Biomedical subjects

Marco Mazzotti

Publications and source records attributed to Marco Mazzotti.

At least 19 recordsLinked to original sources

PubMed2006

Optimization of simulated moving bed and column chromatography for a plasmid DNA purification step and for a chiral separation.

This work analyzes the performance of the SMB and the column chromatography processes for two different case studies: the first stage of the plasmid DNA (pDNA) polishing, and the Tröger's base enantiomer separation, in which the adsorption isotherms are linear and non-linear, respectively. Simulation tools are used together with an optimization routine (Non-Sorting Genetic Algorithm (NSGA)) in order to find the optimum operating conditions leading to maximum productivity and minimum solvent consumption; the optimum solution for each of the processes is a curve on the productivity-solvent consumption plane, the so-called Pareto set. The comparison between the column and the SMB processes is based on the relative position of the two Pareto sets calculated at equal conditions and for the same final purity and recovery of the target species. The results show that SMB is superior to column chromatography in the two case studies investigated, i.e. in the case of the linear isotherm (pDNA), the productivity gain is up to a factor two for a given value of the solvent consumption. Furthermore, the flexibility of the SMB operation is larger, since the Pareto sets are flatter and they prolong into regions of the productivity-solvent consumption plane that are not accessible with the column chromatography process.

Adsorption↗

PubMed2006

Equilibrium theory based design of simulated moving bed processes for a generalized Langmuir isotherm.

In the frame of the local equilibrium theory of chromatography, design criteria for complete separation of binary mixtures in simulated moving bed (SMB) separations are developed, presented and discussed. These apply to systems, whose retention behavior is characterized by a generalized Langmuir isotherm. By allowing for negative terms in the denominator of the classical Langmuir isotherm, this newly introduced adsorption model captures a broad class of competitive or synergistic adsorption, including anti-Langmuir behavior for both adsorbates, and mixed cases where one species behaves in a Lagmuirian and the other in an anti-Langmuirian manner. By extending classical equilibrium theory results for the binary Langmuir isotherm, and by generalizing the approach followed earlier to derive SMB design criteria for the binary and multi-component Langmuir isotherm, exact algebraic equations for the boundary of the complete separation region in the operating parameter space are derived for all possible generalized Langmuir isotherm. The effect of changing feed composition on the shape of the complete separation region and on the position of the optimal operating point is analyzed and discussed.

Chromatography↗

PubMed2006

A continuous, counter-current multi-column chromatographic process incorporating modifier gradients for ternary separations.

The existing literature of continuous chromatographic process indicates the scarcity of processes which allow the continuous separation of a ternary mixture and which also exploit the power of modifier gradients and counter-currency. A new process filling this gap is presented and analyzed using an equilibrium theory model and linear isotherms. The analysis leads to the explicit formulation of an operating region, where 100% purity and yield can be obtained. A normalized flow rate ratio is introduced, which allows an easy description and understanding of the process behavior. The gained insights are verified using a detailed simulation model, where the influence of changes in the normalized flow rate ratios on the unit performance is investigated.

Computer Simulation↗

PubMed2006

Experimental verification of sample-solvent induced modifier-solute peak interactions in biochromatography.

In a previous theoretical analysis based on equilibrium theory it has been shown how differences in the sample and elution modifier concentrations can lead to unexpected behavior of the solute eluted peaks such as retention time distortion, peak deformation and peak doubling. All these features are verified experimentally in this work using the polypeptide calcitonin and a variant of a specific monoclonal antibody as chromatographic model systems. For both experimental systems, the retention time distortion can be predicted with high accuracy by the solution of the equilibrium theory model. For the polypeptide, the predictions from the theory about the occurrence of peak deformation and double peaks has been successfully verified by a series of tailored experiments with positive as well as negative modifier perturbations.

Antibodies, Monoclonal↗

PubMed2006

Experimental implementation of identification-based optimizing control of a simulated moving bed process.

