We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Critical gases for critical issues: CO2 technologies for oral drug delivery

    Hana Danan

    SiTec PharmaBio, Baldiri Reixac 10, 08028 Barcelona, Spain

    Sitec Consulting, BioIndustry Park, Via Ribes 5, 10010 Colleretto Giacosa (TO), Italy

    &
    Pierandrea Esposito

    * Author for correspondence

    SiTec PharmaBio, Baldiri Reixac 10, 08028 Barcelona, Spain. .

    Published Online:https://doi.org/10.4155/tde.13.146

    In recent years, CO2-based technologies have gained considerable interest in the pharmaceutical industry for their potential applications in drug formulation and drug delivery. The exploitation of peculiar properties of gases under supercritical conditions has been studied in the last 20 years with mixed results. Promising drug-delivery technologies, based on supercritical CO2, have mostly failed when facing challenges of industrial scaleability and economical viability. Nevertheless, a ‘second generation‘ of processes, based on CO2 around and below critical point has been developed, possibly offering technology-based solutions to some of the current issues of pharmaceutical development. In this review, we highlight the most recent advancements in this field, with a particular focus on the potential of CO2-based technologies in addressing critical issues in oral delivery, and briefly discuss the future perspectives of dense CO2-assisted processes as enabling technologies in drug delivery.

    Papers of special note have been highlighted as: ▪ of interest

    References

    • European Environmental Agency. Pharmaceuticals in the environment. Results of an EEA workshop. Technical report No 1 /2010. European Environmental Agency. Copenhagen, Denmark, 1725–2237 (2010).
    • European Medicines Agency. Road map to 2015. The European Medicines Agency‘s contribution to science, medicines and health. European Medicine Agency. Adopted by the Agency‘s Management Board on December 2010. European Medicines Agency. London, UK (2011).
    • Department of Health and Human Services, US Food and Drug Administration. Innovation, Stagnation, Challenge and Opportunity on the Critical Path to New Medical Products. Silver Spring, MD, USA (2004).
    • Department of Health and Human Services, US Food and Drug Administration. Pharmaceutical Development Q8 (R2). ICH Harmonized Tripartite Guidelines. Current Step 4 Version. ICH Expert Working Group. Geneva, Switzerland (2009).
    • Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm. Res.25(4),781–791 (2008).
    • Bossart J, Sedo K, Kararli TT. Delivery report drug delivery products & technologies, a decade in review: approved products 2000 to 2009. Drug Deliv. Technol.10(4),28–31(2010).
    • BCC Research. Advanced Drug Delivery Systems: Technologies and Global Markets. BCC Research Pharmaceutical Report, Market Forecasting. Wellesley, MA, USA (2011).
    • Stegemann S, Klebovich I, Antal I et al. Improved therapeutic entities derived from known generics as an unexplored source of innovative drug products. Eur. J. Pharm. Sci.44,447–454 (2011).▪ Highlights the importance and impact of innovative formulation and process technologies in future development of known drug products.
    • Eickenbaum G. Chair‘s Opening Address. Presented at: Pharma IQ conference on Improving Solubility 09. Thistle Marble Arch, London, UK, 29 June–1 July 2009.
    • 10  Stegemann S. Design Drug Delivery for individual patient populations. Presented at: The 5th Annual Drug Delivery Systems conference. London, UK, 10–11 February 2010.
    • 11  Stegemann S, Ecker F, Maio M et al. Geriatric drug therapy: neglecting the inevitable majority. Aging Res. Rev.9,384–398 (2010).
    • 12  Girotra P, Singh SK, Nagpal K. Supercritical fluid technology: a promising approach in pharmaceutical research. Pharm. Dev. Technol.18(1),22–38 (2013).
    • 13  Zarena AS, Sankar KU. Design of submicron and nanoparticle delivery using supercritical carbon dioxide-mediated processes: an overview. Ther. Deliv.2(2),259–277 (2011).
