Design of diastereomeric salt resolution <i>via</i> multicomponent system characterization: a case study with hydrate formation

Bosits, Miklós Hunor; Bereczki, Laura; Bombicz, Petra; Szalay, Zsófia; Pataki, Hajnalka; Demeter, Ádám

doi:10.1039/d2ce01490d

Cited by 6 publications

(5 citation statements)

References 40 publications

(51 reference statements)

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“…The applied concentration domain was designed according to solubility: at the seeding temperature, the solution was nearly saturated with respect to ( S )-pregabalin l -tartrate, and at the isolation temperature, the concentration of the other diastereomer was yet below saturation. This thermodynamical domain was analyzed and determined in a previous publication Table comprises the parameter values set in each experiment.…”

Section: Methodsmentioning

confidence: 99%

“…This thermodynamical domain was analyzed and determined in a previous publication. 67 The experimental procedure is as follows. The specified amount of racemic pregabalin hydrate, L-tartaric acid, and water was mixed and heated until complete dissolution, verified with the FBRM, and then cooled back to the predetermined seeding temperature (Figure 2).…”

Section: Resolution Experimentsmentioning

confidence: 99%

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Population Balance Modeling of Diastereomeric Salt Resolution

Bosits

Orosz

Szalay

et al. 2023

Crystal Growth & Design

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Diastereomeric salt crystallization is a classical, widely applicable chiral resolution technique, which enables the separation of the enantiomers of both racemate and conglomerate-forming compounds. A resolution method for racemic pregabalin with l-tartaric acid was developed to obtain pure (S)-pregabalin l-tartrate monohydrate crystals with the yield ranging from 43 to 50%. A series of designed resolution experiments were executed at different cooling rates and temperature end points to estimate the crystallization kinetics using population balance modeling. Inline ATR-FTIR measurements of these experiments were used to calculate concentrations in the crystallization phase and to collect solid–liquid equilibrium data by the solubility trace method after product sampling. Since diastereomeric salts are dissociable ionic compounds, solubility product expressions were used in the model to express the relative supersaturation as the driving force of crystallization. As a result, a population balance model with secondary nucleation, growth, and agglomeration mechanisms was identified, and the simulated supersaturation profiles and product size distributions well reproduced the measured data.

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Section: Methodsmentioning

confidence: 99%

Section: Resolution Experimentsmentioning

confidence: 99%

Population Balance Modeling of Diastereomeric Salt Resolution

Bosits

Orosz

Szalay

et al. 2023

Crystal Growth & Design

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“…10,11 Various techniques for analyzing racemic compounds include high-performance liquid chromatography (HPLC), which is accurate but costly and complex 12 ; capillary electrophoresis, efficient but with sample size limitations 13 ; supercritical fluid chromatography, effective but equipment-specific with limited mobile phase options 14 ; and diastereomeric crystallization, simple but slow and unsuitable for large-scale production. 15,16 Chiral stationary phases (CSPs) are preferred for enantioseparation due to their simplicity, selectivity, and versatility, although cost and durability issues require more research. 17,18 Molecularly imprinted polymers (MIPs)-based CSPs are a groundbreaking class of materials engineered for selective chiral molecule separation.…”

Section: Introductionmentioning

confidence: 99%

Molecularly imprinted hydrazidine‐derived poly(acrylonitrile‐co‐divinylbenzene for enantio‐recognition of S‐fenoprofen

Alhawaiti,

Almutairi,

Elsayed

2024

J of Applied Polymer Sci

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The drug fenoprofen (FN) is available in two forms, R‐ and S‐enantiomers, which need to be separated for optimal therapeutic use. A novel poly(acrylonitrile‐co‐divinylbenzene) (PNB)‐based polymer sorbent designed specifically for S‐fenoprofen (S‐FN) enantioseparation was synthesized. This process began with creating low cross‐linked PNB microparticles through suspension polymerization. Next, hydrazine was introduced to react with the prevalent nitrile groups. The produced cationic hydrazidine‐functionalized polymer particles (HYD‐P) were then combined with anionic S‐FN. The imprinting of S‐FN was achieved by further cross‐linking with glutaraldehyde, which interacted with the NH2 groups. Subsequent acidic elution released the S‐FN enantiomers, leaving behind their specific receptor‐like cavities in the imprinted polymer particles (S‐FN‐P). The properties of the resulting polymers were analyzed using Fourier‐transform infrared (FTIR), 13C NMR, and x‐ray diffraction. Scanning electron microscopy was used to examine the surface structures of the sorbents. Under optimal conditions at pH 7, the sorbent showed an adsorption capacity of 240 mg/g for S‐FN. The chiral separation of the FN racemate achieved high enantiomeric excess (ee) levels, with 96% for R‐FN during loading and 94% for S‐FN during recovery.

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“…For these latter cases, the drug can only be marketed as an enantiopure compound. [1][2][3][4][5] The most prominent approach to enantiopure drugs still involves the formation of a racemic mixture by non-asymmetric synthesis. The eutomer can then be resolved using a chiral resolution agent.…”

mentioning

confidence: 99%

“…To establish the resolution processes isoplethal ternary phase-diagrams of both the (rac)-Binol-(R,R)-DADPE-toluene and (rac)-Binol-(R,R)-DADPE-benzene systems were constructed. These are cross-sections of the full quaternary diagram, 3,[18][19][20] for which the apexes are composed of (R)-Binol; (S)-Binol; (R,R)-DADPE and the solvent. For both isoplethal diagrams the overall composition in Binol (solid and solution phases combined) is always racemic.…”

mentioning

confidence: 99%