Supercritical antisolvent micronization of cyclodextrins

Micronization of α- and β-cyclodextrins solubilized in dimethylsulfoxide (DMSO) has been successfully performed using the Supercritical AntiSolvent (SAS) precipitation. We obtained sub-microparticles, microparticles and expanded microparticles of both cyclodextrins, ranging from about 0.1 to 11 μm, varying the concentration of the liquid solution from 5 to 200 mg/mL, process temperature (40-60 °C) and pressure (90-180 bar). Particularly, we observed for both materials that, increasing the concentration of the liquid solution, decreasing the pressure or increasing the temperature, the mean particle size increased and the particle size distribution enlarged.We also tried to relate the morphologies obtained to the position of the process operating point with respect to the mixture critical point (MCP) of the ternary system cyclodextrin-DMSO-CO₂.     

Nanostructured cellulose acetate filaments produced by supercritical antisolvent precipitation

The supercritical antisolvent precipitation technique was used to precipitate cellulose acetate in form of nanostructured filaments. Two different solvents were used: acetone, chosen because it is a typical laboratory solvent, and a mixture acetic acid + water, that is industrially used in the cellulose acetylation process. The influence of the operating parameters, such as concentration of the liquid solution, pressure and temperature, on the structure of cellulose acetate filaments was studied. Several centimeter long structures, formed by nanoelements ranging from about 50 to 250 nm, were obtained. Some experiments were replicated on a pilot plant to demonstrate the scalability of the process.     

Organic nanoparticles recovery in supercritical antisolvent precipitation

One of the major problems in dry nanoparticles production and handling is their recovery. Indeed, they tend to disperse in all the precipitation chamber and, due to their dimensions, are very difficult to collect.Supercritical antisolvent precipitation (SAS) was frequently used to produce nanoparticles at very mild conditions of pressure and temperature, but the issues of sedimentation mechanisms and nanoparticles recovery as single units, have not been evaluated yet.In this work, SAS nanoparticles were produced for samarium acetate, rifampicin, astemizole, amoxicillin trihydrate, tetracycline hydrochloride, clemastine, cellulose acetate and disperse red 60; the powders were collected as aggregates, due to the specific sedimentation mechanism that characterizes the process. SAS produced nanoparticles of the previously listed materials were precipitated from different organic solvents. Then, they were post-processed by ultrafiltration, ultracentrifugation and ultrasound based techniques, demonstrating that they can be easily separated in single nano-units. Nanoparticles showed mean diameters in the range 50-150 nm.     

Supercritical AntiSolvent micronization of nalmefene HCl on laboratory and pilot scale

Supercritical AntiSolvent precipitation (SAS) has been used to produce micronized particles of nalmefene hydrochloride, a selective narcotic antagonist and a promising adjunctive for the treatment of several kinds of addiction. Experiments have been performed using a laboratory scale apparatus and a semi-industrial scale plant. Ethyl alcohol (EtOH) has been used as liquid solvent because of its acceptability in processing pharmaceutical compounds.The effects of SAS process parameters such as temperature, pressure, at a constant concentration of the solute in the liquid solution (1.9 wt.%) have been studied.We have related the different powder morphologies obtained to the position of the process operating point with respect to the vapor-liquid equilibria (VLEs) of the ternary system nalmefene HCl/EtOH/CO₂. Operating SAS well above the mixture critical point (MCP) of the mixture, nano-particles have been generated with a mean diameter ranging from 200 to 300 nm, near and below the MCP in the gas phase region, we have obtained submicro- and micro-particles with mean diameters ranging from 0.5 to 2 μm. Balloons larger than 10-20 μm in diameter and crystals have been also obtained.The results of interest obtained on the laboratory scale plant have been successfully reproduced on the semi-industrial scale plant.The micronized product has also been characterized using powder diffraction X-ray (XRD) and differential scanning calorimetry (DSC), to verify the influence of the micronization process on the final product properties. XRD analysis demonstrated that it is possible to obtain amorphous or crystalline precipitates, depending on the process conditions.     

