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Green chemistry approaches for the purification of pharmaceuticals
Accepted Manuscript Green Chemistry Approaches for the Purification of Pharmaceuticals Keith Galyan, John Reilly PII:
S2452-2236(17)30096-2
DOI:
10.1016/j.cogsc.2018.04.018
Reference:
COGSC 158
To appear in:
Current Opinion in Green and Sustainable Chemistry
Received Date: 13 December 2017 Revised Date:
29 March 2018
Accepted Date: 24 April 2018
Please cite this article as: K. Galyan, J. Reilly, Green Chemistry Approaches for the Purification of Pharmaceuticals, Current Opinion in Green and Sustainable Chemistry (2018), doi: 10.1016/ j.cogsc.2018.04.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Green Chemistry Approaches for the Purification of Pharmaceuticals Keith Galyan, John Reilly
RI PT
Novartis Institutes for BioMedical Research Inc., Cambridge, MA 02139, USA Abstract
Solvent Consumption
Setup Time
Expertise Level Needed
Scale
High
Low
Low
mg-kg
SFC
Medium
SSR
Medium
SMB
Low
Low
mg-kg
Medium
Low
Medium
mg-kg
High
High
g-ton
TE D
Batch HPLC
M AN U
SC
To enable R&D of new drug products with a more green process emphasis, a full understanding of the impact of chromatography in the discovery phase of drug development is crucial. With large quantities of small scale (<1000mg) separations typically evaluated and purified, a chromatographic technique needs to be easily integrated into workflows and readily robust. At Novartis, integration of supercritical fluid chromatography (SFC) has allowed for increases in productivity, decreases in toxic/hazardous solvent consumption and a more green approach to chromatography. The purpose of this review is to introduce the reader to new techniques available to organizations for the analysis and purification of mg-kg scale purifications that are routinely handled within discovery. Evaluation of a variety of techniques available to the industry has led to the implementation of SFC, with some of the pros of each technique noted below: An overview of enantiomeric purification methodologies is highlighted below in Table 1.
Review
EP
Table 1. High level evaluation of Preparative Purification Techniques
AC C
Within Separation Sciences Departments in Pharmaceutical Industry there are a range of techniques focused on the analytical separation and purification isolation of pure products. A variety of techniques have been developed to improve analysis efficiencies and concurrently decrease the use of toxic solvents and modifiers to maximize impact in a green approach [1]. HPLC has been generally accepted in the Pharmaceutical Industry as a technique for analysis and purification, utilizing either normal phase or reverse phase conditions, with reverse phase being generally accepted as a much more green approach than that of normal phase. Although the use of acetonitrile within reversed phase is a widely accepted solvent, it is acutely toxic to aquatic life and effluent from laboratories has to be controlled and incinerated which increases costs and environmental impact.. There has been some progress into the evaluation of fully aqueous mobile phases in RP-HPLC using superheated water chromatography [2], however this is not yet a viable purification technique Water at elevated temperatures exhibits reduced viscosity and an
ACCEPTED MANUSCRIPT
SC
RI PT
increase in elutropic strength and when a thermal gradient is applied analytical results are comparable to organic solvent mobile phase mixes [2].There are other analytical techniques that have a lower environmental impact than even that of traditional RP-HPLC. Utilizing capillary electrophoresis (CE) allows for the use of a 100% aqueous buffer that uses electroosmotic flow to provide the separation of mass to charged species [3]. This technique has been widely adapted in the pharmaceutical industry for analytical small molecule separations [4]. Another technique that has been identified as green is counter current chromatography (CCC). CCC utilizes liquidliquid partitioning to separate pharmaceutical compounds with minimal flow [5] therefore having an overall lower rate of solvent consumption. CCC has not been widely adopted for routine analysis and purification (internal data deeming it labor intensive) although future advances in the robustness of this technology would be appreciated.
TE D
M AN U
Implementation of chromatographic techniques to purify synthetically derived material has been integral to providing clean and consistent batches of pharmaceuticals for decades. The utilization of normal phase (NP)-HPLC allowed for significantly higher rates of production with improved consistency and overall operational efficiency compared with traditional gravity flow chromatography. This is still the default technique in many organizations and industries for chiral and achiral purifications. There are significant disadvantages of this technique due to increased health and safety precautions and waste disposal ref. There have been ways in which NP-HPLC has been improved to reduce the overall solvent consumption, including the utilization of the technique noted as Steady-State Recycling (SSR). Using SSR techniques reduces solvent consumption and increases productivity in purification.. The environmental impact is decreased by reducing solvent consumption and improving sample production rates as shown in Table 2. by a factor of 3 in this example [6]. Even with these advances, NP-HPLC is an expensive option when we begin to include the solvent and waste removal associated required for the efficient optimization of the methodology.
