Comminution of pharmaceutical substances by the adiabatic expansion of supercritical fluid solutions

The adiabatic expansion of supercritical fluid solutions and solubility in pharmaceutical substance–carbon dioxide systems have been investigated. The solubility and average particle size of pharmaceutical substances depend on thermodynamic and geometric parameters of the process. Experimental data on the solubility of pharmaceutical substances in supercritical carbon dioxide have been gained, and empirical binary molecular interaction parameters for the Peng–Robinson equation have been derived. A numerical solution has been obtained for the unified model of nucleation and particle growth (in the drop theory approximation) in the expansion of a steady-state, two-dimensional, viscous, axisymmetric, compressible, supercritical carbon dioxide–pharmaceutical substance flow in a channel with a constant cross section and in a free jet. The correlation parameter of the condensation function, which characterizes the particle growth kinetics, has been determined.     

Formation of deagglomerated PLGA particles and PLGA-coated ultra fine powders by rapid expansion of supercritical solution with ethanol cosolvent

Rapid expansion of supercritical solution (RESS) was used for preparing polymer particles and polymer coating of ultra fine powders. The polymer of pharmaceutical interest was Poly(lactic-co-glycolic acid) (PLGA with PLA: PGA ratio of 85: 15 and MW of 50,000–75,000) and the simulated core particles were 1.4-μm SiO₂ and 70-nm TiO₂ particles. The supercritical solution was prepared by dissolving PLGA in supercritical carbon dioxide with ethanol as a cosolvent. Supercritical solution of CO₂-PLGA was sprayed through capillary nozzles to ambient conditions, resulting in formation of submicron PLGA particles. Similarly, rapid expansion of supercritical solution of CO₂-PLGA suspended with the core particles could provide solvent evaporation and deposition of submicron PLGA particles on the surface of the core particles, resulting in the formation of coating films on dispersed particles of SiO₂ and agglomerates of TiO₂. The influences of the core particle size, spray nozzle diameter as well as powder-to-polymer weight ratio were also investigated and discussed with respect to the coating performance.     

Recrystallization of phenylbutazone using supercritical fluid antisolvent process

Phenylbutazone was recrystallized from its solutions by using a supercritical fluid antisolvent process. It was dissolved in acetone and supercritical carbon dioxide was injected into the solution, thereby inducing supersaturation and particle formation. Variation in the physical properties of the recrystallized phenylbutazone was investigated as a function of the crystallizing temperature and the carbon dioxide injection rate. The recrystallized particles showed cleaner surfaces and more ordered morphology compared to the particles obtained by other methods such as solvent evaporation. X-ray diffraction patterns indicated that the crystallinity of the particles had been modified upon the recrystallization. Differential scanning calorimetry measurement revealed that the crystallizing temperature influenced the thermal stability of the resulting crystals. Larger crystals were produced when the carbon dioxide injection rate was reduced.     

Processing naproxen with supercritical CO2

Naproxen has been processed with supercritical fluids in order to improve the dissolution rate and bioavailability. Microparticles of naproxen have been obtained by a Rapid Expansion of Supercritical Solutions (RESS) process in which carbon dioxide has been used as a solvent and methanol as a cosolvent. The influence of extraction pressure (200–300 bar) and extraction temperature (60 °C and 100 °C) on the naproxen precipitation has also been investigated. In general, the morphology of the precipitated particles improved and particle size (PS) decreased in comparison to the raw material. Lower extraction pressure and higher extraction temperature led to a smaller particle size. On the other hand, a supercritical antisolvent (SAS) process has been applied due to the relative medium solubility values of naproxen in supercritical carbon dioxide, with precipitation obtained successfully in all cases. The initial concentration of the solution and the solvent effect has both been analysed. Morphologies and mean diameter ranges have been analysed by scanning electron microscopy (SEM) and the influence on crystallinity of both supercritical processes has been evaluated by X-ray diffraction (XRD) measurements.     