    • 14  Bettini R. Microparticles by supercritical fluids technologies: myth, challenge or reality? Presented at: The 18th International Symposium on Microencapsulation. Antalya, Turkey, 12–14 September 2011.
    • 15  Pasquali I, Bettini R. Are pharmaceutics really going supercritical? Int. J. Pharm.364,176–187 (2008).▪ Critical review on actual applicability and perspectives of supercritical fluid (SCF) technologies in the pharmaceutical industry.
    • 16  Jessop PG, Subramanian B. Gas-expanded liquids. Chem. Rev.107,2666–2694 (2007).▪ Complete review on the basic principles and application of dense gases. Discusses the consequences of CO2 expansion and properties changes.
    • 17  Foster N, Mammucari R, Dehgani F, Barrett A, Bezanehtak K, Coen E. Processing pharmaceutical compounds using dense gas technology. Ind. Eng. Res.42,6476–6493 (2003).▪ Introductory concepts on dense gases, supercritical and subcritical.
    • 18  Dobbs JM, Wong JM, Johnston KP. Nonpolar co-solvent for solubility enhancement in supercritical fluid carbon dioxide. J. Chem. Eng. Data31,303–308 (1986).
    • 19  Beckman EJ. Supercritical and near critical CO2 in green chemical synthesis and processing. J. Supercrit. Fluids28,121–191 (2004).
    • 20  Tabernero A, Martín del Valle EM, Galán MA. Supercritical fluids for pharmaceutical particle engineering: methods, basic fundamentals and modelling. Chem. Eng. Process.60,9–25 (2012).▪ Compendium of SCF processes for pharmaceutical particles, with relevant information on process modelling.
    • 21  Carr AG, Mammucari R, Foster NR. A review of subcritical water as a solvent and its utilization for the processing of hydrophobic organic compounds. Chem. Eng. J.172,1–17 (2011).
    • 22  Carr AG, Mammucari R, Foster NR. Particle formation of budesonide from alcohol-modified subcritical water solutions. Int. J. Pharm.405,169–180 (2011).
    • 23  Hao J, Whitaker MJ, Wong B, Serhatkulu G, Shakesheff KM, Howdle SM. Plasticization and spraying of poly(dl-lactic acid) using supercritical carbon dioxide: control of particle size. J. Pharm. Sci.93(4),1083–1090 (2004).
    • 24  Jimenénez A, Thompson GL, Mathews MA et al. Compatibility of medical-grade polymers with dense CO2. J. Supercrit. Fluids42,366–372 (2007).
    • 25  Tian J, Thallapally PK, Dalgarno SJ, Atwood JL. Free transport of water and CO2 in nonporous hydrophobic clarithromycin form II Crystals. J. Am. Chem. Soc.131,13216–13217 (2009).
    • 26  Kikic I, Vecchione F. Supercritical impregnation of polymers. Curr. Opin. Solid State Mater. Sci.7,399–405 (2003).
    • 27  Üzer S, Akman U, Hortaçsu Ö. Polymer swelling and impregnation using supercritical CO2: A model-component study towards producing controlled-released drugs. J. Supercrit. Fluids38,119–128 (2006).
    • 28  Natu MV, Gil MH, de Sousa HC. Supercritical solvent impregnation of poly(ε-caprolactone)/poly(oxyethylene-b-oxypropylene-b-oxyethylene) and poly(ε-caprolactone)/poly(ethylene-vinyl acetate) blends for controlled release applications. J. Supercrit. Fluids47(2008) 47,93–102 (2008).
    • 29  Banchero M, Manna L, Ronchetti S, Campanelli P, Ferri A. Supercritical solvent impregnation of piroxicam on PVP at various polymer molecular weight. J. Supercrit. Fluids49,271–278 (2009).
    • 30  Yasuji T, Takeuchi H, Kawashima Y. Particle design of poorly water-soluble drug substances using supercritical fluid technologies. Adv. Drug Deliv. Rev.60,388–398 (2008).▪ Compendium about SCF properties relevant for poorly water soluble molecules, and application in particle formation.