AC C
EP
In order to decrease the overall environmental impact of the chromatographic process, integration of an aqueous based mobile phase can significantly decrease the consumption of organic solvents as has been demonstrated in reverse phase purifications. This orthogonal technique utilizes a more green approach to decrease overall cost, specifically for achiral purifications [7]. Utilizing reverse phase (RP)-HPLC once again allowed for high rates of production and a robust platform that utilizes a predominately aqueous mobile phase and significantly decreased amounts of organic solvents. This technique is widely accepted in both the analytical and preparative world, with utilization of experts for difficult separation and a walk up open-access platform for simpler separations [7]. Even with the environmental benefits of using RP-HPLC due to decreased amounts of organic solvent there are areas for improvement as there is an offset of energy required to distill out the aqueous portion. For example the high level of water-organic solvent mixes leads to a relatively large amount of time dedicated to dry down with the removal of toxic solvents like methanol or acetonitrile and then the subsequent lyophilization of the material. The additional water removal requires dedicated instrumentation
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
such as lyophilizers and rotary evaporators which adds to the additional cost and increased carbon footprint to run these instruments effectively. Sample solubility can also become a significant barrier if the material is not soluble in water. For Large Scale campaigns RP-Prep is often not chosen due to the time taken to dry down solvent, and the high cost of the organic solvents used throughout the process including waste disposal. To address the challenges of all HPLC based methodologies in large scale purifications, Simulated Moving Bed (SMB) chromatography was developed. [8]. SMB is generally a normal phase method used for the production-scale chromatographic purification of enantiomers. Although a practical method for large scale separations, the costs, maintenance, method development time and overall level of expertise needed to operate SMB efficiently decreases its utilization for small to medium scale purification campaigns. A productivity, solvent usage, purity and yield comparison between SMB, SSR, SFC and HPLC (in batch mode) has been assessed by Amgen [6] with a table displaying a summary of the results shown in Table 2.
Productivity (g racemate/KgCSP/day)
Solvent Consumption (L/g racemate)
Purity (%ee
Yield (desired enantiomer %)
110
2.10
99
~97.5
0.76
~99
>95
0.80
~99
~95.2
0.55
~99
~91.7
362
SSR
358
SMB
500
TE D
Batch HPLC SFC
Table 2. Productivity, solvent usage, purity and yield of SMB, SFC, SSR and Batch HPLC [6]
AC C
EP
In efforts to find new and innovative ways to improve chromatographic processes, drug discovery operations have increasingly employed Super Critical Fluid Chromatography (SFC) to decrease the overall environmental footprint and increase productivity for small to large (mg-kg) scale purification campaigns. This technology uses supercritical (sc)CO2 to replace the more toxic and hazardous normal phase eluents (e.g. heptane, dichloromethane). The inherently low viscosity of the scCO2 also allows for higher flow rates, improving per gram production rates compared to batch NP-HPLC while reducing organic solvent usage by 3 fold [6]. This is particularly beneficial in chiral chromatography where multiple isolates are generated. A typical example separation comparison between SFC and HPLC is shown in Table 1 where the enormous benefits in efficiency, time, solvent consumption and evaporation time are highlighted
ACCEPTED MANUSCRIPT
3 hours
Purification by HPLC 46 hours
5L of Methanol
40L of Acetonitrile
1 hour 95%
8 hours 80%
Purification by SFC
RI PT
Separation Time Organic Solvent Used Total Workup Time Recovery
Table 3. Comparison of Prep SFC v Prep HPLC (Courtesy of Waters Corporation)
EP
TE D
M AN U
SC
Another example of SFC v RP-HPLC for a discovery sample within Novartis is shown in the chromatogram displayed in Figure 1 where the same analyte is purified (25mg injection). The sample was processed in a third of the time by SFC with equivalent purity and recovery.
