Theophylline polymorphs by atomization of supercritical antisolvent induced suspensions

The Atomization of Supercritical Antisolvent Induced Suspensions (ASAIS) is a small volume supercritical antisolvent process characterized by the inline dissolution of the antisolvent before the liquid atomization for the solvent extraction step. The antisolvent (CO₂) is mixed with the solute-containing solution in a small volume mixer immediately before the nozzle orifice in conditions such that cause the precipitation of the solutes. The generated suspension is then spray-dried for solvent separation. Compared to other similar particle-producing techniques, this approach allows a more efficient control of the antisolvent process and reduces the volume of the high-pressure precipitator by several orders of magnitude. Theophylline (TPL) particles produced by ASAIS are the polymorph previously obtained elsewhere by conventional SAS. Yet, the normal (non-polymorph) crystal form is obtained under non-antisolvent conditions. The required phase equilibria of the system TPL/tetrahydrofuran/CO₂ between 308 K and 328 K were also obtained. The results presented here demonstrate that, under selected conditions, ASAIS is a continuous-regime alternative to conventional SAS for the production of unique products, such as crystal polymorphs.     

Process performances and characteristics of powders produced using supercritical CO2 as solvent and antisolvent

A carbon dioxide (CO₂) soluble compound (cholesterol) was successfully precipitated either by rapid expansion of SCCO₂ solutions (RESS process, acronym for Rapid Expansion of Supercritical Solution), or from methylene chloride solutions by antisolvent precipitation (SAS-process, acronym for Supercritical Antisolvent process). The same fluid was thus used either as a solvent or as an antisolvent to precipitate cholesterol. Performances of RESS and SAS were compared through the analysis of the particle characteristics and production rates. Differences were related to supersaturation and time scale of nucleation/growth involved in both processes. Polydispersity, large size and elongated shape were characteristics of particles produced by SAS, especially when experiments were performed under conditions of total miscibility of CO₂ and organic solvent. Conditions where vapor-liquid equilibrium exists promoted a confinement of the growth that consequently reduced the final particle size. RESS, by comparison, produced smaller and monodispersed particles. Production of small particles is a key advantage for RESS, but lower production rates and yield might be disadvantages. The combination of the two processes offers the opportunity of tunable sizing of powder, switching from a large production of particles ranging from 10 to 100 μm, to a limited production of fine crystals below 10 μm.     

A new system for particle formation using the principle of the SAS process: The Concentric Tube Antisolvent Reactor (CTAR)

This paper presents a new system to produce micrometric narrow size distribution particles. The principle is the same as for a conventional supercritical antisolvent process (SAS), with the contact of the organic solution containing the solute to be precipitated and the supercritical CO₂ playing the role of an antisolvent. This paper exposes the functioning of the system used for the contact of the two phases. It is constituted by two concentric tubes; an external one partially for the CO₂ and an internal one for the organic solution. Its name is the Concentric Tube Antisolvent Reactor (CTAR). This system is a compacted and simple one. It has been tested with a usual polymer (l-poly lactic acid) often processed by the use of the SAS methods. Different experiments have shown that this system is convenient for the production of particles, leading to almost equivalent results as in other processes with identical operating conditions. There are still remaining problems for the recovery of the powder formed, which is usual for this kind of process. This system could be very useful for the scaling up of the process, by multiplying the number of tubes with an easy permanent control on the operating conditions. Some improvements have been made for operating parameters, as the concentration of LPLA in the organic solution and the molar ratio solvent/supercritical CO₂ that can be processed.     

Reactivity of α-pinene epoxide in supercritical solvents

Thermal transformations of α-pinene epoxide in composite supercritical solvents that contain CO₂, lower alcohols (ethanol, isopropyl alcohol) and water were studied in the temperature range of 387-575 K at pressure 13.5-21.5 MPa. Campholenic aldehyde and carveol were shown to be the main products of α-pinene epoxide reactions in supercritical solvents containing water. In the absence of water, thermolysis of α-pinene epoxide in supercritical solvent yields campholenic aldehyde and pinocamphone, with their total amount in the reaction mixture attaining 80%. Suggestions were made on the mechanism of α-pinene epoxide thermal isomerization depending on acidity of supercritical solvent.     

