Crystallization and relaxation dynamics of amorphous loratadine under different quench-cooling temperatures

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Jan 082017

CrystEngComm, 2017, 19,335-345
DOI: 10.1039/C6CE01645F, Paper

Ruimiao Chang, Qiang Fu, Yong Li, Mingchan Wang, Wei Du, Chun Chang, Aiguo Zeng
In this paper, four amorphous samples of loratadine were prepared by quench-cooling the melted drug at different temperatures.

In this paper, four amorphous samples of loratadine were prepared by quench-cooling the melted drug at different temperatures. With these samples, the crystallization tendencies were tested by powder X-ray diffraction (PXRD), and non-isothermal cold crystallization kinetics was investigated by using differential scanning calorimetry (DSC) and the molecular dynamics both in super-cooled liquid and in glassy states was analyzed by using broadband dielectric spectroscopy (BDS) at a temperature range from 213 to 393 K. From the PXRD results, it was established that the four amorphous loratadine samples were apt to crystallize at a temperature below the glass transition temperature. From the DSC results, it was found that the non-isothermal crystallization mechanism of these four loratadine forms was similar. However, the fast crystallization tendency (low physical stability) was also observed for the amorphous loratadine which was obtained at a low quench-cooling temperature. The tendency was analyzed based on the BDS results which demonstrated that rapid molecular mobility could generate a low physical stability and was closely related to Johari–Goldstein relaxation. These results suggested that loratadine had a weak frustration against crystallization and its physical stability was affected by the quench-cooling temperature. This study laid a foundation for choosing the right technique to prepare the amorphous form of loratadine and improving its physical stability.

Crystallization and relaxation dynamics of amorphous loratadine under different quench-cooling temperatures

Ruimiao Chang,^a^b Qiang Fu,^a Yong Li,^c Mingchan Wang,^a Wei Du,^a Chun Chang^a and Aiguo Zeng*^a

*Corresponding authors

^aSchool of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, PR China
E-mail: agzeng@mail.xjtu.edu.cn
Fax: +86 29 82655382
Tel: +86 29 82655136

^bCollege of Pharmacy, Shanxi Medical University, Taiyuan, PR China

^cDepartment of Pharmacy, Shanxi Dayi Hospital, Taiyuan 030032, PR China

CrystEngComm, 2017,19, 335-345

DOI: 10.1039/C6CE01645F

http://pubs.rsc.org/en/Content/ArticleLanding/2017/CE/C6CE01645F?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FCE+%28RSC+-+CrystEngComm+latest+articles%29#!divAbstract

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Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-dihydrobenz[b,e]oxepin-2-acetate

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Jan 062017

Figure imgf000014_0002

E/Z

WO2014147647

White solid; Ή NMR (200 MHz, CDC1₃ + CC1₄): δ 2.38-2.49 ( m,0.8H, E- Form), 2.63-2.73 ( m,1.2H, Z-Form), 3.53 (s, 2H), 3.68 (s, 3H), 3.75 (m, 0.8H, E-Form), 3.81 (t, J=6.3 Hz, 1.2H)_, 5.19 (brs, 2H), 5.73 (t, J=7.8 Hz, 0.6H, Z-Form), 6.06 (t, J=7.8 Hz, 0.4H, E-Form), 6.70 (d, J=8.2 Hz, 0.4 H, E-Form), 6.79 (d, J=8.2 Hz, 0.6 H, Z- Form), 7.00-7.34 (m, 6H), HRMS m/r. Calculated for C₂₀H₂,O₄-325.1434, observed- 325.1437.

CLIP 2

Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-dihydrobenz[b,e]oxepin-2-acetate

916243-39-5 cas

mf C₂₀ H₂₀ O₄

Dibenz[b,e]oxepin-2-acetic acid, 6,11-dihydro-11-(3-hydroxypropylidene)-, methyl ester, (11Z)-

Molecular Weight, 324.37

white colorless crystal;

¹H NMR (CDCl₃, 300 MHz) δ 7.34–7.23 (m, 4H), 7.17 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.74 (t, J = 7.5 Hz, 1H), 5.18 (brs, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.69 (s, 3H), 3.53 (s, 2H), 2.68 (dt, J = 7.5, 6.1 Hz, 2H);

¹³C NMR (CDCl₃, 75 MHz): δ 172.4, 154.6, 145.3, 141.4, 133.6, 132.1, 130.0, 129.1, 127.5, 126.2, 125.7, 124.0, 119.7, 70.5, 62.6, 52.1, 40.1, 33.3;

MS ESI (+) m/z 325 [M + H]⁺.

Org. Process Res. Dev., 2012, 16 (2), pp 225–231

DOI: 10.1021/op200312m

CLIP 3

https://www.thieme-connect.de/DOI/DOI?10.1055/s-0033-1340008

Synthesis 2013; 45(24): 3399-3403
DOI: 10.1055/s-0033-1340008

CLICK ON IMAGE

1H AND 13C NMR PREDICT

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

//////O=C(OC)Cc1ccc2OCc3ccccc3C(=C\CCO)\c2c1

A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

PROCESS, spectroscopy, SYNTHESIS Comments Off

Jan 062017

Graphical abstract: A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

We have reported herein a catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles by which a series of five-ring-fused tetrahydroisoquinolines featuring an indoline scaffold were obtained as single diastereomers in moderate to high yields without any additives under mild conditions. Moreover, the current method provides a novel and convenient approach for the efficient incorporation of two biologically important scaffolds (tetrahydroisoquinoline and indoline).

