Patent Description:
The present invention relates to systems and computer-implemented methods for analyzing a product stream of a chemical reaction.

Liquid chromatography (LC) is a chemical analysis method that utilizes the partition coefficients of the constituents of a mixture between a mobile phase and a stationary phase. LC has several advantages over other chemical analysis methods. First, LC can aid in determining a chemical makeup of a solution of mixture with high specificity. Additionally, LC has excellent linear quantification properties. In other words, sample concentrations can be calculated from a calibration curve of standard values plotted linearly.

LC and chromatography in general also have several drawbacks. LC typically includes several process steps that are difficult to implement manually. First, samples are withdrawn and then diluted. Dilution of samples aids in making the samples injectable into a chromatography column. The diluted sample is transferred to a liquid chromatography device, where the chemical makeup of the sample can be measured or determined. Each of the steps in the LC process are prone to operator error and imprecisions in execution. Any imprecision that occurs during either step of the LC process can be compounded and propagated throughout the LC process. LC is also difficult to implement for hydrolytically unstable species, and derivatization of hydrolytically unstable species is often practiced to make the species more stable for LC implementation. In addition, data retrieved and analyzed from an LC column can be subject to a time delay. In other words, once proper adjustments have been made to a reactor in response to the data retrieved from the LC column, the data retrieved from the LC column may no longer be accurate. A general automated LC sample dilution and injection system often uses large sample volumes and has a significant carryover from one sample to the next. Some automated LC dilution/injection systems are only applicable to homogeneous reaction samples from flow or batch processes, but not capable of sampling from flow reactor systems (e.g., CSTR, PFR) and batch systems with heterogeneous reaction mixture. An enduring goal is to develop a system and computer-implemented method, in which real-time adjustments can be made to reaction conditions to influence products with minimal sample volume and minimal carryover from one sample to the next.

The article "<NPL>) discloses a computer-implemented method for analyzing a product stream of a chemical reaction.

The present disclosure relates to a computer-implemented method for analyzing a product stream of a chemical reaction. The method includes withdrawing a portion of the product stream of the chemical reaction from a reactor, the portion of the product stream having a volume of less than about <NUM>µL. The method further includes mixing the portion of the product stream with a diluent to produce a sample and then transferring the sample to a liquid chromatography device. A measured chemical profile is then developed, via the liquid chromatography device, which can be used for process monitoring or real time decision making. In some embodiments, the method can include adjusting a reaction condition in the reactor based on differences between the measured chemical profile and a desired chemical profile. In some embodiments, the reaction condition can include at least one of a pump rate, a flow rate, a temperature, a pressure, and an application of light. In some embodiments, the diluent can be added to the portion of the product stream at a ratio of at least about <NUM>:<NUM>. In some embodiments, the product stream can be a first product stream, and the method can include analyzing a second product stream with less than about <NUM>% carryover from the first product stream, and without implementing a priming run. In other words, two product streams can be analyzed in back-to-back orders with less than about <NUM>% carryover.

Various embodiments are described in the following, and are only considered to relate to the invention when unambiguously covered by the scope defined in the appended claims. Embodiments described herein relate to systems and computer-implemented methods for analyzing a product stream of a chemical reaction. In some embodiments, the product stream can be analyzed via LC. LC is a separation technique that includes mixing of a reaction product with a liquid. The liquid acts as a mobile phase. The reaction product is dissolved or mixed with the liquid, and the resulting solution or mixture is fed into an LC column or plane. The column or plane includes a stationary phase with very small packing particles and is often maintained at a high pressure. The mobile phase then forces the reaction product through the stationary phase, where the partition coefficients of the different components of the reaction product determine whether each component of the reaction product has more of an affinity for the mobile phase or for the stationary phase. The partition coefficients of the different components of the reaction product are largely determined by the polarities, or the dipole moments of the components of the reaction product. However, van der Waals forces, affinity for hydrogen bonding, and other intermolecular forces can also play a role in determining partition coefficients.

LC (and chromatography in general) has several technical advantages over other chemical identification methods (e.g., vibrational spectroscopy, direct mass spectroscopy, infrared spectroscopy, nuclear magnetic resonance). LC can identify compounds with excellent specificity, including isomers. Linear quantification is also applicable in the use of LC. LC is generally the desired chemical identification method for quality target product protocols in the pharmaceutical industry. LC is however not without its drawbacks. Analysis and reaction adjustment is often a long process, not executable in real time. Sample preparation in LC is also a laborious process with fairly low margin for error. LC is not a suitable direct analysis method for hydrolytically unstable species. Derivatization or quenching is often implemented to convert a hydrolytically unstable species to a hydrolytically stable species.

Automation of LC sample preparation can address several of the aforementioned shortcomings of LC. Firstly, an automated LC sample preparation system can analyze and adjust reaction conditions in real time, rather than being subject to delays or inconsistencies due to analysis time by the operator. Process delays brought on by operator analysis time can be significant enough, such that the information the operator applies when adjusting reaction conditions (e.g., temperature, pressure, flow rates) is no longer current. The faster feedback of an automated system can aid in addressing this issue, as reaction conditions can be adjusted appropriately via instant or substantially instant communications from a computer or central processing unit. LC sample preparation (e.g., via dilution, transport of sample) is also a process that can be automated to remove or substantially reduce measurement error associated with sample preparation. Derivatization or quenching can also be automated such that delay associated with derivatization or quenching are minimized.

Automated LC systems in the current state of the art (e.g., <NPL>) often require withdrawal of a large amount of product (i.e., <NUM> to <NUM>) when preparing a sample. Sample carryover and fouling are also issues in currently implemented systems, unless significant priming runs are executed prior to the withdrawal and analysis of each sample. Samples containing particulates or dissolved solids can potentially leave residue behind in tubes and vessels of currently implemented systems. Additionally, automated LC systems have heretofore not been implementable for monitoring batch reactor systems. Embodiments described herein address each of the issues of product withdrawal minimization, sample carryover, minimization of fouling, and reactor type versatility. Embodiments described herein include methods of implementing automated LC sample preparation apparatuses, as well as systems for implementing automated LC sample preparation apparatuses.

As used in this specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the term "a member" is intended to mean a single member or a combination of members, "a material" is intended to mean one or more materials, or a combination thereof.

The term "substantially" when used in connection with "cylindrical," "linear," and/or other geometric relationships is intended to convey that the structure so defined is nominally cylindrical, linear or the like. As one example, a portion of a support member that is described as being "substantially linear" is intended to convey that, although linearity of the portion is desirable, some non-linearity can occur in a "substantially linear" portion. Such non-linearity can result from manufacturing tolerances, or other practical considerations (such as, for example, the pressure or force applied to the support member). Thus, a geometric construction modified by the term "substantially" includes such geometric properties within a tolerance of plus or minus <NUM>% of the stated geometric construction. For example, a "substantially linear" portion is a portion that defines an axis or center line that is within plus or minus <NUM>% of being linear.