Supercritical CO2 extraction of Helichrysum italicum: Influence of CO2 density and moisture content of plant material

Kinetics and selectivity of supercritical carbon dioxide (SC CO₂) extraction of Helichrysum italicum flowers were analyzed at pressures in the range of 10-20 MPa and temperatures of 40 °C and 60 °C (density of SC CO₂ from 290 to 841 kg/m³) and also at 10 MPa and 40 °C using flowers with different moisture contents (10.5% and 28.4%). Increased moisture content of H. italicum flowers resulted in enchased solubility of solute enabling decrease of SC CO₂ consumption necessary for achieving desired extraction yield. The most abundant compounds in the supercritical extracts are sesquiterpenes and waxes while monoterpenes and sesquiterpenes are the main constituents of essential oil obtained by hydrodistillation. The optimal set of working parameters with respect to extraction yield, SC CO₂ consumption and chemical composition of extract were defined related to moisture content of raw material and SC CO₂ density.     

Green tea encapsulation by means of high pressure antisolvent coprecipitation

In this work, green tea polyphenols were coprecipitated with a biodegradable polymer (poly-?-caprolactone, MW: 25,000) by a semi continuous supercritical antisolvent process (SAS). Carbon dioxide was used as antisolvent in addition to be a dispersing agent. Green tea extracts were obtained by microwaved assisted extraction (MAE) technique with acetone. The influence of different process parameters, including the operating pressure (8-12 MPa) and temperature (283-307 K), the polymer to solutes concentration (w/w) ratio (4-58), and the CO₂ to solution mass flow rate ratio (4-10) have been studied experimentally. Total content of polyphenols, quantified according to the Folin-Cicalteu method, showed concentrations from 60 to 100% of the maximum theoretical composition. Also HPLC analyses were performed to verify the presence of some of the major tea catechins. SEM images of the products show small particles (3-5 μm) with narrow particle size distribution with a high degree of agglomeration. Drug release profiles in phosphate buffer (pH = 6.8) reveal that the majority of catechins are encapsulated in the crystalline domains of the polymer.     

Interactions of phase equilibria,jet fluid dynamics and mass transfer during supercritical antisolvent micronization

Supercritical antisolvent (SAS) precipitation has been successfully used in the micronization of several compounds. Nevertheless, the role of high-pressure vapor–liquid equilibria, jet fluid dynamics and mass transfer in determining particle size and morphology is still debated. In this work, CO₂ has been adopted as supercritical antisolvent and elastic light has been used to acquire information on jet fluid dynamics using thin wall injectors for the investigation of the liquid solvents acetone and DMSO at operating conditions of 40 °C in the pressure range between 6 and 16 MPa. The results show that two-phase mixing after jet break-up is the phenomenon that characterizes the jet fluid dynamics at subcritical conditions. When SAS is performed at supercritical conditions a transition between multi-phase and single-phase mixing is observed by increasing the operating pressure. Single-phase mixing is due to the very fast disappearance of the interfacial tension between the liquid solvent and the fluid phase in the precipitator. The transition between these two phenomena depends on the operating pressure, but also on the viscosity and the surface tension of the solvent. Indeed, single-phase mixing has been observed for acetone very near the mixture critical point, whereas DMSO showed a progressive transition for pressures of about 12 MPa.In the second part of the work, a solute was added to DMSO to study the morphology of the microparticles formed during SAS precipitation at the different process conditions, to find a correlation between particle morphology and the observed jet. Expanded microparticles were obtained working at subcritical conditions; whereas spherical microparticles were obtained operating at supercritical conditions up to the pressure where the transition between multi- and single-phase mixing was observed. Nanoparticles were obtained operating far above the mixture critical pressure. The observed particle morphologies have been explained considering the interplay among high-pressure phase equilibria, fluid dynamics and mass transfer during the precipitation process.     

