Methods and instrumentation for during-synthesis monitoring of polymer functional evolution   

CROSS-REFERENCE TO RELATED APPLICATIONS

Priority of U.S. Provisional Patent Application Ser. No. 61/059,050, filed 5 Jun. 2008, hereby incorporated herein by reference, is hereby claimed.

U.S. patent application Ser. No. 11/865,589, filed 1 Oct. 2007, and International Application Number PCT/US2007/80116, filed 1 Oct. 2007, are hereby incorporated herein by reference.

U.S. Provisional Patent Application Ser. No. 60/827,559, filed 29 Sep. 2006, and U.S. Provisional Patent Application Ser. No. 60/884,821, filed 12 Jan. 2007, are hereby incorporated herein by reference.

This is not a continuation, continuation-in-part, or divisional of any patent application.

Not applicable

Not applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a ‘second generation of ACOMP’ (Automatic Continuous Online Monitoring of Polymerization reactions). The present document also sets out principles and uses, for the first time, of ACOMP (U.S. Pat. No. 6,653,150) coupled to SMSLS (simultaneous multiple sample light scattering, a Reed patent (U.S. Pat. No. 6,618,144) held by Tulane), and expands the uses of SMSLS through specific design changes.

The present invention is particularly suited to monitoring special characteristics of polymers and colloids as they evolve during reactions, such as polymer synthesis or postpolymerization modification reactions. Special characteristics include the polymers\' and/or colloids\' ability to respond to environmental stimuli, such as temperature, light, and solution characteristics such as pH, ionic strength, presence of specific other substances, such as toxins, drugs, surfactants, and other molecules, including other polymers, colloids, and nanostructures, their ability to go through structural changes, such as conformational collapse, their ability to self-assemble into supramolecular structures, and their ability to encapsulate and bind other agents, and to release them. The use of the present invention in conjunction with multiple similar detectors in some contexts can allow determination of polymer and/or colloid phase behavior during reactions, and how the phase behavior changes during reactions.

Although the samples are prepared automatically and continuously, detection can be intermittent. Interrupted, chromatographic detection, such as size exclusion chromatography, can be used. A recent publication the inventor and his colleagues made in this area is: “Simultaneous continuous, non-chromatographic monitoring and discrete chromatographic monitoring of polymerization reactions”, Alina M. Alb, Michael F. Drenski, Wayne F. Reed, J. Appl. Polym. Sci., 13, 190-198, 2009. A stop-flow method is also described below.

2. General Background of the Invention

As polymers become more complex and sophisticated in architecture and composition, they gain the ability to perform more ‘intelligent’ functions than traditional polymers. The frontier of advanced polymeric materials in the 21st century will be dominated by these increasingly sophisticated polymers. The upcoming polymers can micellize, aggregate, and respond to stimuli, such as temperature, light, solvent polarity, different solvents and solvent mixtures, the presence of specific agents, metal ions, surfactants, multivalent ions, proteins, anti-bodies, receptors, etc. (see Langmuir (2007), 23, 1, 1-2; Polymer (2004), 45(2), 367-378; Macromolecular Chemistry II, University of Bayreuth, Bayreuth, Germany. Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008 (2008), POLY-599; Nano letters (2007), 7(1), 167-71; Journal of Materials Chemistry (2007), 17(38), 4015-4017; Langmuir, (1990), 6, 514-516; Macromolecules (2002), 35, 10182-10288; J. Phys. Chem. C (2007), 111, 8916-8924). The polymers and/or colloids may also undergo chemical reactions with other species.

Applications include sensing, encapsulation and release of agents (e.g. drugs, cosmetics, etc.), micropatterning, bioconjugated polymers for medical applications, self-healing, photosensitivity and/or electrically conductive properties for optical and electronics applications, photovoltaics etc. There is considerable interest in ‘fine tuning’ polymers to have well behaved stimuli responsiveness characteristics, interaction properties, specific phase behavior, etc.

Henceforth ‘stimuli responsiveness’ will be used to refer to one or more of the diverse types of behaviors that polymers and/or colloids can manifest, depending on their own structure, composition and other macromolecular and chemical characteristics, the conditions of their synthesis, and the details of the environment where they may be synthesized, transferred to, or otherwise used or applied. Such behaviors can include but are not limited to conformational changes, intra- and/or intermolecular micellization, intermolecular aggregation and/or supramolecular assemblage into organized structures, solubility, phase separation, ability to interact with other polymers or colloids or small molecules, such as metal ions, organic molecules, salts, surfactants, etc., abililty to no longer interact with certain substances, ability to encapsulate and/or release drugs and other biologically active agents, lower critical solution temperature (LCST), color changes, and ability to react chemically with other species.

For example, polymers in solution can acquire stimuli responsiveness in sharp or gradual ways; e.g. LCST (lower critical solution temperature), micellization, aggregation, helix-coil, and other intra- and intermolecular transitions. Such transitions are of fundamental and applied interest. Fundamentally, they arise from the thermodynamics of complex, interacting systems. Whether sharp or gradual, these transitions, and stimuli responsiveness in general, depend on many factors, such as pH, ionic strength, solvent type and polarity, solvent mixture types, solvent chaotropicity or cosmotropicity, temperature, irradiation by electromagnetic waves, including light, and addition of interacting agents (e.g. small molecules, dyes, etc.), as well as the molecular weight and copolymeric composition and microstructure of the polymers themselves. Other examples concern the many types of associations that can take place between polymers and other polymers, micelles, emulsions, vesicles, liposomes, proteins, polypeptides, etc. These often involve formation of supramolecular (non-covalent) structures promoted by electrostatic, hydrophobic, depletion, and other forces.

Another very important application for the present invention is in the field of polymers derived from natural products. Because of the increasing demand for renewable sources for polymeric materials, as well as biodegradability and environmental concerns, there is a growing number of natural products that are being used for medicine, food, cosmetics, water treatment, oil recovery, composite materials, etc. These include, but are not limited to polysaccharides such as xanthans, alginates, cellulose derivatives, chitin derivatives, galactomannans, pectins, etc. as well as proteins and fibers. In order to make use of these natural products it is necessary to extract the desired agents, and then often modify them chemically, enzymatically, or by radiation, until desired characteristics are obtained, such as solubility in a given solvent (e.g. water), ability to interact with other substances (e.g. surfactants), achieve desired levels of viscosification, self-assemble into nano and microstructures, etc. The present invention will allow all of these processes-extraction, modification, and special properties- to be monitored. This will allow for optimization of the processes used in extracting, modifying, and deploying natural product derived polymers and colloids. The ability to monitor and control these steps is particularly important for natural products because the raw material, of vegetable or animal origins are normally highly variable in the content and characteristics of the desired materials to be extracted, which is a perennial problem for natural product manufacturers.