    • 31  Türk M, Crone M, Kraska T. A comparison between models based on equations of state and density-based models for describing the solubility of solutes in CO2. J. Supercrit. Fluids55,462–471 (2010).
    • 32  Riviera CA, Khalloufi S, Jansen J, Bongers P. Mathematical Description of Mass Transfer in Supercritical-Carbon-Dioxide-Drying Process. Proceedings of the 21st European Symposium on Computer Aided Process Engineering-ESCAPE 2. Pistikopoulos EN, Georgiadis MC, Kokossis AC (Eds). Elsevier, Amsterdam, The Netherlands, 36–40 (2011).
    • 33  Bouchard A, Jocanovic N, Hofland GW, Mendes E, Crommelin DJA, Witkamp GJ. Supercritical fluid drying carbohydrates: SELECTION of suitable excipients and process conditions. Eur. J. Pharm. Biopharm.68(3),781–794 (2008).
    • 34  Cansell F, Aymonier C, Serani AL. Review on material science and supercritical fluids. Curr. Opin. Solid State Mater. Sci.7(4–5),331–340 (2003).
    • 35  Rodier E, Lochard H, Sauceau M, Letoumeau JJ, Freiss B, Fages J. A three step supercritical process to improve the dissolution rate of Eflucimibe. Eur. J. Pharm. Sci.26(2),184–193 (2005).
    • 36  Lee MY, Ganapathy HS, Lim KT. Controlled drug release applications of the inclusion complex of percetylated-β-cyclodextrin and water-soluble drugs formed in supercritical carbon dioxide. J. Phys. Chem. Solids71,630–633 (2010).
    • 37  Sultana T, Jung JM, Hong SS et al. Characteristic profiles of the inclusion complex of omeprazole/peracylated-β-cyclodextrin formed in supercritical carbon dioxide. J. Incl. Phenom. Macrocycl. Chem.72,207–212 (2012).
    • 38  Ugaonkar S, Nunes AC, Needham TE. Effect of n-sc-CO2 on crystalline to amorphous conversion of carbamazepine. Int. J. Pharm.333,152–161 (2007).
    • 39  Tian J, Dalgarno SJ, Atwood JL. A new strategy of transforming pharmaceutical crystal forms. J. Am. Soc.133,1399–1404 (2011).▪ Description of CO2-induced transformations of crystal structures controlled by different pressure and temperature conditions.
    • 40  Shan N, Zaworothko MJ. The role of cocrystals in pharmaceutical science. Drug Discov. Today13(9/10),440–446 (2008).
    • 41  Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth Des.9(6),2950–2967 (2009).
    • 42  US Department of Health and Human Services, FDA, CDER. Guidance for Industry, Regulatory Classification of Pharmaceutical Co-Crystals. US Department of Health and Human Services, FDA, CDER. Silverspring, MD, USA (2011).
    • 43  Padrela L, Rodrigues MA, Velga SP, Matos HA, de Azevedo EG. Formation of indomethacin-saccharin cocrystals using supercritical fluid technology. Eur. J. Pharm. Sci.38(1),9–17 (2009).
    • 44  Padrela L, Rodrigues MA, Velga SP, Fernandes AC, Matos HA, de Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J. Supercrit. Fluids53(1–3),156–164 (2010).
    • 45  Sekhon BS. Supercritical fluid technology: an overview of pharmaceutical applications. Int. J. Pharm Tech Res.2(1),810–826 (2010).▪ Complete review on SCF technology in pharmaceutics.
    • 46  Martin del Valle EM, Galan MA. Supercritical fluid technique for particle engineering: drug delivery applications. Rev. Chem. Eng.21(1),33–69 (2005).▪ Overview of technologies including considerations on scale-up and industrial costs of SCF technique processes.
    • 47  Quirk RA, France RM, Shakesheff KM, Howdle SM. Supercritical fluid technologies and tissue engineering scaffolds. Curr. Opin. Solid State Mater. Sci.8(3–4),313–321 (2004).
