Particle generation for pharmaceutical applications using supercritical fluid technology Jacques Fages, Hubert Lochard, Jean-jacques Letourneau, Martial Sauceau, Élisabeth Rodier To cite this version: Jacques Fages, Hubert Lochard, Jean-jacques Letourneau, Martial Sauceau, Élisabeth Rodier. Particle generation for pharmaceutical applications using supercritical fluid technology. Powder Technology, Elsevier, 2004, 141 (3), pp.219-226. 10.1016/j.powtec.2004.02.007. hal-01668423 HAL Id: hal-01668423 https://hal.archives-ouvertes.fr/hal-01668423 Submitted on 15 Mar 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Particle generation for pharmaceutical applications using supercritical fluid technology Jacques Fages*, Hubert Lochard, Jean-Jacques Letourneau, Martial Sauceau, Elisabeth Rodier E´ cole des Mines d’Albi-Carmaux, Chemical Engineering Laboratory for Particulate Solids, UMR-CNRS 2392, 81013 Albi, France Abstract Inthepharmaceuticalindustry,anevengreaternumberofproductsareintheformofparticulatesolids.Theirformation,formulationand thecontroloftheiruserpropertiesarestillnotwellunderstoodandmastered.Sincethemid-1980s,anewmethodofpowdergenerationhas appearedinvolvingcrystallisationwithsupercriticalfluids.Carbondioxideisthemostwidelyusedsolventanditsinnocuityand‘‘green’’ characteristicsmakeitthebestcandidateforthepharmaceuticalindustry.RapidExpansionofSupercriticalSolutions(RESS),Supercritical AntiSolvent(SAS)andParticlesfromGasSaturatedSolutions(PGSS)arethreefamiliesofprocesseswhichleadtotheproductionoffine andmonodispersepowders,includingthepossibilityofcontrollingcrystalpolymorphism.FortheRESSprocess,thesuddendecompression of the fluid in which a solute has been dissolved is the driving force of nucleation. CO2 is, however, a rather feeble solvent and this is obviouslythemainlimitationofthedevelopmentofRESS.IntheSASprocess,CO2actsasanon-solventforinducingthecrystallisationofa solutefromanorganicsolution.TheversatilityofSAS(thereisalwaysapropersolvent–antisolventcoupleforthestudiedsolute)ensures futuredevelopmentsforverydifferenttypesofmaterials.PGSSusesthefactthatitismucheasiertodissolveCO2 inorganicsolutions(or melted compounds) than the contrary. It presents very promising perspectives of industrial development. After almost 20 years of active research,andmorethan10yearsofprocessdevelopment,thistechnologyisreachingmaturity,andverysooncommercialdrugproducedby thesetechniquesarelikelytoappear. Keywords: Particle generation; Pharmaceutical application; Supercritical fluid technology 1. Introduction excipients or host molecules like cyclodextrins. In addition, several other advantages can be noted depending on the About two thirds of the products used in the pharmaceu- chosen process configuration: tical industry are in the form of particulate solids [1]. Consequently, a lot of effort has been put into research in high purity of products; particle generation processes. The standard processes, control of crystal polymorphism; crushing/milling and crystallisation/precipitation are still possibility of processing thermolabile molecules; the most used. However, supercritical fluid (SCF) technol- single-step process; ogy presents a new and interesting route for particle forma- easy downstream processing; tion, which avoids most of the drawbacks of the traditional environmentally acceptable technology. methods. Supercritical processes give micro- or even nano- particles with narrow size distribution, and can also be used Among these advantages, most of them due to the use of to achieve microencapsulation, surface coating of an active carbon dioxide (CO2) of which properties of nontoxicity and substance particle with a polymer or co-crystallisation with mild critical conditions make it an ideal substitute to organic solvents. Moreover, CO2 is gaseous at ambient conditions, * Corresponding author. Tel.: +33-563-49-31-41; fax: +33-563-49-30- which simplifies the problem of solvent residues. 