AC C
Figure 1. HPLC-RP v SFC comparison for discovery purification SFC has been adopted in many labs as an approach to improve upon traditional flash chromatography technologies, for example purification of diastereomers, typically performed using traditional disposable silica cartridges on flash chromatography systems, can be much more efficiently processed using SFC [9]. Because of the improved reliability and robustness of the instrumentation and stationary phases available the pharmaceutical industry has readily adopted SFC as a means for the analysis and purification of small molecules [10]. These improvements, as well as the benefits noted above, have also led to additional advancements in an open access (OA) format. OA-SFC has become a beneficial tool within Novartis to effectively manage project advancement with reduced resources and accommodate greater
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
RI PT
demand. Several stationary phases can be rapidly evaluated analytically to identify suitable purification conditions. With a set of conditions identified, walk up open access prep scale integration allows for the immediate use of preparative scale purification technology in an easy to use platform. This in conjunction with an open bed fraction collection module allows for small scale purifications to be performed rapidly with smaller environmental impact than the traditionally utilized OA-RP-HPLC techniques. An example of a chiral purification performed using OA-SFC scaling from analytical to preparative scale is noted in Figure 2.
Conclusions
EP
Figure 2: Analytical to prep scale purification using open access instrumentation
AC C
By taking advantage of the advances in technology, chromatographers are also able to capitalize on the improvements in reducing environmental impact whilst also improving efficiency. With an overall greater understanding, chromatographers are able to decrease the environmental impact by manipulating a variety of factors. Further ways to reduce the environmental impact has been shown by using supercritical fluid extractions (SFE) as a technique where excipients are removed, isolated and analyzed eliminating toxic solvent extraction procedures [11]. By integrating multiple green techniques to minimize environmental impact chromatographers are integral to the long term reduction in toxic waste from Discovery Chemistry laboratories. References
ACCEPTED MANUSCRIPT
[1] Kaljurand M., Koel M. “Recent Advancements on Greening Analytical Separation” Critical Reviews in Analytical Chemistry 2011, 41: 2-20, [2] Edge T. “Super Heated water chromatography – a hot topic for LC and LC-MS. Chromatography Today” 2008, Sep/Oct issue, 11-14,
RI PT
[3] Xie H.Y., He Y.Z. “Green analytical methodologies combining liquid-phase microextraction with capillary electrophoresis” Trends in Analytical Chemistry 2010, Vol 29 #7, 629-635 [4] Holland L.A., Chetwyn N.P., Perkins M.D., Lunte S.M.. “Capillary electrophoresis in pharmaceutical analysis” Pharm Res. 1997, Apr;14(4):372-87.
SC
[5] Sumner N., “Developing Counter Current Chromatography to meet the needs of Pharmaceutical Industry. Journal of Chromatography A, 2011, 1218 6107-6113
M AN U
[6] Yan, T., Orihuela, C., Swanson D. The Application of Preparative Batch HPLC, Supercritical Fluid Chromatography, Steady State Recycling and Simulated Moving Bed for the Resolution of a Racemic Pharmaceutical Intermediate. Chirality 2008, 20:139-146 * This article discusses the chromatographic resolution of a racemic pharmaceutical intermediate by preparative batch high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), steadystate recycling (SSR), and simulated moving bed (SMB) The productivities and solvent costs of SFC versus HPLC are compared. The productivities and solvent costs of SMB, SSR, and HPLC are also compared.
TE D
[7] Blom, K.F, Glass B., Sparks R. and Combs A.P. Preparative LC-MS Purification: Improved Compound –Specific Method Optimization” 2004, Journal of Comb. Chem. 6, 874-883
EP
[8]. Freund, E., Abel, S., Huthmann, E., Jorg L.”Chiral Chromatography in the early phases of Pharmaceutical Development” Chemistry Today 2009 Vol 27, 62-64.
AC C
[9] Ghinet A., Zehani Y., Lipka E. Supercritical fluid chromatography approach for a sustainable manufacture of new stereoisomeric anticancer agent. Journal of Pharmaceutical and Biomedical Analysis 145 2017, 845–853 [10] Desfontaine V., Guillarme D., Francotte E., Novakova L. “Supercritical fluid chromatography in pharmaceutical analysis” Journal of Pharmaceutical and Biomedical Analysis,113 2015 56-71 * In this review, the instrumentation and experimental conditions (i.e. stationary phase chemistry and dimensions, mobile phase nature, pressure and temperature) to perform “advanced SFC” are discussed. The applicability of SFC in pharmaceutical analysis, including the determination of drugs in formulations and biofluids are critically discussed.