As used herein, the term "product stream" is not limited to reaction products that flow (e.g., an outlet stream from a CSTR, PFR), but can also refer to a stationary product, such as a product solution or mixture withdrawn from a batch reactor after a chemical reaction has occurred in the batch reactor.

As used herein, the term "set" and "plurality" can refer to multiple features or a singular feature with multiple parts. Thus, a set of portions or a plurality of portions may include multiple portions that are either continuous or discontinuous from each other. A plurality of particles or a plurality of materials can also be fabricated from multiple items that are produced separately and are later joined together (e.g., via mixing, an adhesive, or any suitable method).

As used herein, the term "semi-solid" refers to a material that is a mixture of liquid and solid phases, for example, such as a particle suspension, a slurry, a colloidal suspension, an emulsion, a gel, or a micelle.

<FIG> is a schematic illustration of a method <NUM> of implementing an online chromatographic sample dilution and preparation, according to an embodiment. The method <NUM> includes executing a chemical reaction at step <NUM>, withdrawing a portion of a product stream at step <NUM>, and adding diluent to the portion of the product stream to produce a sample at step <NUM>. The method <NUM> further includes transferring the sample to a liquid chromatography device at step <NUM>, developing/measuring a chemical profile for the sample at step <NUM>, and analyzing/interpreting the measured chemical profile at step <NUM>. At this point, the method <NUM> includes a comparison of the measured chemical profile to a desired chemical profile at step <NUM>. If the measured chemical profile matches the desired chemical profile within a prescribed margin of error, reaction conditions employed at step <NUM> remain the same and the method <NUM> resumes from step <NUM> without any change to the reaction conditions. If the measured chemical profile does not match the desired chemical profile within a prescribed margin of error, a reaction condition is adjusted at step <NUM>, and then the reaction proceeds at step <NUM> with one or more reaction conditions adjusted.

Executing the chemical reaction at step <NUM> is done in a reactor. In some embodiments, the reactor can include a continuous stirred tank reactor (CSTR), a plug flow reactor (PFR), a batch reactor, or a semi-batch system. In some embodiments, the reactor can be a photoreactor, a photobioreactor, or a mixer. In some embodiments, step <NUM> can include a derivatization or quenching step. In some embodiments, the derivatization or quenching step can be implemented via an attachment to the reactor that applies a quenching or derivatizing reagent to a reaction product stream as the reaction product stream exits the reactor. In some embodiments, executing the chemical reaction at step <NUM> can include the use of pumps, pipes, tubes, and/or valves to deliver one or more chemical reagents to the reactor. In some embodiments, step <NUM> can include adjusting the pressure and/or temperature of conditions inside the reactor. In some embodiments, step <NUM> can include adjusting physical forces (e.g., photon flux, electrical power) applied to the reactor.

In some embodiments, withdrawal of the portion of the product stream at step <NUM> can be executed using a withdrawal apparatus with minimal dead volume, thereby minimizing the volume of the portion of the product stream withdrawn during step <NUM>. Withdrawal of a small portion of the product stream at step <NUM> can aid in minimizing the amount of fouling that occurs in a system, in which the method <NUM> is implemented. In other words, if the portion of the product stream withdrawn at step <NUM> has a small volume, the total amount of solids, either dissolved or suspended in the portion of the product stream is also a small amount. This can help minimize the amount of particulates that flow through the tubes, pipes, and vessels of the system, in which the method <NUM> is implemented. In some embodiments, the portion of the product stream withdrawn at step <NUM> can be less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, less than about <NUM>µL, inclusive of all values and ranges therebetween.

In some embodiments, step <NUM> can be optimized via computed fluid dynamics for representative sampling and minimal carryover. A computed fluid dynamics implementation at step <NUM> can aid in assuring that the portion of the product stream withdrawn at step <NUM> is accurately representative of the product stream. In some embodiments, step <NUM> can include cleaning and priming of a system and tubes used in the method <NUM>. In some embodiments, a sampling apparatus used for executing step <NUM> can also clean and prime the system and the tubes used in the method <NUM>. In some embodiments, the method <NUM> can exclude cleaning and/or priming steps. In some embodiments, withdrawal of the portion of the product stream at step <NUM> can be done via a mechanical scoop.

In some embodiments, the portion of the product stream can be withdrawn at step <NUM> at a prescribed pressure. In some embodiments, step <NUM> can be executed at a reactor pressure of at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, at least about <NUM> bar, or at least about <NUM> bar. In some embodiments, step <NUM> can be executed at a reactor pressure of no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, no more than about <NUM> bar, or no more than about <NUM> bar. Combinations of the above-referenced values are also possible for the reactor pressure at the execution of step <NUM> (e.g., at least about <NUM> bar and no more than about <NUM> bar or at least about <NUM> bar and no more than about <NUM> bar). In some embodiments, step <NUM> can be executed at a reactor pressure of about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar, about <NUM> bar.

In some embodiments, the portion of the product stream can be withdrawn at step <NUM> at a prescribed temperature. In some embodiments, step <NUM> can be implemented at a temperature of at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about -<NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. In some embodiments, step <NUM> can be implemented at a temperature of no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, no more than about -<NUM>, or no more than about -<NUM>. Combinations of the above-referenced values for the temperature of step <NUM> are also possible (e.g., at least about -<NUM> and no more than about <NUM> or at least about <NUM> and no more than about <NUM>), inclusive of all values and ranges therebetween. In some embodiments, step <NUM> can be executed at a temperature of about -<NUM>, about -<NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>. In some embodiments, step <NUM> can be executed via a device with a pressure rating of about <NUM> bar to about <NUM> bar. In some embodiments, step <NUM> can be executed via a device with a temperature rating of about -<NUM> to about <NUM>.

In some embodiments, the portion of the product stream can be withdrawn at step <NUM> from a homogeneous or substantially homogeneous system. In other words, the portion of the product stream can be withdrawn from a portion of the reactor with a homogeneous or substantially homogeneous concentration of a reagent. In some embodiments, the portion of the product stream can be withdrawn at step <NUM> from a heterogeneous system. In other words, the portion of the product stream can be withdrawn from a portion of the reactor with a heterogeneous concentration of a reagent.

In some embodiments, the portion of the product stream withdrawn at step <NUM> can include particulates, or suspended solids. In some embodiments, the particulates or suspended solids can have a total suspended solids (TSS) content of at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, or at least about <NUM>/L. In some embodiments, the portion of the product stream withdrawn at step <NUM> can have a TSS content of no more than about <NUM>,<NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, or no more than about <NUM>/L. Combinations of the above-referenced TSS values in the portion of the product stream withdrawn at step <NUM> are also possible (e.g., at least about <NUM>/L and no more than about <NUM>,<NUM>/L or at least about <NUM>/L and no more than about <NUM>/L), inclusive of all values and ranges therebetween. In some embodiments, the portion of the product stream withdrawn at step <NUM> can have a TSS content of about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, or about <NUM>,<NUM>/L. In some embodiments, the particulates or suspended solids can have a minimal fouling effect in subsequent sample runs. In other words, the portion of the product stream withdrawn at step <NUM> can have a TSS content of up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, or up to about <NUM>/L without any significant effect on the quality of subsequent samples.

