Molecular dynamics simulation of the formation of pharmaceutical particles by rapid expansion of a supercritical solution

The formation of pharmaceutical particles by the rapid expansion of a supercritical solution is investigated by molecular dynamics simulation. As a pharmaceutical model substance naproxen, a pain reliever and anti-inflammatory drug, is used. The expansion process is modeled in the simulation method by stepwise increasing the size of the simulation box. Comparison with an accurate reference equation of state for the pure solvent carbon dioxide shows that the simulation system follows an adiabatic expansion path. The expansion of a solution of naproxen in supercritical carbon dioxide leads to a highly supersaturated system that starts to form particles. The nucleation and growth kinetics of this particle formation process is investigated and the effect on the particle structure is analyzed.     

Role of tungsten in promoting selective reduction of NO with CO over Ir/WO3–SiO2 catalysts

Catalytic hydrogenation of naphthalene to decalin was studied over a carbon-supported rhodium catalyst in supercritical carbon dioxide solvent at 333 K, and the results were compared with those in an organic solvent. cis-, trans-Decalin and tetralin were formed from the beginning of the reaction in supercritical carbon dioxide. Higher concentration of hydrogen in carbon dioxide solvent and on the active site, and also the suppression of desorption of partially hydrogenated tetralin molecules from the active site would be responsible for higher selectivity to cis-decalin in supercritical carbon dioxide than that in an organic solvent.     

Modeling of drug solubility in supercritical carbon dioxide using equation of state based on hole theory with molecular surface charge density

Equation of state based on hole theory with molecular surface charge density was developed for the modeling of drug solubility in supercritical carbon dioxide. In the hole theory, the density change of supercritical carbon dioxide can be represented by the number of holes in the system. The molecular interaction energy parameter was estimated using the interactions of segments on the molecular surface given by a quantum calculation using conductor-like screening model. The only one parameter, coordination number around a molecule was fitted to the experimental data of the drug solubility in supercritical carbon dioxide. The solubilities of the eighteen drugs in supercritical carbon dioxide were modeled by the equation of state with the molecular surface charge density. The effect of the molecular pair for the coordination number on the correlated results was investigated. It is found that the results using the fitted parameter of the solute–solute pair coordination number result in the modeling performance better than those of carbon dioxide–solute coordination number. The results of the modeling of drug solubility in supercritical carbon dioxide are compared with the experimental data. The average absolute relative deviation between the experimental and calculated results of the solubility for the drug composed of C, H and O atoms acetylsalicylic acid, benzoic acid, ferulic acid, (S)-naproxen, p-benzoquinone, propyl gallate, salicylic acid and vanillic acid is 0.38 smaller than those for compounds including N, F, I and S atoms, amical-48, benzocaine, caffeine, carbamazepine, (±)-flurbiprofen, methimazole, phenazopyridine, theobromine, theophylline and uracil, 0.59.     

超临界或高压CO2中无限稀释扩散系数的模拟

采用分子动力学模拟的方法对超临界二氧化碳的自扩散系数及甲醇和乙醇在超临界二氧化碳中的无限稀释扩散系数进行了模拟计算。结果表明,分子动力学模拟方法可较准确地反映二氧化碳的扩散性质,计算无限稀释扩散系数取得了与实验值较吻合的结果。采用这种新方法可以准确有效的地预测超临界体系的扩散性质,将会更加广泛应用于工程设计,因此分子动力学模拟作为先进的研究手段会得到越来越广泛的应用。     

Highly Efficient Hydrogenation of Cinnamaldehyde Catalyzed by Pt-MCM-48 in Supercritical Carbon Dioxide

In supercritical carbon dioxide medium, a platinum-containing cubic mesoporous molecular sieve was shown to promote markedly the selective hydrogenation of trans-cinnamaldehyde, giving an excellent selectivity for cinnamyl alcohol. In contrast to the other platinum-containing conventional catalysts, Pt-MCM-48 can be recycled a number of times without showing any deactivation in the studied reaction condition. The selectivity mainly depends on the pressure of carbon dioxide, while the conversion depends on the pressure of carbon dioxide as well as hydrogen pressure.     