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02517J?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

Xihong Liu,^a Dongxu Yang,^a Kezhou Wang,^a Jinlong Zhang^a and Rui Wang*^a^b

*Corresponding authors

^aSchool of Life Sciences, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, P. R. China
E-mail: wangrui@lzu.edu.cn

^bState Key Laboratory of Chiroscience, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, P. R. China
E-mail: bcrwang@polyu.edu.hk

Green Chem., 2017,19, 82-87

DOI: 10.1039/C6GC02517J

Supplementary information
PDF (4392K)

ethyl 13b-nitro-8-tosyl-8,8a,13b,13c-tetrahydro-5H-indolo[2′,3′:3,4]pyrazolo[5,1- a]isoquinoline-9(6H)-carboxylate: White solid, m.p. 153 – 154 oC; 94% yield;

1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.30 – 7.13 (m, 5H), 7.1 (s, 1H), 7.05 – 6.94 (m, 1H), 6.94 – 6.87 (m, 1H), 6.59 (t, J = 7.6 Hz, 3H), 6.28 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.80 – 2.58 (m, 2H), 2.33 (s, 3H), 2.31 – 2.11 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (75 MHz, CDCl3) δ 152.1, 144.6, 142.6, 134.0, 132.1, 129.3, 129.0, 128.7, 128.3, 127.5, 127.3, 126.2, 122.8, 121.1, 115.5, 104.5, 84.9, 70.7, 62.8, 48.5, 29.1, 21. 6, 14.3 ppm;

HRMS (ESI): C27H26N4NaO6S [M + Na]+ calcd: 557.1465, found: 557.1476.

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

/////////// catalyst-free, 1,3-dipolar cycloaddition, C,N-cyclic azomethine imines, 3-nitroindoles, five-ring-fused tetrahydroisoquinolines

Towards automation of chemical process route selection based on data mining

PROCESS Comments Off

Jan 062017

Graphical abstract: Towards automation of chemical process route selection based on data mining

A methodology for chemical routes development and evaluation on the basis of data-mining is presented. A section of the Reaxys database was converted into a network, which was used to plan hypothetical synthesis routes to convert a bio-waste feedstock, limonene, to a bulk intermediate, benzoic acid. The route evaluation considered process conditions and used multiple indicators, including exergy, E-factor, solvent score, reaction reliability and route redox efficiency, in a multi-criteria environmental sustainability evaluation. The proposed methodology is the first route evaluation based on data mining, explicitly using reaction conditions, and is amenable to full automation.

In the field of process and synthetic chemistry ‘clean synthesis’ has become one of the standard criteria for good, commercially viable synthesis routes. As a result synthetic and process chemists must be equipped with adequate methodologies for quantification of ‘cleanness’ or ‘greenness’ of alternative routes at the early phases of the development cycle. These new criteria, and the traditional criteria of cost, security of supply, health and safety (H&S), and risk, provide a balanced picture of sustainability of a future technology. Thus, there are two separate aspects to process chemistry: developing the chemistry and the process, and evaluating the overall process, which must occur in parallel. Evaluation of the proposed routes requires data. As data science rapidly evolves, chemistry will inevitably use more of the new tools of data mining and data analysis to automate the routine tasks, such as evaluation of process metrics. In this paper we show some initial results in automation of process evaluation based on deep data mining of process chemistry and multi-criteria decision making.

The evaluation of greenness is a mature field, with a large number of published and standardised approaches, of which many are adopted by industry. 1 However, all published methods are highly case-specific and rather labour-intensive. In the field of synthetic routes development one of the most exciting new areas is the potential for automation of synthesis planning using data mining.² What has never been attempted before is to automate route generation and evaluation in a coherent methodology, which would aid process development at the early, data-lean, stages. For this we show how to automatically generate process options using a network representation of a section of Reaxys database,³ followed by their screening using multi-criteria decision making, see Fig. 1. As the methods mature and become commercially available, such integration and automation will produce significant savings of time, and would deliver a far more detailed view of the competing synthesis route options than is generally possible at the early stages of design.

To date, obtaining the data, assembling the network and finding potential synthesis routes can already be carried out in a fully automated fashion. Due to issues around data availability the connection to the analysis of the routes still has to be initiated manually, involving a data curation step. The subsequent analysis and multi-criteria decision making have been largely automated in this study. To our knowledge this is the first example of the analysis of synthesis routes generated from the network representation of Reaxys obtained through datamining, using reaction conditions and process data.

image file: c6gc02482c-f2.tif

Fig. 2 A section of a network of organic chemistry. Dots are species and arrows represent reactions.

D. J. C. Constable, C. Jimenez-Gonzalez and A. Lapkin, in Green Chemistry Metrics, John Wiley & Sons, Ltd, Chichester, UK, 2009, pp. 228–247
S. Szymkuć, E. P. Gajewska, T. Klucznik, K. Molga, P. Dittwald, M. Startek, M. Bajczyk and B. A. Grzybowski, Angew. Chem., Int. Ed., 2016, 55, 5904–5937
Reed Elsevier Properties SA, Login – Reaxys Login Page [Internet], 2014 [accessed 2014 Jun 8]. Available from: https://www.reaxys.com/. Reaxys is a trademark, copyright owned by Relex Intellectual properties SA and used under licence.

Towards automation of chemical process route selection based on data mining

P.-M. Jacob,^a P. Yamin,^a C. Perez-Storey,^a M. Hopgood^a and A. A. Lapkin*^a

*Corresponding authors

^aDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK
E-mail: aal35@cam.ac.uk

Green Chem., 2017,19, 140-152

DOI: 10.1039/C6GC02482C, http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02482C?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Professor Alexei Lapkin, FRSC

Professor Alexei Lapkin FRSC

Professor of Sustainable Reaction Engineering

Fellow of Wolfson College

Catalytic Reaction Engineering

Sustainable Chemical Technologies

Office Phone: 330141

Image result for Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK

Biography:

MChem in Biochemistry, Novosibirsk State University, 1994

PhD in Chemical Engineering, University of Bath, 2000

Boreskov Institute of Catalysis, Novosibirsk, Russia (1994-1997)

University of Bath, Department of Chemical Engineering, Research Officer (1997-2000)

University of Bath, Department of Chemical Engineering, Lecturer-SL-Reader (2000-2009)

University of Warwick, School of Engineering, Professor of Engineering (2009-2013)

Research Interests

Reaction Engineering group

Our group is developing cleaner manufacturing processes within chemical and chemistry using industries. We are mainly focusing on liquid- and multi-phase catalytic and biochemical processes. Within the group we have pursued projects on developing functional materials for catalysts, adsorbents and reactors, design of multi-functional intensive reactors, modelling of reaction kinetics and integrated processes, linking reaction kinetics with computational fluid dynamics (CFD) and linking process modelling with life cycle assessment (LCA), integration of reactions and separation.