Micronization of Three Active Pharmaceutical Ingredients Using the Rapid Expansion of Supercritical Solution Technology

The rapid expansion of supercritical solution (RESS) technology was applied to recrystallize and micronize three active pharmaceutical ingredients (APIs) of monobenzone, ethylparaben, and kojic acid. All unprocessed (original) APIs had a large mean particle size over 200 μm with wide particle size distribution. Supercritical carbon dioxide served as the solvent to extract each API in a high-pressure vessel. The nearly saturated supercritical solution was then expanded through a capillary spray nozzle to ambient pressure state. The APIs were recrystallized in a very short time period. The final API particles with submicron sizes were obtained with much less intensity of crystallinity. The optimal RESS process parameters and the improved result of the in vitro dissolution test for the API of ethylparaben are reported.     

用石蜡-CO_2超临界流体快速膨胀在流化床中进行细颗粒包覆

对超临界流体快速膨胀技术在流化床中进行细颗粒的表面包覆进行了研究 ,以实现细颗粒中关键成分的有效控制释放 .实验研究了含有包覆剂———石蜡的超临界二氧化碳流体通过微细喷嘴快速膨胀到装有细颗粒的流化床中 ,膨胀射流中所产生的微核在细颗粒表面均匀沉积 ,形成细颗粒表面薄层包覆 .结果分析表明 ,超临界流体快速膨胀前的温度是包覆过程的关键参数 ,通过控制操作过程参数可以获得良好的包覆结果     

Molecular modeling and experimental verification of lipase-catalyzed enantioselective esterification of racemic naproxen in supercritical carbon dioxide

Experimental and simulation analyses were performed on the lipase-catalyzed esterification reaction of racemic naproxen by CALB (candida antarctica lipase B) enzyme in supercritical carbon dioxide. The reaction pathways were investigated by quantum mechanical analysis, and the enantioselectivity of the products was predicted by molecular dynamics simulation analysis. Calculated results from molecular modeling in supercritical carbon dioxide were qualitatively compared with experimental data by using racemic naproxen as a substrate. All molecular modeling results and experimental data were acquired and compared with those in ambient and supercritical condition. Moreover, to verify the stability of enzymatic reaction in each solvent condition, reaction pathways were investigated in several solvent conditions (vacuum, water, hexane and supercritical carbon dioxide), and the stability of enzymatic reaction in supercritical carbon dioxide was compared with other solvent conditions. This paper is dedicated to Professor Chul Soo Lee on the occasion of his retirement from Korea University.     

In situ optical monitoring of the solution concentration influence on supercritical particle precipitation

We report a novel approach for the measurement of the location of particle formation in the supercritical antisolvent process (SAS). The measurement strategy is based on in situ Raman and elastic light scattering. In the SAS process, paracetamol was used as the solute, ethanol as the solvent and carbon dioxide as the antisolvent. Experiments were performed under miscible conditions for the binary system ethanol and carbon dioxide at 313 K and pressures between 10 MPa and 17.5 MPa. For high paracetamol concentrations in the injected ethanol solution, particles were found to start precipitating after jet breakup in a multi-phase flow. For low paracetamol concentrations, precipitation starts later in a one-phase flow, when the transient interface (phase boundary) between the injected solution and the supercritical carbon dioxide has diminished.     

