Traditional Chinese Medicines (TCM) are a style of traditional medicine built on a foundation of more than 2500 years of Chinese medical practice. Current techniques used to generate formulations of complex TCM mixtures (Fufang) are time consuming, complicated and often result in a low quality product. There are numerous steps involved, frequently including a combination of plant extraction, concentration of the extract by solvent evaporation, drying and milling to generate powders. These powders are then formulated in to modern medicine dosage forms including tablets, capsules and granules (to be added to water for drinking).
There is considerable interest within the Chinese Pharmaceutical industry in bringing the benefits of TCM to the western world but there are key challenges with current methodologies, which pose problems in passing TCM through pharmaceutical regulatory agencies worldwide. The main issues include a limited ability to control the quality and uniformity of the product, resulting in significant inconsistency between batches. In addition, the activity of the active constituents within the Fufang can be greatly diminished, or even lost, in the complicated and expensive high temperature processing steps.
Crystec’s mSAS® supercritical fluid (SCF) technology is a powerful tool which can facilitate transition to a more uniform, regulatory acceptable product. The main advantages are the relatively mild processing conditions applied (low temperatures), high levels of uniformity between and within batches, potential to improve absorption and dissolution and the ability to open up new routes of administration (e.g. inhaled). In addition, SCF TCM tends to have improved chemical and physical stability given removal of impurities from the starting material and lower levels of residual solvent in the final product.
Crystec mSAS® Case Study
The target product profile for material in this case study was production of a dry powder from a herbal mixture of two TCM plant extracts. The starting material was a viscous wet slurry, containing high levels of residual solvent, moisture and numerous impurities. The project aimed to produce a ‘consumer friendly’ dry powder with high levels of uniformity (both in content and appearance), which could be easily formulated into a tablet or capsule. Overall the following properties were targeted in the initial feasibility assessment:
- Good compressibility and flowability
- Low residual solvent levels adhering to strict ICH guidelines
- Retained active ingredient concentration
- Reduction of impurities
- Good chemical and physical stability
- High yields (of the desired active components)
- Indication of ability to reduce particle size and increase surface area
Product Development
- An initial feasibility study to check compatibility of the Fufang with Crystec’s mSAS® technology. This involved studying a range of solvents and solvent mixtures to selectively remove impurities whilst retaining the active ingredients of interest.
- Testing the solubility of the active ingredients in the solvent/supercritical carbon dioxide mixture to determine if high yields of powder could be recovered.
- Development of a research program to study the effects of thermodynamic and kinetic variables on the product API within a mSAS® environment.
- Design of experiment approach to study the effects of thermodynamic and kinetic variables on the product driving understanding of critical control parameters to finely tune supersaturation / precipitation, particle growth and particle properties.
- Analysis of the product to determine particle habit, size, morphology, and residual solvent levels.
Product Analysis and Performance
Sympatec laser particle size analysis (PSA) data showing particle size control (targeted particle size with tight size distribution).