Public funding:

The group is currently involved in an EU project ‘RECOBA’ (http://www.spire2030.eu/recoba/), in which our group collaborates with Materials and Electronic Engineering at Cambridge to work on innovative measurement techniques for monitoring processes under reaction conditions.

We are involved in the EPSRC project on developing novel routes to platform and functional molecules from waste terpenes, led by University of Bath.

We are involved in “Dial a Molecule 2” network funded by EPSRC.

Keywords

Reaction Engineering
flow
sustainability
heterogeneous catalysis
catalysis

Key Publications

J. Zakrzhewski, A.P. Smalley, M. Kabeshov, A. Lapkin, M. Gaunt, Continuous flow synthesis and derivatization of aziridines via palladium-catalyzed C(sp3)-H activation, Angew. Chem. Int. Ed., 55 (2016) 8878-8883.

P. Yaseneva, P. Hodgson, J. Zakrzewski, S. Falss, R.E. Meadows, A.A. Lapkin, Continuous flow Buchwald-Hartwig amination of a pharmaceutical intermediate, React. Chem. Eng., 1 (2016) 229-238.

P. Yaseneva, D. Plaza, X. Fan, K. Loponov, A. Lapkin, Synthesis of the antimalarial API artemether in a flow reactor, Catal. Today, 239 (2015) 90-96.

N. Peremezhney, E. Hines, A. Lapkin, C. Connaughton, Combining Gaussian processes, mutual information and a generic algorithm for multi-targeted optimisation of expensive-to-evaluate functions, Engineering Optimisation, 46 (2014) 1593-1607.

P. Yaseneva, C.F. Marti, E. Palomares, X. Fan, T. Morgan,P.S. Perez, M. Ronning, F. Huang,T. Yuranova, L. Kiwi-Minsker, S. Derrouiche, A.A. Lapkin, Efficient reduction of bromates using carbon nanofibre supported catalysts: experimental and a comparative life cycle assessment study, Chem. Eng. J., 248 (2014) 230-241

K.N. Loponov, J. Lopes, M. Barlog, E.V. Astrova, A.V. Malkov, A.A. Lapkin, Optimization of a Scalable Photochemical Reactor for Reactions with Singlet Oxygen, Org.Process Res.Dev., 18 (2014) 1443-1454.

X. Fan, V. Sans, P. Yaseneva, D. Plaza, J.M.J. Williams, A.A. Lapkin, Facile Stoichiometric Reductions in Flow: an Example of Artemisinin, Org.Process Res.Dev., 16 (2012) 1039-1042.

M.V. Sotenko, M. Rebros, V.S. Sans, K.N. Loponov, M.G. Davidson, G. Stephens, A.A. Lapkin, Tandem transformation of glycerol to esters, J. Biotechnol., 162 (2012) 390-397.

A.A. Lapkin, A. Voutchkova, P. Anastas, A conceptual framework for description of complexity in intensive chemical processes, Chem. Eng. Processing. Process intensification, 50 (2011) 1027-1034.

Lapkin, A., Peters, M., Greiner, L., Chemat, S., Leonhard, K., Liauw, M. A. and Leitner, W., Screening of new solvents for artemisinin extraction process using ab-initio methodology, Green Chem., 12 (2010) 241-251.

Lapkin, A. A. and Plucinski, P. K., Engineering factors for efficient flow processes in chemical industries, in Chemical reactions and processes under flow conditions, pp. 1- 43, Eds: Luis, S. V. and Garcia-Verdugo, E., Royal Society of Chemistry, Cambridge, 2010.

Iwan, A., Stephenson, H., Ketchie, W. C. and Lapkin, A. A., High temperature sequestration of CO2 using lithium zirconates, Chem. Eng. J., 146 (2009) 249-258.

Constable, D. J. C., Jimenez-Gonzalez, C. and Lapkin A., ‘Process metrics’, in Green chemistry metrics: measuring and monitoring sustainable processes, pp. 228- 247, Eds.: Lapkin, A. and Constable, D. J. C., Wiley-Blackwell, Chichester, 2008.

L.Torrente-Murciano, A.Lapkin, D.V. Bavykin, F.C. Walsh, K. Wilson, Highly selective Pd/titanate nanotubes catalysts for the double bond migration reaction, J. Catal., 245 (2007) 270-276.

A. Lapkin, P. Plucinski, Comparative assessment of technologies for extraction of artemisinin, J. Natural Prod., 69 (2006) 1653-1664.

D.V. Bavykin, A.A. Lapkin, S.T. Kolaczkowski, P.K. Plucinski, Selective oxidation of alcohols in a continuous multifunctional reactor: ruthenium oxide catalysed oxidation of benzyl alcohol, Applied Catal. A: General, 288 (2005) 165-174.

////////automation, chemical process, route selection, data mining

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

SYNTHESIS, Uncategorized Comments Off

Jan 062017

Image result for Frank Roschangar

Scheme 1. Pfizer’s Commercial Synthesis of sildenafil citrate (Viagra™)

Image result for Overcoming Barriers to Green Chemistry in the Pharmaceutical Industry - The Green Aspiration Level™ Concept

Image result for Frank Roschangar

“Green chemistry” refers to the promotion of safe, sustainable, and waste-minimizing chemical processes. The proliferation of green chemistry metrics without any clear consensus on industry standards is a significant barrier to the adoption of green chemistry within the pharmaceutical industry. We propose the Green Aspiration Level™ (GAL) concept as a novel process performance metric that quantifies the environmental impact of producing a specific pharmaceutical agent while taking into account the complexity of the ideal synthetic process for producing the target molecule. Application of the GAL metric will make possible for the first time an assessment of relative greenness of a process, in terms of waste, versus industry standards for the production process of any pharmaceutical. Our recommendations also include a simple methodology for defining process starting points, which is an important aspect of standardizing measurement to ensure that Relative Process Greenness (RPG) comparisons are meaningful. We demonstrate our methodology using Pfizer’s Viagra™ process as an example, and outline aspiration level opportunities for industry and government to dismantle green chemistry barriers.