Particle design using supercritical fluids: Literature and patent survey

As particle design is presently a major development of supercritical fluids applications, mainly in the pharmaceutical, nutraceutical, cosmetic and specialty chemistry industries, number of publications are issued and numerous patents filed every year. This document presents a survey (that cannot pretend to be exhaustive!) of published knowledge classified according to the different concepts currently used to manufacture particles, microspheres or microcapsules, liposomes or other dispersed materials (like microfibers):RESS: This acronym refers to ‘Rapid Expansion of Supercritical Solutions’; this process consists in solvating the product in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapid nucleation of the product into a highly dispersed material. Known for long, this process is attractive due to the absence of organic solvent use; unfortunately, its application is restricted to products that present a reasonable solubility in supercritical carbon dioxide (low polarity compounds).GAS or SAS: These acronyms refer to ‘Gas (or Supercritical fluid) Anti-Solvent’, one specific implementation being SEDS (‘Solution Enhanced Dispersion by Supercritical Fluids’); this general concept consists in decreasing the solvent power of a polar liquid solvent in which the substrate is dissolved, by saturating it with carbon dioxide in supercritical conditions, causing the substrate precipitation or recrystallization. According to the solid morphology that is wished, various ways of implementation are available:GAS or SAS recrystallization: This process is mostly used for recrystallization of solid dissolved in a solvent with the aim of obtaining either small size particles or large crystals, depending on the growth rate controlled by the anti-solvent pressure variation rate;ASES: This name is rather used when micro- or nano-particles are expected; the process consists in pulverizing a solution of the substrate(s) in an organic solvent into a vessel swept by a supercritical fluid;SEDS: A specific implementation of ASES consists in co-pulverizing the substrate(s) solution and a stream of supercritical carbon dioxide through appropriate nozzles.PGSS: This acronym refers to ‘Particles from Gas-Saturated Solutions (or Suspensions)’: This process consists in dissolving a supercritical fluid into a liquid substrate, or a solution of the substrate(s) in a solvent, or a suspension of the substrate(s) in a solvent followed by a rapid depressurization of this mixture through a nozzle causing the formation of solid particles or liquid droplets according to the system.The use of supercritical fluids as chemical reaction media for material synthesis. Two processes are described: thermal decomposition in supercritical fluids and hydrothermal synthesis.We will successively detail the literature and patents for these four main process concepts, and related applications that have been claimed. Moreover, as we believe it is important to take into account the user's point-of-view, we will also present this survey in classifying the documents according three product objectives: particles (micro- or nano-) of a single component, microspheres and microcapsules of mixtures of active and carrier (or excipient) components, and particle coating.     

Preparation of anthracene fine particles by rapid expansion of a supercritical solution process utilizing supercritical CO<Subscript>2</Subscript>

The rapid expansion of a supercritical solution (RESS) process is an attractive technology for the production of small, uniform and solvent-free particles of low vapor pressure solutes. The RESS containing a nonvolatile solute leads to loss of solvent power by the fast expansion of the supercritical solution through an adequate nozzle, which can cause solute precipitation. A dynamic flow apparatus was used to perform RESS studies for the preparation of fine anthracene particles in pure carbon dioxide over a pressure range of 150–250 bar, an extraction temperature range of 50–70 °C, and a pre-expansion temperature range of 70–300 °C. To obtain fine particles, 100, 200 and 300 μm nozzles were used to disperse the solution inside of the crystallizer. Both average particle size and particle size distribution (PSD) were dependent on the extraction pressure and the pre-expansion temperature, whereas extractor temperature did not exert any significant effect. Smaller particles were produced with increasing extraction pressure and preexpansion temperature. In addition, the smaller the nozzle diameter, the smaller the particles and the narrower the PSD obtained.     

Crystallization of sulfamethizole using the supercritical and liquid antisolvent processes

Sulfamethizole was crystallized using both the supercritical and liquid antisolvent processes. Acetone and N,N-dimethyl formamide (DMF) were selected as solvents for the pharmaceutical compound, and carbon dioxide and distilled water were used as antisolvents. In the supercritical antisolvent process, the effects of experimental conditions such as carbon dioxide injection rate, type of solvent, and temperature were investigated. In the liquid antisolvent process, the effect of ultrasound on the properties of crystal was examined. The various crystal habits such as tabular, platy, acicular, and prismatic were observed depending on the process and experimental conditions. Differential scanning calorimetry (DSC) measurement revealed that the carbon dioxide injection rate affected the crystallinity of sulfamethizole particles. Larger crystals were obtained at higher temperatures in the two antisolvent processes. The particle size distribution was mostly affected by the antisolvent injection rate and the application of ultrasound.     

