Description:STEREOSELECTIVE SYNTHESIS OF ATORVASTATIN ANALOGUES FOR PHARMACEUTICAL MANUFACTURING
Field of the Invention
[0001] The present disclosure relates to stereoselective synthesis methods for atorvastatin analogues optimized for pharmaceutical production and process scalability.
Background
[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Statins, including atorvastatin, are widely prescribed cholesterol-lowering agents that act as competitive inhibitors of HMG-CoA reductase. Owing to their structural complexity, the stereochemical configuration of each chiral center within their molecular framework is critical to therapeutic efficacy and metabolic stability. Prior synthetic methods have encountered significant challenges in achieving high enantiomeric excess across multiple stereocenters while maintaining reaction yield, particularly in steps involving aldol reactions and subsequent lactonization. Traditional routes often require extensive protection and deprotection strategies, chromatographic purification at several stages, and harsh conditions that may lead to racemization or undesirable side products.
[0004] Numerous patents and publications describe processes involving racemic synthesis followed by resolution or enzymatic separation, but such techniques are often inefficient and industrially impractical. Moreover, previously reported asymmetric methods frequently involve expensive chiral catalysts or non-recyclable auxiliaries that hinder cost-effective scaling. For atorvastatin and its analogues, which include structural variations on the pyrrole or lactone ring, a lack of stereocontrol at crucial synthetic junctures severely limits their pharmacological predictability.
[0005] Given the need for enantioselective construction of the β-hydroxy acid framework, selective incorporation of aryl substituents on the pyrrole ring, and controlled hydrogenation without compromising chiral integrity, a robust synthetic route that integrates stereoselective techniques with modular downstream operations remains absent in current pharmaceutical manufacturing workflows. The present disclosure overcomes these limitations by presenting a stereodefined synthesis system amenable to batch or semi-continuous modes, with integrated purification and analytics enabling process intensification and regulatory compliance.
[0006] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[0007] It also shall be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. This invention can be achieved by means of hardware including several different elements or by means of a suitably programmed computer. In the unit claims that list several means, several ones among these means can be specifically embodied in the same hardware item. The use of such words as first, second, third does not represent any order, which can be simply explained as names.
Summary
[0008] Various objects, features, and advantages of the disclosed subject matter can be more fully appreciated with reference to the following detailed description of the disclosed subject matter when considered in connection with the following drawings, in which like reference numerals identify like elements.
[0009] The present disclosure relates to stereoselective synthesis methods for atorvastatin analogues optimized for pharmaceutical production and process scalability.
[00010] The disclosed system and method pertain to a stereoselective synthetic route for producing atorvastatin analogues with high enantiomeric purity and industrial compatibility. The synthesis begins with a protected dihydroxy acid precursor which is subjected to an aldol condensation with a functionalized pyrrole aldehyde. The reaction is conducted in the presence of a chiral auxiliary, selected from oxazolidinone derivatives, which governs facial selectivity and sets the stereochemistry at the β-hydroxy center. Upon completion of the aldol reaction, the auxiliary is cleaved through controlled hydrolysis using mixed aqueous-organic solvents, and the resulting intermediate is extracted and dried.
[00011] The hydroxy acid intermediate is then converted into a lactone through acid-catalyzed ring closure conducted under reflux or azeotropic conditions, forming the core of the atorvastatin framework. At this stage, a boron-mediated cross-coupling step is implemented to append desired substituents such as fluorophenyl or isopropyl groups onto the pyrrole ring, preserving the stereocenters established earlier. Final hydrogenation of residual unsaturated bonds is carried out under mild catalytic conditions using palladium or ruthenium systems.
[00012] Optionally, the system incorporates real-time process monitoring using NMR or chiral HPLC tools and employs programmable logic control for reaction sequencing, thermal regulation, and solvent recycling. An in-line purification module, such as preparative chromatography, ensures that the final compound meets pharmaceutical-grade specifications. This system architecture offers advantages in modularity, scalability, and regulatory adaptability, making it suited for both pilot-scale and full-scale pharmaceutical manufacturing of atorvastatin analogues.