ACCEPTED MANUSCRIPT
[11] Murugaver B., Voorhees K.J. On-Line Supercritical Fluid Extraction/Chromatography System for Trace Analysis of Pesticides in Soybean Oil and Rendered Fats, J. Microcol. Sep. 1991, 3, 11-16 (1991)
AC C
EP
TE D
M AN U
SC
RI PT
*Articles of special interest
S2452-2236(17)30096-2
DOI:
10.1016/j.cogsc.2018.04.018
Reference:
COGSC 158
To appear in:
Current Opinion in Green and Sustainable Chemistry
Received Date: 13 December 2017 Revised Date:
29 March 2018
Accepted Date: 24 April 2018
Please cite this article as: K. Galyan, J. Reilly, Green Chemistry Approaches for the Purification of Pharmaceuticals, Current Opinion in Green and Sustainable Chemistry (2018), doi: 10.1016/ j.cogsc.2018.04.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Green Chemistry Approaches for the Purification of Pharmaceuticals Keith Galyan, John Reilly
RI PT
Novartis Institutes for BioMedical Research Inc., Cambridge, MA 02139, USA Abstract
Solvent Consumption
Setup Time
Expertise Level Needed
Scale
High
Low
Low
mg-kg
SFC
Medium
SSR
Medium
SMB
Low
Low
mg-kg
Medium
Low
Medium
mg-kg
High
High
g-ton
TE D
Batch HPLC
M AN U
SC
To enable R&D of new drug products with a more green process emphasis, a full understanding of the impact of chromatography in the discovery phase of drug development is crucial. With large quantities of small scale (<1000mg) separations typically evaluated and purified, a chromatographic technique needs to be easily integrated into workflows and readily robust. At Novartis, integration of supercritical fluid chromatography (SFC) has allowed for increases in productivity, decreases in toxic/hazardous solvent consumption and a more green approach to chromatography. The purpose of this review is to introduce the reader to new techniques available to organizations for the analysis and purification of mg-kg scale purifications that are routinely handled within discovery. Evaluation of a variety of techniques available to the industry has led to the implementation of SFC, with some of the pros of each technique noted below: An overview of enantiomeric purification methodologies is highlighted below in Table 1.
Review
EP
Table 1. High level evaluation of Preparative Purification Techniques
AC C
Within Separation Sciences Departments in Pharmaceutical Industry there are a range of techniques focused on the analytical separation and purification isolation of pure products. A variety of techniques have been developed to improve analysis efficiencies and concurrently decrease the use of toxic solvents and modifiers to maximize impact in a green approach [1]. HPLC has been generally accepted in the Pharmaceutical Industry as a technique for analysis and purification, utilizing either normal phase or reverse phase conditions, with reverse phase being generally accepted as a much more green approach than that of normal phase. Although the use of acetonitrile within reversed phase is a widely accepted solvent, it is acutely toxic to aquatic life and effluent from laboratories has to be controlled and incinerated which increases costs and environmental impact.. There has been some progress into the evaluation of fully aqueous mobile phases in RP-HPLC using superheated water chromatography [2], however this is not yet a viable purification technique Water at elevated temperatures exhibits reduced viscosity and an
ACCEPTED MANUSCRIPT
SC
RI PT
increase in elutropic strength and when a thermal gradient is applied analytical results are comparable to organic solvent mobile phase mixes [2].There are other analytical techniques that have a lower environmental impact than even that of traditional RP-HPLC. Utilizing capillary electrophoresis (CE) allows for the use of a 100% aqueous buffer that uses electroosmotic flow to provide the separation of mass to charged species [3]. This technique has been widely adapted in the pharmaceutical industry for analytical small molecule separations [4]. Another technique that has been identified as green is counter current chromatography (CCC). CCC utilizes liquidliquid partitioning to separate pharmaceutical compounds with minimal flow [5] therefore having an overall lower rate of solvent consumption. CCC has not been widely adopted for routine analysis and purification (internal data deeming it labor intensive) although future advances in the robustness of this technology would be appreciated.
TE D
M AN U
Implementation of chromatographic techniques to purify synthetically derived material has been integral to providing clean and consistent batches of pharmaceuticals for decades. The utilization of normal phase (NP)-HPLC allowed for significantly higher rates of production with improved consistency and overall operational efficiency compared with traditional gravity flow chromatography. This is still the default technique in many organizations and industries for chiral and achiral purifications. There are significant disadvantages of this technique due to increased health and safety precautions and waste disposal ref. There have been ways in which NP-HPLC has been improved to reduce the overall solvent consumption, including the utilization of the technique noted as Steady-State Recycling (SSR). Using SSR techniques reduces solvent consumption and increases productivity in purification.. The environmental impact is decreased by reducing solvent consumption and improving sample production rates as shown in Table 2. by a factor of 3 in this example [6]. Even with these advances, NP-HPLC is an expensive option when we begin to include the solvent and waste removal associated required for the efficient optimization of the methodology.
