How about mixing?
VCM is a small-scale batch process that mimics ASD manufacturing. In contrast to manufacturing techniques, it does not use convective shear mixing. Thus, diffusive mixing must be maximized. At small-length scales, diffusive mixing is unbeaten. Different premixing steps before going into the VCM Tool can be deployed to obtain homogeneous mixtures at small length scales.
For scales between below 100 mg (close to lossless)
In the New Chemical Entities (NCE) domain, we usually deal with materials that are in the same value ballpark as diamonds used for jewelry. Losing a diamond hurts, but wasting NCEs even more, as they are typically custom-synthesized molecules with long lead times. From that angle, diamonds appear almost as a commodity as they are readily available.
Small quantities of material, as little as 1 mg, are obtainable with thin film solvent casting. The solvent route can generate an ASD when the residuals try up. Recrystallization might occur quickly or even during the drying. The final VCM cycle removes solvent residuals and usually yields higher formulation stability as the thermal processing equals out concentration differences and can kinetically stabilize the formulation by quench cooling.
For intermediate scale 100 mg to 50 grams (some losses)
When larger quantities are necessary to obtain a larger sample geometry or provide some material for stability or tableting studies, cryogenic material can reduce the material size and ensure proper mixing. The final VCM processing turns the remaining concentration differences into a uniform melt inside, and kinetically stabilization can be obtained by quench cooling.
The mill in the video below can go up to 5 grams of material per batch. Larger mills with larger vials can go up to 50 grams per batch. The larger mills can also take up adapters to use multiple smaller milling vials in one milling process, which can be handy when working on multiple formulations at once.
For quantities larger than 10 grams (significant losses for small scale, higher yield when >50g)
In contrast to the methods above, hot melt extrusion is a continuous process designed to produce materials at scale. However, when used for small-scale processing, the yield is lower and lower, and less material is produced as dead volumes are inevitable by the process principles. Also, the process development requires some time and causes losses.
At high material costs, doing viscosity measurement on VCM samples produced via the small-scale methods from above saves time and material for the extrusion work. Suppose higher material requirements are necessary for the project. In that case, extrusion is the preferred choice as even small-scale equipment can produce at throughputs of 50 to 500g per hour, and scaling via time allows the manufacturing of larger quantities (kilograms per day).
With batch sizes up to 5 grams and losses of less than 10 mg, cryogenic ball milling is an excellent process for micronization and powder homogenization before the VCM process. Nevertheless, for small quantities, a lossless homogenization is preferred. Thin film casting is a powerful method of mixing API and polymer with a minimum amount of solvent. The thin layer dries within minutes after dispersing the solution on a glass plate. The film is removed with a razor blade and can be shaped with the VCM process.
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.
Powder mixing processes can be categorized into two main systems: batch mixing and continuous mixing.
In batch mixing, the ingredients are loaded into the mixer, processed until the powder achieves homogeneity, and discharged as a single batch.
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.
Shear mixing, frequently utilized in twin-screw extrusion, consists of blending materials through forces that induce particle movement between layers. Unlike shear mixing in twin-screw extrusion, VCM leverages diffusion for mixing. The smaller the particles, the more dominant the transfer via diffusion gets compared to shear. Cryogenic ball milling is an excellent option to reduce particle size and homogenize the powder mixture. This will give extrusion-like VCM results without the risk of shear degradation. See how cryogenic milling helps you improve the homogeneity of your starting material to obtain perfect samples for your analysis.
Hot Melt Extrusion
The processing equipment is available in different sizes by various vendors. The major vendor for manufacturing equipment is Leistritz.
This is the major manufacturing process for amorphous solids dispersion when it comes to green processing. The footprint of hot melt extrusion is significantly smaller compared to spray drying. The process is described in our dedicated page for the principles of hot melt extrusion.