[00013]
Brief Description of the Drawings
[00014] The features and advantages of the present disclosure would be more clearly understood from the following description taken in conjunction with the accompanying drawings in which:
[00015] FIG. 1 illustrates a system architecture diagram representing the modular arrangement and interconnection of functional units for stereoselective synthesis of atorvastatin analogues, including precursor handling, chiral induction, catalytic transformation, and programmable process regulation.
[00016] FIG. 2 illustrates a method flow diagram depicting the ordered sequence of chemical processing stages involved in the stereoselective synthesis pathway, showing transformations from precursor activation to final hydrogenation and purification.
[00017] FIG. 3 illustrates a data flow diagram representing the signal transmission and analytical feedback architecture among real-time process monitoring units, programmable controllers, and operational decision modules for automated synthesis control and stereochemical precision.
[00018]
Detailed Description
[00019] The following is a detailed description of exemplary embodiments to illustrate the principles of the invention. The embodiments are provided to illustrate aspects of the invention, but the invention is not limited to any embodiment. The scope of the invention encompasses numerous alternatives, modifications and equivalent; it is limited only by the claims.
[00020] In view of the many possible embodiments to which the principles of the present discussion may be applied, it should be recognized that the embodiments described herein with respect to the drawing figures are meant to be illustrative only and should not be taken as limiting the scope of the claims. Therefore, the techniques as described herein contemplate all such embodiments as may come within the scope of the following claims and equivalents thereof.
[00021] Throughout the present disclosure, the term “network” relates to an arrangement of interconnected programmable and/or non-programmable components that are configured to facilitate data communication between one or more electronic devices and/or databases, whether available or known at the time of filing or as later developed. Furthermore, the network may include, but is not limited to, one or more peer-to-peer network, a hybrid peer-to-peer network, local area networks (LANs), radio access networks (RANs), metropolitan area networks (MANS), wide area networks (WANs), all or a portion of a public network such as the global computer network known as the Internet, a private network, a cellular network and any other communication system or systems at one or more locations.
[00022] Throughout the present disclosure, the term “process”* relates to any collection or set of instructions executable by a computer or other digital system so as to configure the computer or the digital system to perform a task that is the intent of the process.
[00023] Throughout the present disclosure, the term ‘Artificial intelligence (AI)’ as used herein relates to any mechanism or computationally intelligent system that combines knowledge, techniques, and methodologies for controlling a bot or other element within a computing environment. Furthermore, the artificial intelligence (AI) is configured to apply knowledge and that can adapt it-self and learn to do better in changing environments. Additionally, employing any computationally intelligent technique, the artificial intelligence (AI) is operable to adapt to unknown or changing environment for better performance. The artificial intelligence (AI) includes fuzzy logic engines, decision-making engines, preset targeting accuracy levels, and/or programmatically intelligent software.
[00024] The detailed description is described with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The use of the same reference numbers in different instances in the description and the figures may indicate similar or identical items.
[00025] Pursuant to the "Detailed Description" section herein, whenever an element is explicitly associated with a specific numeral for the first time, such association shall be deemed consistent and applicable throughout the entirety of the "Detailed Description" section, unless otherwise expressly stated or contradicted by the context.
[00026] The present disclosure relates to stereoselective synthesis methods for atorvastatin analogues optimized for pharmaceutical production and process scalability.
[00027] Pursuant to the "Detailed Description" section herein, whenever an element is explicitly associated with a specific numeral for the first time, such association shall be deemed consistent and applicable throughout the entirety of the "Detailed Description" section, unless otherwise expressly stated or contradicted by the context.
