A growing and significant percentage of developmental drug substances exhibit poor dissolution, solubility, and bioavailability. To achieve therapeutically relevant bioactivity, it is necessary to enhance dissolution and solubility. Preparation of amorphous solid dispersions via hot-melt extrusion (HME) and spray drying are two increasingly popular approaches.1
Dispersion of an amorphous rather than a crystalline form of the active pharmaceutical ingredient (API) as a solid solution within a polymer matrix enables pre-dissolution of the API before administration. Dispersion in the solid polymer matrix also stabilizes the highly energetic amorphous structure. Once in the intestine, the polymer dissolves, releasing the API in a supersaturated concentration.
HME is an option for thermally stable APIs that are soluble in dispersion polymers. It produces a solid glassy solution without the use of solvent, which is attractive from a safety and environmental perspective.2 In addition to tablets and capsules, HME is applicable for the production of controlled-release implants.
At small batch sizes (e.g., 5 g), a miniaturized extruder used for HME contains a significant dead volume: as much as 50% to 80% of the material remains inside the extruder. This material loss is a major issue with high-value APIs, and it often prevents product developers from choosing HME as a formulation option.
MeltPrep has developed a new instrument to address this issue. Vacuum compression molding (VCM) mimics HME but avoids the loss of material that makes HME unsuitable for formulation screening, owing to the unique design of the sample chamber and the use of Teflon liners. With no need for cleaning — just replacement of foil liners — 5- to 20-mg samples of thermoplastic materials with viscosities above 100 Pa can be rapidly processed in a very small space (approximately 1 m on a lab bench) by operators with little training.
Once in place, a vacuum is applied to compact the powder without bubble formation. Rapid melting is achieved by heating, leading to particle fusion and formation of a homogenous melt. Cooling occurs via convection and conduction on a separate cooling unit, solidifying the sample. Defined sample geometries are obtained through compensation of density changes by the adaptable sample chamber. The Teflon liners are then removed from the sample without loss of material.
The VCM tool comes with disc inserts ranging from 2 to 25 mm and a 10 × 40 mm bar insert. The sample height can be adjusted between 0.1 and 10 mm by changing the filling weight.
Importantly, the dissolution results for samples produced using VCM, including multilayer samples, correlate highly with those produced using HME. VCM is an effective screening technique for all types of solid dosage forms, including abuse-resistant and solubility-enhancement formulations and implants. As the first fusion-based technique, it is well suited for formulations that use thermoplastic carriers.
MeltPrep was established in 2016, and by 2019 already had more than 20 international customers, including four of the largest pharma companies, who are using the VCM technology in their standard development process. MeltPrep is about to develop a 0.5-mm tool that will allow the production of ocular implants directly via VCM, as well as additional modular components that will support a wider range of sample sizes. Add-ons can be mounted on the VCM Tool for offline evaluation of appropriate spectroscopic methods (e.g., NIR, UV-Vis in reflectance or refraction) for later inline PAT implementations.
MeltPrep has three product lines. In 2018, MeltPrep introduced the VChamber, which turns any hot plate into a vacuum oven. In 2019, the third line, ExtruVis, was acquired. This technology enables easy and automated optical measurement of residence time distributions (RTD).
The ExtruVis acquisition is in line with MeltPrep’s goal of providing a suite of tools to aid process and formulation development for extruded products. MeltPrep has also established agreements for the distribution of VCM tools across the globe. Within the next few years, the company hopes to be selling 50 to 100 instruments annually.
Temtem, Márcio. “The Coming of Age of Amorphous Solid Dispersions.” Pharma’s Almanac. 26 Oct. 2018. Web.
“Enhancing Bioavailability with Hot-Melt Extrusion.” Pharmaceutical Technology. 43:25 (2019). Web.
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