    • 48  Cardea S, Pisanti P, Reverchon E. Generation of chitosan nanoporous structures for tissue engineering applications using a supercritical fluid assisted process. J. Supercrit. Fluids45(3),290–295 (2010).
    • 49  Martín Á, Weidner E. PGSS-drying: mechanism and modelling. J. Supercrit. Fluids55,271–281 (2010).▪ Provides good understanding of the basics of PGSS drying mechanism, and its implications for particles formation.
    • 50  Meterc D, Petermann M, Weinder E. Drying of aqueous green tea extracts using a supercritical fluid process. J. Supercrit. Fluids45,253–259 (2008).
    • 51  Martín Á, Pham HM, Kilzer A, Kareth S, Weinder E. Micronization of polyethylene glycol by PGSS (Particles from Gas Saturated Solutions)-drying of aqueous solutions. Chem. Eng. Process.49,1259–1266 (2010).
    • 52  Vezzù K, Borin D, Bertucco A, Bersani S, Salmaso S, Caliceti P. Produciton of lipid microparticles containing bioactive molecules functionalized with PEG. J. Supercrit. Fluids54,328–334 (2010).
    • 53  Salmaso S, Elvassore N, Bertucco A, Caliceti P. Production of solid lipid submicron particles for protein delivery using a novel supercritical gas-assisted melting atomization. J. Pharm. Sci.98(2),640–650 (2009).
    • 54  Reverchon E, Adami R, Caputo G, de Marco I. Spherical microparticles production by supercritical antisolvent precipitation: interpretation of results. J. Supercrit. Fluids47,70–84 (2008).▪ Compendium of microparticle systems produced by supercritical antisolvent, rationalization of results and data interpretation.
    • 55  Tropainen T, Velga S, Heikkilä T, Matilainen L, Jarho P, Carlfors J. Preparation of budesonide/γ-cyclodextrin complexes in supercritical fluids with a novel SEDS method. J. Pharm. Sci.95(10),2235–2245 (2006).
    • 56  Thote AJ, Gupta RB. Formation of nanoparticles of hydrophilic drug using supercritical CO2 and microencapsulation for sustained release. NSTI-Nanotech.1,116–119 (2005).
    • 57  Ventosa N, Veciana J, Sala S, Myntó M, Cano M, Gimeno M. New technologies for the preparation of micro-and nanostructured materials with potential applications in drug delivery and clinical diagnostics. Contrib. Sci.3(1),11–18 (2005).
    • 58  Sievers RE, Huang ETS, Villa JA, Engling G, Brauer PR. Micronizaiton of water-soluble or alcohol-soluble pharmaceuticals and model compounds with a low temperature Bubble Dryer®. J. Supercrit. Fluids26(1),9–16 (2003).
    • 59  Cape SP, Villa JA, Huang ETS, Yang TH, Carpenter JF, Sievers RE. Preparation of active proteins, vaccines and pharmaceuticals as fine powders using supercritical or near-critical fluids. Pharm. Res.25(9),1967–1990 (2008).
    • 60  Reverchon E, Antonacci A. Polymer microparticles production by supercritical assisted atomization. J. Supercrit. Fluids39,444–452 (2007).
    • 61  Pathak P, Prasad GL, Meziani MJ, Joudeh AA, Sun YP. Nanosized paclitaxel particles from supercritical carbon dioxide processing and their biological evaluation. Langmuir23(5),2674–2679 (2007).
    • 62  Sane A, Limtrakul J. Formation of retinyl palmitate-loaded poly (l-lactide) nanoparticles using rapid expansion of supercritical solutions into liquid solvent (RESOLV). J. Supercrit. Fluids51,230–237 (2009).
    • 63  Chattopadhyay P, Huff R, Shekunov BY. Drug encapsulation using supercritical fluid extraction of emulsions. J. Pharm. Sci.95(3),667–679 (2006).
    • 64  Kluge J, Fusaro F, Casas N, Mazzotti M, Muhrer G. Production of PLGA micro and nanocomposites by supercritical fluid extraction of emulsions: encapsulation of lyosozyme. J. Supercrit. Fluids50(3),327–335 (2009).