Synthesis of biodiesel from edible and non-edible oils in supercritical alcohols and enzymatic synthesis in supercritical carbon dioxide

Biodiesel is an attractive alternative fuel because it is environmentally friendly and can be synthesized from edible and non-edible oils. The synthesis of biodiesel from edible oils like palm oil and groundnut oil and from crude non-edible oils like Pongamia pinnata and Jatropha curcas was investigated in supercritical methanol and ethanol without using any catalyst from 200 to 400 °C at 200 bar. The variables affecting the conversion during transesterification, such as molar ratio of alcohol to oil, temperature and time were investigated in supercritical methanol and ethanol. Biodiesel was also synthesized enzymatically with Novozym-435 lipase in presence of supercritical carbon dioxide. The effect of reaction variables such as temperature, molar ratio, enzyme loading and kinetics of the reaction was investigated for enzymatic synthesis in supercritical carbon dioxide. Very high conversions (>80%) were obtained within 10 min and nearly complete conversions were obtained at within 40 min for the synthesis of biodiesel in supercritical alcohols. However, conversions of only 60–70% were obtained in the enzymatic synthesis even after 8 h.     

Kinetics and rate of enzymatic hydrolysis of cellulose in supercritical carbon dioxide

Experiments were carried out on the application of supercritical fluid to the hydrolysis of cellulose by the enzyme, cellulase. The stability of cellulase was sustained at the pressures of up to 160 atm for 90 min at 50 ‡C in supercritical carbon dioxide. In the hydrolysis of cellulose the glucose yield was 100% at supercritical condition. Kinetic constants of hydrolysis at supercritical condition were increased as compared to those at atmospheric condition. The hydrolysis reaction was found competitively inhibited by glucose at supercritical condition.     

Penicillium expansum脂肪酶选择性拆分外消旋萘普生

为了实现固定化扩展青霉TS414(Penicillium expansum TS414)脂肪酶在有机相中对外消旋萘普生的高效拆分,实验考察了水分、温度、有机溶剂、酶浓度、醇结构和醇浓度对酶促拆分反应的影响,确立了优化的酯化反应条件为：异辛烷为溶剂,外消旋萘普生2.15 mmol/L,正丙醇34.3 mmol/L,固定化酶量12 g/L,水0.05%(j), 40℃恒温摇床中200 r/min反应100 h. 在此条件下,酯化拆分反应的转化率为48.3%. 结果表明,固定化Penicillium expansum脂肪酶是一种较为理想的用于外消旋萘普生拆分的工具酶.     

Ring hydrogenation of naphthalene and 1-naphthol over supported metal catalysts in supercritical carbon dioxide solvent

Catalytic ring hydrogenations of naphthalene and 1-naphthol were studied over several supported metal catalysts in supercritical carbon dioxide solvent at low temperature. Higher concentration of hydrogen in supercritical carbon dioxide and lower reaction temperature were responsible for higher catalyst activity and selectivities to the desired partial ring hydrogenated products as compared with those observed in organic solvent for the same catalyst.     

Tert‐butyl peroxyacetate initiated semibatch polymerization of 1,1‐difluoroethylene in supercritical carbon dioxide

Due to its inertness and solubility in vinylidene fluoride, (VF2), supercritical carbon dioxide is used as a replacement solvent for producing polyvinylidene fluoride (PVDF). tert‐butyl peroxyacetate (TBPA) was evaluated for the first time as a free radical initiator for radical chain polymerization of VF2 producing PVDF without use of a dispersion agent in a semibatch reactor using supercritical carbon dioxide. Diethyl peroxydicarbonate (DEPDC) at 75°C has been evaluated in many publications as an initiator in batch and continuous reactors for polymerization of VF2 in supercritical carbon dioxide. The effects of monomer and initiator concentration, agitation, and reaction time upon average molecular weight and polydispersity were evaluated using TBPA as an initiator at 104°C and compared with DEPDC initiated polymerization. It was found that as agitation rate, monomer concentration, and reaction time increased, the average molecular weight of PVDF using TBPA as an initiator increased. Lower concentrations of TBPA were needed compared to DEPDC to produce comparable molecular weights of PVDF. Using TBPA as an initiator at the conditions investigated resulted in lower polydispersity at similar monomer concentrations compared to DEPDC. Average molecular weights using TBPA ranged from 49,900 g/mol to 1.3 million g/mol and polydispersity ranged from 1.3 to 5.4. POLYM. ENG. SCI., 56:435–440, 2016. © 2016 Society of Plastics Engineers     

LIPASE ACTIVITY AND STABILITY IN SUPERCRITICAL CARBON DIOXIDE

The use of a supercritical fluid as a medium for enzymatic reaction was investigated with respect to its application and reaction mechanism. Lipase could catalyze the reaction of hydrolysis and interes-terification in supercritical carbon dioxide at 35°C and 137 bar. There was no difference in the time course of interesterification between the untreated lipase and the lipase exposed to supercritical carbon dioxide indicating that the enzyme was not severely damaged.     