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

F. Roschangar,*^a R. A. Sheldon^b and C. H. Senanayake^a

*Corresponding authors

^aChemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com

^bDelft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands

Green Chem., 2015,17, 752-768

DOI: 10.1039/C4GC01563K, http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01563k#!divAbstract

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

///////////green chemistry, pharmaceutical industry

A deeper shade of green: inspiring sustainable drug manufacturing

drugs Comments Off

Jan 062017

Graphical abstract: A deeper shade of green: inspiring sustainable drug manufacturing

Green and sustainable drug manufacturing go hand in hand with forward-looking visions seeking to balance the long-term sustainability of business, society, and the environment. However, a lack of harmonization among available metrics has inhibited opportunities for green chemistry in industry. Moreover, inconsistent starting points for analysis and neglected complexities for diverse manufacturing processes have made developing objective goals a challenge. Herein we put forward a practical strategy to overcome these barriers using data from in-depth analysis of 46 drug manufacturing processes from nine large pharmaceutical firms, and propose the Green Aspiration Level as metric of choice to enable the critically needed consistency in smart green manufacturing goals. In addition, we quantify the importance of green chemistry in the often overlooked, yet enormously impactful, outsourced portion of the supply chain, and introduce the Green Scorecard as a value added sustainability communication tool.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02901A?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

The Green Aspiration Level (GAL) has been constructed on four pillars to ensure consistent application, namely (1) clearly defined synthesis starting points,1 (2) unambiguous complete E factor (cEF)2,3 or Process Mass Intensity (PMI) waste metrics, (3) historical averages of industrial drug manufacturing waste, and (4) complexity of the drug’s ideal manufacturing process (Supplementary Figure 6). cEF or PMI can be used interchangeably in GAL-based analysis enabling organizations using either to calculate their green performance scores. cEF and PMI differ by just one unit (Supplementary Equation 6) and share the same commercial waste goal for an average manufacturing step4 – the transformation-GAL or tGAL – that results in negligible numerical differences from the inclusion of one or the other. The pharmaceutical industry has generally adopted PMI. However, our publication utilizes cEF values due to literature prevalence and potentially broader appeal of E factors.5 It is important to note that all reaction and workup materials are included in the analysis, but excluded are reactor cleaning6 and solvent recycling.7 Standardized process starting points are a critical component of the GAL methodology. A starting material for some may be an intermediate for others. Until recently, the scientific community lacked an unambiguous definition of process starting points in the assessment of process greenness. This has been a bothersome source of inconsistency. Failure to define an appropriate starting material can lead to exclusion of significant amounts of intrinsic raw material waste created during earlier stages of manufacture. We therefore utilize these updated definitions of process analysis starting points to ensuring higher quality of data:8

1) The material is commercially available from a major reputable chemical laboratory catalog company, and its price is listed in the (online) catalog. Materials requiring bulk or custom quotes do not qualify as process starting material. AND 2) The laboratory catalog cost of the material at its largest offered quantity does not exceed US $100/mol. Therefore, published literature must be researched if the material does not qualify as process starting material in order to determine its correct intrinsic cEF. However, we realized that determination of literature cEF values is tedious and involves making assumptions since literature procedures are often incomplete compared to internal or external manufacturing batch records. Thus, standardizing Literature cEF quickly became a desirable goal. In order to facilitate literature analysis we introduced Supplementary Equation 7 that just requires determination of literature step count from ≤$100/mol starting materials without having to retrieve literature waste information.9 The literature step multiplier of 37 kg/kg represents the average literature step cEF across the analyzed projects (Supplementary Table 1), so it equals their average literature cEF (76 kg/kg) divided by average literature step count (2.1). The process cEF and Relative Process Greenness (RPG) derived from the simplified calculated cEF literature values are shown next to their progenitors in Supplementary Table 3. We observe that average calculated and manually determined cEF and RPG values are comparable and within 10% of their means across the three development phases. Thus, we consider the simplified method sound and an importtant element to achieving consistency in green process analysis.

A deeper shade of green: inspiring sustainable drug manufacturing

Frank Roschangar,*^a Juan Colberg,^b Peter J. Dunn,^c Fabrice Gallou,^d John D. Hayler,^e Stefan G. Koenig,^f Michael E. Kopach,^g David K. Leahy,^h Ingrid Mergelsberg,ⁱ John L. Tucker,^j Roger A. Sheldon^k^l and Chris H. Senanayake^a

*Corresponding authors

^aChemical Development, Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com

^bPharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA

^cPfizer, Sandwich, UK

^dChemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland

^eAPI Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK

^fSmall Molecule Process Chemistry, Genentech, a Member of the Roche Group, South San Francisco, USA

^gSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA

^hChemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA

ⁱProcess Chemistry, Merck, Rahway, New Jersey 07065, USA

^jProcess Development, Amgen, Thousand Oaks, USA

^kMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa

^lDelft University of Technology, 2628 BL Delft, Netherlands

Green Chem., 2017,19, 281-285

DOI: 10.1039/C6GC02901A

Frank Roschangar, PhD MBA

Pharmaceutical process research director, passionate about accelerating drug development and driving green chemistry.

Boehringer Ingelheim

Research and Development Sites

Ingelheim am Rhein, Germany

Research experience

Feb 2002–Sep 2015

Director

Boehringer Ingelheim

Germany · Nieder-Ingelheim
Aug 1996–Feb 1998

Postdoc

The Scripps Research Institute · Skaggs Institute for Chemical Biology · Prof. K.C. Nicolaou

United States · La Jolla
Aug 1992–Aug 1996

PhD Candidate

Rice University · Department of Chemistry

United States · Houston

Supplementary References

1. The $100 per mol laboratory catalog pricing requirement described in Supplementary Discussion 1 does not apply to reagents, catalysts, ligands, and solvents, since they are produced for widespread application and are not specific to the process being evaluated.

2. Since the original E factor has been applied inconsistently, the cEF metric was introduced for the purpose of GAL analysis. cEF accounts for all process reaction and process workup materials, including raw materials, intermediates, reagents, process aids, solvents, and water.

3. All E factors reported herein represent the cEF or sEF contributions of the overall manufacturing process or the sub-process (e.g. external cEF, literature cEF) to produce 1 kg of drug substance.