In some embodiments, the portion of the product stream withdrawn at step <NUM> can include dissolved solids. In some embodiments, the portion of the product stream withdrawn at step <NUM> can have a total dissolved solids (TDS) content of at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, at least about <NUM>/L, or at least about <NUM>/L. In some embodiments, the portion of the product stream withdrawn at step <NUM> can have a TDS content of no more than about <NUM>,<NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, no more than about <NUM>/L, or no more than about <NUM>/L. Combinations of the above-referenced TDS values in the portion of the product stream withdrawn at step <NUM> are also possible (e.g., at least about <NUM>/L and no more than about <NUM>,<NUM>/L or at least about <NUM>/L and no more than about <NUM>/L), inclusive of all values and ranges therebetween. In some embodiments, the portion of the product stream withdrawn at step <NUM> can have a TDS content of about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, about <NUM>/L, or about <NUM>,<NUM>/L. In some embodiments, the particulates or suspended solids can have a minimal fouling effect in subsequent sample runs. In other words, the portion of the product stream withdrawn at step <NUM> can have a TDS content of up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, up to about <NUM>/L, or up to about <NUM>/L without any significant effect on the quality of subsequent samples.

In some embodiments, the portion of the product stream withdrawn at step <NUM> can be transferred to a mixing device. At step <NUM>, a diluent can be added to the portion of the product stream to produce a sample. In some embodiments, step <NUM> can be performed in a mixing device. In some embodiments, the diluent can be miscible or substantially miscible with the portion of the product stream. In some embodiments, the sample produced at step <NUM> can be homogenized or substantially homogenized. In some embodiments, the diluent can be added to the portion of the product stream at a v:v ratio (diluent:portion of the product stream) of at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, at least about <NUM>:<NUM>, or at least about <NUM>:<NUM>. In some embodiments, the diluent can be added to the portion of the product stream at a v:v ratio of no more than about <NUM>,<NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, no more than about <NUM>:<NUM>, or no more than about <NUM>:<NUM>. Combinations of the above-referenced v:v ratios of diluent to portion of the product stream are also possible (e.g., at least about <NUM>:<NUM> and no more than about <NUM>,<NUM>:<NUM> or at least about <NUM>:<NUM> and no more than about <NUM>:<NUM>), inclusive of all values and ranges therebetween. In some embodiments, the diluent can be added to the portion of the product stream at a v:v ratio of about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, about <NUM>:<NUM>, or about <NUM>,<NUM>:<NUM>.

In some embodiments, step <NUM> can be executed repeatedly at time intervals of at least about <NUM> seconds, at least about <NUM> minute, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, at least about <NUM> minutes, or at least about <NUM> minutes. In some embodiments, step <NUM> can be executed repeatedly at time intervals of no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, no more than about <NUM> minutes, or no more than about <NUM> minute. Combinations of the above-referenced time intervals for execution of step <NUM> are also possible (e.g., at least about <NUM> seconds and no more than about <NUM> minutes or at least about <NUM> minutes and no more than about <NUM> minutes, inclusive of all values and ranges therebetween. In some embodiments, step <NUM> can be executed repeatedly at time intervals of about <NUM> seconds, about <NUM> minute, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, or about <NUM> minutes.

In some embodiments, a quenching agent can be added to the portion of the product stream prior to step <NUM>. In some embodiments, the quenching agent can be added during step <NUM>. In some embodiments, the quenching agent can be added during step <NUM> in a separate stream from the diluent. In some embodiments, the quenching agent can be added during step <NUM> in the same stream as the diluent. In some embodiments, the quenching agent can be added to the sample after step <NUM>. In some embodiments, a stoichiometric amount of the quenching agent can be added before step <NUM>, during step <NUM>, and/or after step <NUM>. In other words, the quenching agent can be added in an appropriate amount to quench the product present in the portion of the product stream or in the sample. In some embodiments, an excess amount of the quenching agent can be added before step <NUM>, during step <NUM>, and/or after step <NUM>. In some embodiments, a derivatizing agent can be added to the portion of the product stream prior to step <NUM>. In some embodiments, the derivatizing agent can be added during step <NUM>. In some embodiments, the derivatizing agent can be added during step <NUM> in a separate stream from the diluent. In some embodiments, the derivatizing agent can be added during step <NUM> in the same stream as the diluent. In some embodiments, the derivatizing agent can be added to the sample after step <NUM>. In some embodiments, a stoichiometric amount of the derivatizing agent can be added before step <NUM>, during step <NUM>, and/or after step <NUM>. In other words, the derivatizing agent can be added in an appropriate amount to quench the product present in the portion of the product stream or in the sample. In some embodiments, an excess amount of the derivatizing agent can be added either before step <NUM>, during step <NUM>, and/or after step <NUM>. In some embodiments, a reaction solvent can be added to the mixing device before step <NUM>, during step <NUM>, and/or after step <NUM>. In some embodiments, the quenching agent can be dissolved in the reaction solvent. In some embodiments, the derivatizing agent can be dissolved in the reaction solvent.

In some embodiments, the mixing device can be flushed with inert gas prior to step <NUM>. In some embodiments, the mixing device can be flushed with inert gas after step <NUM>. In some embodiments, the inert gas can include nitrogen, helium, argon, or any combinations thereof.

The sample produced in step <NUM> is transferred to an LC device at step <NUM>. In some embodiments, the sample can be pumped through a valve or a series of valves that regulate flow to the LC device. In some embodiments, the sample can move through a series of tubes and/or pipes prior to reaching the LC device. In some embodiments, the sample can be filtered before reaching the LC device. In some embodiments, a portion of the sample can be diverted away from the LC device to a waste stream. In some embodiments which do not form part of the present invention, the sample can flow through a vial, where an LC needle autosampler withdraws an aliquot of sample and injects into the LC device for analysis. In some embodiments, the vial can include a transient flow vial. In some embodiments, the sample can flow through the transient flow vial via pneumatic pressure. In some embodiments, the sample can flow through an injection loop or flow cell, where a pump withdraws an aliquot of sample and injects into the LC device for analysis. In some embodiments, the sample can be injected into an LC device via a valve switch.

At step <NUM>, the LC device develops a measured chemical profile of the sample. In some embodiments, the LC device can be a high performance liquid chromatography (HPLC) device. In some embodiments, the LC device can be an ultra-high performance liquid chromatography (UHPLC) device. In some embodiments, the LC device can be an ion exchange chromatography device, a size-exclusion chromatography device, an expanded bed adsorption chromatographic separation device, a reversed-phase chromatography device, a hydrophobic interaction chromatography device, a two-dimensional chromatography device, a simulated moving-bed (SMB) chromatography device, a fast protein liquid chromatography (FPLC) device, a counter current chromatography (CCC) device, a periodic counter-current chromatography (PCC) device, a chiral chromatography device, a bioaffinity chromatography device, an aqueous normal-phase chromatography device, or any combination thereof. In some embodiments, multiple LC devices can be used at step <NUM>.