[00028] FIG. 1 illustrates the overall structural configuration of a stereoselective synthesis system for atorvastatin analogues, composed of sequentially arranged processing units and automated control architecture. The diagram identifies a precursor activation module, wherein raw dihydroxy acid substrates undergo solubilization and deprotection under inert conditions, prior to engaging in stereochemical modification. The output from the activation module flows into a chiral auxiliary installation unit designed to covalently attach oxazolidinone-based auxiliaries onto the substrate, thereby enabling facial stereocontrol for downstream aldol condensation reactions. The chiral-functionalized substrate is then conveyed into an enantioselective condensation reactor, which incorporates a pyrrole-based aldehyde and catalytically active Lewis acid under precisely controlled conditions to produce β-hydroxy intermediates of defined chirality. The post-reaction mixture is subsequently processed in a hydrolysis and extraction chamber wherein the auxiliary is cleaved using aqueous-organic solvent reflux, and the liberated product is extracted through liquid-liquid separation. The intermediate is advanced into a lactonization chamber that promotes ring closure via acid catalysis, followed by transfer to an aryl coupling reactor where palladium-catalyzed borylation introduces specific substituents on the pyrrole moiety. Subsequent hydrogenation occurs in a dedicated chamber using supported metal catalysts under mild pressures, selectively reducing double bonds without disturbing stereocenters. An analytical feedback loop interfaces with chiral HPLC and NMR sensors to monitor the structural integrity and enantiomeric excess of intermediates and products. A programmable control unit coordinates timing, sequencing, interlocks, and safety constraints across the system. The figure captures the modular yet interconnected structure of the synthesis setup optimized for stereochemical fidelity, pharmaceutical compliance, and scalability. The synthesis system initiates with the introduction of a protected dihydroxy acid precursor into a reaction chamber containing a chiral auxiliary agent selected to control the stereochemical pathway of subsequent reactions. The protected precursor is N-acylated using an oxazolidinone derivative, such as (S)-4-benzyl-2-oxazolidinone, under basic conditions in a dry solvent system, forming a diastereomeric intermediate suitable for enantioselective transformation. The resulting acylated precursor is then transferred to an aldol reaction module where it is combined with a pyrrole-based aldehyde in the presence of a Lewis acid catalyst. The facial selectivity imparted by the chiral auxiliary promotes formation of a β-hydroxy intermediate with high diastereoselectivity.
[00029] Following aldol condensation, the intermediate is subjected to hydrolysis to remove the chiral auxiliary. A hydrolytic mixture containing water and tetrahydrofuran is heated under reflux to selectively cleave the N-acyl bond, liberating the β-hydroxy acid intermediate while maintaining stereochemical integrity. The hydrolysate is neutralized, and organic extraction is conducted using ethyl acetate. The resulting organic layer is dried over anhydrous sodium sulfate and concentrated under vacuum to yield a crude intermediate.
[00030] Subsequent conversion to the lactone is performed in a ring closure module, wherein the β-hydroxy acid is refluxed in toluene or xylene in the presence of para-toluenesulfonic acid. Water formed during the esterification is removed through azeotropic distillation, driving the reaction toward lactone formation. The product is cooled and precipitated by the addition of hexanes, followed by filtration and drying under vacuum to yield the purified lactone.
[00031] In the next step, the pyrrole ring of the lactone is modified through a boron-mediated coupling reaction. The system introduces 4-fluorophenylboronic acid in a mixture with a palladium(II) acetate catalyst, a phosphine ligand, and cesium fluoride base in dimethylformamide. The reaction is conducted at 80°C for several hours to facilitate selective carbon-carbon bond formation at the desired site of the pyrrole ring, producing the desired substitution pattern while maintaining prior stereocenters.
[00032] The molecule then undergoes catalytic hydrogenation. The solution of the coupled lactone is introduced into a hydrogenation chamber containing palladium on carbon and a methanol solvent under hydrogen gas at 4 atm pressure. The system maintains temperature at 30°C and monitors reaction progress using in-line NMR spectroscopy to ensure full conversion without affecting chiral centers. Catalyst is removed via filtration and the product is dried and stored in a nitrogen-purged vessel.
[00033] In an alternative embodiment, the chiral auxiliary is replaced with a bis-sulfonamide ligand and used in conjunction with titanium(IV) isopropoxide to drive asymmetric induction. This embodiment avoids the use of oxazolidinone but achieves similar enantiomeric control. The subsequent stages mirror the original pathway but include microwave-assisted lactonization for reduced cycle time.
[00034] In another embodiment, a flow-reactor configuration is employed for the aldol condensation and lactonization stages, allowing for semi-continuous operation. Reagents are fed at programmed intervals and temperature is regulated dynamically. The configuration includes pressure sensors and flow meters to prevent reactor overloading, and product is extracted continuously via an in-line separator.
[00035] In a third embodiment, the pyrrole ring is substituted prior to aldol condensation. A pre-functionalized pyrrole aldehyde bearing an isopropyl or phenyl substituent is employed, simplifying downstream arylation. The rest of the process proceeds as in the primary method, but hydrogenation is performed under increased pressure to saturate additional aromaticity if required.
