In the past fifteen years, research and process development activity has focused on utilizing supercritical carbon dioxide technology in processing fine chemicals, pharmaceutical intermediates and nutraceuticals to obtain ultra-purity products. In this context, supercritical fluids (SCFs) have been widely employed in different processes. This is due to the solvent power, high diffusivity and low viscosity, apt for these applications. Supercritical fluid technology allows pharmaceutical and nutraceutical companies to develop products of standardized concentration of active ingredients, and simultaneously produces nutraceutical and pharmaceutical products of much higher concentration (higher yields and purity) and quality (with less creation of artifacts), than possible by conventional chemical engineering unit operations. Research has led to several important applications of supercritical fluids including pharmaceutical productions, biological waste disposal and semiconductor. The unique properties of supercritical fluids are due to the existence of a single phase beyond the critical point.
Usually, carbon dioxide (CO2) is used as a main solvent as it has a low critical temperature (31.1oC) and a moderate critical pressure (73 bar). Due to these fairly mild critical point conditions, the use of carbon dioxide can be beneficial for many applications. Additionally, carbon dioxide is inexpensive, leaves no toxic residue, and is non-flammable. In addition to being a solvent for extraction and fractionation (purification) of organic compounds, carbon dioxide is increasingly being utilized as a medium for reactions, as a micronizing agent in Rapid Expansion in a Supercritical Solution process (RESS), as an anti-solvent for crystallization in Gas Anti-Solvent process (GAS), and as a carrier solvent for coating and depositing materials onto or into a solid matrix. Carbon dioxide technology is one of the fastest growing new process technologies being adopted by the food, pharmaceutical and nutraceutical industries.
Particle engineering and drug formulation
Particle size is a key factor for the performance in the use of different organic and inorganic materials. Particle design process using supercritical fluids are now the subject of increasing interest, especially in the pharmaceutical industry, to increase bioavailability of poorly soluble drugs, to design formulations for sustained release and to develop less invasive alternatives to parenteral drug delivery (oral, pulmonary and transdermal). The most complex challenge relates to the therapeutic proteins, as it is extremely difficult to deliver bio-molecules due to their instability, and short half life in vivo.
RESS
If a material is highly soluble in liquid or supercritical carbon dioxide, then a process known as Rapid Expansion from Supercritical Solution should be considered. A supercritical solution that contains a dissolved solute is rapidly (~10-6 sec) expanded across a micro-orifice (nozzle). With the dramatic decrease in solvent density, fine particles are formed under highly supersaturated conditions and then quickly quenched. RESS is an attractive technology for the production of small, uniform and solvent-free particles of low vapour pressure solutes. The RESS containing a nonvolatile solute leads to the loss of solvent power by the fast expansion of the supercritical solution through an adequate nozzle, which can cause solute precipitation. The nozzle configuration plays an important role in RESS method and has a great effect on the size and morphology of the precipitated particles. A co-solvent may be used to improve the solubility of the solute in the solvent. The main features of the rapid expansion apparatus consists of (i) a high pressure pump, (ii) a variable-volume view cell, and (iii) an expansion section.
The RESS can be schematically presented as in figure 1
Fig.1.Experimental set-up for the RESS process
Researchers have modified RESS to decrease the particle size further. One of such modification called rapid expansion of supercritical solutions into liquid solvents (RESOLV), has been developed to reduce the coagulation rate in the free jet expansion of RESS. The supercritical solution is expanded through an orifice or tapered nozzle into an aqueous solution containing a stabilizer to minimize particle aggregation during free jet expansion. Young et al have demonstrated the ability for Tween 80, a nonionic polysorbitan ester, to stabilize 400 to 700 nm cyclosporine particles produced by RESOLV.