Experimental implementation of an optimizing controller based on identified model for the separation of nucleosides in a laboratory scale simulated moving bed (SMB) unit is reported in this study. The manipulative variables are the three external and one internal flow rates while the outputs are productivity, solvent consumption, and purities of extract and raffinate streams averaged over a switching period. The feedback information is the concentration profile of extract and raffinate measured online using two ultraviolet (UV) detectors. Experimental results show that the designed controller is able to operate the SMB units under optimal condition fulfilling the purity requirements. Besides, the controller demonstrated excellent performance in terms of rejecting disturbances that may occur during SMB operations.

Chromatography↗

PubMed2005

Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: generation of drug microparticles and drug-polymer solid dispersions.

The classical anticonvulsant drug phenytoin (5,5-diphenyl hydantoin, C(15)H(12)N(2)O(2)) has been used as a model compound to investigate the possibility of enhancing the dissolution rate of poorly water-soluble drugs using dense gas antisolvent techniques. In a first step, microcrystals of neat phenytoin have been generated using the gas antisolvent (GAS) and precipitation with compressed antisolvent (PCA) processes, thereby assessing process performances and elucidating similarities and differences between the two techniques. In a second step, the PCA process has been used to generate solid dispersions of phenytoin in the hydrophilic polymer poly(vinyl-pyrrolidone)-K30 (PVP). In vitro dissolution results reveal a substantially better performance of the PCA-processed co-formulations compared to unprocessed phenytoin and to GAS- and PCA-precipitates of neat drug crystals. A comparison of the product quality of phenytoin-PVP co-formulations with solid dispersions obtained by spray drying convincingly underlines the potential of dense gas antisolvent techniques for the production of pharmaceutical formulations with enhanced oral bioavailability.

Chemical Precipitation↗

PubMed2005

Optimization of a hybrid chromatography-crystallization process for the separation of Tröger's base enantiomers.

This paper presents an analysis of a hybrid process consisting of simulated moving bed (SMB) chromatography and crystallization and studies its performance for the separation of the Tröger's base enantiomers. The SMB is simulated using a detailed model including column efficiency, thus, implying a proper evaluation of the effect of column size on column efficiency and separation performance. The crystallization operations are accounted for through material balances, assuming equilibrium between enantiopure crystals and mother liquor. A genetic algorithm is used to optimize the combined process, using proper definitions of objective functions. Multi-objective optimization of this hybrid process for productivity and evaporation cost in terms of operating parameters, column length, and SMB feed concentration shows an optimum SMB purity value as a trade off between increased SMB performance and recycle of the mother liquor.

Adsorption↗

PubMed2005

Enantioseparation of 1-phenyl-1-propanol by supercritical fluid-simulated moving bed chromatography.

The enantioseparation of 1-phenyl-1-propanol through the supercritical fluid-simulated moving bed (SF-SMB) process is studied. Non-linear isotherms were measured on an analytical column, and used together with the triangle theory for SMB design to select operating conditions for the SF-SMB. Experiments were carried out on a pilot-scale SF-SMB plant at conditions that corresponded to the non-linear range of the isotherm. Under conditions of low feed concentration, complete separation (extract purity = 99.5%; raffinate purity = 98.4%) was achieved. Under conditions of larger feed concentration, the best separation corresponded to an extract purity of 98.0% and a raffinate purity of 94.0%, and yielded a productivity of 110 g of racemate per kg stationary phase per day.

Adsorption↗

PubMed2005

Optimizing control of simulated moving beds--experimental implementation.

The operation of simulated moving beds (SMBs) at their optimal operating conditions is difficult and not robust. Therefore, it is common practice to operate SMB units far from their economic optimum in order to tolerate uncertainties in the system and minimize the effect of disturbances. Recently, we have proposed an on-line optimization based SMB control scheme that allows to exploit the full economic potential of SMB technology. The goal of this work is two-fold. Firstly, to experimentally evaluate and demonstrate the capability of the controller to optimize and operate the SMB units, thus delivering the products with maximum productivity and minimum solvent consumption. Secondly, to show the suitability of the controller even using a minimum of system information, thus making the detailed isotherm measurements redundant and saving time in the separation design phase. This paper reports and discusses the first experimental implementation of the control concept on a high purity separation of nucleosides (uridine, guanosine) with an eight-column four-section SMB where the species to be separated are retained on the source 30RPC stationary phase according to a linear isotherm.