用含夹带剂丙酮的超临界CO2快速膨胀法制备灰黄霉素的微细颗粒

Griseofulvin (GF) is an antifungal drug whose pharmaceutical activity can be improved by reducingparticle size. In this study the rapid expansion of supercritical solution (RESS) was employed to micronize GF.Carbon dioxide with cosolvent acetone was chosen as a supercritical mixed solvent. The solubility of GF in super-critical CO2 with cosolvent acetone was measured using a dynamic apparatus at pressures between 12 and 32 MPa,temperatures at 313, 323 and 333K and cosolvent concentration at 1.5, 3.0, 4.5 and 6.0% (by mole). The effect ofpre-expansion pressure, extraction temperature, spraying distance, nozzle size and concentration of cosolvent on theprecipitated particles was investigated. The results show that the mean particle size of griseofulvin precipitated byRESS was less than 1.2 μm. An increase in pre-expansion pressure, extraction temperature, spraying distance andconcentration of cosolvent resulted in a decrease in particle size under the operating condition studied. With thedecrease of nozzle diameter the particle size reduces. The crystallinity and melting point of the original material andthe processed particle by RESS were tested by X-ray diffraction (XRD) and differential scanning calorimetry (DSC).No evident modification in the crystal habit was found under the experimental conditions tested. The morphologyof particles precipitated was analyzed by scanning electron microscopy (SEM).     

Precipitation kinetics of PMMA sub-micrometric particles with a supercritical assisted-atomization process

Sub-micrometric particles of PMMA were successfully prepared via a supercritical assisted-atomization (SAA) process using acetone as a solvent and supercritical carbon dioxide as a spraying medium. The effects of several key factors on the particle size were investigated. These factors included the concentration of polymer solution, temperature in saturator and volumetric flow rate ratio of carbon dioxide to polymer solution. The shape of the polymer's primary particles is spherical with the arithmetic mean size ranging from 82 nm to 176 nm and the mass-weighted mean size ranging from 127 nm to 300 nm. As evidenced from the experimental results, the lower concentrations of polymer solution, optimized volumetric flow rate ratios, and higher temperatures in saturator can effectively reduce the mean particle size. The precipitation kinetic parameters were determined from the particle size distributions with the aid of the population balance theory. This study found the primary nucleation to be dominant in the precipitation and diffusion may govern particle growth.     

Preparation of poly(L-lactic acid) submicron particles in aerosol solvent extraction system using supercritical carbon dioxide

The aerosol solvent extraction system process (ASES), which is one of the supercritical anti solvent processes (SAS), was used to produce poly(L-lactic acid) (PLLA) into the submicron particles. Dichloromethane (DCM, CH₂Cl₂) and carbon dioxide were selected as a solvent and as an antisolvent for PLLA, respectively. The objective of this study was to investigate the effect of the various process parameters such as temperature, pressure, and solution concentration on PLLA particles. With increasing temperature and pressure, particle size was increased. Also, higher PLLA concentration led to larger particle size and broader particle size distribution. A scanning electron microscope (SEM) was used to observe the morphology and size of PLLA particles recrystallized by ASES process. The mean particle size and its distribution of processed particles were measured by using a laser diffraction particle size analyzer (PSA).     

A computational fluid dynamics study of supercritical antisolvent precipitation: Mixing effects on particle size

Supercritical fluids have been extensively used for particle production of many natural and pharmaceutical substances providing useful alternatives for pharmaceutical and nutraceutical particulate system formulation. Among the different methods, the gas or supercritical antisolvent (GAS or SAS) process and its variants, have received a considerable interest due to the wide range of materials that can be micronized. Controlling particle formation in order to nucleate small particles is a key issue in GAS and SAS processes and this is directly related to mixing at all scales. In this work, we focus on numerical simulation of the process, emphasizing mixing modeling. Different mixing devices characterized by different nozzles are analyzed, to get an insight into mixing dynamics and its influence on the final particle size distribution. Results show that mixing is determinant in obtaining small particles, and that mixing at the microscale is a significant parameter to account for in the proper design of precipitators. © 2011 American Institute of Chemical Engineers AIChE J, 2012     

Preparation and Physicochemical Properties of Vinblastine Microparticles by Supercritical Antisolvent Process

