Matthew Lam

One of the widely used approaches for improving the dissolution of poorly water-soluble drugs is particle size reduction. Ball milling is a mechanical, top-down technique used to reduce particle size. The effect of ball number, ball size and milling speed on the properties of milled Aprepitant is evaluated. A full factorial design was employed to investigate the influence of affecting factors on particle size reduction. The initial suspension was made by suspending the drug in distilled water using excipients followed by milling in a planetary ball mill. Ball size, ball number and milling speed modulated particle size distribution of Aprepitant. Increasing the number of balls from minimum to maximum for each ball size led to approximately a 28% reduction in mean particle size, a 37% decrease in D_90%, and a 25% decrease in the ratio of volume mean particle diameter to numeric mean particle diameter. On average, using 10 mm balls instead of 30 mm balls reduced mean particle size by 1.689 µm. As a result, ball size, ball number, and milling speed are three effective factors in the process of ball milling. By increasing the ball number and decreasing the ball size, efficient micronization of drug particles takes place and the particle size is more uniform.

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 (3) 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.

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.

Purpose: Liqui-Tablet is a dosage form derived from Liqui-Mass technology. It has proven to be a promising approach to improve drug dissolution rate of poorly water-soluble drugs. So far, Liqui-Tablet is feasible for low-dose drugs. In this study, an attempt was made to produce high-dose Liqui-Tablet, whilst maintaining ideal physicochemical properties for ease of manufacturing. Methods: Liqui-Tablets containing 100 mg of ketoprofen were produced using various liquid vehicles including PEG 200, Span 80, Kolliphor EL, PG, and Tween 85. Investigations that were carried out included saturation solubility test, dissolution test, tomographic study, and typical quality control tests for assessing flowability, particle size distribution, friability, and tablet hardness. Results: The weight of these Liqui-Tablets was acceptable for swallowing (483.8 mg), and the saturation solubility test showed PEG 200 to be the most suitable liquid vehicle (493 mg/mL). Tests investigating physicochemical properties such as flowability, particle size distribution, friability, and tablet hardness have shown no issue concerning quality control and manufacturability. The drug release test of the best formulation has shown extremely rapid drug release at pH 7.4 (100% after 5 min). At pH 1.2 the drug release was reasonable considering the formulation was yet to be optimized. Conclusion: Despite the high amount of API and liquid vehicle, it is possible to produce a high-dose dosage form with acceptable size and weight for swallowing using the novel Liqui-Mass technology. This has the potential to diversify the technology by removing the restriction of high dose drug that has been seen in liquisolid technology.

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.

Objective(s): Liqui-Mass technology has shown promising advantages in terms of commercial production and formulation manipulation. This study attempts to further explore the potential of enhanced drug release of effervescent Liqui-Pellet by optimizing certain parameters. Materials and Methods: In the current study, pellets containing co-solvent, naproxen, coating and carrier materials were prepared via extrusion and spheronisation (Liqui-Pellet). Parameters investigated included polysorbate 80 concentration (as a co-solvent), water content and the presence or absence of neusilin US2 as part of the new binary carrier mixture approach. Results: It was found that the success of the Liqui-Pellet production was determined by the amount of polysorbate 80 and water used, where above a certain limit, agglomeration occurred, and the formulation failed. Liqui-Pellet formulation showed an excellent flow, narrow size distribution and was robust to pass friability testing. The key findings in the investigation were that the Liqui-Pellet was capable of a remarkably fast drug release, and 100% drug release achieved within 20 min at pH 1.2, wherein naproxen has been known to be practically insoluble in such pH. Conclusion: Liqui-Pellets display the potential to enhance explosive dissolution where a combination of effervescent powders and binary carriers with the high surface area were used. Furthermore, X-ray microtomography revealed that the pellets were very uniform and homogenous.

Aim: Liqui-Pellet is potentially an emerging next-generation oral pill, which has shown promising results with unique advantages as well as displaying potential for commercial feasibility. Since Liqui-Pellet technology is still in its infancy, it is important to explore the parameters that can affect its performance, particularly the drug release rate. Therefore, the aim of this study is to investigate thoroughly the effect of Avicel PH101 (carrier) and Aerosil 300 (coating material) ratio (R-value) in Liqui-Pellet. Methods: Key parameter for Liqui-Pellet formulation in this study was the ratio of carrier and coating material. Tests were carried out to assess the physicochemical properties of different formulations. This involved looking into particle size, robustness, flowability, solid-state and drug release profile. The morphology of Liqui-Pellet was investigated by SEM. Results: It is found that R-value does not have a major effect on the success of Liqui-Pellet production. However, R-value does seem to have an effect on Liqui-Pellet size at a certain water content level and a slight effect on the drug release rate. A decrease in Avicel PH101 concentration and an increase in Aerosil 300 concentration in Liqui-Pellet formulations can reduce Liqui-Pellet size and slightly increase drug release rate by 9% after 2 h. The data shows Liqui-Pellet is resistant to friability, able to achieve exceptional flow property and have smooth surfaces, which is critical for applying coatings technology. Such properties are ideal in terms of commercial manufacturing. The XRPD and DSC both show the reduction in formulation crystallinity, which is expected in Liqui-Pellet formulation as a result of solubility of the drug in the co-solvent used in the preparation of Liqui-Pellets. Conclusion: Overall it seems that R-value can affect Liqui-Pellet drug release rate and size but not on the production success rate. Graphical