Polymeric microparticles prepared by supercritical antisolvent precipitation

This work has as main objective the development of a model process to obtain microparticles of an acrylate-methacrylate copolymer (Eudragit L100^® and Eudragit EPO^®) using supercritical carbon dioxide (SC-CO₂) as antisolvent (GAS). After studying the behaviour of the copolymers in SC-CO₂ at different operation conditions (pressure, temperature and presence of ethanol (EtOH)), efforts were invested in the optimization of Eudragit EPO^® precipitation from an organic solution using carbon dioxide as antisolvent in batch mode. After loading the precipitation vessel with a fixed quantity of the copolymer dissolution, the SC-CO₂ has been added until the pressure of operation has been reached. Three process parameters, namely, solution nature, presence of surfactants and organic solvent removal step, have been evaluated. Microparticles with mean diameter from about 2 to 12 μm are obtained.     

Supercritical antisolvent micronization of PVP and ibuprofen sodium towards tailored solid dispersions

The supercritical antisolvent technology is used to precipitate polyvinylpyrrolidone (PVP) particles and crystallise ibuprofen sodium (IS) crystals separately and in the form of solid dispersion together. Supercritical carbon dioxide (scCO₂) is used as antisolvent. For PVP particle generation, ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 wt% and 1.5 wt%, the operation pressure between 10 MPa and 30 MPa and the composition of ethanol/acetone solvent mixtures between 100 wt% and 0 wt% of ethanol at a constant temperature of 313 K. Furthermore, the mean molecular weight of the polymer was varied between 40 kg mol⁻¹, 360 kg mol⁻¹ and 1300 kg mol⁻¹. An increase of the content of the poor solvent acetone in the initial solvent mixture as well as the usage of PVP with a higher molecular weight, leads to a significant decrease in mean particle size. At all the investigated parameters always fully amorphous PVP powder precipitates. For IS, only ethanol was used as the solvent, the initial IS concentration in the solution was varied between 1 wt% and 3 wt% and the operation pressure between 10 MPa and 16 MPa. A variation of these parameters leads to a manipulation of the size and the morphology of the crystallised IS crystals. Irrespective of the parameters used, always the same polymorphic form of ibuprofen sodium is produced. The solid dispersions were generated at different compositions of PVP to IS and with two different molecular weights of PVP at otherwise constant conditions. Fully amorphous solid dispersions consisting of IS and PVP together were generated at different ratios of PVP to IS.The mechanisms that control the final particle properties are discussed taking into account two different models for “ideal” and “non-ideal” solutes. Furthermore, the study of the “unconventional” SAS parameters, molecular weight and solvation power of the solvent shows that these parameters qualify to tailor polymer particle properties via SAS processing. Next to the investigation into the behaviour of both solutes separately, fully amorphous solid dispersions consisting of IS and PVP together were generated. While X-ray diffraction was used to analyze the crystalline structure of the particles, respectively, solid dispersions, their morphology was analysed using scanning electron microscopy (SEM).     

Use of solvent mixtures in supercritical antisolvent process to modify precipitates morphology: Cellulose acetate microparticles

In the supercritical antisolvent precipitation (SAS), the jet fluid dynamics is characterized by two-phase mixing at subcritical conditions, and by one-phase mixing at completely developed supercritical conditions. The amplitude of the pressure range, in which binary systems organic solvent/scCO₂ exhibit the transition between two-phase to one-phase mixing, depends on the organic solvent that is in contact with supercritical carbon dioxide (scCO₂) and conditions the morphology of the microparticles produced by SAS. When this pressure range is wide, as in the case of dimethylsulfoxide (DMSO), solutes solubilized in the organic solvent can be precipitated as microparticles by atomization, droplets formation and drying; when this pressure range is narrow, as for acetone, gas mixing prevails and only nanoparticles are generally observed. Therefore, generally speaking, solutes that are soluble only in solvents exhibiting gas mixing in scCO₂, do not exhibit microparticles morphology and this fact is a limitation for several industrial applications.In this work, a model compound, cellulose acetate (CA), that is slightly soluble in DMSO and freely soluble in acetone, was processed by SAS using mixtures of the two solvents that exhibit intermediate behaviors between the two pure solvents, to extend two phase mixing and produce CA microparticles. Using different DMSO/acetone mixture percentages, the effects of the polymer concentration in the liquid solution and of the pressure were studied. A mixture of DMSO/Acetone 50/50 (v/v), at a pressure of 85 bar and a concentration of the liquid solution equal to 40 mg/mL, efficiently produced non-coalescing CA microparticles with a mean diameter of 0.42 μm and a standard deviation of about 0.15 μm, demonstrating that this SAS strategy can be successful.     