At step <NUM>, the measured chemical profile developed in step <NUM> is analyzed. In some embodiments, the analysis method can include an asymmetric least squares smoothing method, Design of Experiment (DoE) analysis, a multivariate chemometric analysis method, a polynomial filter method, a principal components analysis method, a supervised pattern recognition method, an unsupervised pattern recognition method, a hierarchical clustering method, a linear quantification method, a quadratic quantification method, a cubic quantification method, a k-nearest neighbor method, a regression analysis method, a multivariate regression analysis method, Stable Noisy Optimization by Branch and FIT (SNOBFIT), deep reaction optimizer (DRO), Bayesian probabilistic optimizer (Phoenics), multi-objective Perato optimizer (Chimera) or any combination thereof.

At step <NUM>, the analyzed chemical profile is compared to a desired chemical profile. In some embodiments, the desired chemical profile can be in the form of absolute LC peak area under the curve (AUC). In some embodiments, the desired chemical profile can be in the form of a quantified ratio (e.g., mass ratio, volumetric ratio, molar ratio) of a first product to a second product. In some embodiments, the desired chemical profile can be in the form of a quantified ratio of the first product to a sum of all other products.

If the measured chemical profile matches the desired chemical profile to within a designated margin of error, then the method <NUM> resumes unchanged from step <NUM>. If the measured chemical profile does not match the desired chemical profile to within the designated margin of error, then step <NUM> is executed, which adjusts one or more parameters of the chemical reaction executed at step <NUM>. In some embodiments, the designated margin of error can be a prescribed value. In some embodiments, the designated margin of error can be a rigid value. In some embodiments, the designated margin of error can be a fluid value that changes based on one or more factors present in the system (e.g., the reactor temperature, flow rate of a reagent A, etc.). In some embodiments, the designated margin of error can be at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>%. In some embodiments, the designated margin of error can be no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, or no more than about <NUM>%. Combinations of the above-referenced margin of error values are also possible (e.g., at least about <NUM>% and no more than about <NUM>% or at least about <NUM>% and no more than about <NUM>%), inclusive of all values and ranges therebetween. In some embodiments, the designated margin of error can be about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%.

In some embodiments, step <NUM> can include an adjustment of a pump rate of one or more reagents. In some embodiments, step <NUM> can include an adjustment of a flow rate of one or more reagents. In some embodiments, step <NUM> can include an adjustment of a valve to increase a flow rate, decrease a flow rate, or block flow of a reagent. In some embodiments, step <NUM> can include adjustment of a temperature of the reactor. In some embodiments, step <NUM> can include adding heat to the reactor. In some embodiments, step <NUM> can include removing heat from a reactor. In some embodiments, step <NUM> can include increasing reactor pressure. In some embodiments, step <NUM> can include pumping more gas into the reactor. In some embodiments, step <NUM> can include reducing or restricting flow of gas into the reactor. In some embodiments, step <NUM> can include modifying the amount of light incident upon the reactor. This can be via an increase in light intensity of an applied light source, a decrease in light intensity of an applied light source, and/or via an increase or decrease in shading. In some embodiments, step <NUM> can include an adjustment of a ratio of a first reagent to a second reagent. In some embodiments, step <NUM> can include an adjustment of a ratio of a first reagent to all other reagents.

<FIG> is a schematic illustration of a system <NUM> for implementation of online chromatographic sample dilution and preparation, according to an embodiment. In some embodiments, the method <NUM>, as described above with reference to <FIG>, can be implemented using the system <NUM>. As shown, the system <NUM> includes a data interpreter <NUM>, a reactor <NUM>, a withdrawal device <NUM>, a mixer <NUM>, and a liquid chromatography device <NUM> (hereinafter LC device <NUM>). As shown, solid lines indicate physical couplings between units, arrows indicate flow of material from one unit to another, and dotted lines indicate a communicative connection between units (e.g., via wired or wireless data transmission).

The data interpreter <NUM> is a device, through which the control logic process to implement the method <NUM> can be executed. In some embodiments, the data interpreter <NUM> can be a computer, a smartphone, a tablet, a laptop, a remote controller, any other computing device, or combination thereof. In some embodiments, the data interpreter <NUM> can be communicatively connected to the other units of the system <NUM> via a wired connection, such as an Ethernet cable, a powerline adapter, power over long reach Ethernet (PoLRE), coaxial cable, or any other suitable wired connection or combinations thereof. In some embodiments, the wired connection can be an analog connection. In some embodiments, the data interpreter <NUM> can be communicatively connected to the other units of the system <NUM> via a wireless connection, such as WiFi or cellular (1x, <NUM>, <NUM> LTE, <NUM>). In some embodiments, the data interpreter <NUM> can be communicatively connected to a first unit via a wired connection and the data interpreter <NUM> can be communicatively connected to a second unit via a wireless connection. For example, the data interpreter <NUM> can be connected to the reactor <NUM> via a wired connection and the data interpreter <NUM> can be connected to the withdrawal device <NUM> via a wireless connection.

In some embodiments, the reactor <NUM> can include a CSTR, a PFR, a batch reactor, a semi-batch reactor, a photoreactor, a photobioreactor, a mixer, or any other suitable reactor type. In some embodiments, the reactor <NUM> can be a reactor that exhibits properties of more than one of the aforementioned reactor types. For example, the reactor <NUM> can be designed as a CSTR, but can exhibit concentration gradients within the main vessel of the CSTR, such that the reactor <NUM> has PFR properties. In some embodiments, the reactor <NUM> can include one or more inlet streams. In some embodiments, the reactor <NUM> can include one or more outlet streams. In some embodiments, the one or more inlet streams can deliver a reagent or reagents to the reactor <NUM>. In some embodiments, the one or more outlet streams can transfer a product or products outside of the reactor. In some embodiments, the flow rate of inlet stream can be controlled via pumps, gravity, and/or valves. In some embodiments, the flow rate of outlet stream can be controlled via pumps, gravity, and/or valves. During operation of the system <NUM>, any operational parameters of the reactor <NUM> can be adjusted. These operational parameters can include, but are not limited to: temperature, pressure, incident light on the reactor <NUM>, flow rates into and/or out of the reactor <NUM>. In some embodiments, the data interpreter <NUM> can adjust the operational parameters of the reactor <NUM>.