4. We define a step as a chemical operation involving one or more chemical transformations that form and/or break covalent or ionic bonds and lead to a stable and isolable intermediate, but not necessarily include its isolation. Examples: • Simultaneous removal of two or more protection groups involves multiple transformations, yet it is carried out in one chemical operation  counted as one step • Sequential transformations via a stable and isolable intermediate that are carried out in two operations but without intermediate workup  counted as two steps • Formation of covalent bonds or salts that occur during workup  not counted as an extra step • Separate operation of salt formation from an isolated intermediate  counted as one step • Isolation of a product, following work-up, as a solution that can be stored  counted as one step.

5. A SciFinder search for the terms ‘Process Mass Intensity’, and ‘E factor’ and ‘Environmental impact factor’ on Nov. 14, 2016 revealed that the PMI concept was present in 12, 8, 9, and 12 publications for the years 2013-2016, respectively, while the E factor concept was mentioned 39, 45, 57, and 46 times (76-86%), respectively.

6. The GAL considers only direct process materials, i.e. materials used in the chemical steps and their workups. It does not include solvents and aqueous detergents required for reactor and equipment cleaning between batches or steps, nor the frequency and duration of the equipment and facility specific cleaning operations. These parameters are considered for comprehensive environmental impact in Life Cycle Assessment (LCA) analysis.

7. In US pharmaceutical manufacturing, recycling accounts for 25% of waste handling, while energy recovery burning and treatment constitute 38% and 35%, based on 2012 data from ‘The Right-To-Know Network’ (RTKNET.ORG), Toxic Releases (TRI) Database: http://rtknet.org/db/tri.

8. The $100 per mol commodity pricing criterion was established in ref. 15 of the main article based on the author’s professional experience. The authors of this manuscript consider this figure appropriate and helpful for providing a consistent analysis.

9. If a detailed procedure is available for a particular literature step, its calculated waste can be used in place of the 37 kg/kg default value.

10. J. Li and M. D. Eastgate, Current Complexity: a Tool for Assessing the Complexity of Organic Molecules. Org. Biomol. Chem. 2015,13, 7164–7176.

11. D. P. Kjell, I. A. Watson, C. N. Wolfe and J. T. Spitler, Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 169– 174.

12. R. P. Sheridan, et al., Modeling a Crowdsourcing Definition of Molecular Complexity. J. Chem. Inf. Model. 2014, 54, 1604–1616.

13. M. F. Faul, et al., Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium. Org. Process Res. Dev. 2014, 18, 594–600.

14. Besides offering simplicity, the GAL’s process complexity model was selected vs. the alternative structural complexity measures due to its inherent ideality-derived consideration for available synthetic methodology.

15. See main article ref. 16: it defines Construction Reactions (CR) as chemical transformations that form skeletal C-C or C-heteroatom bonds. Strategic Redox Reactions (SRR) are construction reactions that directly establish the correct functionality found in the final product, and include asymmetric reductions or oxidations. All other types of non-strategic reactions are considered as Concession Steps (CS), and include functional group interconversions, non-strategic redox reactions, and protecting group manipulations.

16. M. E. Kopach, et al., Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3- yl]methanone. Org. Process Res. Dev. 2010, 14, 1229–1238.

17. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Improved Synthesis of 1-(Azidomethyl)-3,5-bis- (trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev. 2009, 13, 152–160. 18. RCI (Process B) = 1 − ( ) = 0.25. RCI (Process C) = 1 − ( ) = 0.38

//////////green chemistry, drugs

4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one

Uncategorized Comments Off

Jan 022017

¹³C NMR (DMSO-d₆, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9;

1H NMR

¹H NMR (DMSO-d₆, 400 MHz): δ = 2.64 (t, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.59 (q, J = 6.8 Hz, 2H), 4.62 (t, J = 5.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 10.30 (s, 1H);

4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one (13)

…………..as a white solid with 99% purity by HPLC (retention time: 19.0 min).

Mp: 145–147 °C (lit. mp 147–149).(Dagger, R. E.; Fortunak, J. M.; Mastrocola, A. J. Heterocycl. Chem. 1995, 32, 875)

¹³C NMR (DMSO-d₆, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9;

ESI-MS (m/z) 178 [M + H]⁺. Anal. Calcd for C₁₀H₁₁NO₂: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.73; H, 6.20; N, 7.82.

Abstract Image

A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nitro reduction/ring-closing/debenzylation takes place in one pot. All the intermediates can be used directly for the next step without purification in this process.

Org. Process Res. Dev., 2013, 17 (4), pp 714–717

1H NMR PREDICT

DOI: 10.1021/op400024a

13C NMR PREDICT

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

///////////

Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

FLOW CHEMISTRY, flow synthesis Comments Off

Jan 022017

Abstract Image

Over the last 20 years organic carbamates have found numerous applications in pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, and as protecting groups and intermediates for polyurethane synthesis. Recently, in order to avoid phosgene-based synthesis of carbamates, many environmentally benign and alternative pathways have been investigated. However, few examples of carbamoylation of aniline in continuous-flow apparatus have been reported. In this work, we report a high-yielding, dimethyl carbonate (DMC)-mediated carbamoylation of aniline in a fixed-bed continuously fed reactor employing basic zinc carbonate as catalyst. Several variables of the system have been investigated (i.e. molar ratio of reagents , flow rate, and reaction temperature) to optimize the operating conditions of the system.

Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

Sandra Grego, Fabio Aricò, and Pietro Tundo*

Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University of Venice, Dorsoduro 2137, 30123 Venezia, Italia

Org. Process Res. Dev., 2013, 17 (4), pp 679–683

DOI: 10.1021/op4000048, http://pubs.acs.org/doi/abs/10.1021/op4000048

*Tel.: (+39) 041 234 8642. Fax: (+39) 041 234 8620. E-mail: tundop@unive.it.

PIETRO TUNDO

Profile:

PIETRO R. TUNDO is Professor of Organic Chemistry at Ca’ Foscari University of Venice (Italy).
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).
He is Member of the Bureau of IUPAC.