‘Polymer and/or colloid synthesis’ includes any type of reaction in which a polymer and/or colloid is produced or modified. An example of the latter is when a polymer is first made and then specific functional groups are attached to it, such as charge groups (e.g. sulfate, quaternary amines, carboxylate, etc.), oligomers, grafted polymers, etc. Other examples include the modifications made to polymers and/or colloids extracted from natural biological sources (e.g. plants, wood, seeds, fruits, etc.), as described above.

Traditional methods for relating polymer characteristics to their stimuli responsiveness. These are time-consuming, cumbersome, and inefficient. They normally involve, even in modern high-throughput systems, the synthesis of a given end-product, or series of end-products, that are then subjected to various types of functionality characterization, and often also to standard polymer characterization methods. In many cases, the mere preparation of the endproduct can be disproportionately time-consuming, and require such steps as precipitation, purification, freeze-drying, re-dissolution, dialysis, etc., of the end-product. The usual ACOMP approach, (see W. F. Reed, U.S. Pat. No. 6,653,150, “Automatic mixing and dilution methods for online characterization of equilibrium and non-equilibrium properties of solutions containing polymers and/or colloids”; and A. M. Alb, M. F. Drenski, W. F. Reed, “Automatic continuous online monitoring of polymerization reactions (ACOMP)”, Polymer International, 57, 390-396, 2008) which has proven successful in a wide variety of contexts avoids these process steps by substituting ‘fluid-fluid’ sample handling. That is, the reactor fluid is continuously extracted, diluted with other fluids, and conditioned to produce a continuously measurable fluid sample of the reactor contents. No intermediate solid phase stages are normally used, and the often high levels of dilution (ranging up to dilution factors of many thousands) can even effectively change solvents by making the original solvent a tiny admixture to the dilution solvent. Such extraction/dilution/conditioning typically occurs on a time scale of tens of seconds to several minutes. The series of handling procedures in traditional methods can take hours, days, and even weeks.

The following references, and all references mentioned herein, are incorporated herein by reference:

Some additional bibliography showing LCST, micellization, bioconjugation, etc.:

Macromolecular Chemistry II, University of Bayreuth, Bayreuth, Germany.

Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008 (2008), POLY-599. Publisher: American Chemical Society, Washington, D.C.;

Abstracts of Papers, 233rd ACS National Meeting, Chicago, Ill., United States, Mar. 25-29, 2007 (2007);

Polymer (2003), 44(22), 6815-6823;

Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) (2003), 44(1), 646-647;

Abstracts of Papers, 235th ACS National Meeting, New Orleans, La., United States, Apr. 6-10, 2008 (2008), POLY-596;

ACS Symposium Series (2008), 977(Polymers for Biomedical Applications), 78-94. Publisher: American Chemical Society;

Soft Matter (2007), 3(6), 725-731;

Macromolecules (Washington, DC, United States) (2007), 40(14), 4772-4779;

Abstracts of Papers, 231st ACS National Meeting, Atlanta, Ga., United States, Mar. 26-30, 2006 (2006), PMSE-224;

Macromolecules (1999), 32(21), 6917-6924;

Polymer Preprints (American Chemical Society, Division of Polymer Chemistry) (2002), 43(2), 969-970

PMSE Preprints (2002), 87 237-238. Publisher: American Chemical Society, CODEN: PPMRA9 ISSN: 1550-6703. Journal; Computer Optical Disk written in English.

SUMMARY

Methods and instrumentation are disclosed for monitoring how polymer stimuli responsiveness evolves during the very process of polymer synthesis. Polymer stimuli responsiveness includes the ability of polymers, when certain characteristics are reached (e.g. molecular weight, composition, degree of postpolymerization modification etc.), to go through phase changes (e.g. micellization, formation of supramolecular structures), conformational changes, solubility changes, and other transformations (e.g. ability to interact with other polymers, or chemical or biochemical agents), often dependent on solution conditions (e.g. temperature, pH, ionic strength, specific electrolyte content, etc.).

A new generation of polymers is being designed with high stimuli responsiveness for diverse purposes such as biomedical assays, drug delivery, sensing, responsiveness to stimuli (e.g. heat, light, etc.), self-healing materials, and much more.

The current invention offers a way of monitoring the evolution of stimuli responsiveness in a continuous way, during polymer synthesis. ‘Polymer synthesis’ includes any type of reaction in which a polymer is produced or modified. An example of the latter is when a polymer is first made and then specific functional groups are attached to it, such as charge groups (e.g. sulfate, quaternary amines, carboxylate, etc.), oligomers, grafted polymers, etc. In its simplest form the present invention is already a high throughput screening platform. In its enhanced form, described below, the present invention becomes a ‘high throughput squared’ platform, and may challenge and even disrupt ongoing high throughput developments that use expensive, robotic, multi-reactor approaches for mere end product analysis.

The current invention builds on Tulane\'s patent estate developed by Wayne F. Reed (U.S. Pat. Nos. 6,052,184, 6,653,150, 6,618,144, others pending), and preferred embodiments of the present invention advantageously use the teachings of some of those same patents (U.S. Pat. Nos. 6,052,184, 6,653,150, 6,618,144, others pending).

The present invention builds on the present inventor\'s last decade of invention and development in monitoring polymerization reactions, denoted as the ACOMP platform (Automatic Continuous Online Monitoring of Polymerization reactions). That work extended ACOMP\'s reach to free radical and controlled radical homo- and copolymerization, other ‘living’ reactions, condensation polymerization, branching, grafting, copolymeric polyelectrolyte synthesis, and polymer modification processes, including postpolymerization modifications and modifications of natural products, in homogeneous, bulk, and emulsion phase, and in batch, semi-batch and continuous reactors, producing corresponding discoveries in fundamental reaction kinetics and mechanisms.

With its broad range of monitoring applicability now secured, the present invention is a ‘2nd generation ACOMP’ as it faces wholly new challenges; moving beyond monitoring to reaction control in order to produce polymers of desired characteristics, and extending the ACOMP platform to monitor, understand and control, the stimuli-responsiveness of polymers. These latter include polymers whose properties change with changing environmental factors, such as temperature, light, pH, solvent quality, presence of specific molecules, etc. The potential applications of these materials make them an exciting interface between chemical and biomolecular engineering, chemistry, materials science, and physics.