    • 65  Henczka M, Baldyga J, Shekunov BY. Modelling of spray-freezing with compressed carbon dioxide. Chem. Eng. Sci.61,2880–2887 (2006).
    • 66  Baldyga J, Czarnocki R, Shekunov B, Smith KB. Particle formation in supercritical fluids-Scale-up problem. Chem. Eng. Res. Des.88,331–341 (2010).▪ Discussion of particle formation mechanisms in solution-enhanced dispersion by supercrticial fluids. Modellization at macro and microscale, and nozzle actuation. Provides an understanding of scale-up issues.
    • 67  Reverchon E, Adami R, Caputo G. Supercritical assisted atomization: Performance comparison between laboratory and pilot scale. J. Supercrit. Fluids37,298–306 (2006).
    • 68  Liu YH, Maruyama H, Matsusaka S. Agglomeration process of dry ice particles produced by expanding liquid carbon dioxide. Adv. Powder Technol.21,652–657 (2010).
    • 69  Andersson P. Enhancing drug formulation of challenging compounds using supercritical fluid (SCF) technologies. Presented at: The 3rd Annual WTG Drug Delivery and Formulation. Berlin, Germany, 16–18 January 2012.
    • 70  Ku MS. Use of the Biopharmaceutical classification System in early drug development. AAPS10(1),208–212 (2008).
    • 71  Amidon G, Lennernas H, Shah V, Crison JR. A theoretical basis for a biopharmaceutics drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res.12,413–420 (1995).
    • 72  Benet L, Broccatelli F, Oprea T. BDDCS Applied to over 900 drugs. AAPS13(4),519–547 (2011).
    • 73  Benet L. The role of BCS (Biopharmaceutics Classification System ) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in drug development. J. Pharm. Sci.102(1),34–42 (2013).▪ Discuss the importance of classification system and practical application in development of new and marketed drugs for oral route.
    • 74  Dressman JB, Vertzoni M, Goumas K, Reppas C. Estimating drug solubility in the gastrointestinal tract. Adv. Drug Del. Rev.59,591–602 (2007).
    • 75  Shono Y, Jantratid E, Dressman JB. Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. Eur. J. Pharm. Biopharm.79,349–356 (2011).
    • 76  Muenster U, Pelzetter C, Backensfeld T et al. Volume to dissolve applied dose (VDAD) and apparent dissolution rate (ADR): tools to predict in vivo bioavailability from orally applied drug suspensions. Eur. J. Pharm. Biopharm.78,522–530 (2011).
    • 77  Bhattachar SN, Deschenes LA, Wesley JA. Solubility: it‘s not just for physical chemists. Drug Discov. Today11(21/22),1012–1018 (2006).
    • 78  Saal C, Petereit AC. Optimizing solubility: kinetics versus thermodynamic solubility temptations and risks. Eur. J. Pharm. Sci.47,589–595 (2012).
    • 79  Martin A, Scholle K, Mattea F, Meterc D, Cocero MJ. Production of polymorphs of ibuprofen sodium by supercritical antisolvent (SAS) precipitation. Cryst. Growth Des.9(5),2504–2511 (2009).
    • 80  Davar N, Ghosh S. Oral controlled release-based products for life cycle management. In: Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice. Wen H, Park K (Eds). John Wiley & Son, Inc, Hoboken, NY, USA, 305–320 (2010).
    • 81  Chen X, Wen H, Park K. Challenges and new technologies of oral controlled release. In: Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice. Wen H, Park K (Eds). John Wiley & Son, Inc, Hoboken, NY, USA, 257–277 (2010).
    • 82  Grassi M, Grassi G, Lapasin R, Colombo I. Drug Dissolution and Partitioning. In: Understanding Drug Release and Absorption Mechanisms, a Physical and Mathematical Approach. CRC Press, MA, USA, 249–331 (2007).
    • 83  Knez Z, Weinder E. Particles formation and particle design using supercritical fluids. Curr. Opin. Solid State Mater. Sci.7,353–361 (2003).
