Chapter 8
Green Process Concepts for the Pharmaceutical Industry 1
2,3
2
Downloaded by NORTH CAROLINA STATE UNIV on September 7, 2012 | http://pubs.acs.org Publication Date: November 9, 2000 | doi: 10.1021/bk-2001-0766.ch008
Bala Subramaniam , Said Saim , Roger Rajewski , and Valentino J. Stella 1
Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS 66045-2223 Center for Drug Delivery Research, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66047-2535 2
Process concepts for producing drug particles using supercritical carbon dioxide (scCO ) as an antisolvent and for substrate coating employing scCO as the fluidizing medium and antisolvent are described. Particle micronization with scCO allows for reproducible crystal formation with the potential for increased surface area and dissolution rates. Coating with scCO allows the use of traditional organic— soluble coatings with complete solvent recovery and virtually no atmospheric emissions. For formation of drug nanoparticles, an ultrasonic nozzle that employs scCO as the energizing medium is used to form droplets of the drug-laden solution. The scCO also selectively extracts the solvent from the droplets, precipitating the drug. Submicron particles of hydrocortisone and ibuprofen (600 nanometers or less) formed in this manner are presented. Advantages include the production of virtually solvent-free drug particles in a narrow size range. For particle coating, scCO is used to fluidize the core substrate particles. The scCO also removes the solvent from the coating solution sprayed on the substrates, thereby precipitating the coating. This coating process expands the range of substrate/coating combinations possible with the conventional air-suspension Wurster coater, making it feasible to coat water-soluble substrates with solutes sprayed from organic solutions. 2
2
2
2
2
2
2
2
3
Current address: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368.
96
© 2001 American Chemical Society
In Green Engineering; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
2
97
Downloaded by NORTH CAROLINA STATE UNIV on September 7, 2012 | http://pubs.acs.org Publication Date: November 9, 2000 | doi: 10.1021/bk-2001-0766.ch008
Introduction Conventional pharmaceutical processing involves extensive use of organic solvents as antisolyents for recrystallizing drugsfromsolutions, as reaction media in the synthesis of drugs or as extracting agents for selectively isolating drugs from solid matrices. This may lead to environmental emissions of toxic solvents (such as methylene chloride) or trace solvent residues in the product. Concerns about solvents have propelled research efforts aimed at developing environmentally-benign chemical processing techniques that either eliminate or significantly mitigate pollution at the source (/). A major research focus in pharmaceutical processing has been the replacement of traditional solvents with scC0 . In this paper, we discuss two applications developed in our laboratory: the formation of nanoparticles of sparingly soluble drugs, and the coating of drugs. Research and scaleup challenges facing successful implementation of these promising technologies in practice are also discussed. 2
Nanoparticles in Pharmaceutical Applications For drugs that show poor intrinsic water-solubility, decreasing the particle size enhances the dissolution rate in the human system, and therefore, the drug bioavailability. Creating nanoparticles of such drugs is therefore desirable. In addition, it has been reported that nanoparticles smaller than 500 nanometers (nm) can cross Peyer's patches and the mesentery on the surface of gastrointestinal mucosa to directly deliver a drug to the systemic circulation (2, 3). For parenteral application, drugs that are 500 nm or less are also suitable for intravenous injection in a suspension form, further enhancing their drug-delivery potential. The development of environmentally-benign methods for production of solvent-free nanoparticles of poorly water-soluble pure drugs is thus highly desirable. For instance, Cyclosporin A (CyA) is a highly lipophilic cyclic peptide that is poorly soluble in water. It is the immunosuppressant of choice for the prevention of allograft rejection of transplanted bone marrow, kidney, heart, liver, lung, pancreas, and skin and appears to be efficacious in the treatment of autoimmune diseases, such as diabetes mellitus and rheumatoid arthritis (4, 5). At present, dosage forms of CyA (intravenous and oral solution) are not very effective therapeutically due to slow and highly variable absorption. The low aqueous solubility of CyA has prevented the development of alternative dosage forms. Other dosage forms such as liposomes and lipophilic carriers have limited in vitro and in vivo stability. Other poorly-soluble drugs whose bioavailability depends on particle size include camptothecin (a potential anti-cancer agent), piposulfam, steroid A, and indomethacin.
Particle Formation Using scC0
2
Conventional techniques for particle size reduction include mechanical comminution (crushing, grinding and milling), recrystallization of the solute
In Green Engineering; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
98 particles from solution using liquid antisolvents, freeze drying and spray drying. Among the limitations associated with these processes are excessive solvent use and disposal, thermal and chemical degradation of products, trace residues, and interbatch particle size variability. Two C0 -based particle formation processes have received increased attention in recent years. In the first process, termed rapid expansion of supercritical solutions (RESS) (tf), the solute is solubilized in scC0 . The solution is then expanded across a nozzle or capillary at supersonic velocities. The rapid expansion leads to supersaturation of the solute and precipitation of virtually contaminant-free particles. The RESS process has been shown to produce contaminant-free drug particles rangingfroma few microns to several hundred microns (7). A major limitation of the RESS process is that at moderate temperatures and pressures (