The discovery and development of new polymers require sophisticated analytical approaches that can solve basic and applied problems, and optimize processes. Currently, post-synthetic analyses on end-products with techniques such as size exclusion chromatography (SEC), nuclear magnetic resonance (NMR), etc. yield little information on the evolution of polymer characteristics and there is no opportunity for control. Utilizing a flexible detection platform that continuously or substantially continuously monitors reactions (e.g. light scattering, viscosity) ACOMP follows conversion kinetics, composition drift, and the evolution of average composition distribution, molar mass, and intrinsic viscosity distributions. The polymer is hence ‘born’ characterized, and there is also the opportunity for reaction control, a primary focus of the proposed work. The onset or change of stimuli responsiveness, such as conformational transformations, ability to interact with target molecules, copolymer micellization, etc. have complex relationships to polymer mass, architecture, and copolymer distribution, ‘blockiness’, sequence length distributions, etc. This work takes the novel approach of monitoring the onset of stimuli responsiveness during synthesis, focusing on lower critical solution temperature (LCST), with the subsequent ability for control, providing a powerful new tool for understanding underlying polymer physics and manipulating polymer structure/function relationships.

The present inventor aims to create a paradigm shift in polymer science, in which online monitoring and control become powerful adjuncts to polymer discovery, development and production, and for understanding stimuli responsive behavior in polymer solutions. Importantly, information-rich ACOMP results also provide a more complete database, and are available for polymer scientists in the broader community involved in modeling and reaction engineering. It is expected that the present invention will also quickly have real economic impact on polymer industries, yielding practical new materials and process monitoring and control that enhance savings of energy, petroleum, and other non-renewable resources, plant and labor time, and lead to better safety, and less greenhouse gas emissions and environmental pollution per kilogram of product.

The present invention includes a multi-purpose, multi-user 2nd generation ACOMP instrument (Automatic Continuous Online Monitoring of Polymerization reactions). The present invention has an even more massive data gathering and analysis capability than its predecessors.

The multi-purpose platform of the present invention allows different time-dependent processes in polymer and colloid solutions to be monitored, and also can be used to automatically map characteristics of multi-component solutions in equilibrium or quasi-equilibrium, such as automatic determination of phase diagrams, and combines sophisticated, interconnected optical detection methods, and a fully integrated multi-detector GPC.

A few Features and Types of Processes to be Monitored are Outlined Below.

Simultaneous monitoring of polymer properties, such as mass and composition, and the onset of stimuli responsiveness during synthesis (including any postpolymerization modifications), such as phase transitions, micellization, conformational changes, microgelation, ability to interact with other substances, such as drugs, etc. The SG-ACOMP will be the only instrument of its kind in the world, able to determine at what point in synthesis, (including postpolymerization reactions and modifications of polymers and colloids extracted from natural products), polymers and copolymers become stimuli responsive, whether sharply or gradually; e.g. the effect of solvent type on LCST (lower critical solution temperature) of an evolving polymer and the relationship with polymer composition and molecular weight distributions could be determined. The transition at the LCST will be automatically detected, and the threshold characteristics of the polymer stimuli responsiveness can be quantified.

High throughput capability for testing stimuli responsiveness of polymers during synthesis. This portion of the system makes use of multiple light scattering and other detectors, built according to the concept of one of Reed\'s earlier patents; SMSLS (Simultaneous Multiple Static Light Scattering). This allows for a plurality of independent SMSLS flow cells to simultaneously measure a highly diluted polymerization sample stream under different conditions; e.g. temperature, solvent ionic strength and dielectric constant, etc.

Other optical detectors will allow for numerous other measurements, including dynamic light scattering, depolarized light scattering, Mie scattering, circular dichroism, UV/visible spectroscopy, fluorescence, and birefringence. Depolarized light scattering will allow anisotropic particles (e.g. nanotubes, rigid nano fibers, bacteria, etc.) to be analyzed.

The entire system can be used with multi-detector GPC in series or in stand-alone mode. Other functions can be switched modularly into the data gathering base, and also separately used.

Applications to biomedical fields, including drug delivery. Core-shell micellization and phase transition of copolymers will be continuously monitored. Amphiphilic block copolymers that self-assemble into micelles in aqueous media can be extensively investigated and their properties of ‘nano-containers’ exploited.

Monitoring any change in particle shape and morphology. Light scattering detection with different polarizability will be customized to allow particle dimensions to be measured for particles with different shapes.

A complete multi-stage front-end that extracts, dilutes, and conditions sample from reactors and other vessels (i.e. also for equilibrium systems) to produce a continuous stream of highly dilute, conditioned sample for detection. This versatile front-end will allow extraction from low viscosity emulsion polymerization fluids up to pure bulk polymerization reactions where the viscosity can approach 106 cP. Conditioning steps will include filtration, debubbling, volatilizing monomers, inverting phase, etc.

There is also provision for interrupted sampling and auto-injection, whereas the system can be modularly switched into use as a comprehensive multi-detector chromatography system. Solenoid or other valves can be provided on those detectors that are flow or shear sensitive to provide a stop-flow capability that does not interfere in any way with the continuously flowing stream. In this mode, the continuous stream is periodically switched into the flow sensitive detector\'s sample cell by a diverter valve, stopped, and a measurement is made on the stationary solution. During the stopped time, the sample stream continues to bypass the flow sensitive detector\'s sample cell. Any time after the measurement the continuous flow can be rediverted through the flow sensitive detector\'s sample cell, then stopped, and another measurement cycle can be made. This strategy is used for example in the NanoDSL (a dynamic light scattering instrument by Brookhaven Instruments Corporation).

The detection end is highly modular, and consists of i) a polymer characterizing detector train—multiangle light scattering, refractive index, viscosity, UV absorption-, ii) a particle characterizing train, such as dynamic and Mie light scattering, and iii) a high throughput, multi-detector train, including a new family of SMSLS cells (simultaneous multiples sample light scattering, a Reed patent held by Tulane), adaptation of SMSLS to high throughput fluorescence detection, and a multi-head peristaltic pump approach to monitoring the effects of multiple solvents and interacting molecules on the polymer. Additionally, polarizing optics and a circular dichroism detector allow a range of new capabilities where particle anisotropy is involved. Where the stimuli responsiveness acquired is the ability to undergo chemical reactions with other specific reagents then it will be possible to use thermography, by mounting a thermally sensitive camera that can thermally image all the different channels in the multidetector train. In this way it can be detected whether an exothermic or endothermic chemical reaction is occurring. Where the stimuli responsiveness changes the color or visual aspect of the polymer and/or colloid, or the color of any complexes or associations that these may form with other agents, then an optical camera can be used to directly visualize and capture the different channels in the multidetector train.

