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Papers by Andrew Lipczynski

Research paper thumbnail of Reversed-phase high-performance liquid chromatographic retention behaviour of benzylpenicillin and its acid-base degradation products

Research paper thumbnail of A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharmaceutical Manufacturing Processes

Organic Process Research & Development, 2010

Research paper thumbnail of Generic approach to chiral separations: Chiral capillary electrophoresis with ternary cyclodextrin mixtures

Journal of Microcolumn Separations, 2000

Roman Szucs, Isabelle Caron, Karen A. Taylor, Steve P. Gee, Paul D. Ferguson, ¨ Martin A. Kelly, ... more Roman Szucs, Isabelle Caron, Karen A. Taylor, Steve P. Gee, Paul D. Ferguson, ¨ Martin A. Kelly, Jon V. Beaman, Andrew M. Lipczynski, Perry A. Hailey Analytical Research and De¨elopment, Pfizer Global Research and De¨elopment, Sandwich, Kent CT13 9NJ, ...

Research paper thumbnail of The degradation of benzylpenicillin in aqueous solution

Research paper thumbnail of Control and analysis of alkyl esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients (APIs)

Journal of Pharmaceutical and Biomedical Analysis, Jan 7, 2008

This article reviews current regulatory guidelines and relevant scientific literature pertaining ... more This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid-liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of sulfonate esters, the challenges in transferring methodology from R&D to QC labs and on the cost of inappropriate limits for genotox impurities. In so doing, the authors seek to inform the debate that the control of genotoxic impurities should be driven primarily by safety and risk/benefit considerations rather than by state-of-the-art analytical and process chemistry capabilities that drive controls to levels 'as low as practicable' regardless of the risk/safety requirements.

Research paper thumbnail of Mechanism and Processing Parameters Affecting the Formation of Methyl Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example for Sulfonate Ester Impurity Formation

Organic Process Research & Development, 2009

Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ... more Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of sulfonate esters as potential genotoxic impurities (PGIs). Whilst sulfonate esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC-MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol (18 O-label) confirm methanol CO bond cleavage in the formation of the methyl methanesulfonate (MMS), consistent with reversal of wellestablished mechanisms for solvolysis of sulfonate esters. Studies of reaction profiles quantify methyl methanesulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower temperatures, in the presence of small amounts of water, or when acid is partially neutralized by substoichiometric amounts of the weak base, 2,6-lutidine, used to mimic conversion of a basic API to a salt in pharmaceutical manufacture. In the presence of a slight excess of base, ester formation was not detected. These findings, particularly those involving an excess of base, are compelling and provide a scientific understanding to allow for the design of processing conditions to minimize and control sulfonate ester formation.

Research paper thumbnail of Separation of Regioisomers of Substituted Bromoindoles of Pharmaceutical Interest by RP-HPLC and Capillary Electrophoresis Based on Interaction with Sulfobutyl Ether-β-cyclodextrin

Journal of High Resolution Chromatography, 1999

Separation of Regioisomers of Substituted Bromoindoles of Pharmaceutical Interest by RP-HPLC and ... more Separation of Regioisomers of Substituted Bromoindoles of Pharmaceutical Interest by RP-HPLC and Capillary Electrophoresis Based on Interaction with Sulfobutyl Ether-β-cyclodextrin-Szücs-1999-Journal of High Resolution Chromatography-Wiley Online Library

Research paper thumbnail of Reversed-phase high-performance liquid chromatographic retention behaviour of benzylpenicillin and its acid-base degradation products

Research paper thumbnail of Development and validation of an automated static headspace gas chromatography–mass spectrometry (SHS-GC–MS) method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid

Journal of Pharmaceutical and Biomedical Analysis, 2008

An automated sample preparation and analysis procedure was developed to monitor the formation of ... more An automated sample preparation and analysis procedure was developed to monitor the formation of ethyl methane sulfonate from reaction mixtures containing ethanol and methane sulfonic acid. The system is based on a liquid handling robot combined with a static headspace module. The formed ethyl methane sulfonate is analysed after derivatisation with pentafluorothiophenol using static headspace-gas chromatography-mass spectrometry (SHS-GC-MS). Using the automated reaction-derivatisation-headspace GC-MS system, the formation of ethyl methane sulfonate can be monitored in different reaction mixtures under different reaction conditions, including temperature, water content and pH. Excellent linearity, repeatability and robustness were obtained, allowing the system to be used in kinetic studies.