Often low solubility of pharmaceutical compounds such as Griseofulvin in supercritical CO2 results in a low processing rate. Small amounts of liquid co-solvents viz. methanol, acetone or tetrahydrofuran are suitable for RESS due to the dissolution of particles in the expansion chamber. Another promising method to overcome the limitation of low solubility is the use of a solid co-solvent to enhance the low solubility in supercritical CO2. In the nineties, Domingo and others used salicylic acid or phenanthrene as the solute and benzoic acid as the co-solute in CO2 for the RESS process. Recently, a modification of the RESS with solid co-solvent (RESS-SC) process has been proposed by Thakur and Gupta. They applied this process for Griseofulvin, Phenytoin, and 2-Aminobenzoic acid by using menthol as the solid co-solvent. In the RESS-SC process, a solid co-solvent is used to enhance the drug solubility in CO2 and avoiding surface-to-surface interaction to other drug particles and therewith hindering particle growth. Later, the solid co-solvent can easily removed from the solute particles by sublimation. As a typical example of the obtained results, the average particle size of Phenytoin produced by RESS-SC is around 120 nm, which is significantly smaller than 200 nm particles obtained from RESS. In addition, the solubility was enhanced approximately 28-fold compared to that of the conventional RESS process without co-solvent. In addition, due to the improved solubility, the Phenytoin production rate in RESS-SC is about 400-fold higher than in the RESS process. The solid co-solvent, menthol, was easily removed from the drug nanoparticles by sublimation and lyophilization, which also allowed the dry powdered nanoparticles to be recovered, all in one step.
Another limitation of RESS is the aggregation of particles. This can be tackled by the modification of the RESS process wherein the solute and the polymer are dissolved in SC-CO2, followed by the rapid expansion of the ternary mixture. Thereby, the sudden depressurization leads to simultaneous co-precipitation of the solutes and formation of composite particles.
The earlier studies performed by Debenedetti and co-workers, investigated a model substance, Pyrene, with l-poly(lacticacid) (l-PLA) and Lovastatin with dl-poly(lacticacid) (dl-PLA). In these investigations, the two solutes were dissolved separately and the supercritical solutions were mixed directly before the precipitation unit. These experiments lead to totally different morphology of the precipitated particles: a uniform distribution of Pyrene within l-PLA and crystalline needles of Lovastatin embedded in dl-PLA microspheres. Kim et al. packed both solutes, Naproxen and l-PLA, into one extraction column and the precipitated composite particles appear as a Naproxen core encapsulated in a polymer coating. Recently Signorell et.al has studied the Influence of polydispersity of poly(lactic acid) on particle formation by RESS, their investigation reveals that the polydispersity of the polymers strongly affects the size but not the shape of the particles. They found larger particles (730 nm) for the PLA with high polydispersity than for the PLA with low polydispersity (270 nm). In both cases, spherical particles were formed. Moreover, results clearly show that PLA with high polydispersity is less suitable for RESS processing because the low-molecular weight chains are depleted over time and process conditions are thus not constant.
Table1. Examples of drugs processed using RESS
Our research group at ICT is working on utilizing this green technology for myriad of applications. Studies have been carried out with various biopolymers and lipids using THARSFC instrument and we are successful in obtaining nano scale particles with good stability. Thar process has built in particle formation systems that meet stringent US and EU standards as well as GMP requirements. SEPAREX Pharmaceutical Technology is another manufacturer for supercritical fluid instruments who owns its entire development tool, including various supercritical units from laboratory to pilot/industrial scale designed for a wide range of processes pertaining to SCF Technology Platform.
Pierre Fabre Medicament is a French company offering many patented technologies and Critical Pharmaceuticals Ltd, a UK based drug delivery technology company is ready to partner for exploitation of technologies using SCFs, indicating strong potential of this technique.
In all, RESS is a very attractive and simple process for the production of submicron and uniform particles with improved dissolution behaviour. These advantages of RESS coupled with its utilization for thermolabile drugs giving solvent-free product have promoted the particle and product design by RESS.
(Authors are with Dept of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400019)