Enhancing the solubility and bioavailability of isoflavone by particle size reduction using a supercritical carbon dioxide-based precipitation process

Isoflavones are a group of small molecular compounds found in many plants. Genistein is the most well studied isoflavones because of its beneficial effects in reducing menopausal symptoms, anti-oxidant and anti-cancer. The major difficulty in developing isoflavone-based healthcare products is their low water solubility. In this study, the solubility and oral bioavailability of genistein were increased by reducing its particle size using supercritical CO₂ as an antisolvent in the precipitation process. The effects of various process parameters including type of solvent, pressure of precipitation, and concentration of genistein solution on particle formation were evaluated. We found that under optimized conditions: dissolving 4 mg/mL genistein in acetone and precipitating them with supercritical CO₂ under 100 bar at 40 °C, the size of genistein particles was reduced from its original width of 10–50 μm to ∼254 nm. The reduction of genistein particle size not only increased its water solubility by 2 fold but more importantly increased its 24 h-plasma concentration by 2.6 fold after orally administrated to rats. These results proof the concept of using supercritical CO₂ as an antisolvent in the precipitation process to reduce particle size of water insoluble compounds such as genistein and to improve its oral bioavailability.     

Co-precipitation of amoxicillin and ethyl cellulose microparticles by supercritical antisolvent process

Microparticles of ethyl cellulose (EC) and amoxicillin (AMC) have been precipitated by a supercritical antisolvent process (SAS) using CO₂ as the antisolvent and a mixture of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) as solvents. Combinations of three temperatures (308, 323 and 333 K) and four pressures (100, 150, 200 and 250 bar) were assessed in the vessel and the rest of the variables were held constant (i.e. CO₂ flow rate, sample flow rate, washing time, nozzle diameter and the amoxicillin:ethyl cellulose ratio). Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and elemental analysis (EA) were used to determine the particle size and shape and to confirm the presence of both compounds in the resulting precipitates. In most cases, mixed amoxicillin and ethyl cellulose particles were produced with sizes in the micrometer range. Pressure and temperature effects on the co-precipitation were investigated. The release behaviour of the microparticles precipitated by the SAS process was evaluated in two biological fluids – simulated gastric and simulated intestinal fluids. Co-precipitated materials allowed a slower drug release rate than pure drug.     

The application of a supercritical antisolvent process for sustained drug delivery

Supercritical processes for drug delivery system design have attracted considerable attention recently. This present work investigates the application of a supercritical antisolvent coating process for controlled drug release design. Hydrocortisone as the host drug particles and poly(lactide-co-glycolide) (PLGA) as the polymer carrier were selected as the model system for this purpose. In this research the drug particles were suspended in a polymer solution of dichloromethane. The suspension was then sprayed into supercritical CO₂ as an antisolvent. A parallel study of co-precipitation of the drug and polymer using the same supercritical antisolvent process at the same operating conditions was performed for comparison with the coating process. SEM images were used to characterize the drug particles before and after and the assay analysis was carried out using HPLC. The coated particles and co-precipitated particles were evaluated in terms of encapsulation efficiency and drug release profiles. The major advantage of this new approach is the ability to physically coat very fine (< 30 μm) particles without having to dissolve them in an organic solvent. It was found that higher polymer to drug ratios produced higher encapsulation efficiencies and the coated drug particles did show sustained release behavior. The co-precipitation of the drug and polymer (at the same operating conditions), however, did not exhibit any sustained release.     