P: Tundo is author of about 300 scientific publications, 40 patents and many books.
His scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry, heteropolyacids, and finally safe alternatives to harmful chemicals.
He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731). He founded and was Chairman (2004-2016) of the Working Party on “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo coordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia, Italy) sponsored by the EU, UNESCO and NATO.
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).

He is holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731) and author of about 260 scientific publications and 30 patents.

Scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry and finally, heteropolyacids.

He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and presently is Chairman of Working Party of “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

P. Tundo co-ordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia), the latter sponsored by the EU, UNESCO and NATO.

Contact:

Professor of Organic Chemistry
Ca’ Foscari University of Venice
IUPAC Bureau Member
Tel. +39 041 2348642
Mob. +39 349 3486191
E-mail: tundop@unive.it

Phone	041 234 8642 / Lab .: 041 234 8669
E-mail	tundop@unive.it green.chemistry@unive.it – 6th IUPAC Conference on Green Chemistry unescochair@unive.it – TUNDO Pietro
Fax	041 234 8620
Web	www.unive.it/persone/tundop

Pietro Tundo

////////Carbamoylation of Aniline, Dimethyl Carbonate, Continuous-Flow Conditions, flow synthesis

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

GMP’s for Early Stage Development of new Drug substances and products

Uncategorized Comments Off

Jan 022017

GMP’s for Early Stage Development of New Drug substances and products

The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 54–58.

Image result for International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)

From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing change into synthetic processes, dosage forms, analytical methods, and specifications. The quality system implemented during this early phase should take into account that these changes and adjustments are intrinsic to the work being performed prior to the determination of the final process and validation of the analytical methods during later stages of development.

FDA guidance is already available on GMP requirements for phase 1 materials. (See Org. Process. Res. Dev. 2008, 12, 817.) Because many aspects of phase 2a clinical studies are similar in their scope and expectations, the working group feels there is an opportunity to extend this guidance across all early phase studies. Because products and processes are less well understood in the early phases of development, activities should focus on accumulating the appropriate knowledge to adequately ensure patient safety. Focusing on this area should ensure that beneficial therapies reach the clinic in an optimum time scale with minimal safety concerns.

A follow-up article ( Pharm. Technol. 2012, 36 (7), 76−84) describes the working group’s approach to the subject of Analytical Method Validation. Their assessment has uncovered the need to differentiate the terms “validation” and “qualification”. Method qualification is based on the type, intended purpose, and scientific understanding of the type of method in use. Although not used for GMP release of clinical materials, qualified methods are reliable experimental methods that may be used for characterization work such as reference standards and the scientific prediction of shelf life. For example, in early development it would be sufficient for methods used for in-process testing to be qualified, whereas those methods used for release testing and for stability determination would be more fully validated.

In early development, a major purpose of analytical methods is to determine the potency of APIs and drug products to ensure that the correct dose is delivered in the clinic. Methods should also indicate stability, identify impurities and degradants, and allow characterization of key attributes. In the later stages, when processes are locked and need to be transferred to worldwide manufacturing facilities, methods need to be cost-effective, operationally viable, and suitably robust such that the methods will perform consistently. irrespective of where they are executed.

The authors advocate that the same amount of rigorous and extensive method-validation experiments, as described in ICH Q2, “Analytical Validation”, is not needed for methods used to support early stage drug development. For example, parameters involving interlaboratory studies (i.e., intermediate precision, reproducibility, and robustness) are not typically performed during early phase development, being replaced by appropriate method-transfer assessments and verified by system suitability requirements. Because of changes in synthetic routes and formulations, the impurities and degradation products formed may change during development.

Accordingly, related substances are often determined using area percentage by assuming that the relative response factors are similar to that of the API. As a result, extensive studies to demonstrate mass balance are typically not conducted during early development.

Detailed recommendations are provided for each aspect of method validation (specificity, accuracy, precision, limit of detection, limit of quantitation, linearity, range, robustness) according to the nature of the test (identification, assay, impurity, physical tests) for both early- and late phase development. These recommendations are also neatly summarized in a matrix form.

Above text drew attention to a series of articles from the IQ Consortium (International Consortium on Innovation and Quality in Pharmaceutical Development) on appropriate good manufacturing practices (GMP) for the early development phases of new drug substances and products. The fifth article in this series(Coutant, M.; Ge, Z.; McElvain, J. S.; Miller, S. A.; O’Connor, D.; Swanek, F.; Szulc, M.; Trone, M. D.; Wong-Moon, K.; Yazdanian, M.; Yehl, P.; Zhang, S.Early Development GMPs for Small-Molecule Specifications: An Industry Perspective (Part V) Pharm. Technol. 2012, 36 ( 10) 86– 94) focuses on the setting of specifications during these early phases (I and IIa).

Due to the high attrition rate in early development, the focus should be on consistent specifications that ensure patient safety, supported by preclinical and early clinical safety studies. On the basis of the cumulative industry experience of the IQ working group members, the authors of this paper propose standardized early phase specification tests and acceptance criteria for both drug substance and drug product. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications, but which may be performed to collect information for product and process understanding or to provide greater control.

Image result for preclinical animal studies

The drug substance used in preclinical animal studies (tox batch) is fundamental in defining the specifications for an early phase clinical drug substance (DS). Here, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities and processing capabilities. At this stage the emphasis should be on ensuring the correct DS is administered, determining the correct potency value, and quantitating impurities for toxicology purposes. For DS intended for clinical studies, additional testing and controls may be required; the testing may be similar to that for the tox batch, but now with established acceptance criteria. For these stages the authors propose a standardized set of DS specifications, as follows.

Description	range of colour
identification	conforms to a reference spectrum
counterion	report results
assay	97–103% on a dry basis
impurities	NMT 3.0% total, NMT 1.0% each
unidentified	NMT 0.3%
unqualified	NMT 0.15%
mutagenic	follow EMA guidelines (pending ICH M7 guidance)
inorganic	follow EMA guidelines (pending ICH Q3D guidance)
residual solvents	use ICH Q3C limits or other justified limits for solvents used in final synthetic step
water content	report results
solid form	report results
particle size	report results
residue on ignition	NMT 1.0%

These may be altered in line with any specific knowledge of the compound in question. For example, if the DS is a hydrate or is known to be hygroscopic or sensitive to water, a specified water content may be appropriate. Of particular note is the use of impurity thresholds which are 3 times higher than those defined in ICH Q3 guidelines. Q3 was never intended to apply to clinical drugs, and higher thresholds can be justified by the limited exposure that patients experience during these early stages. Mutagenic impurities are the exception here, since in this area the existing official guidance does cover clinical drugs.