AC C
EP
In order to decrease the overall environmental impact of the chromatographic process, integration of an aqueous based mobile phase can significantly decrease the consumption of organic solvents as has been demonstrated in reverse phase purifications. This orthogonal technique utilizes a more green approach to decrease overall cost, specifically for achiral purifications [7]. Utilizing reverse phase (RP)-HPLC once again allowed for high rates of production and a robust platform that utilizes a predominately aqueous mobile phase and significantly decreased amounts of organic solvents. This technique is widely accepted in both the analytical and preparative world, with utilization of experts for difficult separation and a walk up open-access platform for simpler separations [7]. Even with the environmental benefits of using RP-HPLC due to decreased amounts of organic solvent there are areas for improvement as there is an offset of energy required to distill out the aqueous portion. For example the high level of water-organic solvent mixes leads to a relatively large amount of time dedicated to dry down with the removal of toxic solvents like methanol or acetonitrile and then the subsequent lyophilization of the material. The additional water removal requires dedicated instrumentation
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
such as lyophilizers and rotary evaporators which adds to the additional cost and increased carbon footprint to run these instruments effectively. Sample solubility can also become a significant barrier if the material is not soluble in water. For Large Scale campaigns RP-Prep is often not chosen due to the time taken to dry down solvent, and the high cost of the organic solvents used throughout the process including waste disposal. To address the challenges of all HPLC based methodologies in large scale purifications, Simulated Moving Bed (SMB) chromatography was developed. [8]. SMB is generally a normal phase method used for the production-scale chromatographic purification of enantiomers. Although a practical method for large scale separations, the costs, maintenance, method development time and overall level of expertise needed to operate SMB efficiently decreases its utilization for small to medium scale purification campaigns. A productivity, solvent usage, purity and yield comparison between SMB, SSR, SFC and HPLC (in batch mode) has been assessed by Amgen [6] with a table displaying a summary of the results shown in Table 2.
Productivity (g racemate/KgCSP/day)
Solvent Consumption (L/g racemate)
Purity (%ee
Yield (desired enantiomer %)
110
2.10
99
~97.5
0.76
~99
>95
0.80
~99
~95.2
0.55
~99
~91.7
362
SSR
358
SMB
500
TE D
Batch HPLC SFC
Table 2. Productivity, solvent usage, purity and yield of SMB, SFC, SSR and Batch HPLC [6]
AC C
EP
In efforts to find new and innovative ways to improve chromatographic processes, drug discovery operations have increasingly employed Super Critical Fluid Chromatography (SFC) to decrease the overall environmental footprint and increase productivity for small to large (mg-kg) scale purification campaigns. This technology uses supercritical (sc)CO2 to replace the more toxic and hazardous normal phase eluents (e.g. heptane, dichloromethane). The inherently low viscosity of the scCO2 also allows for higher flow rates, improving per gram production rates compared to batch NP-HPLC while reducing organic solvent usage by 3 fold [6]. This is particularly beneficial in chiral chromatography where multiple isolates are generated. A typical example separation comparison between SFC and HPLC is shown in Table 1 where the enormous benefits in efficiency, time, solvent consumption and evaporation time are highlighted
ACCEPTED MANUSCRIPT
3 hours
Purification by HPLC 46 hours
5L of Methanol
40L of Acetonitrile
1 hour 95%
8 hours 80%
Purification by SFC
RI PT
Separation Time Organic Solvent Used Total Workup Time Recovery
Table 3. Comparison of Prep SFC v Prep HPLC (Courtesy of Waters Corporation)
EP
TE D
M AN U
SC
Another example of SFC v RP-HPLC for a discovery sample within Novartis is shown in the chromatogram displayed in Figure 1 where the same analyte is purified (25mg injection). The sample was processed in a third of the time by SFC with equivalent purity and recovery.