A versatile platform of pumps and detectors is preferred to allow customized methods to be applied in the study of various processes. Components of the apparatus of the present invention and preparation of the apparatus for use can include the following:

Two Q-pumps (Fluid metering);

Five Shimadzu HPLC pumps;

Shimadzu quaternary mixer;

One Zenith gear pump;

Micro-flow controller w/feedback capability;

Mixing chambers/plumbing;

National Instruments comprehensive data interface;

Hardware and GUI integration software;

Software development;

Two multi-head peristaltic pumps;

Machining of SMSLS cells;

Nano-DLS (BIC), dynamic light scattering;

BI-MwA (BIC) 7 angle multi-angle light scattering;

Shimadzu UV/visible diode array flow capable;

Shimadzu refractometer;

Technical support for construction of instrumentation;

Polarization components/analyzers/optoelectronics;

GPC columns, autoinjector; and

Circular dichroism flow ready detector.

Thermal imaging camera

Optical imaging camera

The evolution of the properties of the polymers and/or colloids during synthesis can be monitored, for example, according to any of the methods of U.S. Pat. No. 6,653,150.

As used herein, a ‘reactive medium’ (sometimes referred to as reactor fluid), includes all reagents (such as monomers, initiators, catalysts, surfactants, natural and/or synthetic polymers, etc.), and any other supporting components or fluids (such as solvent or mixtures of solvents in which the reagents are dissolved or suspended, and components which control the characteristics of the reactive medium, such as temperature, pressure, viscosity, color, ionic strength, pH, concentration of the reagents, etc.). Note that not all of the components or fluids in the reactive medium are reagents; i.e. some just control characteristics of the reactive medium (e.g pH, ionic strength, viscosity) without themselves reacting.

The reactor is preferably ‘sampled’ continuously, or if not continuously substantially continuously. Detector measurements might better be termed ‘detector measurement rates’ rather than ‘sampling rates’, and they could also be called ‘detector readings’. Typically when a detector measurement is made, it means that at that time the signals from the multiplicity of detectors are captured and stored by the computer. E.g. every second one might measure the signals from all the detectors and store them. This act of measurement might include hundreds or even thousands of data points; e.g. 600 data points from a UV/visible detector, seven or more angles from light scattering, two or more signals from viscosity, multiple thermocouple (temperature) readings, etc.

Preferably, the material from the reactor is drawn continuously or substantially continuously, and readings are taken continuously or substantially continuously. Whether the withdrawals from the reactor are continuous or substantially continuous, the detector measurements are preferably taken at a frequency adequate to provide useful information about the process to allow the process to be advantageously modified to optimize desired results. Detector measurement intervals can be anywhere from every 0.01 s to hundreds of seconds to thousands of seconds, depending on how fast the reaction is. Typically one would set up the detector measurement interval so that there will be roughly ten thousand time points at which the ensemble of detector readings are made during the course of the experiment. E.g. for a three hour reaction one would likely record measurements from all the detector signals every second and get about 10,000 total detector measurement points. It is also frequently the case that different detector signals are measured at different rates.

For example, when interrupted chromatographic (GPC) detection is used, there will necessarily be a delay of at least several minutes between detector measurement due to the separation process, so that there will normally be only a few GPC measurement per hour (e.g. 6), and there will not be thousands of measurements.

The present invention can potentially provide continuous phase diagrams, which could be of immense value. As examples, one could determine, with the multi-head peristaltic approach and the temperature controlled SMSLS cells, an LCST phase diagram for a polymer during synthesis, which would demarcate the LCST transition as a function of both temperature and ionic strength. This is a major advance, because such phase diagrams take considerable time to determine individually using standard methods, and the possibility of having virtually a continuous set of phase diagrams at each point of a polymer\'s and/or colloid\'s synthetic evolution will be of critical importance in developing new polymers and/or colloids and formulations involving these. Other examples of determining phase diagrams at each moment of evolution can include how a given polymer and/or colloid at each instant of its synthesis interacts with different types and/or concentrations of surfactants, salts, and other agents.

Typical temperatures during polymer and/or colloid synthesis range from −20 C to 300 C, but are more usually in the range of 20 C to 180 C.

For a further understanding of the nature, objects, and advantages of the present invention, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements and wherein:

FIG. 1 is a schematic flow chart of a preferred embodiment of the apparatus of the present invention;

FIG. 2 is an alternate preferred embodiment of the apparatus of the present invention;

FIG. 3 is schematic flow chart of an alternative embodiment of the apparatus of the present invention;

FIG. 4 is a specific embodiment for using the invention to characterize the salt sensitivity of micellization, polymer dimensions, and interactions during the synthesis of a copolymeric polyelectrolyte, of the block, random, or gradient type—this is just an example of numerous applications of the invention;

FIG. 5 shows examples of weight average molecular weight for a polyelectrolyte free radical copolymerization using styrene sulfonate and acrylamide (Adapted from T. Kreft and W. Reed, Publication Date (Web): May 22, 2009 (Letter) DOI: 10. 1021/jp903520s, J. Phys. Chem B, web edition, hard version in press);

FIG. 6 shows the type of composition drift for these same reactions;

FIG. 7 shows how conductivity changes for several of these reactions;

FIG. 8 is an anticipated result for viscosity signals for the experiment starting at 80% styrene sulfonate and 20% acrylamide, for which there is little composition drift;

FIG. 9 is a sharp contrast to FIG. 8, showing the type of behavior expected for viscosity signals for the experiment starting at 25% styrene sulfonate and 75% acrylamide, for which there is large composition drift, and the chains produced have decreasing amounts of styrene sulfonate (charged monomer) and so have decreasing viscosities. Since this system is not expected to micellize, there would be no expected change in pyridine fluorescence vs. time for the different ionic strengths;

FIG. 10 shows the average instantaneous fraction of vinyl benzene sulfonic acid Na+ form (VB) FINST,VB vs. conversion during VB/acrylamide copolymerization (top); linear charge density ξ v. FINST, VB (bottom);

FIG. 11 shows MW Vs. conversion, f: from uncontrolled free radical to controlled radical behavior (RAFT polymerization of butyl acrylate);

FIG. 12 shows simultaneous monitoring with ACOMP of particle and polymer/monomer features: emulsion polymerization of methyl methacrylate;

FIG. 13 shows continuous non-chromatographic ACOMP data coupled with continuous discrete, chromatographic data furnished by SEC for the RAFT polymerization of butyl acrylate;

FIG. 14 shows predictive and experimental MW trends for the semibatch acrylamide polymerization (#2, #3); #1: MW for a batch reaction;

FIG. 15 shows comonomer ACOMP conversion from BA/MMA copolymerization reactions in emulsion and solution;

FIG. 16 shows that ACOMP monitors deviations from livingness in MW for BA/MMA copolymerization by RAFT, Inset: CBA and CMMA; and

FIG. 17 shows experimental and theoretical light scattering signatures for the MMA/BA diblock copolymerization by RAFT.