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.     

Manipulating the size,the morphology and the polymorphism of acetaminophen using supercritical antisolvent (SAS) precipitation

The supercritical antisolvent technology is used to crystallize paracetamol particles. Supercritical carbon dioxide (scCO₂) is used as antisolvent. Ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of paracetamol in the solution was varied between 1 and 5 wt%, the composition of the ethanol/acetone solvent mixture between 50 and 90 wt% of ethanol and the operation pressure between 10 and 16 MPa at a temperature of 313 K. The most important finding is that the polymorph of paracetamol crystals can be adjusted between monoclinic and orthorhombic by varying the content of ethanol in the solution. The second important finding is that the occurrence of primary and secondary crystal structures can be explained solely by the overall supersaturation during the crystallization process. While X-ray diffraction was used to analyze the polymorph of the particles, their morphology was analyzed using scanning electron microscopy.     

反溶剂沉淀法制备阿托伐他汀钙微粉

采用反溶剂沉淀法制备阿托伐他汀钙微粉,考察了表面活性剂类型、药物溶液浓度、体系温度和干燥方法对颗粒形貌和大小的影响,得到了适宜的微粉化条件。实验分别利用扫描电镜（SEM）、X射线衍射（XRD）、红外光谱分析（FT-IR）和比表面积（BET）等分析方法对原料及产品的性质进行了表征。研究结果表明：表面活性剂甲基纤维素（MC₂₀）可以有效地控制颗粒形貌;改变溶液浓度及体系温度可以调整颗粒大小;混悬液经喷雾干燥得到的干粉是粒度分布均匀的团粒状类球形颗粒,粒径约为1 μm。微粉化产品为无定形,比表面积高于原料药。此外,还探讨了团粒状类球形颗粒的形成机理。     

Preparation and characterization of camptothecin powder micronized by a supercritical antisolvent (SAS) process

Micronized camptothecin (CPT) is prepared with a supercritical antisolvent (SAS) apparatus using dimethyl sulfoxide (DMSO) as solvent and carbon dioxide as antisolvent. Four factors, namely CPT solution concentration and flow rate, precipitation temperature and pressure are optimized by a four-level orthogonal array design (OAD). By analysis of variance (ANOVA), only precipitation pressure has a significant effect on the MPS of micronized CPT. The optimum micronization conditions are determined as follows: CPT solution concentration 1.25 mg/ml, CPT solution flow rate 6.6 ml/min, precipitation temperature 35 °C and precipitation pressure 20 MPa. Under the optimum conditions, micronized CPT with a MPS of 0.25 ± 0.020 μm is obtained. The micronized CPT obtained was characterized by Scanning Electron Microscopy (SEM), Atomic Force Microscope (AFM), High performance liquid chromatography-mass spectrometry (LC-MS), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Differential scanning calorimeters (DSC) and Gas chromatography (GC) analyses. The results showed that the obtained CPT particles have lower crystallinity and SAS micronization process does not induce degradation of CPT. In addition, the residual DMSO is less than the ICH limit for class 3 solvents.     