AC C
Figure 1. HPLC-RP v SFC comparison for discovery purification SFC has been adopted in many labs as an approach to improve upon traditional flash chromatography technologies, for example purification of diastereomers, typically performed using traditional disposable silica cartridges on flash chromatography systems, can be much more efficiently processed using SFC [9]. Because of the improved reliability and robustness of the instrumentation and stationary phases available the pharmaceutical industry has readily adopted SFC as a means for the analysis and purification of small molecules [10]. These improvements, as well as the benefits noted above, have also led to additional advancements in an open access (OA) format. OA-SFC has become a beneficial tool within Novartis to effectively manage project advancement with reduced resources and accommodate greater
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
RI PT
demand. Several stationary phases can be rapidly evaluated analytically to identify suitable purification conditions. With a set of conditions identified, walk up open access prep scale integration allows for the immediate use of preparative scale purification technology in an easy to use platform. This in conjunction with an open bed fraction collection module allows for small scale purifications to be performed rapidly with smaller environmental impact than the traditionally utilized OA-RP-HPLC techniques. An example of a chiral purification performed using OA-SFC scaling from analytical to preparative scale is noted in Figure 2.
Conclusions
EP
Figure 2: Analytical to prep scale purification using open access instrumentation
AC C
By taking advantage of the advances in technology, chromatographers are also able to capitalize on the improvements in reducing environmental impact whilst also improving efficiency. With an overall greater understanding, chromatographers are able to decrease the environmental impact by manipulating a variety of factors. Further ways to reduce the environmental impact has been shown by using supercritical fluid extractions (SFE) as a technique where excipients are removed, isolated and analyzed eliminating toxic solvent extraction procedures [11]. By integrating multiple green techniques to minimize environmental impact chromatographers are integral to the long term reduction in toxic waste from Discovery Chemistry laboratories. References
ACCEPTED MANUSCRIPT
[1] Kaljurand M., Koel M. “Recent Advancements on Greening Analytical Separation” Critical Reviews in Analytical Chemistry 2011, 41: 2-20, [2] Edge T. “Super Heated water chromatography – a hot topic for LC and LC-MS. Chromatography Today” 2008, Sep/Oct issue, 11-14,
RI PT
[3] Xie H.Y., He Y.Z. “Green analytical methodologies combining liquid-phase microextraction with capillary electrophoresis” Trends in Analytical Chemistry 2010, Vol 29 #7, 629-635 [4] Holland L.A., Chetwyn N.P., Perkins M.D., Lunte S.M.. “Capillary electrophoresis in pharmaceutical analysis” Pharm Res. 1997, Apr;14(4):372-87.
SC
[5] Sumner N., “Developing Counter Current Chromatography to meet the needs of Pharmaceutical Industry. Journal of Chromatography A, 2011, 1218 6107-6113
M AN U
[6] Yan, T., Orihuela, C., Swanson D. The Application of Preparative Batch HPLC, Supercritical Fluid Chromatography, Steady State Recycling and Simulated Moving Bed for the Resolution of a Racemic Pharmaceutical Intermediate. Chirality 2008, 20:139-146 * This article discusses the chromatographic resolution of a racemic pharmaceutical intermediate by preparative batch high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), steadystate recycling (SSR), and simulated moving bed (SMB) The productivities and solvent costs of SFC versus HPLC are compared. The productivities and solvent costs of SMB, SSR, and HPLC are also compared.
TE D
[7] Blom, K.F, Glass B., Sparks R. and Combs A.P. Preparative LC-MS Purification: Improved Compound –Specific Method Optimization” 2004, Journal of Comb. Chem. 6, 874-883
EP
[8]. Freund, E., Abel, S., Huthmann, E., Jorg L.”Chiral Chromatography in the early phases of Pharmaceutical Development” Chemistry Today 2009 Vol 27, 62-64.
AC C
[9] Ghinet A., Zehani Y., Lipka E. Supercritical fluid chromatography approach for a sustainable manufacture of new stereoisomeric anticancer agent. Journal of Pharmaceutical and Biomedical Analysis 145 2017, 845–853 [10] Desfontaine V., Guillarme D., Francotte E., Novakova L. “Supercritical fluid chromatography in pharmaceutical analysis” Journal of Pharmaceutical and Biomedical Analysis,113 2015 56-71 * In this review, the instrumentation and experimental conditions (i.e. stationary phase chemistry and dimensions, mobile phase nature, pressure and temperature) to perform “advanced SFC” are discussed. The applicability of SFC in pharmaceutical analysis, including the determination of drugs in formulations and biofluids are critically discussed.
ACCEPTED MANUSCRIPT
[11] Murugaver B., Voorhees K.J. On-Line Supercritical Fluid Extraction/Chromatography System for Trace Analysis of Pesticides in Soybean Oil and Rendered Fats, J. Microcol. Sep. 1991, 3, 11-16 (1991)
AC C
EP
TE D
M AN U
SC
RI PT
*Articles of special interest