The fourth article in the series(Acken, B.; Alasandro, M.; Colgan, S.; Curry, P.; Diana, F.; Li, Q. C.; Li, Z. J.; Mazzeo, T.; Rignall, A.; Tan, Z. J.; Timpano, R.Early Development GMPs for Stability (Part IV) Pharm. Technol. 2012, 36 ( 9) 64– 70) considers appropriate approaches to stability testing during early clinical phases. Appropriate stability data at suitable storage conditions are required to support filing the clinical trial application (CTA/IND/IMPD) and use of the clinical material through the end of the clinical study. Several factors from business, regulatory, and scientific perspectives need to be taken into account when designing early stability studies, such as the risk tolerance of the sponsoring organization, the inherent stability of the drug substance and prior product, process and stability knowledge, the regulatory environment in the countries where the clinical trial will be conducted, and the projected future use of the product.

Often non-GMP DS batches are manufactured first and placed on stability to support a variety of product development activities.In many cases these batches will be representative of subsequent GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. In early development, it is common for the manufacturing process to be improved; therefore, as the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted.

The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability—otherwise not. Typical changes encountered at this stage include changes in synthetic pathway, batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps.

In most cases, these changes will not result in changes in DS stability. Changes to the impurity profile are unlikely to affect stability, since most organically related impurities will be inert. On the other hand, catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents may affect stability; thus, changes to these attributes would typically require the new batch to be placed in the stability program. Similarly, any changes to polymorphic form, particle size, or counterion would warrant extra testing. Packaging changes of the bulk material to a less protective package may require stability data to support the change.

Three approaches to stability data collection are commonly used. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH), and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). A second approach is to use high stress conditions such as a high temperature and high humidity with a short time. A third approach is the use of stress studies at several conditions coupled with modelling. The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

Ref

http://www.rcainc.com/wp-content/uploads/2014/06/RCA-GMPs-for-Early-Stage-Development-Projects.pdf

http://www.pharmtech.com/gmps-method-validation-early-development-industry-perspective-part-ii

http://www.pharmtech.com/gmps-small-molecule-drugs-early-development-part-i

https://iqconsortium.org/images/Publications/Presentations/GMPs_Workshop_-_Early_Development_Stability_(Industry_Perspective_-_Tony_Mazzeo,_BMS).pdf

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

////////

Reflections on Chirality in the Pharmaceutical Industry: Past, Present and Future Dr. Christopher J. Welch, Distinguished Scientist Process Research & Development Merck Research Laboratories, USA

Presentations Comments Off

Dec 262016

Image result for Christopher J. Welch

Christopher Welch

New Technologies, Postdoc Program, Science Lead, Analytical Chemistry at Merck

christopher_welch@merck.com

Reflections on Chirality in the Pharmaceutical Industry: Past, Present and Future
Dr. Christopher J. Welch, Distinguished Scientist
Process Research & Development Merck Research Laboratories, USA

A PRESENTATION
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At Chiral India 2016, New horizons in Drug development, Harnessing the power of Chirality .Organised by chemical weekly at Holiday inn international, Mumbai, India, Nov 8 2016

Christopher J. Welch

Science Lead for Analytical Chemistry
Merck Research Laboratories

Christopher J. Welch is Science Lead for Analytical Chemistry within the Process and Analytical Chemistry area at Merck Research Laboratories in Rahway, NJ. Chris leads the New Technologies Review and Licensing Committee (NT-RLC), the organization that oversees identification, acquisition and evaluation of new technologies of potential value to Merck Research Laboratories. Chris also leads the MRL Postdoctoral Research Fellows Program. He received his BS degrees in Chemistry and Biochemistry from the University of Illinois at Urbana-Champaign in 1982 and a Ph.D. degree in Organic Chemistry (also U of I) in 1992. Dr. Welch has worked in a variety of fields within the chemical industry, including discovery synthesis of agrochemicals (Velsicol-Sandoz), development of reagents for improved immunodiagnostic assays (Abbott Laboratories), and development and commercialization of chromatographic stationary phases, reagents and enantioselective catalysts within a small chemical business environment (Regis Technologies). Since joining Merck in 1999, he has focused on developing and applying improved methods and equipment for purification, synthesis and analysis of pharmaceuticals and intermediates. Dr. Welch has authored more than 230 scientific publications and patents. He is co-founder of the journal, Enantiomer, a current or past member of the editorial advisory boards for the journals, Chirality, Organic & Biomolecular Chemistry, Journal of the Korean Chemical Society, Chemistry World, Chemical & Engineering News and ACS Central Science. Chris is past chair of the ACS Division of Organic Chemistry (ORGN), a member of the Executive Committee for the International Symposia on Chirality, a member of the ACS steering committee for Pacifichem and a member of the PittCon Program Resource Team. Honors and awards include the NJCG Award for Excellence in Chromatography (2004), the PACS Activated Carbon Hall of Fame award (2007), MRL Presidents Award for Environmental Achievement (2009), Microsoft Life Science Innovation Award (2010), Fellow of the American Chemical Society (2010), Fellow of the American Association for the Advancement of Science, AAAS (2013), the Chirality Medal (2015) and the University of Nebraska Industrial Advisory Board Award (2016).

Experience

Distinguished Scientist, Process & Analytical Chemistry

Merck & Co., Inc.