DETAILED DESCRIPTION

Herein, ‘evolution of stimuli responsiveness’ refers to how the ability of polymers and/or colloids to go through phase and conformational transitions, associations with other molecules, synthetic and biomacromolecules, supramolecular and self-organizing assemblage, reactivities with other species, etc., as defined above, changes as the properties of the polymers and/or colloids themselves change during synthesis; i.e. how changing properties such as molecular mass, composition, comonomer sequentiality (e.g. block, gradient, random), grafting, cross-linking, microgelation, bioconjugation, association with nanoparticles, whether covalent or non-covalent, and post-polymer chemical and physical modifications (such modifications can include, but are not limited to quaternization, PEGylation, sulfonation, carboxylation, amination, ‘clicking’ on of any one or combination of functional groups or oligomers or polymers) etc. affect these types of stimuli responsiveness, and how the polymer medium—its temperature, pH, ionic strength, solvent type, including use of ionic liquids and including mixtures of solvents, content of surfactants, small molecules, including drugs and other bioactive agents, irradiation by light or other electromagnetic radiation, ultrasound, etc.—affect stimuli responsiveness.

The types of reactions that can produce polymers and colloids with stimuli responsiveness include, but are not limited to free radical polymerization, polycondensation and other step-growth reactions, ‘living’ type polymerizations, including Ring Opening Metathesis Polymerization (ROMP), Nitroxide Mediated Polymerization (NMP), Atom Transfer Radical Polymerization (ATRP), Reversible Addition Fragmentation chain Transfer (RAFT), anionic and cationic polymerization, post-polymerization reactions that add, subtract, or modify specific chemical groups or moitities, etc. The invention can be applied to many different scenarios for polymerization; in solvent, in bulk, in heterogeneous phase, such as emulsion, suspension, miniemulsion, micelle, and inverse emulsion.

Moreover, the invention can be used for different approaches to carrying out the polymerization process; batch reactions in which all reagents are added to the reactor at once, or in discrete amounts as the reaction proceeds, ‘semi-batch’ reactions, in which the reagents are added to the reactor continuously over intervals or throughout the reaction with constant or changing flow rates for one or more reagents, and continuous reactors, in which reactants are continuously fed together, react together, and are retrieved continuously from the reactor. The latter include, but are not limited to tubular reactors, plug flow reactors, and continuously stirred tank reactors.

In the case of semi-batch and continuous reactors it will be possible to make predictive control of the reactions, that is, by understanding the kinetics of the reaction, such as composition and molecular weight drift, and by understanding how these characteristics produce the desired stimuli responsiveness of the polymers produced, it will be possible to produce the desired polymers ‘on-command’, by being able to predictively set the reaction conditions to achieve this; e.g. by setting the temperature and concentration of reagents, and by semi-batch flow addition of reagents to control the reaction pathway. Recently the inventor has demonstrated how this predictive approach can be used to control kinetics, molecular weight and composition drift during free radical homopolymerization and copolymerization.

Ultimately, it will also be possible to use full feedback control of reaction conditions, such as reagent flows into the reactors to produce polymers with desired stimuli responsiveness. In this scenario the sensing of the polymer characteristics (conversion, molecular weight, etc.) and/or the sensing of the stimuli responsiveness can be used to automatically adjust reaction conditions (e.g. temperature) and reagent flow conditions to control the reaction towards the desired product.

Best current approaches to assaying stimuli responsiveness involve high throughput screening of end-products, such as multiple well, channel plates, or even continuous gradient devices (e.g. Bergbreiter et al., Macromolecules, 37, 2004, 1031-1036) on which detection of transitions can be made with any appropriate spectroscopic or other method. These, however, test only the endproduct, and so have no means of determining when during synthesis the particular phase transition properties of the polymer appeared or began to appear. It would take many more polymerization reactions to explore even a finite number of compositions and molecular weights, etc., whereas the proposed during-synthesis method allows one to continuously, and in a single experiment, make precise determinations of the polymer characteristics required for sharp or gradual threshold behavior.

The idea of during-synthesis monitoring presented here is that the evolution of stimuli responsiveness can be monitored versus continuously changing molecular weight, composition, and other molecular features (e.g. polyelectrolyte linear charge density, polymer branching, cross-linking, ‘clicking’ to other molecules and polymers, etc.) as the polymers evolve during their synthesis. This sets the method totally apart from all traditional methods and even the most modern high-throughput methods that analyze only end-products of multiple reactions carried out in parallel, which hence only measure discrete variations in polymer parameters. In other words, the present invention allows stimuli responsiveness to be assessed on the equivalent of a complete continuum of endproducts, rather than a mere sampling of individually synthesized endproducts. The invention, even in its simplest form, is a high throughput screening platform. In fact, if carried out vigorously and successfully, this approach could directly challenge and perhaps even disrupt the currently growing area of multiple, simultaneous, robotically controlled reactions, whose endproducts are analyzed (Wiesbrock, F.; Schubert, U.S. “New challenges in combinatorial polymer research: 3rd DPI workshop on automated synthesis and high-throughput experimentation in polymer and materials research at the Eindhoven University of Technology.” Macromolecular Rapid Communications (2004), 25(17), 1579-1582); e.g. Symyx Corporation, Chemspeed AG. For example, those very expensive technologies (which easily run into the million dollar range and more per system), are often used to produce merely a series of polymer end products of the same composition but different molecular weight in order to assess the dependence of stimuli responsiveness on this latter property. They may also be used to produce a variety of endproducts of different compositions, masses, and other properties, but they are still limited to endproduct analysis.

The present invention is quite elegant as it both provides the equivalent of a continuum of endproducts while vastly reducing the number of reactions to be run. This idea is particularly well-suited to many ‘living’ types of polymer reactions; e.g. controlled radical polymerization reactions such as nitroxide mediated polymerization (NMP); reversible addition fragmentation chain transfer (RAFT); atom transfer radical polymerization (ATRP); and other ‘living’ type reactions, such as ring opening metathesis polymerization (ROMP), where growing chains usually share similar mass and composition averages. The invention will also be applicable to post-polymerization modifications (hydrolysis, PEGylation, ‘click’ coupling, etc.), step growth, free radical chain growth, grafting, branching, bioconjugation, etc. It is suited to many types of reaction scenarios, including batch reactors, ‘semi-batch’ reactors, that is, controlled feed of one or more reagents affecting polymerization into the reactor during the reaction, and continuous reactors.

A major advantage of the proposed method is that it can provide a fast track towards optimization of polymer properties required to carry out desired functions, such as sensing, encapsulation, coating, etc. by precisely quantifying how stimuli responsiveness evolves. Once it is known when during synthesis a polymer achieves desired stimuli responsiveness, and under what types of reaction conditions, polymers of precisely those characteristics at that point of synthesis can then be targeted as end products in subsequent experiments, scale-up operations, or manufacturing.