    • 84  Pasquali I, Bettini R, Giordano F. Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics. Eur. J. Pharm. Sci.27,399–310 (2006).▪ Review of SCF processing affecting solid state properties of formulated microparticles.
    • 85  Moribe K, Tozuka Y, Yamamoto K. Supercritical carbon dioxide processing of active pharmaceutical ingredients for polymorphic control and for complex formation. Adv. Drug Deliv. Rev.60,328–338 (2008).
    • 86  de Zordi N, Kikic I, Moneghini M, Solinas D. Piroxicam solid state studies after processing with SAS technique. J. Supercrit. Fluids55,340–347 (2010).
    • 87  Meng D, Falconer J, Krauel-Goellner K, Chen J, Farid M, Alany R. Self-built supercritical CO2 anti-solvent unit design, construction and operation using carbamazepin. AAPS Pharm. Sci. Tech.9(3),944–952 (2008).
    • 88  Mandzuka Z, Kenz Z. Influence of temperature and pressure during PGSS™ micronization and storage time on degree of crystallinity and crystal forms of monostearate and tristearate. J. Supercrit. Fluids, 45,102–111 (2008).
    • 89  Cocero MJ, Martín A, Mattea F, Varona S. Encapsulation and co-precipitation processes with supercritical fluids: fundamentals and applications. J. Supercrit. Fluids47,546–555 (2009).
    • 90  Duarte AR, Sousa Costa M, Simplício AL, Cardoso MM, Duarte C. Preparation of controlled release microspheres using supercritical fluid technology for delivery of anti-inflammatory drugs. Int. J. Pharm.308,168–174 (2006).
    • 91  Reverchon E, Lamberti G, Antonacci A. Supercritical fluid assisted production of HPMC composite microparticles. J. Supercrit. Fluids46,185–196 (2008).▪ Describes use of energy-dispersive x-ray spectroscopy microanalysis to characterize drug distribution in drug-polymer microcomposites.
    • 92  Elizondo E, Córdoba A, Santiago S, Ventosa N, Veciana J. Preparation of biodegradable poly(methyl vinyl ether-co-maleic anhydride) nanostructured microparticles by precipitation with compressed antisolvent. J. Supercrit. Fluids53,108–114 (2010).
    • 93  Belhadj-Ahmed F, Badens E, Llewellyn P, Denoyel R, Charbit G. Impregnation of vitamin E acetate on silica mesoporous phases using supercritical carbon dioxide. J. Supercrit. Fluids51(2),278–286 (2009).
    • 94  Varona S, Rodríguez-Rojo S, Martín A, Cocero MJ, Duarte CM. Supercritical impregnation of lavandin (Lavandula hybrid) essential oil in modified starch. J. Supercrit. Fluids58,313–319 (2011).
    • 95  Comin LM, Temelli F, Saldaña MD. Impregnation of flax oil pregelatinized corn starch using supercritical CO2. J. Supercrit. Fluids51,221–228 (2012).
    • 96  Manna L, Banchero M, Sola D, Ferri A, Ronchetti S, Sicardi S. Impregnation of PVP microparticles with ketoprofen in the presence of supercritical CO2. J. Supercrit. Fluids42,378–384 (2007).
    • 97  López-Periago A, Argemí A, Anderson JM et al. Impregnation of biocompatible polymer aided by supercritical CO2: evaluation of drug stability and drug-matrix interactions. J. Supercrit. Fluids48,56–63 (2009).
    • 98  Miura H, Kanebako M, Shirai H, Nakao H, Inagi T, Terada K. Influence of particle design on oral absorption of poorly water-soluble drug in a silica particle-supercritical fluid system. Chem. Pharm. Bull.59(6),686–691 (2011).
    • 99  Ahern R, Crean A, Ryan K. The influence of supercritical carbon dioxide (sc-CO2) processing conditions on drug loading and physicochemical properties. Int. J. Pharm.439,92–99 (2012).
    • 100  Alnaief M, Smirnova I. In situ production of spherical aerogel microparticles. J. Supercrit. Fluids55,1118–1123 (2011).