The withdrawal device <NUM> withdraws a portion of a product stream from the reactor <NUM>. In some embodiments, the data interpreter <NUM> can direct the volume of the portion of the product stream the withdrawal device <NUM> withdraws. In some embodiments, the volume of the portion of the product stream the withdrawal device <NUM> withdraws can be the same or substantially similar to the volume of the volume of the portion of the product stream withdrawn at step <NUM>, as described above with reference to <FIG>. In some embodiments, the pressure rating of the withdrawal device <NUM> can be the same or substantially similar to the pressure rating of the device employed at step <NUM>, as described above with reference to <FIG>. In some embodiments, the temperature rating of the withdrawal device <NUM> can be the same or substantially similar to the temperature rating of the device employed at step <NUM>, as described above with reference to <FIG>. In some embodiments, the withdrawal device <NUM> can include wetted parts. In some embodiments, the wetted parts can be composed of alloy c-<NUM>, Polytetrafluoroethylene (PTFE), and/or any other suitable material.

In some embodiments, the withdrawal device <NUM> can include an inlet port that receives a diluent. In other words, the inlet port that receives the diluent can be fluidically coupled to a reservoir of diluent (not shown). In some embodiments, the diluent can be added to the withdrawal device <NUM>, as described above in step <NUM>, with reference to <FIG>. In some embodiments, the withdrawal device <NUM> can include an inlet port that receives a quenching agent. In other words, the inlet port that receives the quenching agent can be fluidically coupled to a reservoir of quenching agent (not shown). In some embodiments, the quenching agent can be added to the withdrawal device <NUM> before, during, and/or after step <NUM>, as described above with reference to <FIG>. In some embodiments, the withdrawal device <NUM> can include an inlet port that receives a reaction solvent. In other words, the inlet port that receives the reaction solvent can be fluidically coupled to a reservoir of reaction solvent (not shown). In some embodiments, the reaction solvent can be added to the withdrawal device <NUM> before, during, and/or after step <NUM>, as described above with reference to <FIG>. In some embodiments, the withdrawal device <NUM> can include an inlet port that receives a derivatizing agent. In other words, the inlet port that receives the derivatizing agent can be fluidically coupled to a reservoir of derivatizing agent (not shown). In some embodiments, the derivatizing agent can be added to the withdrawal device <NUM> before, during, and/or after step <NUM>, as described above with reference to <FIG>. In some embodiments, the flow rate of the diluent, the quenching agent, the reaction solvent, and/or the derivatizing agent can be directed by the data interpreter <NUM>.

The mixer <NUM> aids in mixing the portion of the product stream with the diluent to form a sample. In some embodiments, the mixer <NUM> can include one or more inlet streams. In some embodiments, the mixer <NUM> can include an inlet stream from the withdrawal device <NUM>. In some embodiments, the mixer <NUM> can include an inlet stream from a reservoir of inert gas (not shown). In some embodiments, the mixer <NUM> can include one or more outlet streams. In some embodiments, the mixer <NUM> can include an outlet stream that that is a waste stream. In some embodiments, the mixer <NUM> can include an outlet stream that is an exhaust stream. In some embodiments, the mixer <NUM> can include an outlet stream that feeds to the LC device <NUM>. In some embodiments, the mixer <NUM> can be composed of an inert material, such as glass. In some embodiments, the mixer <NUM> can include perfluoralkoxy alkane (PFA) connection seals. In some embodiments, the mixer <NUM> can include a clean-in-place mechanism.

In some embodiments, the mixer <NUM> can have a volume of at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. In some embodiments, the mixer <NUM> can have a volume of no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, or no more than about <NUM>. Combinations of the above-referenced volumes of the mixer <NUM> are also possible (e.g. at least about <NUM> and no more than about <NUM> or at least about <NUM> and no more than about <NUM>), inclusive of all values and ranges therebetween. In some embodiments, the mixer <NUM> can have a volume of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>.

In some embodiments, the mixer <NUM> can include an inlet port that receives the diluent. In other words, the inlet port that receives the diluent can be fluidically coupled to a reservoir of diluent (not shown). In some embodiments, the diluent can be added to the mixer <NUM>, as described above in step <NUM>, with reference to <FIG>. In other words, the inlet port that receives the quenching agent can be fluidically coupled to a reservoir of quenching agent (not shown). In some embodiments, the quenching agent can be added to the mixer <NUM> before, during, and/or after step <NUM>, as described above with reference to <FIG>. In some embodiments, the mixer <NUM> can include an inlet port that receives the reaction solvent. In other words, the inlet port that receives the reaction solvent can be fluidically coupled to a reservoir of reaction solvent (not shown). In some embodiments, the reaction solvent can be added to the mixer <NUM> before, during, and/or after step <NUM>, as described above with reference to <FIG>. In some embodiments, the mixer <NUM> can include an inlet port that receives the derivatizing agent. In other words, the inlet port that receives the derivatizing agent can be fluidically coupled to a reservoir of derivatizing agent (not shown). In some embodiments, the derivatizing agent can be added to the mixer <NUM> before, during, and/or after step <NUM>, as described above with reference to <FIG>. In some embodiments, the flow rate of the diluent, the quenching agent, the reaction solvent, and/or the derivatizing agent can be directed by the data interpreter <NUM>.

The mixer <NUM> delivers the sample to the LC device <NUM>. In some embodiments, as described above in step <NUM> with reference to <FIG>, the LC device <NUM> can be an HPLC device, a UHPLC device, an ion exchange chromatography device, a size-exclusion chromatography device, an expanded bed adsorption chromatographic separation device, a reversed-phase chromatography device, a hydrophobic interaction chromatography device, a two-dimensional chromatography device, an SMB chromatography device, an FPLC device, a CCC device, a PCC device, a chiral chromatography device, a bioaffinity chromatography device, an aqueous normal-phase chromatography device, or any combination thereof. In some embodiments, the sample run in the LC device <NUM> can be initiated by the data interpreter <NUM>. In some embodiments, multiple samples can be run in the LC device <NUM> simultaneously. In some embodiments, a second sample can be transferred to the LC device <NUM> while a first sample is running in the LC device <NUM>.

<FIG> is a schematic illustration of a system <NUM> for implementation of online chromatographic sample dilution and preparation, according to an embodiment. The system <NUM> includes a data interpreter <NUM>, a reactor <NUM>, a withdrawal device <NUM>, a mixer <NUM>, and a liquid chromatography device <NUM> (hereinafter LC device <NUM>). In some embodiments, the data interpreter <NUM>, the reactor <NUM>, the withdrawal device <NUM>, the mixer <NUM>, and the LC device <NUM> can be the same or substantially similar to the data interpreter <NUM>, the reactor <NUM>, the withdrawal device <NUM>, the mixer <NUM>, and the LC device <NUM>, as described above with reference to <FIG>. Thus, certain aspects of the data interpreter <NUM>, the reactor <NUM>, the withdrawal device <NUM>, the mixer <NUM>, and the LC device <NUM> are not described in greater detail herein. As shown, solid lines indicate physical couplings between units, arrows indicate flow of material from one unit to another, and dotted lines indicate a communicative connection between units (e.g., via wired or wireless data transmission).