May 1999 – Present (17 years 8 months)Rahway, NJ

Current responsibilities:
Scientific Lead, Analytical Chemistry
co-chair, New Technologies Review & Licensing Committee (NT-RLC)
co-chair, Merck Research Laboratories Postdoctoral Research Fellows Committee

Previous Positions at Merck:
Science Lead, Global Analytical Chemistry 8/10 – 8/12
Distinguished Senior Investigator, Process Research 7/07 – 8/10
Associate Director. Process Research 1/06 – 6/07
Senior Research Fellow, Process Research 6/03 – 12/05
Research Fellow, Process Research 5/99 – 6/03

Director of Research

Regis Technologies

May 1992 – March 1999 (6 years 11 months)Morton Grove, IL (Chicago area)

– New product development and commercialization (chromatography columns, reagents, enantioselective catalysts)
– Scientific evaluation of custom organic synthesis business
– Set up contract synthesis/preparative chromatographic separation business – first of kind

Honors & Awards

Fellow

American Association for the Advancement of Science (AAAS)

October 2012

Fellow

American Chemical Society (ACS)

August 2010

Chirality Medal 2015

January 2015

Presidential Green Chemistry Award

US Environmental Protection Agency

June 2014

– for precompetitive collaboration between Merck, Pfizer, Eli Lilly and University of Wisconsin on Aerobic Oxidation Methods for Pharmaceutical Synthesis – co-awardees: Shannon Stahl and Thatcher Root (U. Wisconsin), Joel Hawkins (Pfizer) and Joe Martinelli (Lilly)

Industrial Advisory Board (IAB) Award

University of Nebraska Department of Chemistry

March 2016

Inaugural IAB award from U. Nebraska recognizing excellence in scientific research in an industry setting

Organizations

American Chemical Society, Division of Organic Chemistry (ORGN)

Councilor and Chair

January 2006 – December 2015

Pacifichem

Member of Steering Committee for Pacifichem 2020

Starting August 2011

Chirality (Journal)

member, editorial board

Starting March 2002

Chemical & Engineering News

member, editorial advisory board

Starting February 2012

Chemistry Today (RSC)

member, editorial advisory board

Starting March 2011

Journal of the Korean Chemical Society

member, international advisory board

Starting February 2011

Pittcon

Member, Pittcon Program Committee Resource Team

Starting May 2012

ACS Central Science

Member of Editorial Advisory Board

Starting January 2015

American Chemical Society

Member, Committee on Science (ComSci

Starting January 2016

Publications

2014 publications, part 1

Use of a Miniature Mass Spectrometer to Support Pharmaceutical Process Research Investigations, Org. Proc. R&D 18, 103-108, 2014.

Chromatographic Separation and Assignment of Absolute Configuration of Hydroxywarfarin Isomers, Chirality 26, 95-101, 2014.

Chromatographic Resolution of Closely Related Species in Pharmaceutical Chemistry: Dehalogenation Impurities and Mixtures of Halogen…more

2014 publications – part 2

Precompetitive Collaboration on Enabling Technologies for the Pharmaceutical Industry, Org. Proc. R&D 18, 481–487, 2014.

Imine-based Chiroptical Sensing Approach for Analysis of Chiral Amines: From Method Design to Synthetic Application, Chem. Sci. 5, 2855-2861, 2014.

Advances in Achiral Stationary Phases for SFC, Amer. Pharm. Rev., April 2014, 36-41.

Liquid Chromatography Methods for…more

2013 Publications

Evaluation of core–shell particle columns for ion-pair reversed-phase liquid chromatography analysis of oligonucleotides, J. Pharm. Biomed. Anal. 72, 25–32, 2013.

Pharmaceutical Industry Practices on Genotoxic Impurities, in Pharmaceutical Industry Practices on Genotoxic Impurities, ed Heewoon Lee, Taylor & Francis, 2013.

Rapid Analysis of Residual Palladium in Pharmaceutical…more

2012 Publications
2012

A Simple Parallel Gas Chromatography Column Screening System, Wes Schafer, Simon E. Hamilton, Zainab Pirzada and Christopher J. Welch, Chirality, 24,1–4, 2012.

Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors, A. Bellomo, N. Celebi-Olcum, X. Bu, N. Rivera, R.T. Ruck, C.J. Welch, K.N. Houk, S.D. Dreher, Angew. Chem. Int. Ed., 51 (2012) 1-5
…more

2011 Publications

Application of Ion Mobility Spectrometry in Drug Substance Development, H. Gao, X. Jia, R. Xiang, X. Gong, C. Welch, Analytical Methods, 3, 1828-1837, 2011.

Analytical Method Volume Intensity Index:A Green Chemistry Metric for HPLC Methodology in the Pharmaceutical Industry, R. Hartman, R. Helmy, M. Al-Sayah, C. Welch, Green Chemistry 13, 934-939, 2011.

Does an Axial Propeller Shape on a…more

2010 Publications

High-throughput metal screening in pharmaceutical samples by ICP-MS with automated flow injection using a modified HPLC configuration, Tu, Wang, Welch, J. Pharm. Biomed. Anal., 51, 90-95, 2010.

Systematic Evaluation of New Chiral Stationary Phases for Supercritical Fluid Chromatography Using a Standard Racemate Library, Pirzada, Personick, Biba, Gong, Zhou, Schafer, Welch, J. Chromaogr.A,…more

Adsorbent Screening for Metal Impurity Removal in Pharmaceutical Process(Link)

Organic Process Research & Development

February 23, 2005

A microtube screening approach affords simple and convenient assessment of the selective adsorption of metal impurities by a variety of different process adsorbents. This approach is helpful in identifying rapid solutions to metal impurity problems in pharmaceutical process research. Several examples illustrating the utility of the approach are presented.

Online Analysis of Flowing Streams Using Microflow HPLC

Organic Process Research & Development

2009

Supercritical fluid chromatography for GMP analysis in support of pharmaceutical development and manufacturing activities(Link)

Journal of Pharmaceutical and Biomedical An

Response to Comment on “Cocktail Chromatography: Enabling the Migration of HPLC to Nonlaboratory Environments”(Link)

ACS Sustainable Chem. Eng. 2015, 3 (9), 1897.

Education

University of Illinois at Urbana-Champaign

Ph.D., Organic Chemistry

1996 – 1999

The University of Chicago

FUELING INNOVATION

Welch helped launch Merck’s new postdoctoral research fellowship program.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

/////////Reflections on Chirality in the Pharmaceutical Industry, Past, Present and Future
Dr. Christopher J. Welch, Distinguished Scientist, Process Research & Development, Merck Research Laboratories, USA, presentation