Mixing Formulation & Empowering Diffusion for Flawless Samples
Vacuum Compression Molding (VCM) is a small-scale batch process that mimics ASD manufacturing. Unlike conventional manufacturing methods that rely primarily on convective shear mixing, VCM leverages diffusion for mixing, making the maximization of diffusive homogenization essential. Effective premixing prior to introducing the material into the VCM Tool is critical to achieving homogeneous samples.
Various premixing approaches can be employed; among these, the MeltPrep Mixer provides controlled shear-and-fold mixing under extrusion-comparable shear rates while operating on a milligram scale. Its lossless design enables efficient material use and reproducible premixing for VCM processing.
MeltPrep Mixer
Solvent Casting
Cryogenic Milling
Twin Screw Extrusion
When it comes to sample preparation of thermoplastics for pharmaceutical applications via the VCM process, obtaining a small-scale particle mixture is essential to ensure the homogeneity of samples. Some formulations may require an additional powder mixing step. These processes can be categorized into two main systems: batch mixing and continuous mixing.
Batch Mixing
In batch mixing, the ingredients are loaded into the mixer, processed until the powder achieves homogeneity, and discharged as a single batch (e.g. cryomilling).
Continuous Mixing
In continuous mixing, an uninterrupted flow of ingredients is introduced into the mixer from above. The material is continuously processed, resulting in a constant stream of homogenized powder flowing from the discharge nozzle.
An additional method is shear mixing, which is utilized in twin-screw extrusion as well as in the MeltPrep Mixer and consists of blending materials through forces that induce particle movement between layers.
Controlled Shear Mixing with the MeltPrep Mixer
Precise blending under defined conditions on a milligram scale.
To enable controlled shear mixing on a milligram scale, MeltPrep offers the MeltPrep Mixer as an add-on that integrates seamlessly with the VCM Essentials platform. Unlike large-scale extrusion systems, the Mixer allows precise, lossless blending of APIs and polymers with defined shear-and-fold action at shear rates similar to hot melt extrusion (~100–1000 s⁻¹), minimizing valuable material consumption while achieving homogeneous premixes. It is particularly suited for early-stage formulation development, where reproducibility, material efficiency, and controlled processing are essential before transferring a formulation to larger-scale equipment.
Thin Film Solvent Casting
For Material Quantities Below 100 mg (close to lossless)
In the realm of New Chemical Entities (NCE), we handle materials as valuable as jewelry diamonds. Losing a diamond stings, but wasting NCEs hurts even more. These custom-synthesized molecules take significant time to produce, making diamonds seem almost ordinary by comparison.
When dealing with material quantities as small as 1 mg, thin film solvent casting provides a method for creating an ASD from your API and carrier. To do this, start by dissolving your particles in a suitable solvent like ethanol or acetone. Then, pour the solution onto a glass plate or into a Petri Dish and allow the solvent to evaporate, leaving a thin layer of your material. Recrystallization may occur rapidly or during the drying process. Once dried, the layer can be scraped off with a razor blade and directly inserted into the VCM tool for processing in a VCM cycle. This cycle eliminates solvent residues, enhancing formulation stability through thermal processing, which evens out concentration differences and can kinetically stabilize the formulation via quench cooling.
Cryogenic Milling
For Material Quantities Between 100 mg and 50 g (some losses)
When larger material quantities are required to obtain a larger sample geometry or to provide specimens for stability or tableting studies, cryogenic milling can be employed to reduce particle size and ensure thorough mixing.
To prepare your material for VCM using a cryogenic ball mill, add your API and carrier to the milling jar after placing the impactor to prevent material discharge due to induced airflow. Seal the vial and place it in the cryo-mill filled with liquid nitrogen. Then, set the desired milling program and let the cryomill operate. During milling, the vial remains stationary while only the impactor is moved using an electromagnet to break up particle size. After the milling process is complete, the VCM cooling unit can quickly warm the milling vial in minutes without any additional equipment. Subsequent processing in a VCM cycle transforms the remaining concentration differences into a consistent melt, while kinetic stabilization is achieved through quench cooling.
Cryogenic ball milling is an excellent option to reduce particle size and homogenize your powder mixture, leading to extrusion-like VCM results without the risk of shear degradation.
Hot Melt Extrusion
For Material Quantities Above 10 g (significant losses, higher yield for >50g)
In contrast to the methods above, hot melt extrusion operates as a continuous process aimed at large-scale material production. When employed for smaller-scale processing, the yield diminishes gradually, with dead volumes becoming inevitable due to process principles. Additionally, process development demands time and results in losses.
When material expenses are high, conducting viscosity measurements on VCM samples generated through the aforementioned small-scale methods conserves time and material. If the project demands greater material quantities, extrusion emerges as the preferred option. Even with small-scale equipment, throughputs ranging from 50 g to 500 g per hour are achievable, and scaling over time enables the production of larger quantities (kilograms per day).
Green Fact: Hot melt extrusion stands as the primary manufacturing process for amorphous solids dispersion in green processing. Its footprint is notably smaller than that of spray drying. For a more detailed understanding of the process, check out our dedicated page outlining the principles of hot melt extrusion.