Research paper thumbnail of Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs)

Journal of Pharmaceutical and Biomedical Analysis, 2008

This paper continues the review of the relevant scientific literature associated with the control... more This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of sulfonate esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is subcategorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial monographs was also reviewed. The continued reliance on relatively non-specific and insensitive TLC methodologies in several monographs was noteworthy.

Research paper thumbnail of A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization–headspace–gas chromatography–mass spectrometry

Journal of Pharmaceutical and Biomedical Analysis, 2007

A simple, reliable and fast procedure for the simultaneous determination of residues of some comm... more A simple, reliable and fast procedure for the simultaneous determination of residues of some common alkylating agents (AAs), such as mesylates, besylates, tosylates and sulfates, employed in drug synthesis, has been developed by in situ derivatization-headspace-gas chromatography-mass spectrometry. Pentafluorothiophenol is used as a derivatizing agent in different water/dimethyl sulfoxide ratios. Compared to former analytical procedures, this approach returns improvements in analysis time, selectivity, analyte stability and method sensitivity (LOD = 0.11 g g −1 for methyl tosylate). The method exhibits low matrix dependence, excellent accuracy, precision (R.S.D. = 2.8-10% range at 1 g g −1) and robustness through the use of deuterated internal standards. Knowledge of the synthetic route allows a targeted approach to the determination of specific AAs since the procedure does not distinguish between acid species. The procedure was successfully applied to different pharmaceutical matrixes, and is particularly suitable for routine analysis with high sample throughput.

Research paper thumbnail of Comparative effects of sodium dodecyl sulfate and sulfobutyl ether-β-cyclodextrin as pseudostationary phases in the electrokinetic chromatographic separation of hydrophobic compounds

Journal of Chromatography A, 1999

An alternative approach to the separation of hydrophobic compounds by electrokinetic chromatograp... more An alternative approach to the separation of hydrophobic compounds by electrokinetic chromatography using a negatively charged cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBE-β-CD), as a pseudostationary phase is described. While the separation power of SBE-β-CD is comparable with sodium dodecyl sulfate for compounds with relatively low retention factors, a considerable improvement in resolution and small differences in selectivity were observed with this pseudostationary

Research paper thumbnail of Control and analysis of alkyl esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients (APIs)

Journal of pharmaceutical and biomedical analysis, Jan 7, 2008

This article reviews current regulatory guidelines and relevant scientific literature pertaining ... more This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid-liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of s...

Research paper thumbnail of Reversed-phase high-performance liquid chromatographic retention behaviour of benzylpenicillin and its acid-base degradation products

Research paper thumbnail of A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharmaceutical Manufacturing Processes

Organic Process Research & Development, 2010

Research paper thumbnail of Generic approach to chiral separations: Chiral capillary electrophoresis with ternary cyclodextrin mixtures

Journal of Microcolumn Separations, 2000

Roman Szucs, Isabelle Caron, Karen A. Taylor, Steve P. Gee, Paul D. Ferguson, ¨ Martin A. Kelly, ... more Roman Szucs, Isabelle Caron, Karen A. Taylor, Steve P. Gee, Paul D. Ferguson, ¨ Martin A. Kelly, Jon V. Beaman, Andrew M. Lipczynski, Perry A. Hailey Analytical Research and De¨elopment, Pfizer Global Research and De¨elopment, Sandwich, Kent CT13 9NJ, ...

Research paper thumbnail of The degradation of benzylpenicillin in aqueous solution

Research paper thumbnail of Control and analysis of alkyl esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients (APIs)

Journal of Pharmaceutical and Biomedical Analysis, Jan 7, 2008

This article reviews current regulatory guidelines and relevant scientific literature pertaining ... more This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid-liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of sulfonate esters, the challenges in transferring methodology from R&D to QC labs and on the cost of inappropriate limits for genotox impurities. In so doing, the authors seek to inform the debate that the control of genotoxic impurities should be driven primarily by safety and risk/benefit considerations rather than by state-of-the-art analytical and process chemistry capabilities that drive controls to levels 'as low as practicable' regardless of the risk/safety requirements.

Research paper thumbnail of Mechanism and Processing Parameters Affecting the Formation of Methyl Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example for Sulfonate Ester Impurity Formation

Organic Process Research & Development, 2009

Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ... more Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of sulfonate esters as potential genotoxic impurities (PGIs). Whilst sulfonate esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC-MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol (18 O-label) confirm methanol CO bond cleavage in the formation of the methyl methanesulfonate (MMS), consistent with reversal of wellestablished mechanisms for solvolysis of sulfonate esters. Studies of reaction profiles quantify methyl methanesulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower temperatures, in the presence of small amounts of water, or when acid is partially neutralized by substoichiometric amounts of the weak base, 2,6-lutidine, used to mimic conversion of a basic API to a salt in pharmaceutical manufacture. In the presence of a slight excess of base, ester formation was not detected. These findings, particularly those involving an excess of base, are compelling and provide a scientific understanding to allow for the design of processing conditions to minimize and control sulfonate ester formation.