As shown, the withdrawal device <NUM> includes inlet streams from a reaction solvent reservoir <NUM>, a quench solution reservoir <NUM>, and a diluent reservoir <NUM>. In some embodiments, the withdrawal device <NUM> can include an inlet stream from a derivatization agent reservoir (not shown). In some embodiments, the derivatization agent can be included in the quench solution reservoir <NUM>. In some embodiments, the derivatization agent can be included in the diluent reservoir <NUM>.

The withdrawal device <NUM> is fluidically coupled to the mixer <NUM>. The withdrawal device <NUM> transfers fluid to the mixer <NUM>. In some embodiments, a valve <NUM> can divert a portion of the sample to a waste reservoir <NUM>. In some embodiments, the valve <NUM> can be a <NUM>-way valve with a first port fluidically coupled to the withdrawal device <NUM>, a second port fluidically coupled to the mixer <NUM>, and a third port fluidically coupled to the waste reservoir <NUM>. The mixer <NUM> mixes the portion of the product stream, diluent, derivatization agent, quenching agent, and/or reaction solvent to form a sample. As shown, the mixer <NUM> include inlets from an inert gas tank <NUM> (regulated by valve <NUM>) and the withdrawal device <NUM> (regulated by valve <NUM>) as well as outlets to exhaust <NUM> (regulated by valve <NUM>) and to the LC device <NUM> (regulated by valve <NUM>). As shown, the inert gas tank <NUM> can is fluidically coupled to a point downstream of the mixer <NUM> (regulated by valve <NUM>). In some embodiments, the data interpreter <NUM> can control the valves <NUM>, <NUM>, <NUM>, <NUM>, <NUM> to regulate flow through the valves <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

The mixer <NUM> transfers the sample to the LC device <NUM>. As shown, the sample moves from the mixer <NUM> to the LC device <NUM> through a bubble sensor <NUM>, the valve <NUM>, an inline filter <NUM>, and a vial <NUM>. The bubble sensor <NUM> detects whether effluent from the mixer <NUM> includes a bubble. Based on data interpreted from the bubble sensor <NUM>, the data interpreter <NUM> can adjust one or more of the valves <NUM>, <NUM>, <NUM>, <NUM>, <NUM> in order to monitor the amount of sample remaining in the flow vial <NUM>. The inline filter <NUM> can remove particulates and/or bacteria from the sample prior to entering the LC device <NUM>. The vial <NUM> can temporarily store an analysis-ready sample prior to being fed to LC device <NUM>. In some embodiments, a liquid portion of the sample can be diverted to the waste reservoir <NUM>. In some embodiments, the LC device <NUM> can include a high-pressure injection portion, decoupled, or fluidically isolated from a low-pressure sampling portion. In some embodiments, the LC device <NUM> can be configured for flow chemistry monitoring. In other words, the LC device <NUM> can be used with flow reactors, such as a CSTR or a PFR. In some embodiments, the LC device <NUM> can be used with a batch or semi-batch reactor. In some embodiments, the LC device <NUM> can include a filter station and a dissolution tester. In some embodiments, the dissolution tester can be configured to fractionate and analyze incoming samples.

<FIG> are illustrations of a sampling device <NUM>, according to an embodiment. <FIG> shows a perspective view of the sampling device <NUM>, while <FIG> shows a cross-sectional view of the sampling device <NUM>. In some embodiments, the sampling device <NUM> can be the same or substantially similar to the sampling device <NUM> or the sampling device <NUM>, as described above with reference to <FIG> and <FIG>. Thus, certain aspects of the sampling device <NUM> are not described in greater detail herein. As shown, the sampling device <NUM> includes a base <NUM> with sample openings 453a, 453b (collectively referred to as sample openings <NUM>), injection ports 455a, 455b (collectively referred to as injection ports <NUM>), a casing <NUM>, and a probe <NUM> (including probe opening <NUM>).

In some embodiments, the sampling device <NUM> can be optimized via computed fluid dynamics to ensure that the sampling device <NUM> withdraws a representative portion of the product stream and does not withdraw from a point of locally rich concentration or locally sparse concentration. In some embodiments, the sampling device <NUM> can be optimized via computed fluid dynamics to minimize carryover from one sample to the next. In some embodiments, sample carryover from a first sample to a second sample can be less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, or less than about <NUM>%.

In some embodiments, the sampling device <NUM> can be designed to minimize dead volume. In some embodiments, the sampling device <NUM> can be integrated into a reactor block. In some embodiments, the sample openings <NUM> can be sufficiently small to limit dead volume in the sampling device <NUM>. In some embodiments, tips of the injection ports <NUM> can be abutted to an inner surface of the base <NUM>. In some embodiments, the sample openings <NUM> can each be cylindrical openings with a diameter of less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>, less than about <NUM>. In some embodiments, the sample opening 453a can be an inlet. In some embodiments, the sample opening 453b can be an outlet.

In some embodiments, the probe <NUM> can rotate within the base <NUM>, such that the probe opening <NUM> can face either of the injection ports <NUM>. As shown, the sampling device <NUM> includes two injection ports <NUM>. In some embodiments, the sampling device <NUM> can include <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> injection ports <NUM>, inclusive of all ranges and subranges therebetween. As shown, the sampling device <NUM> includes two sample openings <NUM>. In some embodiments, the sampling device <NUM> can include <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> sample openings <NUM>, inclusive of all ranges and subranges therebetween. In some embodiments, the sampling device <NUM> or components thereof can be constructed of inert materials. In some embodiments, the base <NUM>, injection ports <NUM>, and/or casing <NUM> can be composed of PTFE, PFA, or any other inert material.

<FIG> are illustrations of a sampling device <NUM>, according to an embodiment. <FIG> shows a perspective view of the sampling device <NUM>, while <FIG> shows a cross-sectional view of the sampling device <NUM>. As shown, the sampling device <NUM> includes a base <NUM> with sample openings 553a, 553b (collectively referred to as sample openings <NUM>), injection ports 555a, 555b (collectively referred to as injection ports <NUM>), a cavity <NUM>, a casing <NUM>, a ferrule <NUM>, a sealing member <NUM>, and a probe <NUM> (including probe opening <NUM>). In some embodiments, the base <NUM>, the sample openings <NUM>, the injection ports <NUM>, the casing <NUM>, the probe <NUM>, and the probe opening <NUM> can be the same or substantially similar to the base <NUM>, the sample openings <NUM>, the injection ports <NUM>, the casing <NUM>, the probe <NUM>, and the probe opening <NUM>, as described above with reference to <FIG>. Thus, certain aspects of the base <NUM>, the sample openings <NUM>, the injection ports <NUM>, the casing <NUM>, the probe <NUM>, and the probe opening <NUM> are not described in greater detail herein.