Supercritical Antisolvent Particle Precipitation: In Situ Optical Investigations

The manner in which the presence of a solute can affect the mixing behavior of a solute, solvent and antisolvent in a supercritical antisolvent (SAS) micronization process is demonstrated. The mixing behavior was analyzed by applying a two‐dimensional (2D) Raman scattering technique. Mole fraction and partial density distributions were measured for the CO₂ antisolvent. The results originating from the optical investigations were correlated with the particle results. The experiments cover the variation of the solute concentration at fixed operating conditions of 10 MPa and 40 °C.     

Micronization of cilostazol using supercritical antisolvent (SAS) process: Effect of process parameters

The aim of this study was to improve dissolution rate of poorly water-soluble drug, cilostazol, using supercritical antisolvent (SAS) process. The effect of process variables, such as pressure, temperature, drug concentration, type of solvents, feed rate ratio of CO₂/drug solution, on drug particle formation during SAS process was investigated. Particles with mean particle size ranging between 0.90 and 4.52 μm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration, solvent type, feed rate ratio of CO₂/drug solution. In particular, mean particle size and distribution were markedly influenced by drug solution concentration during SAS process. Moreover, the drug did not change its crystal form and the operating parameters might control the ‘crystal texture’ due to the change in crystallinity and preferred orientation during SAS process, as confirmed by differential scanning calorimetry and powder X-ray diffraction study. In addition, the dissolution rate of drug precipitated using SAS process was highly increased in comparison with unprocessed drug. Therefore, it is concluded that the dissolution rate of drug is significantly increased by micronization of cilostazol, leading to the reduction in particle size and increased specific surface area after SAS process.     

Optimization of total alkannin yields of Alkanna tinctoria by using sub- and supercritical carbon dioxide extraction

The effects of supercritical carbondioxide extraction was investigated to compare previously validated extraction methods on total alkannin yield with Alkanna tinctoria collected form Antalya, Turkey. A two-step process was used; extraction of alkannin derivatives with supercritical CO₂ followed by alkaline hydrolysis of alkannin derivatives. A Box-Behnken exprerimental design was used to evaluate the effect of three variables, pressure (50-350 bar), temperature (30-80 °C) and CO₂ flow (5-20 g min⁻¹) at 1:30 ratio of alkanna root:CO₂ amount. Response surface analysis revealed that the data were adequately fitted to a second-order polynomial model with R² 0.9665 and the most effective variable was pressure (P ≤ 0.05). Optimum conditions were determined as 80 °C, 175 bar, 5 g min⁻¹ CO₂ flow yielding the highest total alkannins (1.47%) which was higher than conventional hexane extraction (1.24%) providing a solvent-free alternative for industrial production.     

Extraction of sage (Salvia officinalis L.) by supercritical CO2: Kinetic data, chemical composition and selectivity of diterpenes

The supercritical carbon dioxide (SFE) extraction of Dalmatian sage (Salvia officinalis L.) was investigated and compared to extraction performed by Soxhlet ethanol-water (70:30) mixture extraction (SE) and hydrodistillation (HD). The supercritical extraction allowed isolation of wide spectrum of phytochemicals, while other applied methods were limited to either volatiles (HD) or high molecular compounds isolation (SE). The kinetics of the supercritical extraction and fractionation within the pressure range of 10-30 MPa at 50 °C were also analyzed as well as the chemical compositions of total extract and partial or differential fractions isolated at different CO₂ consumption. Volatile fraction could be isolated at low pressure and low CO₂ consumption, whereby the pressures between 10 and 15 MPa followed by increased CO₂ consumption were favourable for obtaining desired selectivity of diterpenes which contain compounds with expressed antioxidative characteristics.     