Research paper thumbnail of Separation of Regioisomers of Substituted Bromoindoles of Pharmaceutical Interest by RP-HPLC and Capillary Electrophoresis Based on Interaction with Sulfobutyl Ether-β-cyclodextrin

Journal of High Resolution Chromatography, 1999

Separation of Regioisomers of Substituted Bromoindoles of Pharmaceutical Interest by RP-HPLC and ... more Separation of Regioisomers of Substituted Bromoindoles of Pharmaceutical Interest by RP-HPLC and Capillary Electrophoresis Based on Interaction with Sulfobutyl Ether-β-cyclodextrin-Szücs-1999-Journal of High Resolution Chromatography-Wiley Online Library

Research paper thumbnail of Reversed-phase high-performance liquid chromatographic retention behaviour of benzylpenicillin and its acid-base degradation products

Research paper thumbnail of Development and validation of an automated static headspace gas chromatography–mass spectrometry (SHS-GC–MS) method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid

Journal of Pharmaceutical and Biomedical Analysis, 2008

An automated sample preparation and analysis procedure was developed to monitor the formation of ... more An automated sample preparation and analysis procedure was developed to monitor the formation of ethyl methane sulfonate from reaction mixtures containing ethanol and methane sulfonic acid. The system is based on a liquid handling robot combined with a static headspace module. The formed ethyl methane sulfonate is analysed after derivatisation with pentafluorothiophenol using static headspace-gas chromatography-mass spectrometry (SHS-GC-MS). Using the automated reaction-derivatisation-headspace GC-MS system, the formation of ethyl methane sulfonate can be monitored in different reaction mixtures under different reaction conditions, including temperature, water content and pH. Excellent linearity, repeatability and robustness were obtained, allowing the system to be used in kinetic studies.

Research paper thumbnail of Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs)

Journal of Pharmaceutical and Biomedical Analysis, 2008

This paper continues the review of the relevant scientific literature associated with the control... more This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of sulfonate esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is subcategorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial monographs was also reviewed. The continued reliance on relatively non-specific and insensitive TLC methodologies in several monographs was noteworthy.

Research paper thumbnail of A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization–headspace–gas chromatography–mass spectrometry

Journal of Pharmaceutical and Biomedical Analysis, 2007

A simple, reliable and fast procedure for the simultaneous determination of residues of some comm... more A simple, reliable and fast procedure for the simultaneous determination of residues of some common alkylating agents (AAs), such as mesylates, besylates, tosylates and sulfates, employed in drug synthesis, has been developed by in situ derivatization-headspace-gas chromatography-mass spectrometry. Pentafluorothiophenol is used as a derivatizing agent in different water/dimethyl sulfoxide ratios. Compared to former analytical procedures, this approach returns improvements in analysis time, selectivity, analyte stability and method sensitivity (LOD = 0.11 g g −1 for methyl tosylate). The method exhibits low matrix dependence, excellent accuracy, precision (R.S.D. = 2.8-10% range at 1 g g −1) and robustness through the use of deuterated internal standards. Knowledge of the synthetic route allows a targeted approach to the determination of specific AAs since the procedure does not distinguish between acid species. The procedure was successfully applied to different pharmaceutical matrixes, and is particularly suitable for routine analysis with high sample throughput.

Research paper thumbnail of Comparative effects of sodium dodecyl sulfate and sulfobutyl ether-β-cyclodextrin as pseudostationary phases in the electrokinetic chromatographic separation of hydrophobic compounds

Journal of Chromatography A, 1999

An alternative approach to the separation of hydrophobic compounds by electrokinetic chromatograp... more An alternative approach to the separation of hydrophobic compounds by electrokinetic chromatography using a negatively charged cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBE-β-CD), as a pseudostationary phase is described. While the separation power of SBE-β-CD is comparable with sodium dodecyl sulfate for compounds with relatively low retention factors, a considerable improvement in resolution and small differences in selectivity were observed with this pseudostationary

Research paper thumbnail of Control and analysis of alkyl esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients (APIs)

Journal of pharmaceutical and biomedical analysis, Jan 7, 2008

This article reviews current regulatory guidelines and relevant scientific literature pertaining ... more This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid-liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of s...