Chromatography, Liquid↗

PubMed2005

Effect of pressure drop on solute retention and column efficiency in supercritical fluid chromatography.

The effect of pressure drop on the performance of supercritical fluid chromatographic systems is studied. Experiments have been conducted at different pressures and at 55 and 65 degrees C. Experiments at conditions leading to large and small pressure drops have been performed. Parameters to describe the pressure drop, retention time and efficiency have been extracted from these experiments. Using these parameters the dynamics of the chromatographic column have been modeled. Darcy's law was used to describe the pressure drop. The efficiency was modeled by considering the contributions from axial dispersion, resistance to mass transfer from the fluid film, and to diffusion in the pores. Good description of the pressure drop, retention time and mass transfer characteristics under normal operating conditions was obtained. The parameters extracted were used to predict the elution profile by numerical simulations. Considerable loss in column efficiency was observed when operating the column at lower values of the back pressure.

Chromatography, Supercritical Fluid↗

PubMed2005

Analysis of sample-solvent induced modifier-solute peak interactions in biochromatography using equilibrium theory and detailed simulations.

Batch liquid chromatographic columns are often equilibrated with an eluent stream being a mixture of inert compounds and so-called modifiers. The sample injected into the eluent stream usually consists of the solutes to be separated and of a mixture of the same solvents as in the eluent but in general with different concentration values. This results in two groups of peaks moving along the column: the solute peaks and the modifier pertubations. If the adsorptivity of the solute depends strongly on the modifier, as it is often the case in biochromatography, the interference between the two groups of peaks leads to peculiar phenomena like double peaks, split peaks, distorted peaks with anti-Langmurian shape, etc. In this work, these phenomena are analyzed based on an analytical solution of the equilibrium theory model and the results are compared with detailed simulations and experimental data. It is shown that the qualitative behavior is well predicted in the frame of equilibrium theory and general guidelines how to avoid these kinds of interactions are developed.

Acetonitriles↗

PubMed2005

Enantioseparation of 1-phenyl-1-propanol on Chiralcel OD by supercritical fluid chromatography. I. Linear isotherm.

The supercritical fluid chromatography (SFC) separation of the enantiomers of 1-phenyl-1-propanol on the chiral stationary phase Chiralcel OD under linear conditions is studied. Supercritical CO2 modified with methanol is used as a mobile phase. The effect of modifier concentration, pressure and temperature is studied. An empirical isotherm to account for the effect of density of the mobile phase and modifier concentration has been used to model the experimental results. It was observed that the selectivity and resolution were higher at 30 degrees C as compared to those at 40 degrees C.

Adsorption↗

PubMed2004

Two-fraction and three-fraction continuous simulated moving bed separation of nucleosides.

A new experimental set-up and a new simulated moving bed (SMB) operation are presented in this work. A desktop SMB unit developed as a modification of the commercial AKTA explorer working platform has been utilized for the separation of different mixtures of nucleosides. Both two fraction and three fraction SMB separations have been carried out, the latter made possible by the adoption of a new SMB configuration and operating mode (three fraction SMB, 3F-SMB, operation). Experiments demonstrate the feasibility of the 3F-SMB operation, and confirm the trends predicted based on considerations about retention of the components to be separated along the unit.

Chromatography↗

PubMed2004

Optimizing control of simulated moving beds--linear isotherm.