As shown, the sample opening 553a is offset from the sample opening 553b by an offset distance do. In other words, there is an offset between an inlet to the sampling device <NUM> and an outlet from the sampling device <NUM>. Offsetting the sample openings <NUM> from one another can facilitate faster equilibration of concentration of chemical species in the sampling device <NUM> (e.g., in the cavity <NUM>). In some embodiments, the offset distance do can be at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, at least about <NUM>, or at least about <NUM>. In some embodiments, the offset distance do can be no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, no more than about <NUM>, or no more than about <NUM>.

Combinations of the above-referenced values of the offset distance do are also possible (e.g., at least about <NUM> and no more than about <NUM> or at least about <NUM> and no more than about <NUM>), inclusive of all values and ranges therebetween. In some embodiments, the offset distance do can be about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>.

As shown, the ferrule <NUM> grips the probe <NUM>, keeping the probe <NUM> from slipping longitudinally within the casing <NUM>. As shown, the sealing member <NUM> seals the probe <NUM> against the cavity <NUM>. In some embodiments, the sealing member <NUM> can include a gasket. In some embodiments, the sealing member <NUM> can include an O-ring. The cavity <NUM> is a section at the bottom of the space into which the probe <NUM> is placed. As shown, the cavity <NUM> has a rounded shape. In some embodiments, the cavity <NUM> can have a hemispherical shape. In some embodiments, the cavity <NUM> can have a rectangular shape with approximately right-angled edges (e.g., similar to the sampling device <NUM> described above with reference to <FIG>). In some cases, a rounded shape of the cavity <NUM> can encourage better mixing in the sampling device <NUM>, such that the concentration of analyte placed into the sampling device <NUM> equilibrates faster, as compared to a rectangular shape. As shown, the probe <NUM> has an elongated neck N. The elongated neck N can aid in forming a better seal at the sealing member <NUM>, as compared to a shorter neck. In some embodiments, the elongated neck N can have a length such that a distance between the sealing member <NUM> and an entry point at the top of the casing <NUM> is about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>, inclusive of all values and ranges therebetween.

<FIG> is a plot of simulated concentrations in sampling devices without an opening offset and with an opening offset of <NUM>. The plot simulates concentrations of an analyte at an entry point into a sampling device (e.g., at the sample opening 453a or the sample opening 553a). The simulated sampling device starts with an analyte concentration of <NUM> mol/m<NUM> and is fed an analyte with a concentration of <NUM> mol/m<NUM> at a velocity of <NUM>/min. As shown, without the offset, the concentration of the analyte takes about <NUM> seconds to reach <NUM>% equilibrium (i.e., <NUM> mol/m<NUM> at the opening). With the offset, the analyte only takes about <NUM> seconds to reach <NUM>% equilibrium concentration.

<FIG> show illustrations of portions of a system for implementation of online chromatographic sample dilution and preparation, according to an embodiment. Shown in <FIG> are a data interpreter <NUM>, a withdrawal device <NUM>, a mixing device <NUM>, a gas tank <NUM>, and an LC device <NUM>. As shown, the mixing device <NUM> includes a mixer <NUM>, a bubble sensor <NUM>, a leak detector <NUM>, a valve manifold <NUM>, a pressure regulator <NUM>, a pressure gauge <NUM>, a gas flowmeter <NUM>, a communication port <NUM>, an AC outlet <NUM>, and a power supply <NUM>. In some embodiments, the data interpreter <NUM>, the withdrawal device <NUM>, the mixer <NUM>, the gas tank <NUM>, and the LC device <NUM> can be the same or substantially similar to the data interpreter <NUM>, the withdrawal device <NUM>, the mixer <NUM>, the gas tank <NUM>, and the LC device <NUM>, as described above with reference to <FIG>. Thus, certain aspects of the data interpreter <NUM>, the withdrawal device <NUM>, the mixer <NUM>, the gas tank <NUM>, and the LC device <NUM> are not described in greater detail herein.

As shown, the mixing device <NUM> includes an inlet that receives a sample from the withdrawal device <NUM> and an outlet that feeds to the LC device <NUM>. The mixing device <NUM> also includes a vent that feeds to exhaust <NUM> and an outlet that feeds to a waste reservoir <NUM>. The mixing device <NUM> also includes an inlet that receives gas from the gas tank <NUM>. The mixing device <NUM> also includes a connection port that couples the data interpreter <NUM> to the communication port <NUM>. In some embodiments, the mixer <NUM> can have the same or substantially similar properties as the mixer <NUM> described above, with reference to <FIG>. In some embodiments, the mixer <NUM> can perform the same or substantially similar actions as the mixer <NUM> described above, with reference to <FIG>. In some embodiments, the bubble sensor <NUM> can be the same or substantially similar to the bubble sensor <NUM>, as described above with reference to <FIG>.

In some embodiments, the leak detector <NUM> can communicate with the data interpreter <NUM> and/or the communication port <NUM> to shut off the mixing device <NUM> if a leak is detected. In some embodiments, the valve manifold <NUM> can include a collection of valves and ports that direct fluid flow between the withdrawal device <NUM> and the mixer <NUM>, fluid flow between the gas tank <NUM> and the mixer <NUM>, fluid flow between the mixer <NUM> and the LC device <NUM>, and/or fluid flow between the mixer <NUM> and the waste reservoir <NUM>. The pressure regulator <NUM> can reduce the pressure of the incoming gas from the gas tank <NUM>, as gas fed from gas tanks is often kept at a higher pressure than desired in the mixing device <NUM>. The pressure gauge <NUM> displays a pressure of the incoming gas and the gas flowmeter <NUM> monitors a flow rate of gas from the gas tank <NUM> into the mixing device <NUM> and the mixer <NUM>.

In some embodiments, the communication port <NUM> can regulate operation of each of the components of the mixing device <NUM>. In some embodiments, the communication port <NUM> can be communicatively coupled to the data interpreter <NUM>. The A/C outlet <NUM> connects the mixing device <NUM> to an external power source, while the power supply <NUM> regulates power delivery throughout the mixing device <NUM>.

<FIG> is a block diagram of an example embodiment of a data interpreter <NUM> upon which embodiments of the present disclosure can execute, and which is compatible with method <NUM> of <FIG>, system <NUM> of <FIG>, and system <NUM> of <FIG>. Some embodiments of the present disclosure are implemented using computer-executable instructions, such as program modules, stored in a memory and executed on one or more processors operably coupled to the memory. Program modules can include routines, programs, objects, components, data structures, etc., that perform particular tasks or implement particular data types. As indicated above, the system as disclosed herein can be spread across many physical hosts.

With reference to <FIG>, an example embodiment extends to a machine in the example form of the data interpreter <NUM> within which instructions for causing the machine to perform any one or more of the methodologies discussed herein may be executed. In alternative example embodiments, the machine operates as a standalone device or may be connected (e.g., networked) to other machines. In a networked deployment, the machine may operate in the capacity of a server or a client machine in server-client network environment, or as a peer machine in a peer-to-peer (or distributed) network environment. Further, while only a single machine is illustrated, the term "machine" shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein.