超临界二氧化碳中丙烯酸乙酯/3-氯丙烯接枝天然橡胶的合成与表征

采用超临界二氧化碳溶胀聚合法,以丙烯酸乙酯（EA）/3-氯丙烯（AC）为单体对天然橡胶进行了接枝改性,合成了接枝共聚物NR-g-(EA/AC)。考察了压力和引发剂用量对接枝聚合反应的影响;对NR-g-( EA/AC)进行了红外光谱、力学性能、耐溶剂性、耐燃性、硬度的测试及接枝效率和接枝率的计算,并与溶液聚合法所得NR-g-( EA/AC)的性能进行了比较。结果发现,在接枝橡胶中成功的引入了—C=O和—Cl基团;接枝橡胶的弹性模量、拉伸强度、硬度、耐燃性和耐溶剂性较天然橡胶的有了显著提高。使用溶液法和超临界二氧化碳溶胀聚合法改性天然胶乳都获得了较高的转化率和接枝率,所得产品的机械力学性能相近,但溶液法所得产品的耐溶剂性能优于后一种方法。由于超临界二氧化碳的绿色溶剂性质,超临界二氧化碳溶胀聚合法有望取代溶液聚合法而发展成一种绿色的接枝改性天然橡胶方法。     

Rapid Hydrogenation of Aromatic Nitro Compounds in Supercritical Carbon Dioxide: Mechanistic Implications via Experimental and Theoretical Investigations

An exceptionally rapid hydrogenation of nitrobenzene to aniline [TOF=252,000 h⁻¹] over palladium containing MCM‐41 (Pd/MCM‐41) with excellent yield of >99% can be achieved in supercritical carbon dioxide at 50 °C and a hydrogen pressure of 2.5 MPa. It has been observed that this promising method preferred a single phase between liquid substrate and carbon dioxide‐hydrogen system. The ascendancy of the supercritical carbon dioxide medium is established in comparison with the conventional organic solvent and solvent‐less conditions. Changes in the reaction parameters such as carbon dioxide and hydrogen pressure, temperature and the reaction time do not affect the selectivity. A combined experimental and theoretical study has elucidated the mechanism under the studied reaction condition because experimental observations revealed a direct conversion of nitrobenzene to aniline. However, density functional theory (DFT) calculation shows that the direct conversion is energetically unfavourable; hence, a stepwise mechanism has been proposed. Theoretical predictions and experimental observations suggested that the rate‐limiting step of nitrobenzene conversion is different from that of the liquid phase hydrogenation. This catalytic process can also be successfully extended to the hydrogenation of other aromatic nitro compounds with different substituents. Easy separation of the liquid product from catalyst and the use of an environmentally friendly solvent make this procedure a viable and an attractive green chemical process.     

Enzymatic synthesis of oleyl oleate in dense fluids

Esterification between oleic acid and oleyl alcohol, catalyzed by theMucor miehei immobilized lipase in a batch-stirred tank reactor with supercritical carbon dioxide as solvent produced higher reaction rates at supercritical conditions than in the solvent-free system. A continuous fixed-bed reactor was designed based on the results obtained from batch experiments. At 150 bar, 40°C, and with water activity 0.46% w/w, the activity of the enzyme preparation is practically unchanged when CO₂ was used as solvent. The addition of small amounts of water increases the conversion rate. The higher conversion also was observed at longer residence time. Whenn-butane was used as reaction medium, a decrease in conversion was observed.     