Extraction of the essential oil of abajeru (Chrysobalanus icaco) using supercritical CO2

Abajeru (Chrysobalanus icaco) is a plant that has hypoglycemic properties and is often used in Brazilian popular medicine. In order to identify the flavoring and hypoglycemic substances present in this plant, this work has an objective for the extraction of the essential oil presented in the leaves of abajeru using the supercritical fluid extraction (SFE). The supercritical solvent used is CO₂, because of its moderate critical temperature and pressure, atoxicity, low cost and volatility. The experiments were conducted using dried leaves in an apparatus containing a high-pressure pump, a stainless steel extractor of 42 mL of volume and a micrometric valve for sampling. Different operational conditions were tested, varying mainly the temperature (313.15-353.15 K) and the pressure (10.5-20 kPa) in order to investigate the efficiency of the process. The results showed that the best operational condition was at 20 kPa and 353.15 K. To compare the supercritical carbon dioxide results, the essential oil was also extracted by hydrodistillation and soxhlet, using ethanol as solvent. The chromatographic analysis showed that the different technologies studied extracted the same classes of compounds but the SFE obtained the extract with potential hypoglycemic activity with the presence of lupenol.     

Co-utilisation of alkaline solid waste and compressed-or-supercritical CO2 to produce calcite and calcite/Se red nanocomposite

The coal combustion fly-ash and alkaline paper mill waste were previously used to sequester CO₂ via waste-water-CO₂ interactions. For this case, a solid mixture (calcite and un-reacted waste) was obtained after carbonation process. In the present study, we propose a solid-water separation of free lime (CaO) or free portlandite (Ca(OH)₂) contained in waste prior to carbonation experiments in order to produce pure calcite or calcite/Se⁰ red composite. The calcite and carbonate composite syntheses have been also independently studied, but for both cases, a commercial powdered portlandite was used as calcium source.For this study, the extracted alkaline-solution (pH = 12.2-12.4 and Ca concentration = 810-870 mg/L) from alkaline solid waste was placed in contact with compressed or supercritical CO₂ at moderate or high temperature, leading a preferential nucleation-growth of submicrometric particles of calcite (<1 μm) with rhombohedral morphology at 90 °C and 90 bar (9 MPa), whereas a preferential nucleation-growth of nanometric particles of calcite (<0.2 μm) with scalenohedral morphology at 30 °C and 20 bar (2 MPa) were observed. When, the extracted alkaline-solution was placed in contact with supercritical CO₂ (90 bar) at high temperature (90 °C) and in presence of unstable seleno-l-cystine compound, the nucleation-growth of calcite/Se⁰ red nano-composite taken place. The composite consisted predominantly of spherical, amorphous nanometric-to-submicrometric of elemental red selenium (<500 nm) deposited on the calcite matrix. Here, the calcite was constituted by nano- to microrhombohedral crystals (<2 μm) and micrometric agglomerates and/or aggregates (<5 μm). These results on the particle size and morphology of crystal faces are very similar to calcite produced using commercial powdered portlandite as alkaline reactant and calcium source. This study is a nice example of feasibility to obtain possible ecological and economical benefits from waste co-utilisation.     

Coprecipitation of Cefuroxime Axetil-PVP composite microparticles by batch supercritical antisolvent process

Batch supercritical antisolvent precipitation (SAS) process was used to coprecipitate Cefuroxime Axetil amorphous (CFA, antibiotic) and Polyvinylpyrrolidone (PVP-K30) for preparing drug-polymer composite particles. Solutions of CFA and PVP-K30 in methanol with overall concentrations of 50-150 mg/ml and polymer/drug ratios of 1/1-4/1 were sprayed into the CO₂ at 70-200 bar and 35-50 °C with drug + polymer solution injection rates of 0.85 and 2.5 ml/min. Spherical particles having mean diameters of 1.88-3.97 μm, distribution ranges of 0.82-9.7 μm (the narrowest distribution) and 0.91-46.64 μm (the broadest distribution) were obtained. Mean particle size was not affected significantly with the change of process parameters. It was only affected by pressure change. On the other hand particle size distribution was affected by pressure, temperature, drug + polymer solution injection rate and concentration. It was observed that temperature and polymer/drug ratio affected the particle morphology most. The drug release rate of SAS-coprecipitated CFA-PVP (1/1) particles was almost 10 times slower than the drug alone. As the ratio of the polymer increased drug release rate also increased due to the wetting effect of PVP.     

