通过模型为基础的溶液选择来调控药品化合物的形貌

In this paper we present a strategy for tuning the crystal morphology of pharmaceutical compounds by the appropriate choice of solvent via an optimization model. A three-stage approach involving a pre-design stage, a product design stage and a post-design experimental verification stage is presented. The pre-design stage addresses the tormulation of the property constraint tor crystal morphology. This involves crystallization experiments aria development of property models and constraints for morphology. In the design stage various property requirements for the solvent along with crystal morphology are considered and the product design problem is formulated as a mixed integer nonlinear programming model.The design stage provides an optimal solvent/list of candidate solvents. Similar to the pre-design stage, in the post design experimental verification stage, the morphology of the crystals （precipitated from the designed solvent） is verified through crystallization experiments followed by product characterization via scanni＇ng electron microscopy, powder X-ray diffraction imaging and Fourier transform spectra analysis.     

Optimization of solvent crystallization process in obtaining high purity anthracene and carbazole from crude anthracene

Solvent crystallization is the main method used for preparing anthracene and carbazole from the crude anthracene. The key to the optimization of this method is improving the solubility selectivity of the solvent by means of solvent modulating and process optimization. In this study, the solubility of anthracene, phenanthrene, and carbazole in xylene, dimethylformamide (DMF), DMF with amine/amide, isopropanolamine, and chlorobenzene is examined and the solid‐liquid ternary anthracene–carbazole–DMF/(DMF+19.96% isopropanolamine) system phase diagram is determined and applied in the solvent crystallization process. The results showed that the solubility selectivity of xylene increases with increased temperature. Also, selectivity increases with an increase of the amount of isopropanolamine in the mixture of DMF and isopropanolamine, while decreases with increased temperature. Through multiple washings of crude anthracene with xylene, DMF+19.96% isopropanolamine, and chlorobenzene, it was possible to obtain anthracene and carbazole of purity higher than 98 wt %. © 2013 American Institute of Chemical Engineers AIChE J, 60: 275–281, 2014     

Incorporation of Mass and Energy Integration in the Optimal Bioethanol Separation Process

A techno‐economic analysis for the separation process in bioethanol production is presented. Optimized azeotropic separation processes in conjunction with process integration (mass and energy) are considered to simultaneously enhance the results from economic and environmental points of view. Process integration improves significantly the separation process because it helps to reduce the overall energy required in the reboilers based on energy integration and additionally to diminish the amount of required solvent based on mass integration. The SYNHEAT optimization model was applied for energy integration whereas a direct recycle strategy was implemented for the mass integration process. The best separation processes obtained correspond to an integrated conventional separation sequence with energy integration to ethanol‐water mixture III and integrated optional separation sequences with energy integration to ethanol‐water mixture III, with significant savings in utility costs and possible recycling of nearly all solvent.     

Networks with large solvent recycle: Dynamics,hierarchical control,and a biorefinery application

A class of networks featuring large recycle of solvent is analyzed. This feature is central to numerous integrated processes which use solvents in various reaction and separation steps. A prototype network capturing the essential features of such networks is identified. Rigorous dynamic analysis reveals the presence of two time‐scale dynamics exhibited by this prototype network. A systematic framework for model reduction and a subsequent hierarchical control design is proposed. The advantages of the proposed design over direct model‐based control are demonstrated via a simulation case study. Finally, the application of the proposed framework to a newly proposed process for the production of 5‐hydroxymethylfurfural from fructose is also presented. © 2011 American Institute of Chemical Engineers AIChE J, 58: 1764–1777, 2012     

Analysis and optimization of continuous organic solvent nanofiltration by membrane cascade for pharmaceutical separation

The major part of the production costs of pharmaceuticals can be imputed to the downstream processing, where membrane technologies have to deal with some challenges as separations involving solutes with similar sizes or solvent recovery and recycling. This work contributes to the progress in the design of continuous organic solvent nanofiltration systems for this purpose and includes the configuration of dual membrane cascades, sensitivity analysis of the operation variables, and economic optimization as innovations. Analyzed configurations include multistage cascades up to three stages, and dual membrane cascades up to five stages. The total costs (TC) were chosen as the formulated objective function to minimize in the economic optimization strategy. The treatment of the residual stream leaving the system resulted the main cost of the process (more than 85% for dual cascades), but the solvent recovery units can significantly reduce the TC (64–77% depending on the required solvent quality). © 2014 American Institute of Chemical Engineers AIChE J, 60: 931–948, 2014     