25. The bioavailability of pharmaceutical molecules depends E-mail address: [email protected] (J. Fages). on their absorption by the gastrointestinal tract, which is Fig. 1. Schematic flow diagram of the RESS process. governed by their dissolution and membrane permeation important role since a thermodynamic equilibrium may or rates. Micronisation techniques, and especially those using may not be reached in the extraction autoclave. In fact, the SC–CO2, which lead to an increase in the specific surface kinetics of the dissolution must not be neglected and diffusion 2 1 area (typically several tens of m gÀ for a nonporous limitations can occur. Additional problems may be encoun- solid), can significantly contribute to this improvement in tered when the solid to be extracted is not a pure component. bioavailability. The development of dry powder inhalers Indeed, fractionation of the load can lead to a variation in the (DPI) in which the drug is directly delivered to the lungs composition of the particles upon depressurisation. requires also fine powders with a mean particle size in the To understand what will happen during fluid expansion, range of 2 to 5 Am. phase diagrams are very useful. Fig. 2 shows the ( P, T) and Microencapsulation, coating and formation of composite ( P, h) diagrams for pure CO2. Phase diagrams and results particles are also extremely desirable for controlled delivery presented in this article have been simulated using multi- systems. Here again, supercritical technology may bring phase equilibrium calculations. The fluid phases are mod- new solutions to old problems. elled using the Peng-Robinson’s equation of state with Rapid Expansion of a Supercritical Solutions (RESS), various mixing rules. What can be noticed is that these phase Supercritical Anti-Solvent (SAS) and, to a lesser extent, equilibria involve pure solid constituents. The pure solid Particles from Gas Saturated Solutions (PGSS) are the chemical potential used in the model does not require the most studied processes. It is known that RESS can be value of the sublimation pressure. When the expressions of used with CO2-soluble molecules, while SAS can process the required properties are unknown, which is the case for nonsoluble molecules. However, the choice between these most of pharmaceutical molecules, this pure solid chemical two methods is not so simple in reality. To choose among potential expression is based on the measurements made these processes and the large domain of possible operating with a differential scanning calorimeter of the melting point (pure) conditions requires a good knowledge of the phase equi- of the solid. The fugacity coefficient ui,S in this chemical libria thermodynamics. potential is the following: pure lnuð Þ P; T 2. The RESS process i;S ð Þ fus fus std pure Tið Þ Dhið Þ Pð Þ lnuð Þ P; T 1 ð Þ 2.1. A two-step process: solubilisation and particle ¼ i;L ð Þþ À T fus ! RTið Þ formation P D vi u; T T L S ð Þ 1 T À du 1 fus RESS is a two-step process: after having solubilised a À P std RT À RT T ð Þ À u Z ð Þ Z i substance in an SCF, the mixture is suddenly depressurised std D cP Pð Þ; u du 1 in a nozzle causing fast nucleation and fine particle gener- Â L S i ð Þ ð Þ À ation (Fig. 1). In designing a RESS process, it is necessary to have the best possible understanding of what happens pure pure where: D vi P; T við;L Þ P; T við;S Þ P; T is the dif- upstream from the nozzle, that is to say during the extraction L S ð Þ¼ ð ÞÀ ð Þ ference betweenÀ pure liquid and pure solid molar volume step. Therefore, it is important either to collect data from the std pure pure (std) and D c P ; T cð Þ T cð Þ T (with P =1 literature when they exist, or to perform experiments or Pi ð Þ Pi;L Pi;S L S ð Þ¼ ð ÞÀ ð Þ modelling, about the solute solubility in the SCF [2,3]. atm)À is the difference between pure liquid and pure solid The key parameters of the extraction step are obviously the molar heat capacities. More details on the numerical calcu- operating T and P. The flow rate of the fluid may also play an lation of these phase equilibria are given elsewhere [4]. Fig. 2. Isenthalpic depressurisation of pure CO2 on P, T (pressure, temperature) and P, h (pressure, molar enthalpy) phase diagrams. An acceptable assumption is to consider that the depres- both phases (fluid and solid), which is related to the activity surisation is an isenthalpic process provided the variation of of the solute in the solution at equilibrium. This supersat- kinetic energy can be neglected. This is, however, a better uration ratio, noted S, is defined as the concentration of the assumption for capillaries than for plain orifices [5]. There- solute divided by the solubility (the concentration at satu- fore, the expansion step will be a vertical line (dashed ration) provided the activity coefficients can be assumed to arrow) on the (P, h) diagram. Such a drop in pressure be close to 1 which is the case for low solubilities. S comes implies an important decrease in temperature, as shown in from the drop in density, which is very large especially near Fig. 2. In the example