The objective of the study was to prepare vinblastine microparticles by supercritical antisolvent process using N-methyl-2-pyrrolidone as solvent and carbon dioxide as antisolvent and evaluate its physicochemical properties. The effects of four process variables, pressure, temperature, drug concentration and drug solution flow rate, on drug particle formation during the supercritical antisolvent process, were investigated. Particles with a mean particle size of 121 ± 5.3 nm were obtained under the optimized process conditions (precipitation temperature 60 °C, precipitation pressure 25 MPa, vinblastine concentration 2.50 mg/mL and vinblastine solution flow rate 6.7 mL/min). The vinblastine was characterized by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, mass spectrometry and dissolution test. It was concluded that physicochemical properties of crystalline vinblastine could be improved by physical modification, such as particle size reduction and generation of amorphous state using the supercritical antisolvent process. Furthermore, the supercritical antisolvent process was a powerful methodology for improving the physicochemical properties of vinblastine.     

Preparation of micro particles of functional pigments by gas-saturated solution process using supercritical carbon dioxide and polyethylene glycol

Particle design is presently a major development of supercritical fluids applications, mainly in the paint, cosmetic, pharmaceutical, and specialty chemical industries. The particles from the gas-saturated solutions (PGSS) process were used to micronize the functional compounds, fucoxanthin and astaxanthin. Fucoxanthin was extracted from brown seaweed using supercritical carbon dioxide (SC-CO₂) at 20 MPa and 45 °C. The particle formation of functional pigments with biodegradable polymer, polyethelene glycol (PEG) was performed by PGSS using SC-CO₂ in a thermostatted stirred vessel. Different temperatures (40 and 50 °C) and pressures (10–30MPa) were applied to optimize the conditions for the formation of functional pigment particles. Two nozzles of different diameter (250 and 300 μm) were used for PGSS and the reaction time was 1 hr. The average diameter of the particles obtained by PGSS at different conditions was about 0.78–1.42 μm.     

Micronization and characterization of drug substances by RESS with supercritical CO2

A RESS (rapid expansion of supercritical solution) process for the preparation of ultra-fine drug particles with no organic solvent has been developed with supercritical CO₂. Three drug substances with different solubility in supercritical CO₂ were used, and orifice disks and capillary tubes were adapted as an expansion device. The solubilities of drug substances in supercritical CO₂ and the effects of various operating parameters on the characteristics of the particles prepared by RESS process were experimentally investigated. The solubility of the drug substance in supercritical CO₂ had a major effect on the average diameter of the particle prepared by RESS process, and the particle diameter decreased with the solubility for all the drugs and operating conditions. The particle diameter also decreased with preexpansion temperature and increased with the hole diameter of the orifice nozzle and aspect ratio (L/D) of the capillary tube.     

Recrystallization of erlotinib hydrochloride and fulvestrant using supercritical antisolvent process

Recrystallization of two anti-cancer active pharmaceutical ingredients (APIs), erlotinib hydrochloride (erlotinib HCl) and fulvestrant, using supercritical antisolvent (SAS) process was investigated in this study. The most commonly used supercritical carbon dioxide was employed as the antisolvent. Effect of three process parameters including the operating temperature, pressure and solution flow rate have been studied. Analyses of the recrystallized erlotinib HCl and fulvestrant were examined by SEM, XRD and DSC. Erlotinib HCl was recrystallized from its mean particle size of 20 μm to 2 μm with different crystal habits. Different polymorphs of erlotinib HCl were obtained and confirmed from the XRD and DSC results. The prior art polymorph form A of erlotinib HCl showed enhanced dissolution rate by 3.6 times to its original polymorph form B. Significant particle size reduction was also obtained for fulvestrant. The mean particle size was reduced from its original value of 22 μm to 2 μm with much narrower particle size distribution. The cross-interaction effect between the operating temperature and pressure observed in the SAS treatment of fulvestrant was verified by the method of calculated mixture critical point (MCP). The micronized fulvestrant particles showed consistent polymorph as the original API, but with different crystal habits. It is confirmed that the SAS method is applicable for controlling the crystal properties of two APIs, erlotinib HCl and fulvestrant, which require rigorous control of physical characteristics.