[00036] Across all embodiments, the integrated process analytics system enables enantiomeric excess verification, impurity profiling, and real-time parameter tuning. This ensures reproducibility across batches and supports documentation necessary for regulatory filing. The synthesis is compatible with GMP guidelines and permits scale-up to commercial quantities without requiring extensive re-optimization.
[00037] The system architecture supports automation through embedded software, reagent metering control, waste solvent recovery, and thermal safety interlocks. These features reduce manual intervention, minimize error, and facilitate safer and cleaner manufacturing environments while maintaining high stereochemical fidelity across the multi-step synthetic sequence.
[00038] FIG. 2 illustrates the procedural workflow governing the stereoselective synthesis of atorvastatin analogues, organized as a linear series of chemical processing steps. The flow initiates with precursor activation involving solubilization and preparative adjustments for the dihydroxy acid compound. The activated precursor then undergoes chiral auxiliary attachment through acylation with an oxazolidinone derivative in a base-mediated reaction. The resultant compound is subjected to aldol condensation with a pyrrole-substituted aldehyde under the influence of a Lewis acid catalyst, forming a stereodefined β-hydroxy intermediate. Upon completion of condensation, hydrolytic removal of the chiral auxiliary is carried out in a controlled mixed-solvent environment, and the intermediate is recovered post-neutralization and extraction. The β-hydroxy acid intermediate is subsequently converted into a lactone via intramolecular esterification conducted under acid reflux or azeotropic conditions. Thereafter, a selective aryl coupling step introduces structural modifications to the pyrrole ring using boronic acid derivatives in the presence of palladium catalysts. The arylated compound then undergoes mild catalytic hydrogenation to eliminate unsaturated bonds without disturbing previously established stereochemistry. The final compound is isolated through crystallization or chromatographic purification, and quality is verified through analytical testing. The figure presents a comprehensive method framework that captures the order and rationale of each synthetic step while emphasizing stereochemical preservation throughout the sequence.
[00039] FIG. 3 illustrates the data flow topology underlying the control and monitoring of the stereoselective synthesis process. The diagram shows that analytical inputs from chiral high-performance liquid chromatography units and nuclear magnetic resonance sensors are routed into a centralized feedback control module responsible for real-time assessment of stereoselectivity and conversion efficiency. Additional data streams from distributed temperature and pressure sensors within each processing chamber are simultaneously directed to the same module. These analytical and environmental data streams converge at a programmable logic controller (PLC), which performs integration, interpretation, and response coordination. The controller regulates downstream reagent feed mechanisms, adjusts thermal input/output systems, and engages emergency safety interlocks in case of threshold violations. Furthermore, operational parameters, real-time status, and analytical data are relayed to a graphical user interface dashboard accessible by operators for process validation and decision support. This configuration enables closed-loop regulation of synthetic parameters to ensure batch uniformity, maintain high enantiomeric purity, and facilitate adherence to pharmaceutical manufacturing standards. The figure encapsulates the digital automation layer that enhances synthetic precision and reproducibility across multiple reaction stages.
[00040] The above description is intended to be illustrative, and not restrictive. Although the present disclosure has been described with references to specific illustrative examples and implementations, it will be recognized that the present disclosure is not limited to the examples and implementations described. The scope of the disclosure should be determined with reference to the following claims, along with the full scope of equivalents to which the claims are entitled.
[00041] Modifications, additions, or omissions may be made to the systems and apparatuses described herein without departing from the scope of the disclosure. The components of the systems and apparatuses may be integrated or separated. Moreover, the operations of the systems and apparatuses may be performed by more, fewer, or other components. Additionally, operations of the systems and apparatuses may be performed using any suitable logic comprising software, hardware, and/or other logic. As used in this document, “each” refers to each member of a set or each member of a subset of a set.

