Applications of 2, 2, 2 trifluoroethanol as a versatile co-solvent in supercritical fluid chromatography for purification of unstable boronate esters, enhancing throughput, reducing epimerization, and for additive free purifications

Asokan, Kathiravan; Shaikh, Khaja Mohinddin; Tele, Shahaji Sopan; Chauthe, Siddheshwar Kisan; Ansar, Shabana; Vetrichelvan, Muthalagu; Nimje, Roshan Y.; Gupta, Anuradha; Gupta, Arun Kumar; Sarabu, Ramakanth; Wu, Dauh‐Rurng; Mathur, Arvind; Bajpai, Lakshmikant

doi:10.1016/j.chroma.2017.11.031

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…Based on the above results, it can be concluded that even 2–5% of water in the HILIC mobile phase might be causing the hydrolysis of boronate esters. As reported earlier in our lab, SFC was used successfully for the separation and purification of boronate esters . Hence, it was decided to explore the possibility of using SFC-MS for the quantitative estimation of these boronate esters.…”

Section: Resultsmentioning

confidence: 95%

“…As reported earlier in our lab, SFC was used successfully for the separation and purification of boronate esters. 29 Hence, it was decided to explore the possibility of using SFC-MS for the quantitative estimation of these boronate esters. Initial trials were conducted to select the appropriate stationary phase with the target of achieving stability, proper retention time, and peak shape.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…One such report was published earlier from our lab about the separation and isolation of a few water-sensitive boronate esters. 29 Based on the latter, it was decided to explore the possibility of using supercritical fluid chromatography (SFC) with mass spectrometry (MS) to address the degradation issues and achieve the quantification of low levels of these boronate esters. In SFC, the mobile phase consists of a high proportion of supercritical CO 2 , supplemented with organic cosolvents such as methanol (MeOH), isopropyl alcohol (IPA), ethanol (EtOH), 2,2,2 trifluoroethanol (TFE), and acetonitrile (ACN), which are commonly used chromatographic solvents.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Numerous studies have been published on the application of hyphenated techniques for the detection of various labile compounds. ,,,, Supercritical fluid chromatography (SFC) offers an orthogonal approach to RPLC, allowing for the analysis of compounds that are susceptible to hydrolysis in the presence of an aqueous environment. One such report was published earlier from our lab about the separation and isolation of a few water-sensitive boronate esters . Based on the latter, it was decided to explore the possibility of using supercritical fluid chromatography (SFC) with mass spectrometry (MS) to address the degradation issues and achieve the quantification of low levels of these boronate esters.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the latter, it was decided to explore the possibility of using supercritical fluid chromatography (SFC) with mass spectrometry (MS) to address the degradation issues and achieve the quantification of low levels of these boronate esters. In SFC, the mobile phase consists of a high proportion of supercritical CO 2 , supplemented with organic cosolvents such as methanol (MeOH), isopropyl alcohol (IPA), ethanol (EtOH), 2,2,2 trifluoroethanol (TFE), and acetonitrile (ACN), which are commonly used chromatographic solvents. − The use of an MS detector offers improved sensitivity for trace-level quantification of boronate esters, which is attributed to better evaporation of the mobile phase, enhancing the detection capabilities. To the best of our knowledge, direct quantification of boronate esters at lower levels using SFC-MS has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

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Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities

Kushwah,

Gandhi,

Purandharan

et al. 2024

Org. Process Res. Dev.

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Boronate esters are commonly used starting materials in the Suzuki−Miyaura coupling reaction for the C−C bond formation due to their cost-effectiveness and ease of manufacturing process. However, most of them are highly sensitive to moisture and pose challenges during their in-process analysis, with conversion to acids under reversed-phase analytical conditions. They are prone to hydrolysis under moisture, pH, and even on-column stationary phases under neutral conditions. At the same time, boronate esters are considered as potential genotoxic substances; hence, their estimation is very important from the patient safety perspective. There are inherent challenges in the existing methods of analysis of these compounds. In this paper, a convenient, simple, highly sensitive, and greener SFC-MS method was developed for the screening of such unstable boronate esters. The optimized method consisted of Celeris Arginine column (250 mm × 4.6 mm; 5 μm) with CO 2 (A) as a solvent with a cosolvent of ACN: MeOH (80:20) containing 0.2% 7N methanolic ammonia (B) in gradient mode [T min /B %: 0.01/05, 0.50/05, 5.00/50, 7.00/50, 7.10/05, and 10.00/05]. Critical method parameters such as ABPR pressure, makeup solvent, additives, and pump flow rate were optimized to enhance the sensitivity with a model compound, i.e., 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo-[2,3-b]pyridine (CAS no. 886547-94-0). The robustness of the method was demonstrated by validating the method as per the ICH guidelines on the same model compound in the concentration range of 0.03−0.3 ppm. The LOD and LOQ for this compound were determined as 0.01 and 0.03 ppm (1 and 3 ppm with respect to API concentrations of 10 mg/mL), respectively. The method was successfully applied for the estimation of 16 structurally different boronate esters with no chemical derivatization or hydrolysis.

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Section: Resultsmentioning

confidence: 95%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities

Kushwah,

Gandhi,

Purandharan

et al. 2024

Org. Process Res. Dev.

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Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P₁ final active pharmaceutical ingredients

Yip

Kempson

et al. 2019

Separation Science Plus

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Large‐scale preparation of two sphingosine‐1‐phosphate‐subtype 1 (S1P1) active pharmaceutical ingredients, BMS‐986166 and compound 2, was achieved through a scalable supercritical fluid chromatography separation of a key common diastereomeric intermediate. Multi‐gram scale chiral supercritical fluid chromatography of the final active pharmaceutical ingredients was time‐consuming and not economical due to low throughput and recovery. An efficient large‐scale chiral supercritical fluid chromatography method was developed to rapidly obtain multi‐gram quantities of a chirally pure (>99% de) common intermediate for the preparation of the two S1P1 active pharmaceutical ingredients in reduced time and cost. Extensive column screening was conducted on two shared chiral intermediates: a methyl ester and an alcohol derivative. The subsequent sample loading comparison of these two compounds indicated that the methyl ester was the preferred intermediate for large‐scale chiral purification. The finalized supercritical fluid chromatography method for the methyl ester was readily scaled up onto a 3 cm I. D. Chiralpak IC column at a total flow rate of 180 mL/min with 52% methanol as co‐solvent in CO2, resulting in a high throughput of 4 g/h, which was equivalent to 96 g/day. In total, 1 kg of the ester intermediate was purified with a recovery of >90%. This efficient chiral supercritical fluid chromatography purification enabled large‐scale preparation of the two S1P1 compounds to support toxicology studies in Discovery Chemistry.

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Recent trends in chiral supercritical fluid chromatography

West

2019

TrAC Trends in Analytical Chemistry

133

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Applications of 2, 2, 2 trifluoroethanol as a versatile co-solvent in supercritical fluid chromatography for purification of unstable boronate esters, enhancing throughput, reducing epimerization, and for additive free purifications

Cited by 4 publications

References 35 publications

Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities

Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities

Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P₁ final active pharmaceutical ingredients

Recent trends in chiral supercritical fluid chromatography

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Applications of 2, 2, 2 trifluoroethanol as a versatile co-solvent in supercritical fluid chromatography for purification of unstable boronate esters, enhancing throughput, reducing epimerization, and for additive free purifications

Cited by 4 publications

References 35 publications

Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities

Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities

Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P1 final active pharmaceutical ingredients

Recent trends in chiral supercritical fluid chromatography

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Product

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Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P₁ final active pharmaceutical ingredients