Measurements and modeling of high-pressure excess molar enthalpies and isothermal vapor-liquid equilibria of the carbon dioxide + N,N-dimethylformamide system

Mixtures of supercritical CO₂ and N,N-dimethylformamide (DMF) are very often involved in supercritical fluid applications and their thermodynamic properties are required to understand and design these processes. Excess molar enthalpies () for CO₂ + DMF mixtures were measured using an isothermal high-pressure flow calorimeter under conditions of temperature and pressure typically used in supercritical processes: 313.15 and 323.15 K at 9.00, 12.00, 15.00 and 18.00 MPa and 333.15 K at 9.00 and 15.00 MPa. The Peng-Robinson and the Soave-Redlich-Kwong equations of state were used in conjunction with the classical mixing rules to model the literature vapor-liquid equilibrium and critical data and the excess enthalpy data. In most cases, CO₂ + DMF mixtures showed very exothermic mixing and excess molar enthalpies exhibited a minimum in the CO₂-rich region. The lowest value (−4526 J mol⁻¹) was observed for a CO₂ mole fraction value of 0.713 at 9.00 MPa and 333.15 K. On the other hand, at 9.00 MPa and 323.15 and 333.15 K varies linearly with CO₂ mole fraction in the two-phase region where a gaseous and a liquid mixture of fixed composition are in equilibrium. The effects of pressure and temperature on the excess molar enthalpy are large. For a given mole fraction, mixtures become less exothermic as pressure increases or temperature decreases. These excess enthalpy data were analyzed in terms of molecular interactions, phase equilibria, density and critical parameters previously reported for CO₂ + DMF. All throughout this paper, the key concepts and modeling tools originate from the work of van der Waals: the paper is intended as a small piece of recognition of van der Waals overwhelming contributions to thermodynamics.     

Supercritical impregnation of lavandin (Lavandula hybrida) essential oil in modified starch

Lavandin (Lavandula hybrida) essential oil contains components with biocide properties that can be used as substitutes of synthetic drugs in livestock. This application requires an appropriate formulation of the essential oil. In this work, supercritical impregnation of lavandin oil has been proposed as a possible formulation process, due to the high solubility of lavandin essential oil in supercritical carbon dioxide. The polymer used in this work as carrier material was starch modified with the n-octenil succinate (OSA) group, in the form of powder with a particle size of 30 μm. The effects of operational pressure (10-12 MPa), temperature (313-323 K) and lavandin oil to starch mass ratio (0.2-1) were studied. Impregnation loads ranging from 25 to 150 mg lavandin oil/g OSA-starch were obtained. The distribution coefficient of essential oil between the starch and the supercritical phase as well as the essential oil load depended on the density of CO₂.     

Preparation of liposomes using the supercritical anti-solvent (SAS) process and comparison with a conventional method

Two methods to produce liposomes encapsulating a fluorescent marker were compared: the supercritical anti-solvent (SAS) method and a conventional one (Bangham). Liposome size and encapsulation efficiency were measured to assess the methods. Micronized lecithin produced by the SAS process was characterized in terms of particle size, morphology and residual solvent content in order to investigate the influence of experimental parameters (pressure, CO₂/solvent molar ratio and solute concentration). It appears that when the lecithin concentration increases from 15 to 25 wt.%, at 9 MPa and 308 K, larger (20-60 μm) and less aggregated lecithin particles are formed. As concerns liposomes formed from SAS processed lecithin, size distribution curves are mainly bimodal, spreading in the range of 0.1-100 μm. Liposome encapsulation efficiencies are including between 10 and 20%. As concerns the Bangham method, more dispersed liposomes were formed; encapsulation efficiencies were about 20%, and problems of reproducibility have been raised.