Supercritical Fluids for Particle Engineering
Although discovered over 120 years ago, the potential of supercritical fluid (SCF) technologies have only been partially realised for the controlled formation of particulates over the last decade. Whilst the SCF technologies have been established at large scale operations for other industrial applications, including controlled reactions for fine and speciality chemicals and extraction processes, securing confidence and experience with pilot and large scale processing, the great potential of SCF methods for meeting ever increasing demands of particulate properties for medicinal and health care products remains relatively untapped. Essentially the formation of particles by SCF processing involves using a supercritical fluid either as a solvent or an antisolvent under supercritical fluid conditions of temperature and pressure. In most cases for pharmaceuticals, supercritical (SC) carbon dioxide is used, and as most therapeutic agents have very low solubility in this fluid, the antisolvent option is preferred, with this SCF having unique properties of liquid-like solvent power combined with gas-like transport properties. However, there is currently an inhalable monohydrate molecule in late stage clinical trials, which two members of the Crystec team had a lead role in developing.
Supercritical Carbon Dioxide
A fluid is defined as supercritical when its temperature and pressure exceed critical values (Tc and Pc respectively). In the supercritical domain, the SCF increases in density as the pressure is raised whilst other physical properties, including diffusivity, change but remain gas-like.
For the pharmaceutical and health care industries SC carbon dioxide is particularly attractive, since temperature and pressure values at its critical point are relatively mild and readily attained (Tc = 31.5C; Pc = 75.8 bar) and has GRAS (Generally Regarded as Safe) status at regulatory agencies. Additionally, SC carbon dioxide is readily available in pure form, inexpensive, non-flammable and, unlike many organic solvents used in large quantities for preparing drug particles, is environmentally acceptable, can be recycled during processing, and can be readily disposed. Other attractive features of SC carbon dioxide include its non-toxicity, does not cause oxidation and its solvation properties can be customised by the addition of co-solvents.
Antisolvent SCF based particle formation
The basic process involves preparing a solution of the therapeutic agent of interest in a suitable solvent, such as ethanol or acetone, and introducing this solution to an SCF environment, typically SC carbon dioxide, in a pressure vessel (see Figure 2).
With the aid of atomisation of both fluids using a proprietary nozzle arrangement, rapid extraction of the solvent into the SCF occurs creating a high level of supersaturation of the material of interest in the diminishing level of solvent causing rapid precipitation of solid particles. As most common solvents are completely miscible with SC carbon dioxide, any remaining solvent is quickly extracted into the SCF stream, to produce fine, dry particulate products The product is retained in the pressure vessel and the SC solution (now SC carbon dioxide and solvent) passes out of the vessel. Solvent recovery can be implemented (by returning the SC carbon dioxide to a gaseous state) and the now virtually solvent free carbon dioxide gas can be recycled.
It has been recognised that a particular attractive feature of the ‘one step’, totally enclosed particle formation process, delivering dry particles, is the generation of well controlled particulate products with well defined physical, chemical, structural and surface characteristics.
In many cases, directed changes in these characteristics can be achieved by modifying the processing conditions and environment, such as temperature or pressure and fluid flow. In many cases, micron sized particles with well defined crystalline morphology are produced, with minimal residual solvents. Opportunities also exist for co-introduction of regulatory approved formulation excipients or other small molecules e.g. antioxidants to yield composite particulates with uniform drug content.
An additional attractive feature for pharmaceuticals is the impressive inter- and intra-batch consistency of product which can be achieved when processing with SCFs. Because of thermodynamic control using GAS antisolvent processes consistency of product can be readily obtained.
Scaled equipment and GMP processing
The operation of scaled-up equipment, operating under GMP conditions for SCF processes, has been demonstrated. Furthermore, staff at Crystec have experience with international tech-transfer, with a plant used for production of material for clinical studies.
With this versatile platform technology, a range of applications for pharmaceutical and biopharmaceutical materials have been reported. Some of the challenging areas of crystal engineering and particle design for therapeutic agents which have been addressed by SCF processing are listed below:
- Particle morphology control
- Stabilisation of therapeutic agents derived from biotechnology
- Polymorph screening
- Improved performance of poorly soluble drugs
- Inhaled therapy
- Taste masking
- Crystallisation seeds
- Low residual solvent in SCF processed drug particles