Claims
I/We Claim:
CLAIM 1
A stereoselective synthesis system for preparing atorvastatin analogues comprising: a protected dihydroxy acid precursor undergoing enantioselective aldol condensation with a pyrrole-based aldehyde under a chiral auxiliary-mediated catalysis condition; a post-condensation hydrolysis stage configured to remove the chiral auxiliary while retaining the stereogenic integrity of the resultant β-hydroxy intermediate; a lactonization module performing intramolecular ring closure under acid-catalyzed reflux to yield a stereodefined lactone; a boron-mediated carbon-carbon coupling reaction unit adapted to introduce a fluorophenyl or isopropyl substituent on the pyrrole moiety with stereoretention; and a terminal hydrogenation stage utilizing a palladium or ruthenium-based catalyst system to reduce any remaining olefinic bonds without perturbing the stereogenic centers, wherein the system is operable in a batch or semi-continuous mode under inert atmosphere.
CLAIM 2
The stereoselective synthesis system of claim 1, wherein the chiral auxiliary comprises an oxazolidinone derivative selected from the group consisting of (S)-4-benzyl-2-oxazolidinone and (R)-4-isopropyl-2-oxazolidinone, and is introduced via N-acylation onto the dihydroxy acid precursor to facilitate facial selectivity during aldol addition, thereby controlling the β-hydroxy stereocenter configuration of the intermediate.
CLAIM 3
The stereoselective synthesis system of claim 1, wherein the boron-mediated carbon-carbon coupling reaction unit includes a trialkylborane or boronic ester reactant selected from 4-fluorophenylboronic acid or isopropylboronic acid, and is carried out in the presence of a palladium catalyst, a phosphine ligand, and a base such as potassium carbonate or cesium fluoride in an anhydrous polar aprotic solvent maintained at 60–90°C for selective cross-coupling.
CLAIM 4
The stereoselective synthesis system of claim 1, wherein the post-condensation hydrolysis stage comprises an acidic or basic hydrolysis solution adapted to cleave the chiral auxiliary under reflux in a mixed solvent system containing tetrahydrofuran and water, followed by pH neutralization and organic extraction of the β-hydroxy acid intermediate.
CLAIM 5
The stereoselective synthesis system of claim 1, wherein the terminal hydrogenation stage comprises the use of a heterogeneous palladium on carbon or ruthenium black catalyst under hydrogen pressure between 2 and 6 atm in a protic solvent such as methanol or ethanol at 25–40°C, the catalyst being recoverable through filtration for reusability in subsequent synthesis cycles.
CLAIM 6
The stereoselective synthesis system of claim 1, wherein the intramolecular lactonization module is configured to induce ring closure of the hydroxy acid intermediate through azeotropic distillation in the presence of para-toluenesulfonic acid or sulfuric acid, the resulting lactone being extracted via phase separation followed by recrystallization in a low polarity solvent.
CLAIM 7
The stereoselective synthesis system of claim 1, wherein the system further includes an in-line chromatographic purification unit comprising reverse-phase high-performance liquid chromatography or preparative thin-layer chromatography configured to isolate and purify each stereoisomer of the final atorvastatin analogue to pharmaceutical grade.
CLAIM 8
The stereoselective synthesis system of claim 1, wherein the reaction system includes a process analytics monitoring module comprising chiral HPLC and NMR spectroscopic interfaces that assess enantiomeric excess, diastereoselectivity, and structural integrity of intermediates and final atorvastatin analogues in real time.
CLAIM 9
The stereoselective synthesis system of claim 1, wherein the synthesis is configured to accommodate structural modifications on the pyrrole core through selective alkylation or arylation at the 3- or 5-position using organolithium or Grignard reagents introduced post-lactonization and prior to hydrogenation, enabling tunability of biological activity.
CLAIM 10
The stereoselective synthesis system of claim 1, wherein the batch or semi-continuous operation mode is regulated through programmable logic control incorporating reaction time sequencing, reagent feed control, and temperature modulation, the control architecture including fail-safe features for overpressure mitigation and thermal runaway containment.

STEREOSELECTIVE SYNTHESIS OF ATORVASTATIN ANALOGUES FOR PHARMACEUTICAL MANUFACTURING
Abstract
A stereoselective synthesis system is disclosed for preparing atorvastatin analogues through enantioselective aldol condensation, chiral auxiliary-mediated stereocontrol, and boron-based aryl coupling. The process includes hydrolysis of chiral auxiliaries, lactonization under acid reflux, and catalytic hydrogenation preserving stereocenters. Real-time analytical feedback and optional programmable control enhance reaction fidelity. The method enables pharmaceutical-grade production in scalable, batch or semi-continuous configurations.