A new optimization based adaptive control strategy for simulated moving beds (SMBs) is proposed. A linearized reduced order model, which accounts for the periodic nature of the SMB process, is used for online optimization and control. The manipulated variables are the four inlet flow rates, the outputs are the raffinate and extract concentrations. Concentration measurements at the raffinate and extract outlets are used as the feedback information. The state estimate from the periodic Kalman filter is used for the prediction of the outlet concentrations over a chosen horizon. Predicted outlet concentrations are the basis for the calculation of the optimal input adjustments, which maximize the productivity and minimize the desorbent consumption subject to constraints on product purities. The realization of this concept is discussed and the implementation on a virtual eight column SMB platform is assessed, in the case of binary linear systems. For a whole series of typical plant disturbances it is shown that the proposed approach is effective in minimizing off-spec products and in achieving optimal SMB operation, also in the case where there are significant model uncertainties.

Models, Theoretical↗

PubMed2004

Solvent gradient operation of simulated moving beds. 2. Langmuir isotherms.

Simulated Moving Bed separations of enantiomers or fine chemicals are usually carried out in the isocratic mode, i.e. by applying the same operating conditions (temperature, pressure, mobile phase composition, pH) in the whole SMB unit. However, it has been recently recognized that by properly modulating operating conditions in the SMB sections. i.e. Sections 1-4 normally, separation performance in terms of productivity and solvent consumption can be significantly improved. In this work, we study solvent gradient SMB (SG-SMB) operation, where the concentration of a modifier in the main solvent constituting the mobile phase is adjusted along the SMB unit, so as to have weaker retention of the species to be separated in the first two sections, and stronger retention in Sections 3 and 4. Overload chromatographic conditions are considered, where the adsorption behavior is characterized by a nonlinear competitive adsorption isotherm, e.g. a binary Langmuir isotherm. Design criteria to achieve complete separation are developed in the frame of the equilibrium theory of chromatography. The theoretical findings are discussed in view of typical effects of the modifier concentration on retention times and solubility of the species to be separated, and an overall assessment of the SG-SMB technology is attempted.

Chromatography↗

PubMed2004

General model for the achiral chromatography of enantiomers forming dimers: application to binaphthol.

This works deals with the development of a model for the description of the chromatographic behavior of enantiomers forming dimers on achiral stationary phases. The model describes the formation of both homochiral and heterochiral dimers by introducing two equilibrium constants, K(homo) and K(hetero), which have to be independently estimated. The adsorption of both monomeric and dimeric species is described by a bi-Langmuir isotherm. Both adsorption and dimerization equilibrium models are implemented in a standard equilibrium-dispersive model of the chromatographic column. The isotherm parameters are determined by fitting of pulses constituted either of the pure enantiomers or of non racemic mixtures of both enantiomers. The validity of the model is then assessed by application to the binaphthol case.

Adsorption↗

PubMed2003

PowerFeed operation of simulated moving bed units: changing flow-rates during the switching interval.

A possible way to improve the separation performance of simulated moving bed (SMB) units is to change the internal and external liquid flow-rates during the switching period. This operation mode, referred to as PowerFeed, is examined in this work through a model analysis. Similar to the Varicol process, which allows for the asynchronous movement of the ports, the PowerFeed process exhibits more degrees of freedom than the classical SMB process and therefore allows more room for optimization. Using an optimization technique based on a genetic algorithm, all three processes have been optimized for a few case studies in order to determine their relative potentials. It is found that PowerFeed and Varicol provide substantially equivalent performances, which are however significantly superior to those of the classical SMB process.

Algorithms↗

PubMed2003

Multiobjective optimization of simulated moving bed and Varicol processes using a genetic algorithm.

The size of the packing material, the total number of columns and the total feed concentration have significant impacts on the economics of a preparative chromatographic separation, through their effects on column pressure drop, column efficiency and thermodynamics. In this work, the role of these parameters on the performances of a simulated moving bed and a Varicol process is investigated on a chiral separation system from literature, using an equilibrium stage model. A multiple objective optimization technique based on a genetic algorithm is adopted, which allows to maximize simultaneously the purity of the extract and productivity of the unit. In this way, it is possible to optimize and compare the performances of both processes in a wide range of parameter values, so as to assess their relative potential under equally optimized conditions. The optimization results, i.e. the so-called Pareto sets, have been discussed in the frame of equilibrium theory and the roles of these three parameters have been clarified.

Algorithms↗