Diffusion coefficients of supercritical carbon dioxide and its mixtures using molecular dynamic simulations

Molecular dynamic simulations have been evaluated for systems containing supercritical carbon dioxide to predict high-pressure diffusion coefficients of binary mixtures. Diffusion coefficients of high boiling compounds in supercritical fluids are important for the design of supercritical extractors, separators and reactors. Since high-pressure experiments are time intensive and difficult to perform, molecular simulations could prove a useful framework to obtain thermodynamic properties; however, their reliability is still in question. In this work, an NVT ensemble single site model molecular dynamic simulation using gear predictor corrector algorithm has been applied to calculate diffusion coefficients of carbon dioxide, naphthalene, 2,6-dimethylnaphthalene and 2,7-dimethylnaphthalene in supercritical carbon dioxide system at 317.5 K. The Lennard-Jones (12?C6) and the Coulomb potential function have been combined into an intermolecular potential function to measure the binary molecular interaction. The simulation results of the diffusion coefficients are being compared with similar experimental data near the critical points. The calculated diffusion coefficients for each system behaved as a monotonic decreasing function of the molar density and the molecular simulations results, and the selected experimental data are in good agreement.     

Supercritical phase behavior for biotransformation processing

In recent works, supercritical carbon dioxide turned out to offer innovative and highly effective alternatives for the workup of biphasic whole-cell biotransformation reaction mixtures. Further optimization of the downstream processing, e.g. by supercritical extraction of the product, requires a reliable simulation of the phase behavior in those systems. In this work, binary and ternary systems containing carbon dioxide and organic components from the biotransformation reaction mixture, such as styrene (substrate), (S)-styrene oxide (product), 2-phenylethanol (byproduct), octane (inducer), and bis-2(ethylhexyl)phthalate (solvent) were measured and modeled for temperatures ranging from 308.15 to 350.15 K and pressures ranging from 5 to 70 MPa using the PC-SAFT equation of state. The obtained results offer the possibility to precisely predict the phase behavior in this system, thus enabling the modeling of e.g. supercritical-fluid extraction steps.     

The selective thermal cis-trans isomerization of 1,2-diphenylsulfonyl ethylene in the presence of carbon dioxide

The selective isomerization of cis-1,2-diphenylsulfonyl ethylene to trans-1,2-diphenylsulfonyl ethylene proceeded in supercritical carbon dioxide above 393 K without an addition of catalyst. The product yield increased with increasing temperature and was almost constant against carbon dioxide density. The 73% of product yield was obtained at 493 K and 10 MPa of carbon dioxide pressure for 60 min. The product yield obtained in supercritical carbon dioxide was larger than those obtained in organic solvents. The supercritical carbon dioxide was a dilute solvent compared with organic solvent, which probably reduced the suppression of the reaction by dense solvent. Further, only cis-sulfonyl ethylenes isomerized among several cis-ethylene derivatives. The sulfonyl group played an important role for the isomerization.     

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.     

超临界二氧化碳化学反应研究进展

二氧化碳（CO₂）资源化技术是减少碳排放、实现碳中和的有效手段。如何将CO₂变废为宝,实现其高效利用是国内外研究者关注的热点。超临界CO₂作为常用的超临界流体之一,既可作为安全环保的反应介质,也可作为反应物参与化学反应合成产品,具有良好的应用前景。本文介绍了超临界CO₂的性质和特点,着重评述了近年来超临界CO₂作为反应物在加氢反应、Kolbe-Schmitt反应、碳酸化反应和作为反应介质在催化加氢反应、羰基化反应及酶催化反应方面的研究进展,提出了今后应开发更为高效的催化剂以进一步改善CO₂反应转化率和化学利用率等建议。     

Management and control of modifier content in preparative SFC solvent cycles

The objective of this work was to establish a solvent cycle with a possibility for modifier control in a preparative supercritical fluid chromatography simulated moving bed plant (SFC-SMB). Fourier transform infrared (FTIR) spectroscopy and flame ionization detection (FID) have been investigated for measuring alcohol concentrations in supercritical carbon dioxide. The integration of these in-line techniques into a modifier control schema allowed the operation of a closed loop SFC-SMB cycle. The applicability of the developed control concept for usage of 2-propanol in supercritical carbon dioxide has been verified by an experimental test series involving an eight column SFC-SMB plant. Different process variations have been compared in terms of energy and solvent consumption. Hereby, savings of almost all CO₂ and 76% modifier could be achieved.