    • 101  García-González CA, Camino-Rey MC, Alnaief M, Zetzl C, Smirnova I. Supercritical drying of aerogels using CO2: effect of extraction time on the material textural properties. J. Supercrit. Fluids66,297–306 (2012).
    • 102  García-González CA, Smirnova I. Use of supercritical fluid technology for the production of tailor-made aerogel particles for delivery systems. J. Supercrit. Fluids79,152–158 (2013).
    • 103  García-González CA, Alnaief M, Smirnova I. Polysaccharide-based aerogels promising biodegradable carriers for drug delivery systems. Carbohyd. Polym.86,1425–1438 (2011).
    • 104  Griffin B. Advances in lipid-based formulations: overcoming the challenge of low bioavailability for poorly water soluble drug compounds. Am. Pharma. Rev.15(2), (2012).
    • 105  Prajapati H, Dalrymple D, Serajuddin A. A comparative evaluation of mono-, di- and triglyceride of medium chain fatty acids by lipid/surfactant/water phase diagram, solubility determination and dispersion testing for application in pharmaceutical dosage form development. Pharm. Res.29,285–305 (2012).
    • 106  Tan A, Rao S, Prestidge CA. Transforming lipid-based oral drug delivery systems inot solid dosage forms: an overview of solid carriers, physicochemical properties, and biopharmaceutical performance. Pharm. Res.30(12),2993–3017 (2013).▪ Compendium on technologies/processes to obtain solid dosage forms from lipid-based delivery systems for oral route.
    • 107  Chun Beh C, Mammucari R, Foster NR. Lipid-based drug carrier systems by dense gas technology: a review. Chem. Eng. J.188,1–14 (2012).▪ Compendium on lipid-delivery systems, produced by different dense-gas technologies. Focused mainly on liposomes and nanoparticles.
    • 108  Berton A, Piel G, Evrard B. Powdered lipid nano and microparticles: produciton and applications. Recent Pat. Drug Deliv. Formul.5,188–200 (2011).
    • 109  Calderone M, Rodier E, Lerourneau JJ, Fages J. Solidification of Precirol® by the expansion of supercritical fluid saturated melt: from the thermodynamic balance towards the crystallization aspect. J. Supercrit. Fluids42,189–199 (2007).▪ Describes physicochemical methodology to understand crystallization processes of lipidic excipients undergoing CO2 expansion.
    • 110  Vijayaraghavan M, Stolnik S, Howdle S, Illum L. Suitability of polymer materials for production of pulmonary microparticles using PGSS supercritical fluid technique: thermodynamic behavior of fatty acids, PEGs and PEG-fatty acids. Int. J. Pharm.438,225–231 (2012).
    • 111  Vijayaraghavan M, Stolnik S, Howdle S, Illum L. Suitability of polymer materials for production of pulmonary microparticles using PGSS supercritical fluid technique: preparation of microparticles using PEG, Fatty acids and physical or chemical blends of PEG and fatty acids. Int. J. Pharm.441,580–588 (2013).
    • 112  Segale L, Giovanelli L, Danan H, Galli L, Pattarino F. Development of metoclopramide microparticles using Variosol® technology. Control. Release Newsl.25(3),16–17 (2008).
    • 113  Segale L, Mannina P, Giovanelli L et al. A novel dense gas CO2 supercritical fluid technology for the development of microparticulate delivery systems containing ketoprofen. Eur. J. Pharm. Biopharm.82(3),491–497 (2012).
    • 114  Lee SJ, Kim YH, Lee SH, Hahn M. Characterization of nano oxaliplatin prepared by novel fat employing supercritical nano system, the FESNS®. Pharm. Dev. Technol.17(2),212–218 (2012).
    • 115  Kim YH, Lee SJ, Lee SH, Hahn M. Preclinical efficacy and safety assessment of nano-oxaliplatin oral formulation prepared by novel Fat Employing Supercritical Nano System, the FESNS®. Pharm. Dev. Technol.17(6),677–686 (2012).▪ Description of oxaliplatin nanoparticles for the oral delivery, obtained by a novel process, based on lipid formulation and subsequent removal by sc-CO2. Preclinical pharmokinetic and efficacy is described.
