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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

 QbD, regulatory  Comments Off on Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents
Nov 032016
 

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The influence of four parameters (temperature, scavenging time, amount of scavenger, and concentration of palladium in the solution) on the efficiency of Pd removal from a cross-coupling reaction, using a commercially available Pd scavenger, SPM32, was studied. The DoE-based method employed yielded more information than is readily attainable from standard adsorption isotherms and kinetics experiments. The optimal regime of scavenging was identified; intuitive and nonintuitive effects of temperature, scavenging time, and scavenger amounts were highlighted; and a mathematical model quantifying predicted Pd removal from the synthetic intermediate was built.

link http://pubs.acs.org/doi/abs/10.1021/op5000336

Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

PhosphonicS Ltd., 44c Western Avenue, Milton Park, Abingdon, OX14 4RU, United Kingdom
Org. Process Res. Dev., 2014, 18 (5), pp 626–635
DOI: 10.1021/op5000336
Publication Date (Web): April 14, 2014
Copyright © 2014 American Chemical Society
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Preparation of tert-butyl 2-[(4-cyanophenyl)amino]propanoate (3).

4-Bromobenzonitrile (18.20 g, 100 mmol), L-alanine tert-butyl ester hydrochloride (21.73 g, 120 mmol), ±BINAP (1.25 g, 2 mmol) and cesium carbonate (48.87 g, 150 mmol) were added to a 3-neck round bottom flask containing a magnetic stirrer. Toluene (167 mL) was added and a reflux condenser, thermometer and a rubber septum were attached. Argon gas was bubbled through as the heterogeneous mixture was warmed to reflux temperature with slow agitation from the magnetic stirrer. Palladium acetate (0.45 g, 2 mmol) was added quickly through one of the side-arm joints and de-gassing was continued for 5 min. The reaction mixture was kept under argon at reflux and the disappearance of 4-bromobenzonitrile was monitored by GC-MS. After 16-24 h, the reaction mixture was filtered through a sinter funnel, washed with toluene and then filtered through a nylon membrane (Sigma Aldrich catalogue no. Z290793, 0.45 µm pore size) and washed with toluene. This crude reaction mixture was used in the DoE matrix without further purification.

Experimental results

NMR δC (62.9 MHz, CDCl3): 172.7, 150.0, 133.7, 120.4, 112.7, 99.3, 82.3, 51.7, 28.0, 18.5 ppm.

NMR δH (250 MHz, CDCl3): 7.39 (2H, d, J = 8.8 Hz, Ph), 6.52 (2H, d, J = 8.8 Hz, Ph), 4.85 (1H, d, J = 7.4 Hz, NH), 4.01 (1H, quintet, J = 7.4 Hz, CH(Me), 1.43 (9H, s, tBu), 1.42 (3H, d, J = 7.4 Hz, Me).

GC/MS: GC method used: hold at 50 °C for 4 min; increase temperature from 50 to 280 °C at 30 °C / min; hold at 280 °C for 5 min. Peaks were recorded and identified as follows: 4-Bromobenzonitrile: 10.05 min. Molecular peak observed at m/z = 181 for the 79Br isotope, m/z = 183 for the 81Br isotope L-alanine tert-butyl ester hydrochloride: not observed. Retention time less than 5 min, peak lost within the solvent front. Product: 13.64 min. Molecular peak observed at m/z = 246, main fragment at m/z = 146 (M – CO2 t Bu) Side product (not identified or quantified, minor peak): 14.56 min.

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Jan Recho

Jan Recho

Jan Recho

Systems developer at Clearsy

Corresponding Author *E-mail: jan.recho@phosphonics.com.

Experience

Systems Developer

Clearsy

– Present (1 year 6 months)

Scientist

PhosphonicS

(3 years 6 months)

• Design and synthesis of silica supported transition metals scavengers and catalysts (Pd, Rh, Ru) for the pharmaceutical industry.
• Management of fine chemistry customer projects
• Process optimisation (Quality by Design – QbD, Design of Experiments – DoE).
• Business development activities for the French market

Junior researcher

Institut des Matériaux de Nantes

(4 years 8 months)Nantes Area, France

Synthesis and characterisation of a cellulose derived, organosilane-based, bio-material for cartilage growth.
Work in imidazolium and pyridinium ionic liquids.

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QbD: Controlling CQA of an API

 QbD  Comments Off on QbD: Controlling CQA of an API
Sep 132016
 

The importance of Quality by Design (QbD) is being realized gradually, as it is gaining popularity among the generic companies. However, the major hurdle faced by these industries is the lack of common guidelines or format for performing a risk-based assessment of the manufacturing process. This article tries to highlight a possible sequential pathway for performing QbD with the help of a case study. The main focus of this article is on the usage of failure mode and effect analysis (FMEA) as a tool for risk assessment, which helps in the identification of critical process parameters (CPPs) and critical material attributes (CMAs) and later on becomes the unbiased input for the design of experiments (DoE). In this case study, the DoE was helpful in establishing a risk-based relationship between critical quality attributes (CQAs) and CMAs/CPPs. Finally, a control strategy was established for all of the CPPs and CMAs, which in turn gave rise to a robust process during commercialization. It is noteworthy that FMEA was used twice during theQbD: initially to identify the CPPs and CMAs and subsequently after DoE completion to ascertain whether the risk due to CPPs and CMAs had decreased.

 

 

 

Image result for Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

Image result for Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

CTO-III, Dr. Reddy’s Laboratories Ltd, Plot 116, 126C and Survey number 157, S.V. Co-operative Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Telangana 502325, India
Department of Chemistry, Osmania University, Hyderabad, Telangana 500007, India
Org. Process Res. Dev., 2015, 19 (11), pp 1634–1644
*Telephone: +919701346355. Fax: + 91 08458 279619. E-mail: amrendrakr@drreddys.com (A.K.R.)., *E-mail:sripabba85@yahoo.co.in (P.S.).

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////// QbD, DoE, FMEA, ANOVA, Design space.
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