Increasing selectivity of the hydroformylation in a miniplant: Catalyst,solvent, and olefin recycle in two loops

The application of thermomorphic solvent systems offers the combination of homogeneous catalysis in a single phase and catalyst recovery via phase separation. To increase economic feasibility the minimization of waste streams and side reactions is desired. For this, a continuous process for the hydroformylation of 1‐dodecene in the solvent system DMF/n‐decane is shown. While the Rh/Biphephos catalyst is recycled in DMF in a first loop, the n‐decane and remaining olefins are separated from the product via distillation to form the second loop. In this process the need for additional solvent supply and the isomerization reaction of 1‐dodecene is reduced significantly. The reaction toward internal olefins decreases from initially 15 to 3%. The stable hydroformylation process with a yield of the linear hydroformylation product of 55% and l/b‐ratio of 95/5 is shown for 120 h. © 2016 American Institute of Chemical Engineers AIChE J, 62: 4377–4383, 2016     

超重力精馏回收果胶沉淀溶剂的应用

同时应用超重力精馏连续与间歇操作分离回收果胶沉淀溶剂中的乙醇,并以不锈钢波纹丝网为填料,在原料乙醇质量分数x_f=55%、回流比R=4、超重力因子β=63.16～252.67、原料流量F=15～50L/h、1.01×10⁵Pa和室温进料下操作,研究了四级超重机在连续精馏过程中的传质性能;并在β=161.71、R=2.5～7及1.01×10⁵Pa操作条件下,考察了间歇精馏过程中不同回流比R对塔顶和塔底乙醇浓度x_d和x_w的影响.结果表明,在连续精馏过程中,理论塔板数N_T随β和F的增大而增加,设备的等板高度HETP为41.12～58.21mm,x_d=93%,x_w=35%;在间歇精馏过程中,x_d随着R的增大先增高后降低,x_w随着R和t的增大而下降,所得产品x_d为92.5%,x_w为1.05%;乙醇分离回收效果良好,回收率为91.28%,单位回收乙醇产品成本为0.644元/L,充分表现出超重力精馏工艺应用于果胶沉淀溶剂的回收再利用的优势.     

A hierarchical method to integrated solvent and process design of physical CO2 absorption using the SAFT‐γ Mie approach

Molecular‐level decisions are increasingly recognized as an integral part of process design. Finding the optimal process performance requires the integrated optimization of process and solvent chemical structure, leading to a challenging mixed‐integer nonlinear programming (MINLP) problem. The formulation of such problems when using a group contribution version of the statistical associating fluid theory, SAFT‐γ Mie, to predict the physical properties of the relevant mixtures reliably over process conditions is presented. To solve the challenging MINLP, a novel hierarchical methodology for integrated process and solvent design (hierarchical optimization) is presented. Reduced models of the process units are developed and used to generate a set of initial guesses for the MINLP solution. The methodology is applied to the design of a physical absorption process to separate carbon dioxide from methane, using a broad selection of ethers as the molecular design space. The solvents with best process performance are found to be poly(oxymethylene)dimethylethers. © 2015 American Institute of Chemical Engineers AIChE J, 61: 3249–3269, 2015     

A computer-aided molecular design framework for crystallization solvent design

One of the key decisions in designing solution crystallization processes is the selection of solvents. In this paper, we present a computer-aided molecular design (CAMD) framework for the design and selection of solvents and/or anti-solvents for solution crystallization. The CAMD problem is formulated as a mixed integer nonlinear programming (MINLP) model. Although, the model allows any combination of performance objectives and property constraints, in the case studies, potential recovery was considered as the performance objective. The latter, needs to be maximized, while other solvent property requirements such as solubility, crystal morphology, flashpoint, toxicity, viscosity, normal boiling and melting point are posed as constraints. All the properties are estimated using group contribution methods. The MINLP model is then solved using a decomposition approach to obtain optimal solvent molecules. Solvent design and selection for two types of solution crystallization processes namely cooling crystallization and drowning out crystallization are presented. In the first case study, the design of single compound solvent for crystallization of ibuprofen, which is an important pharmaceutical compound, is addressed. One of the important issues namely, the effect of solvent on the shape of ibuprofen crystals is also considered in the MINLP model. The second case study is a mixture design problem where an optimal solvent/anti-solvent mixture is designed for crystallization of ibuprofen by the drowning out technique. For both case studies the performance of the solvents are verified qualitatively through SLE diagrams.     

