficacy and avoid frequent daily doses, extending drug release profile is of great interest in pharmaceutical industry. Hot-Melt Extrusion (HME) has gained great attention in pharmaceutical industry since it is one of the continuous manufacturing processes, which can cut down production steps and human errors as opposed to batch to batch process. This controlled and continuous process can improve product quality and reproducibility. HME is a versatile technology, where controlled/sustained oral dosage forms have been one of its important production lines. With the emergence of 3D printing, the future of personalized medicine has become more applicable. Recently, there is a great orientation towards the combination of HME and Fused Deposition Modelling (FDM), in an aim to be a continuous process for personalized and telemedicine. Several extended-release formulations have been manufactured successfully through HME coupled with FDM. This review will shed light on pharmaceutical approaches used to control and sustain drug release in oral formulations by HME and its combination with FDM 3D printing. Quality by design approaches and critical process- and formulation-related factors that affect the release profiles in both HME and FDM will be also discussed clearly in this review.