While many methods exist for observing polymeric phase transitions and/or stimuli responsiveness, e.g. turbidity, fluorescence, conductivity, surface tension, light scattering, circular dichroism and birefringence, including high throughput measurements on reaction endproducts, etc., the present inventor believes that few, if any, during-synthesis methods exist, which simultaneously measure polymer properties, such as mass and composition, and phase transitions.

One of the several advantages of this approach is that it will allow precise knowledge of at what point in synthesis, polymers and copolymers obtain, whether sharply or gradually, their stimuli responsiveness. For example, an evolving polymer (which henceforth means any type of polymer, whether copolymeric, terpolymeric, etc., gradient, block, grafted, branched, star, dendrimeric, produced through chemical, enzymatic or other modifications, etc.) may have an LCST, for a given solvent type (whether mixed or pure solvent) and polymer composition and molecular weight, or molecular weight distribution. With an appropriate detector in an ACOMP system, the phase transition at the LCST can be automatically detected, and it is then known what the threshold mass and composition characteristics of the polymer are for the phase transition to occur.

In fact, one can couple extra detectors to the system to make multiple determinations and hence convert the approach to a sort of ‘high throughput squared’ platform. An example of this would be the use of SMSLS (Simultaneous Multiple Static Light Scattering, patented by W. F. Reed) (W. F. Reed U.S. Pat. No. 6,618,144, “Device and method of simultaneously measuring the light scattering from multiple liquid samples containing polymers and/or colloids”; M. F. Drenski, W. F. Reed, “Simultaneous Multiple Sample Light Scattering for Characterization of Polymer Solutions”, J. App. Polym. Sci., vol. 92, 2724-2732, 2004), flow sample cells held at different temperatures in the detector train. In this particular example, one could determine the LCST for as many molecular masses and compositions of polymer as there are SMSLS flow cells at different temperatures. These latter are relatively easy and inexpensive to fabricate, and current data collection systems can handle large numbers. SMSLS flow cells can be modified to measure absorbance and turbidity (as opposed to scattering or fluorescence) if the detection fiber is mounted at an angle of 0° for detection. With the advent of flow-cell equipped dynamic light scattering (DLS)—e.g. the NanoDLS by Brookhaven Instruments Corporation (Holtsville, N.Y.), single mode detection fibers, and inexpensive autocorrelators, it is possible to create a train of SMSLS type cells for DLS to make measurements of hydrodynamic diameter.

It is noted that where detected properties may be sensitive to flow, e.g. optical measurements of anisotropic particles in shear flow, each detection cell can be equipped with a stop-flow means, whereby a solenoid valve or other automatically switchable element can periodically divert the continuous flow stream into the cell, where it remains stationary during measurement, the continuous flow bypassing it during this interval, and the cell contents being subsequently swept out as the flow again diverts through it until the flow is again diverted from the cell and a new measurement cycle is made on the stopped flow cell contents.

The SMSLS cells can be adapted to become multiple fluorescence detecting flow cells; e.g. for a right angle SMSLS cell, one could add an optical notch filter at the photodetector (e.g. CCD) to exclude scattered light and detect only fluorescence.

Newport Corporation (Irvine, Calif.), for example, offers a wide variety of narrow bandpass optical filters (e.g. 10BPF10-330). One could also use two right angle fibers (e.g. one on each side of the cell, or both on the same side) each with its own notch or cut-off optical filter for detecting ratios of fluorescence intensities at different wavelengths, as is frequently done with fluorescent probes, for example with pyrene (Narrainen, Amilcar Pillay; Pascual, Sagrario; Haddleton, David M. “Amphiphilic diblock, triblock, and star block copolymers by living radical polymerization: synthesis and aggregation behavior.” Journal of Polymer Science, Part A: Polymer Chemistry (2002), 40(4), 439-450.). While incident light is usually provided by lasers in SMSLS flow cell banks, broad band ultraviolet and visible light sources (e.g. xenon and deuterium lamps) could be used where broader ranges of UV/visible excitation than afforded by monochromatic lasers are needed. In such cases filters or monochromators for excitation wavelength selection can be used.

As concerns further optical variations of the SMSLS detection platform, additional power for functional evolution can be gained by using polarizing properties. Polarization preserving fibers and inline fiber optical polarizers are readily available to allow sensing of the various states of linear or elliptical polarization of scattered or emitted light. For example Newport Corporation has a whole series of inline fiber optical polarizers available; e.g. F-ILP-1-N-SP-FP. Areas in which polarization sensitive monitoring can be useful include, but are not limited to, formation of anisotropic structures—e.g. self-assembly of rod-like micelles—that lead to depolarized scattering, and inhibited rotations of symmetric or asymmetric probe-containing structures leading to fluorescence emission anisotropy, (Tusa, S. I; Sakakibara, a.; Yamammoto, T.; Morishima, Y. “Fluorescence Studies of pH-responsive unimolecular micelles formed from amphiphilic polysulfonates possessing long chain alkyl carboxyl pendants”, Macromolecules (2002), 35, 10182-10288) etc.

Similarly, in this single example, one can conceive of many other ways of making simultaneous determinations during synthesis. For example, one reactor stream may feed a typical ACOMP detection train for determining all the relevant polymer parameters as they evolve (composition, mass, conversion, linear charge density, etc.), whereas a separate stream(s) could be drawn and then independently diluted with a series of different diluents, e.g. with a multiple-channel peristaltic pump, the stream for each of which would flow through one or more SMSLS cells. Such multiple-channel pumps are widely available; e.g. the Rainin 7103-058 RP-1 8-channel peristaltic pump. Again, since SMSLS cells are inexpensive and large numbers can be brought under the control of a single computer, each mixed solvent stream could also have a series of SMSLS cells at different temperatures so that now, polymer characteristics for LCST thresholds could additionally be determined as a function of solvent mixture. When the threshold phenomenon is dependent on the concentration of polymer in solution, this same dual or multiple extraction stream could be also used to vary polymer concentration in multiple sub-streams for determination of such concentration dependent effects on LCST and other types of stimuli responsiveness.

There are no limits to the types of multiple diluents that could be assayed simultaneously. They could be different solvents, mixtures of solvents, solutions of different pH, ionic strength, concentrations of metal ions, uni- or multivalent ions, solutions containing aromatic molecules, drugs or their analogs, other synthetic or natural polymers, micelles, vesicles, emulsions, or liposomes that may interact with the evolving polymer, etc.

Besides light scattering, absorbance, and fluorescence detection, it is possible to use optical rotary dispersion and circular dichroism (e.g. useful for detecting helix to coil transitions, denaturation, etc.), conductance, etc., in short, any of the usual means of observing polymer transitions, associations, etc.