Screening design of experiment applied to supercritical antisolvent precipitation of amoxicillin: Exploring new miscible conditions

Microparticles of amoxicillin (AMC) have been precipitated by supercritical antisolvent process (SAS) using carbon dioxide and N-methylpyrrolidone (NMP) as antisolvent and solvent, respectively. A fractional factorial design of experiment (DOE) with 2⁷⁻⁴ experiments has been used. Mean particle size (PS) and particle size distribution (PSD) of the processed amoxicillin have been chosen as responses to evaluate the process performance. In a previous work, a DOE was applied too, but now, the range of operating conditions investigated has been changed to let the process take place in a single supercritical phase. Within this range, concentration is again the key factor having most effect on both PS and PSD and thus, the most important factor for controlling the formation of sub-microparticles of amoxicillin by the SAS technique. Moreover, all the experiments included in the new design matrix led to a successful precipitation of amoxicillin.     

Cavitation behavior and mixing performance of antisolvent precipitation process in an ultrasonic micromixer

A facile and robust ultrasonic micromixer was developed to intensify antisolvent precipitation via ultrasonic cavitation. The gas supersaturation created from solvent–antisolvent mixing was found to be a novel driving force which facilitated the generation of cavitation bubbles (CBs). Instead of being attached on the channel wall, numerous CBs translated across the microchannel at a speed up to 1.7 m/s, inducing intense transverse flow over the cross-section. The unique cavitation behavior enabled rapid mixing (mixing time 15–45 ms at 30 W) of solvent–antisolvent over wide Reynolds number range (70–500) and flow rate ratio (5:1–2:3), providing better operability for antisolvent precipitation. The effects of ultrasonic power, total flow rate, flow rate ratio, and solvent on cavitation behavior and mixing performance were quantitatively studied. Finally, the potential of the ultrasonic micromixer as a new tool for antisolvent precipitation was demonstrated by synthesizing size-controllable and monodisperse polymeric nanoparticles in a high-throughput and reproducible manner.     

Supercritical antisolvent precipitation of andrographolide from Andrographis paniculata extracts: Effect of pressure, temperature and CO2 flow rate

Andrographis paniculata extracts were precipitated using the so-called supercritical antisolvent (SAS) technique. Ethanol was used as the solvent and compressed CO₂ as the antisolvent. The effects of process operating conditions (pressure: 5-24 MPa, temperature: 308-328 K and CO₂ flow rate: 0.5-1.5 g/min) on particle size and morphology of precipitated andrographolide were evaluated. X-ray diffraction (XRD) patterns showed significant changes in andrographolide morphology depending on process operating conditions; both column-like and slice-like crystals were observed depending on operating conditions. Crystals with mean diameters of 3.30-228.35 μm were produced, smaller crystals were obtained at high pressure, low temperature and high CO₂ flow rate and vice versa for large crystals. In addition, SAS process also produced high precipitation yields, since solubility of andrographolide is small in the supercritical CO₂ plus ethanol. When operating under subcritical conditions, amorphous particles were produced.     

超临界CO2抗溶剂法制备乙基纤维素微球试验

通过自行设计的超临界CO2微球制备装置,利用乙基纤维素丙酮混合溶液,制备了粒径偏差较小、表面光滑与球形度较好的乙基纤维素微球,采用正交试验讨论了温度、压力、溶液质量浓度、CO2流量对微球粒径与粒径分布的影响,分析了进气与进液方式对试验过程的影响。试验结果表明:改变工艺参数,可在较大范围内调控微球大小,所制微球平均粒径为0.2—2.6μm,粒径偏差为0.07—0.85μm;溶液质量浓度是主要影响因素;不同的汽液接触方式也将影响微球的大小。     

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.     

Nanoparticle formation of lycopene/β-cyclodextrin inclusion complex using supercritical antisolvent precipitation

With a view to promoting dispersion of lycopene in water, the precipitation of an inclusion complex of lycopene and β-cyclodextrin was investigated using the solution-enhanced dispersion by supercritical fluids (SEDS) process. The inclusion complex, which was prepared in N,N-dimethylformamide (DMF), was dissolved in the same solvent and then micronized by SEDS, using carbon dioxide (CO₂) as a supercritical antisolvent. The effects of the initial concentrations of lycopene and β-cyclodextrin, the CO₂ flow rate, the solution flow rate, and the pressure and temperature at which the process was conducted were examined. The morphologies of the resulting particles were observed by scanning electron microscopy (SEM) and field emission-scanning electron microscopy (FE-SEM). Small spherical particles were obtained at all operating conditions. At high pressure, high temperature, high CO₂ flow rate and low solution flow rate, particles with an average particle size of about 40 nm were obtained.     