The example data interpreter <NUM> of <FIG> includes a processor <NUM> (e.g., a central processing unit (CPU), a graphics processing unit (GPU) or both), a main memory <NUM> and a static memory <NUM>, which communicate with each other via a bus <NUM>. The data interpreter <NUM> may further include a video display unit <NUM> (e.g., a liquid crystal display (LCD) or a cathode ray tube (CRT)). In example embodiments, the data interpreter <NUM> also includes one or more of an alpha-numeric input device <NUM> (e.g., a keyboard), a user interface (UI) navigation device or cursor control device <NUM> (e.g., a mouse), a disk drive unit <NUM>, a signal generation device <NUM> (e.g., a speaker), and a network interface device <NUM>.

The disk drive unit <NUM> includes a machine-readable medium <NUM> on which is stored one or more sets of instructions <NUM> and data structures (e.g., software instructions) embodying or used by any one or more of the methodologies or functions described herein. The instructions <NUM> may also reside, completely or at least partially, within the main memory <NUM> or within the processor <NUM> during execution thereof by the data interpreter <NUM>, the main memory <NUM> and the processor <NUM>, also constituting machine-readable media.

While the machine-readable medium <NUM> is shown in an example embodiment to be a single medium, the term "machine-readable medium" may include a single medium or multiple media (e.g., a centralized or distributed database, or associated caches and servers) that store the one or more instructions. The term "machine-readable medium" shall also be taken to include any tangible medium that is capable of storing, encoding, or carrying instructions for execution by the machine and that cause the machine to perform any one or more of the methodologies of embodiments of the present disclosure, or that is capable of storing, encoding, or carrying data structures used by or associated with such instructions. The term "machine-readable storage medium" shall accordingly be taken to include, but not be limited to, solid-state memories and optical and magnetic media that can store information in a non-transitory manner, i.e., media that is able to store information. Specific examples of machine-readable media include non-volatile memory, including by way of example semiconductor memory devices (e.g., Erasable Programmable Read-Only Memory (EPROM), Electrically Erasable Programmable Read-Only Memory (EEPROM), and flash memory devices); magnetic disks such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

The instructions <NUM> may further be transmitted or received over a communications network <NUM> using a signal transmission medium via the network interface device <NUM> and utilizing any one of a number of well-known transfer protocols (e.g., FTP, HTTP). Examples of communication networks include a local area network (LAN), a wide area network (WAN), the Internet, mobile telephone networks, Plain Old Telephone (POTS) networks, and wireless data networks (e.g., WiFi and WiMax networks). The term "machine-readable signal medium" shall be taken to include any transitory intangible medium that is capable of storing, encoding, or carrying instructions for execution by the machine, and includes digital or analog communications signals or other intangible medium to facilitate communication of such software. In some embodiments, the second sample can include no peaks or substantially no peaks associated with the first sample.

Some embodiments described herein, and which do not form part of the present invention, relate to a computer storage product with a non-transitory computer-readable medium (also can be referred to as a non-transitory processor-readable medium) having instructions or computer code thereon for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include transitory propagating signals per se (e.g., a propagating electromagnetic wave carrying information on a transmission medium such as space or a cable). The media and computer code (also can be referred to as code) may be those designed and constructed for the specific purpose or purposes. Examples of non-transitory computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as Compact Disc/Digital Video Discs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules; and hardware devices that are specially configured to store and execute program code, such as Application-Specific Integrated Circuits (ASICs), Programmable Logic Devices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM) devices. Other embodiments described herein relate to a computer program product, which can include, for example, the instructions and/or computer code discussed herein.

Some embodiments and/or methods described herein can be performed by software (executed on hardware), hardware, or a combination thereof. Hardware modules may include, for example, a general-purpose processor, a field programmable gate array (FPGA), a programmable logic controller (PLC), and/or an application specific integrated circuit (ASIC). Software modules (executed on hardware) can be expressed in a variety of software languages (e.g., computer code), including C, C++, Java™, ladder logic, Python™, Ruby, Visual Basic™, and/or other object-oriented, procedural, or other programming language and development tools. Examples of computer code include, but are not limited to, micro-code or micro-instructions, machine instructions, such as produced by a compiler, code used to produce a web service, and files containing higher-level instructions that are executed by a computer using an interpreter. For example, embodiments may be implemented using imperative programming languages (e.g., C, Fortran, etc.), functional programming languages (Haskell, Erlang, etc.), logical programming languages (e.g., Prolog), object-oriented programming languages (e.g., Java, C++, etc.) or other suitable programming languages and/or development tools. Additional examples of computer code include, but are not limited to, control signals, encrypted code, and compressed code. Various concepts may be embodied as one or more methods, of which at least one example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments. Put differently, it is to be understood that such features may not necessarily be limited to a particular order of execution, but rather, any number of threads, processes, services, servers, and/or the like that may execute serially, asynchronously, concurrently, in parallel, simultaneously, synchronously, and/or the like in a manner consistent with the disclosure. As such, some of these features may be mutually contradictory, in that they cannot be simultaneously present in a single embodiment. Similarly, some features are applicable to one aspect of the innovations, and inapplicable to others.

As used herein, in particular embodiments, the terms "about" or "approximately" when preceding a numerical value indicates the value plus or minus a range of <NUM>%. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. That the upper and lower limits of these smaller ranges can independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

The phrase "and/or," as used herein in the specification and in the embodiments, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases.

As used herein in the specification and in the embodiments, "or" should be understood to have the same meaning as "and/or" as defined above. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the embodiments, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. " "Consisting essentially of," when used in the embodiments, shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the embodiments, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.

While specific embodiments of the present disclosure have been outlined above, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, the embodiments set forth herein are intended to be illustrative, not limiting. Various changes may be made without departing from the scope of the disclosure. Where methods and steps described above indicate certain events occurring in a certain order, those of ordinary skill in the art having the benefit of this disclosure would recognize that the ordering of certain steps may be modified and such modification are in accordance with the variations of the invention. Additionally, certain of the steps may be performed concurrently in a parallel process when possible, as well as performed sequentially as described above. The embodiments have been particularly shown and described, but it will be understood that various changes in form and details may be made.

Samples of analyte were collected with a sample collection device described herein, varying dilution factors ranging from <NUM> to <NUM>. Five samples were collected at each dilution factor. The relative standard deviation (RSD) of each set was measured, and carryover from earlier samples was measured. Table <NUM> shows these data.

Claim 1:
A computer-implemented method for analyzing a product stream of a chemical reaction, comprising:
withdrawing from a reactor (<NUM>), a portion of the product stream of the chemical reaction, the portion of the product stream having a volume of less than about <NUM>µL;
mixing the portion of the product stream with a diluent to produce a sample;
transferring the sample to a liquid chromatography device (<NUM>);
and
developing, via the liquid chromatography device, a measured chemical profile of the sample for process monitoring or real time decision-making.