There are many examples that can be given besides LCST. For example, copolymers can micellize or form other types of uni- or multi-chain aggregates, depending also on their composition, molecular mass, etc. Use of a fluorescent dye in the ACOMP dilution stream, for example, could give precise information on when micellization occurs, giving a fast track to polymer optimization.

Another example is encapsulation. The desired agent, or an analog of the desired agent, could be put either in the ACOMP dilution stream, and/or in the reactor, and its encapsulation monitored by fluorescence or other method. In this way, one would know under precisely what polymer properties encapsulation occurs. In the same experiment one could also use the multiple stream approach and hence test for the effects of solvent polarity (e.g. through mixtures), pH, ionic strength, different types of agents to be encapsulated (e.g. a series of agents), etc. Yet another example is the use of agents, such as multivalent or metal ions, to produce supramolecular (non-covalent) associations between polymers.

An interesting feature of this approach is that it builds off of instrumentation and methods platforms already patented by Reed and held by Tulane. To utilize the present invention as outlined here, at least, would preferably involve use of the patented ACOMP platform. To use the multiple temperature on a single stream, or in the multiple stream approach would preferably involve use of patented SMSLS instrumentation.

The SMSLS instrumentation, as noted above, can be modified to become Simultaneous Multiple Sample Fluorescence Detection, Simultaneous Multiple Sample Absorption Detection, etc. These cells can also be fitted with light sources to form other functions besides detection; e.g. photodecomposition, photoactivation, photoassociation, photoacidification, etc. That is, instead of irradiating the cells with electromagnetic radiation used solely as a probe, such as for scattering or fluorescence, the incident radiation could actually excite functional properties of the polymers, such as photoacidification where a proton is photostimulated to leave its parent molecule. In general the invention can monitor radiation sensitivity of the polymers, whether the radiation be electromagnetic, such as visible light, ultraviolet, x-rays, etc., or charged particles, such as electrons. Each sample cell could be constructed to each have a different intensity or type of radiation (e.g. different wavelengths or colors of light) incident on it, for example, through windows that are in contact with the flow channels.

In fact, the present invention can be viewed as a ‘next generation’ ACOMP system in that it benefits from the information (molecular mass, conversion, composition, etc.) provided by the ‘first generation’ ACOMP and uses this information to correlate detection of phase transitions and associations therewith. It is also next generation in the sense that it moves into the important realm of mapping out the functional behavior of the explosively growing number of ‘intelligent’ polymers that will be at the heart of major materials science innovations in the 21st century.

The principles outlined above can be readily adapted to the vast area of natural product modification and use. Natural products are frequently modified by chemical, enzymatic, or photomodifications in order to achieve properties such as solubility, biocompatibility, micellization, nano-structuration, etc. This same type of approach could be used as a high throughput platform for monitoring how these properties of natural products evolve as they are extracted, modified, and processed.

ACOMP has matured to the point where reactions can be controlled predictively (i.e. using precise reaction kinetics and characteristics furnished by ACOMP to predict optimal reaction processes) and, eventually, by feedback. In those scenarios, the monitoring is used to guide the production of desired molecular weight and composition distributions, degrees of grafting, etc.

FIG. 1 shows a scheme for multiple temperature monitoring of phase transition and association phenomena. The multiple detectors can be of the light scattering, fluorescence, and absorbance types, among others, including any combination that can be used in the train. A separate extraction/dilution/conditioning stage is shown here with the solid arrow. A simpler version uses the ACOMP stream directly (dotted line) so that the multiple transition/association monitoring detectors are simply in series with the rest of the ACOMP detectors.

FIG. 2 shows a scheme for multiple composition monitoring of phase transition and association phenomena. A multi-head peristaltic pump, or other device(s), can be used to withdraw multiple small sample streams for separate and simultaneous dilution with ‘selected diluents’. These latter can be an assortment of any factors desired; e.g. mixed solvents, different solvents, different pH, ionic strength, metal ions, uni- or multivalent ions, diluents containing specific molecules for binding or ‘recognition’ of the polymer, enzymes, polypeptides, etc. The multiple detectors can be of the light scattering, fluorescence, and absorbance types, among others, such as capillary viscometers, including any combination that can be used in the train.

Shown in FIG. 3 is a polymerization reactor 1, which is preferably controllable, thermostatted temperature, with mechanical stirring, inlet/outlet access ports, and optional condenser (e.g. Ace Glass). There can be optional reactor probes 2, such as pH and/or conductivity sensors, and/or near infrared and/or mid-infrared probes, and/or Raman probe.

The ACOMP front end 3 comprises one or more of the following components (see Polymer International, 57, 390-396, 2008)—this list is not necessarily exhaustive: a pump for extraction from the reactor, e.g. Zenith Corp. gear pump; an optional recirculation loop from the reactor through the extraction pump and back into the reactor; an optional pressure transducer in the recirculation loop that measures reactor content viscosity; an optional mass flow controller that provides a controllable steady pick-off from the recirculation loop into the low pressure mixing chamber (LPMC), e.g. Bronkhorst; an LPMC, such as a stirred, thermostatted vial with inlet and outlet connections for fluid entrance and egress; reactor fluid is diluted to any desired level in the LPMC, and it is preferably vented to the atmosphere to allow release of any gas bubbles generated in the reactor; an LPMC level control, such as an auxiliary pump with extraction tube at fixed height within the LPMC; an optional high pressure mixing stage and pump or LPMC and pump to achieve higher levels of dilution, if desired; a capillary tube leading to the detector train.

The solvent reservoir 4 can be a vessel (four-liter capacity, for example) containing dilution solvent or solvent mixture of choice, with tubes in the vessel for extraction by the various pumps for diluting and mixing the sample flow, and feeding the detector train. The ACOMP detector train 5 preferably comprises one or more of the following instruments: multi-angle static light scattering detector, e.g. Brookhaven Instruments Corp. BI-MwA; dynamic light scattering detector, e.g. Brookhaven Instruments Corp. nano-DLS; Mie light scattering detector, e.g. Malvern Mastersizer; single or multiple capillary viscometer, e.g. using Validyne pressure transducers; ultraviolet/visible spectrophotometer, e.g. Shimadzu Diode Array SPD-M20A; differential refractometer, e.g. Shimadzu RID-10A; near infra red or mid-infra red detector, e.g. Shimadzu.

The microcomputer control 6, for data gathering and analysis, can comprise: an integrated instrument control device and signal processor for detector train signals, e.g. the National Instruments NI Compact Field Point Model CFP-2020 Part #: 188539G-03; a software program(s) allowing control of the instruments and graphical display of the incoming and analyzed data, e.g. Labview software modules; software for numerical data analysis of signals; e.g. written in C++ or other programming language (Power Basic, Visual Basic, Fortran), and embedded into control program, or running simultaneously with it; a computer for running the control, data gathering and analysis software, e.g. any standard desktop or laptop computer, such as from Gateway, Hewlett Packard, Apple or Dell.