    • 116  Soares da Silva M, Nobrega FL, Aguiar-Ricardo A, Cabrita EJ, Casimiro T. Development of molecularly imprinted co-polymeric devices for controlled delivery of flufenamic acid using supercritical fluid technology. J. Supercrit. Fluids58,150–157 (2011).
    • 117  Soares da Silva M, Viveiros R, Morgado PI, Aguiar-Ricardo A, Correia IJ, Casimiro T. Development of 2-(dimethylamino)ethyl methacrylate-based molecular recognition devices for controlled drug delivery using supercritical fluid technology. Int. J. Pharm.416,61–68 (2011).
    • 118  Manion JR, Cape SP, McAdams DH, Rebits LG, Evans S, Sievers RE. Inhalable antibiotics manufactured through use of near-critical supercritical fluids. Aerosol Sci. Technol.46,403–410 (2012).
    • 119  Overhoff KA, McConville JT, Yang W, Johnston KP, Peters JI, William III RO. Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing. Pharm. Res.25(1),167–175 (2008).
    • 120  Sauceau M, Fages J, Common A, Nikitine C, Rodier E. New challenges in polymer foaming: a review of extrusion process assisted by supercritical carbon dioxide. Prog. Polym. Sci.36,749–766 (2011).▪ Compendium of extrusion processes relevant to pharmaceutical application. Gives an example of ‘hybrid technologies‘.
    • 121  Kluge J, Mazzotti M. CO2 high pressure homogenization: a solvent-free process for polymeric microspheres and drug-polymer composites. Int. J. Pharm.436,394–402 (2012).▪ Example of new, ‘hybrid process‘ based on SCFs combined with established technology.
    • 122  Lesoin L, Crampon C, Badens E. Development of a continuous dense gas process for the production of liposomes. J. Supercrit. Fluids60,51–62 (2011).
    • 123  Chen AZ, Zhao Z, Wang SB, Li Y, Zhao C, Liu YG. A continuous RESS process to prepare PLA-PEG-PLA microparticles. J. Supercrit. Fluids59,92–97 (2011).
    • 124  de Zordi N, Moneghini M, Kikic I et al. Applications of supercritical fluids to enhance the dissolution behaviors of Furosemide by generation of microparticles and solid dispersions. Eur. J. Pharm. Biopharm.81,131–141 (2012).
    • 125  Segale L, Mannina P, Giovannelli L et al. Celecoxib loaded microparticles by VarioSol® technology. Presented at: 19th International Symposium on Microencapsulation. Pamplona, Spain, 9–11 September 2013.
    • 201  Fries-land brands B.V.: WO097626 A1(2007).
    • 202  Messer Italia S.p.A.: EP2298286A1 (2011).
    • 203  Pierre Fabre Medicament.: US0270379A1(2007).
    • 204  Ortho-McNeil Pharmaceutical, Inc.: US6627246B2 (2003).
    • 205  Thar Pharmaceuticals Inc.: WO096144A1 (2008).
    • 206  Xspray Microparticles ab.: WO072950A1 (2009).
    • 301  Sitec-pharmabio. www.sitec-pharmabio.com/principle.php
    • 302  Thompson C, Harris R, James J. Do you know SSO? PFQ. www.pharmaquality.com
    • 303  Nanoparticles by supercritical fluid precipitation, new method for particle size reduction. www.micro-macinazione .com/news_2php
    • 304  Supercritical solutions. www.supercriticalsolutions.com/en/technologies/formulplex
    • 305  Xspray. www.xspray.com/process
    • 306  Aktiv-dry. www.aktiv-dry.com/canbdprocess.html
    • 307  Stanipharm. www.stanipharm.com/technologyapi.html
    • 308  Natex. www.natex.at/download/PGSS_CPF.pdf
    • 309  Nanotechnology: the next silver bullet? www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=605695