Influence of pressure, temperature and concentration on the mechanisms of particle precipitation in supercritical antisolvent micronization

In this work, supercritical antisolvent micronization (SAS) is used to produce nanoparticles, microparticles and expanded microparticles of a model compound, gadolinium acetate (GdAc), using dimethylsulfoxide (DMSO) as the liquid solvent with the aim of studying the dependence of particles’ diameter and morphology on some process parameters like pressure, temperature and concentration of the starting solution. Experiments are performed varying the precipitation pressure between 90 and 200 bar, the precipitation temperature between 35 and 60 °C and the concentration of GdAc in the liquid solution in the range from 20 to 300 mg/mL. The experimental evidences show that the formation of particles with specific sizes in the micrometric and nanometric range depends on specific values of each one of these parameters. An explanation of the results is proposed in terms of the competition between two characteristic times of the SAS process that can control the precipitation process. The time of jet break-up of the liquid solution that produces liquid droplet formation, and the dynamic surface tension vanishing time, that induces gas mixing with the precipitation of nanoparticles from the gaseous phase. Indeed, GdAc sub-microparticle, or microparticle (diameter in the range 0.23-1.6 μm with mean diameters in the range 0.28-0.52 μm) formation can be attributed to micro-droplet drying, whereas nanoparticles (mean diameter in the range 90-210 nm) are consistently produced when gas mixing is the possible governing process. In conclusion, the precipitation mechanisms can be modulated varying one SAS parameter a time, thus selecting the range of particle diameters required for the specific application.     

Observation of liquid solution volume expansion during particle precipitation in the supercritical CO2 antisolvent process

An optical measurement technique, which is based on the Foerster resonant energy transfer (FRET) between two different dye molecules, has been applied successfully to observe volume expansion of a liquid solution, when it is pressurized with CO₂. Rhodamine-B and Rhodamine-700 were dissolved in ethanol to form the FRET active dye solution. In a first “prove of principle” experiment, the sensitivity of the FRET efficiency towards volume expansion was demonstrated by pressurizing the liquid dye solution in a cuvette with CO₂. From the rise of the meniscus of the solution inside the cuvette as a function of CO₂ pressure, the simultaneously acquired FRET spectra could be correlated with the volume expansion of the dye solution. In a second experiment, the dye solution was injected into CO₂ at different supercritical antisolvent operation pressures. FRET spectra were recorded 3 mm downstream of the injector nozzle, always upstream of the breakup of the injected liquid solution. At pressures below the thermodynamic mixture critical pressure (7.9 MPa @ 313 K) of the system ethanol/CO₂ no liquid phase volume expansion was observed. At pressures between the thermodynamic and the dynamic mixture critical pressure (8.5 MPa @ 313 K) of the same system, volume expansion could be evidenced before the breakup of the injected liquid solution.     

Gas antisolvent fractionation of semicrystalline and amorphous poly(lactic acid) using compressed CO2

Semicrystalline and amorphous poly(lactic acid) (l-PLA and d,l-PLA, respectively) were fractionated from chloroform solutions using compressed CO₂ as an antisolvent. The following process variables were used to precipitate normalized molecular weight fractions (NMW) of l-PLA ranging from 0.81 to 1.54 relative to the starting material: polymer concentration, initial organic solution volume, and the rate of antisolvent addition. An analysis of variance (ANOVA) used to quantify the importance of these variables determined that polymer concentration had the most significant impact on the NMW of l-PLA precipitated in this gas antisolvent (GAS) precipitation process. The results of the ANOVA also suggest a predictive approach to polymer fractionation in this complex system. The analysis also highlights the differences and similarities between the fractionation of semicrystalline and amorphous polymers using compressed antisolvents.