The optional auto-SEC (Size Exclusion Chromatography) 7 is connected to the waste stream from the ACOMP detector train 5, or directly to the outlet stream of the ACOMP front end 3 if no continuous detector train 5 is used. The auto-SEC 7 can be equipped with: an auto-injector valve connected to the stream as mentioned, and set to automatically make injections of small volumes (e.g. 100 microliters) into the SEC columns at desired intervals (e.g. every 10 minutes); a high pressure liquid chromatography pump; e.g. Shimadzu LC10-AD; a solvent reservoir, which can be the same as solvent reservoir 4 if desired and appropriate; one or more SEC columns; a software program for gathering and analyzing the data from the periodically injected samples; any combination of the following detectors: multi-angle static light scattering detector, e.g. Brookhaven Instruments Corp. BI-MwA; dynamic light scattering detector, e.g. Brookhaven Instruments Corp. nano-DLS; Mie light scattering detector, e.g. Malvern Mastersizer; single or multiple capillary viscometer, e.g. using Validyne pressure transducers; ultraviolet/visible spectrophotometer, e.g. Shimadzu Diode Array; differential refractometer, e.g. Shimadzu; near infra red or mid- infra red detector, e.g. Shimadzu.

Waste vessel 8 is preferably provided to accumulate the waste streams of solvent and sample produced by the system and can be e.g. a safety sealed metal drum. Desired dilution/conditioning 9 can have the same function as ACOMP front-end 3. In some applications it can be ACOMP front-end 3 itself, in other applications it can contain those elements of ACOMP front-end 3 necessary to provide the dilution/conditioning needed to monitor stimuli responsiveness of the polymers. Multiple detection modules 10 are preferably independently controlled, and monitored, e.g. for temperature, illumination, and can include multiple individual capillary viscometers, static light scattering cells (e.g. SMSLS—see (U.S. Pat. No. 6,618,144)), dynamic light scattering, fluorescence, and turbidity cells. Optional multiple detection modules 11 in parallel with modules 10, including a valve or ‘T’ for splitting the flow between modules 10 and modules 11. These can be used to incorporate more banks of individually controlled and monitored detectors.

FIG. 4 is a specific embodiment for using the invention to characterize the salt sensitivity of micellization, polymer dimensions, and interactions during the synthesis of a copolymeric polyelectrolyte, of the block, random, or gradient type—this is just an example of numerous applications of the invention.

Elements 1-8, and 10 in FIG. 3 can the same for FIG. 4. Element 9 from FIG. 3 is replaced by pump 12. Element 11 from FIG. 3 is omitted and replaced by detectors 14. Elements 12, 13, and 14 are described below. For this specific embodiment those elements corresponding to elements 1-10 in FIG. 3 are specified more exactly than in FIG. 3 to avoid too many optional features. The specific items used and their combinations are not construed as limiting. A jacketed polymerization reactor 101, is preferably thermostatted with temperature control from 2° C. to 220° C., using recirculating oil from a thermostatted batch. Reactor 101 preferably has a mechanical stirring paddle, controllable from 10 to 1000 RPM, inlet ports for purging with nitrogen or other gas, introducing reagents either with a syringe or with a pump, a tube for extracting the reactor contents, access ports for sensors 102, and a condenser fitted to the top. Reactor 101 is normally sealed and kept under a blanket of nitrogen at slightly higher than atmospheric pressure. A copolymeric polyelectrolyte synthesis reaction is chosen in this example, and long, electrically charged polymer chains are produced during the reaction. Reactor conductivity sensors 102 can include a Jenway conductivity probe and pH probe, for example. ACOMP front end 103 in this configuration preferably comprises the following components. The list is not necessarily exhaustive: a Shimadzu HPLC pump for extraction from the reactor; a pressure transducer with a capillary in the outlet flow of the HPLC pump that measures undiluted reactor content viscosity; an LPMC, consisting of a thermostatted vial with an inlet tube from the HPLC reactor withdrawal pump that has a perforated outlet orifice to promote viscous liquid dispersal, and an outlet tube for continuous extraction of the diluted LPMC content; reactor fluid is diluted to any desired level in the LPMC, and the LPMC is preferably vented to the atmosphere to allow release of any gas bubbles generated in the reactor; an LPMC level control, consisting of an HPLC or peristaltic auxiliary pump with extraction tube at fixed height within the LPMC. This guarantees maintaining the same level and volume in the LPMC throughout the reaction. The outlet of this level controlling pump goes to waste vessel 108; a high pressure mixing stage, an Upchurch Corp. 10 microliter high pressure mixing ‘T’. One end of the ‘T’ is fed by the diluted fluid leaving the LPMC using a separate HPLC pump, and another, separate HPLC pump feeds the other end of the ‘T’, and provides the desired final dilution level and also feed the detector train via a capillary tube leaving the high pressure mixing ‘T’ chamber.

A solvent reservoir 104 can be a vessel (e.g., a four liter glass container) containing dilution solvent, with tubes in the vessel for extraction by the various pumps for diluting and mixing the sample flow, and feeding the detector train. An ACOMP detector train 105 preferably the following instruments. a multi-angle static light scattering detector; e.g. Brookhaven Instruments Corp. BI-MwA. The expansion board on this preferably accepts signals from all the other detectors; a dynamic light scattering detector, e.g. Brookhaven Instruments Corp. nano-DLS; a Mie light scattering detector, e.g. Malvern Mastersizer; a single capillary viscometer, using a Validyne pressure transducer, according to the design of Norwood and Reed (see Int. J. Polym. Ana. and Char., 4, 99-132, 1997); a two wavelength ultraviolet/visible spectrophotometer, e.g. Shimadzu Diode Array; a differential refractometer, e.g. Shimadzu. A microcomputer control 106 for data gathering and analysis preferably comprises: a Brookhaven Instruments Corp. software program that gathers, via an A/D expansion board on the BI-MwA detector, and graphically displays, the incoming and analyzed data. software for numerical data analysis of signals written for example in Power Basic; a Dell microcomputer with an Intel Core 2 duo processor and USB connection. Auto-SEC (Size Exclusion Chromatography) 107 is connected to the waste stream from the ACOMP detector train 105. The auto-SEC 107 is preferably equipped with: a Rheodyne MXP 7900 auto-injector valve with a 100 μl sample loop attached; an Amperite solid state DFA series adjustable recycling timer is used to control the valve for periodic injections; a Shodex 804 SEC column; a Shimadzu high pressure liquid chromatography pump;

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