Integrating product and process design with optimal control: A case study of solvent recycling

This paper proposes the simultaneous integration of environmentally benign solvent selection (product design), solvent recycling (process design) and optimal control for the separation of azeotropic systems using batch distillation. The previous work performed by Kim et al. (2004. Entrainer selection and solvent recycling in complex batch distillation. Chemical Engineering Communications 191(12), 1606-1633) combines the chemical synthesis and process synthesis under uncertainty. For batch distillation, optimal operation is also important due to the unsteady state nature of the process and high operating costs. Optimal control allows us to optimize the column operating policy by selecting a trajectory for the reflux ratio. However, there are time-dependent uncertainties in thermodynamic models of batch distillation due to the assumption of constant relative volatility. In this paper, the uncertainties in relative volatility were modeled using Ito processes and the stochastic optimal control problem was solved by combined maximum principle and non-linear programming (NLP) techniques. Then the previous work of optimal solvent selection and recycling was coupled with optimal control. As a real world example for this integrated approach, a waste stream containing acetonitrile-water was studied. The optimal design parameters obtained by Kim et al. (2004. Entrainer selection and solvent recycling in complex batch distillation. Chemical Engineering Communications 191(12), 1606-1633), for this separation were used and the optimal control policy is computed first without considering uncertainties by variable transformation technique. The deterministic optimal control policy improves the product yield by 4.0% as compared to the base case, verified using a rigorous simulator for batch distillation. When the stochastic optimal control policy was computed representing the relative volatility as an Ito process, a similar recovery rate was obtained from simulations, but the batch time was reduced significantly, producing the most profitable operation.     

考虑选择性和反应速率的多目标制药反应溶剂设计

药物研制过程存在着大量的液–液均相有机反应,合适的反应溶剂能够大幅提高此类反应的反应速率与选择性,从而提高合成效率,提升药物质量。以2,4-二氯-5-硝基嘧啶与对氨基苯腈的芳香亲核反应（S_NAr）为研究对象,采用计算机辅助分子设计（computer-aided molecular design, CAMD）的方法进行反应溶剂设计。首先使用量子力学（quantum mechanics, QM）计算的方法获得少量溶剂中的反应速率常数并通过反应动力学模型与溶剂性质关联,然后构建同时考虑选择性和反应速率常数的混合整数非线性规划（mixed-integer nonlinear programming, MINLP）的多目标优化模型,最后采用分解式算法对模型优化求解,实现制药反应溶剂设计的目标。     

异戊橡胶单体及溶剂回收套用研究

异戊橡胶凝聚得到的油相(母液)中除含有己烷和未反应的异戊二烯(IP)外还含有水、防老剂和阻聚剂等.由于这些微量杂质的存在影响IP聚合,因此母液不能直接用于异戊橡胶聚合.溶剂能否循环套用已经成为制约异戊橡胶开发的一个重要问题.通过母液分离,使己烷达到重复利用,解决了回收己烷循环套用问题.     

Nanofiltration membrane cascade for continuous solvent exchange

This paper proposes a continuous process for solvent exchange, a key unit operation for organic synthesis in pharmaceutical manufacturing. This process comprises a counter-current membrane cascade using organic solvent nanofiltration (OSN) membranes. The effect of process parameters, such as number of stages and flow rate ratio of replacing solvent to initial solvent, on solvent exchange performance are tested through simulations and experiments. Experimental results show 47.8%, 59.2%, and 75.3% solvent exchange for single-stage, two-stage and three-stage cascades, values which are close to the 50.0%, 66.6%, and 75.0% predicted by simulations. In general, the feasibility of OSN membrane cascades for continuous solvent exchange is demonstrated in this work.     

Novel phase inversion process for symmetric membrane formation through thermal quenching of polymer solution in same solvent

A new and useful form of phase inversion for the formation of porous polymeric membranes is presented herein. As in the case of thermally induced phase separation (TIPS), this new form involves only two components (polymer and solvent) and a thermal quench; here the quench is accomplished via immersion in a cold bath of the micromolecular component (solvent) of the dope. Ιn terms of a fixed‐pressure two‐component phase diagram the quench is a non‐vertical one. We will refer to the new method as cold‐solvent induced phase separation (CIPS). In the present work we study mainly the poly(ethylene‐co‐vinyl alcohol)/1,3‐propanediol system which leads to bi‐continuous structures stemming from a combination of liquid‐liquid demixing and crystallization. In addition, we compare with the case of the Nylon‐l2/formic acid system that we have briefly considered before and study further herein; the consequences of the TIPS to CIPS shift of method are different for the two systems, and the two situations are representative of two general possibilities. We also report general properties such as porosity, tensile strength, water permeation flux, and crystallinity of the produced poly(ethylene‐co‐vinyl alcohol) membranes. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42282.     