, Claims:Claims
I/We Claim:
CLAIM 1
A stereoselective synthesis system for preparing atorvastatin analogues comprising: a protected dihydroxy acid precursor undergoing enantioselective aldol condensation with a pyrrole-based aldehyde under a chiral auxiliary-mediated catalysis condition; a post-condensation hydrolysis stage configured to remove the chiral auxiliary while retaining the stereogenic integrity of the resultant β-hydroxy intermediate; a lactonization module performing intramolecular ring closure under acid-catalyzed reflux to yield a stereodefined lactone; a boron-mediated carbon-carbon coupling reaction unit adapted to introduce a fluorophenyl or isopropyl substituent on the pyrrole moiety with stereoretention; and a terminal hydrogenation stage utilizing a palladium or ruthenium-based catalyst system to reduce any remaining olefinic bonds without perturbing the stereogenic centers, wherein the system is operable in a batch or semi-continuous mode under inert atmosphere.
CLAIM 2
The stereoselective synthesis system of claim 1, wherein the chiral auxiliary comprises an oxazolidinone derivative selected from the group consisting of (S)-4-benzyl-2-oxazolidinone and (R)-4-isopropyl-2-oxazolidinone, and is introduced via N-acylation onto the dihydroxy acid precursor to facilitate facial selectivity during aldol addition, thereby controlling the β-hydroxy stereocenter configuration of the intermediate.
CLAIM 3
The stereoselective synthesis system of claim 1, wherein the boron-mediated carbon-carbon coupling reaction unit includes a trialkylborane or boronic ester reactant selected from 4-fluorophenylboronic acid or isopropylboronic acid, and is carried out in the presence of a palladium catalyst, a phosphine ligand, and a base such as potassium carbonate or cesium fluoride in an anhydrous polar aprotic solvent maintained at 60–90°C for selective cross-coupling.
CLAIM 4
The stereoselective synthesis system of claim 1, wherein the post-condensation hydrolysis stage comprises an acidic or basic hydrolysis solution adapted to cleave the chiral auxiliary under reflux in a mixed solvent system containing tetrahydrofuran and water, followed by pH neutralization and organic extraction of the β-hydroxy acid intermediate.
CLAIM 5
The stereoselective synthesis system of claim 1, wherein the terminal hydrogenation stage comprises the use of a heterogeneous palladium on carbon or ruthenium black catalyst under hydrogen pressure between 2 and 6 atm in a protic solvent such as methanol or ethanol at 25–40°C, the catalyst being recoverable through filtration for reusability in subsequent synthesis cycles.
CLAIM 6
The stereoselective synthesis system of claim 1, wherein the intramolecular lactonization module is configured to induce ring closure of the hydroxy acid intermediate through azeotropic distillation in the presence of para-toluenesulfonic acid or sulfuric acid, the resulting lactone being extracted via phase separation followed by recrystallization in a low polarity solvent.
CLAIM 7
The stereoselective synthesis system of claim 1, wherein the system further includes an in-line chromatographic purification unit comprising reverse-phase high-performance liquid chromatography or preparative thin-layer chromatography configured to isolate and purify each stereoisomer of the final atorvastatin analogue to pharmaceutical grade.
CLAIM 8
The stereoselective synthesis system of claim 1, wherein the reaction system includes a process analytics monitoring module comprising chiral HPLC and NMR spectroscopic interfaces that assess enantiomeric excess, diastereoselectivity, and structural integrity of intermediates and final atorvastatin analogues in real time.
CLAIM 9
The stereoselective synthesis system of claim 1, wherein the synthesis is configured to accommodate structural modifications on the pyrrole core through selective alkylation or arylation at the 3- or 5-position using organolithium or Grignard reagents introduced post-lactonization and prior to hydrogenation, enabling tunability of biological activity.
CLAIM 10
The stereoselective synthesis system of claim 1, wherein the batch or semi-continuous operation mode is regulated through programmable logic control incorporating reaction time sequencing, reagent feed control, and temperature modulation, the control architecture including fail-safe features for overpressure mitigation and thermal runaway containment.