Generalized LIQUAC model for the single‐ and mixed‐solvent strong electrolyte systems

A generalized strong electrolyte LIQUAC model is presented to describe the vapor–liquid equilibria, osmotic coefficients, mean ion activity coefficients, and solid–liquid equilibria for the single‐ and mixed‐solvent electrolyte systems over the entire concentration range from infinite dilution to saturated solutions. An appropriate reference state for the ions was first applied to test the capability of the model in simultaneously describing the mean ion activity coefficients and the solubility of a salt in a binary solvent mixture. The influence of salt on the vapor–liquid equilibrium behavior is predicted with the new correlated parameters. The generalized activity coefficient formulations are presented through the investigation of thermodynamic properties and phase phenomena in the single‐ and mixed‐solvent electrolyte systems. This work is a continuous study for the LIQUAC activity coefficient model. A reliable representation of the single‐ and mixed‐solvent salt solutions is obtained. © 2010 American Institute of Chemical Engineers AIChE J, 2011     

Separation of conglomerate forming enantiomers using a novel continuous preferential crystallization process

Providing enantiomerically pure products is of key importance in the fine chemicals, food, and pharmaceutical industries. A continuous preferential crystallization process is presented that allows the separation of conglomerate forming enantiomers in a stable, robust, and flexible way. This is achieved by coupling two continuous crystallizers by exchanging their clear liquid phases. Each crystallizer is connected to a suspension mill responsible for in situ seed generation through particle breakage. The dynamic and steady‐state behavior of this process is extensively analyzed for racemic feed streams through process simulations, and parameter regions, which yield pure enantiomers in both crystallizers, are identified. For enriched feed streams, it is further shown when this novel flow sheet is capable of outperforming an ideal batch process in terms of solvent consumption per unit mass of desired enantiopure product produced. © 2015 American Institute of Chemical Engineers AIChE J, 61: 2810–2823, 2015     

A novel method for solvent fractionation of two CLA isomers

Conjugated linoleic acid (CLA) is commercially available as a mixture consisting of almost equal amounts of the cis-9,trans-11-CLA (c9, t11) and trans-10, cis-12-CLA (t10, c12) isomers. Separation of the two isomers is highly significant since each exhibits different biochemical properties. Highly efficient separation could be accomplished by crystallization in acetone (solvent) of the two CLA isomers (solutes) in the presence of medium-chain fatty-acid (MCFA) additives. The relative concentration ratios of the two CLA isomers in the solvent-crystallized materials varied depending on which MCFA were added. Addition of lauric and decanoic acids resulted in the crystals predominantly containing t10,c12, whereas octanoic acid yielded those predominantly containing c9,t11. We have confirmed that onetime solvent crystallization using decanoic acid and octanoic acid additives increased the t10,c12 and c9,t11 concentrations, and that repeated solvent crystallization resulted in the ratio of c9,t11 to t10,c12 of at least 4∶96 or 98∶2.     

Machine learning-based atom contribution method for the prediction of surface charge density profiles and solvent design

Solvents are widely used in chemical processes. The use of efficient model-based solvent selection techniques is an option worth considering for rapid identification of candidates with better economic, environment and human health properties. In this paper, an optimization-based MLAC-CAMD framework is established for solvent design, where a novel machine learning-based atom contribution method is developed to predict molecular surface charge density profiles (σ-profiles). In this method, weighted atom-centered symmetry functions are associated with atomic σ-profiles using a high-dimensional neural network model, successfully leading to a higher prediction accuracy in molecular σ-profiles and better isomer identifications compared with group contribution methods. The new method is integrated with the computer-aided molecular design technique by formulating and solving a mixed-integer nonlinear programming model, where model complexities are managed with a decomposition-based strategy. Finally, two case studies involving crystallization and reaction are presented to highlight the wide applicability and effectiveness of the MLAC-CAMD framework.