Pharmaceutical process chemistry: evolution of a contemporary data-rich laboratory environment.

Over the past 20 years, the industrial laboratory environment has gone through a major transformation in the industrial process chemistry setting. In order to discover and develop robust and efficient syntheses and processes for a pharmaceutical portfolio with growing synthetic complexity and increased regulatory expectations, the round-bottom flask and other conventional equipment familiar to a traditional organic chemistry laboratory are being replaced. The new process chemistry laboratory fosters multidisciplinary collaborations by providing a suite of tools capable of delivering deeper process understanding through mechanistic insights and detailed kinetics translating to greater predictability at scale. This transformation is essential to the field of organic synthesis in order to promote excellence in quality, safety, speed, and cost efficiency in synthesis.

[1]  M. Snowden,et al.  Identification of New Catalysts to Promote Imidazolide Couplings and Optimisation of Reaction Conditions Using Kinetic Modelling , 2004 .

[2]  Srinivas Tummala,et al.  Emerging technologies supporting chemical process R&D and their increasing impact on productivity in the pharmaceutical industry. , 2006, Chemical reviews.

[3]  W. C. Still,et al.  Rapid chromatographic technique for preparative separations with moderate resolution , 1978 .

[4]  Ivan Marziano,et al.  Critical assessment of pharmaceutical processes--A rationale for changing the synthetic route. , 2006, Chemical reviews.

[5]  C. Heathcock The Enchanting Alkaloids of Yuzuriha , 1992 .

[6]  A. Kamatani,et al.  Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066) , 2011 .

[7]  David J W Grant,et al.  Identifying the Stable Polymorph Early in the Drug Discovery–Development Process , 2005, Pharmaceutical development and technology.

[8]  Nga M. Do,et al.  Application of quantitative 19F and 1H NMR for reaction monitoring and in situ yield determinations for an early stage pharmaceutical candidate. , 2011, Analytical chemistry.

[9]  Robin Smith,et al.  Optimization of batch cooling crystallization , 2004 .

[10]  A. Newman Specialized Solid Form Screening Techniques , 2013 .

[11]  Narayan Variankaval,et al.  From Form to Function: Crystallization of Active Pharmaceutical Ingredients , 2008 .

[12]  A. S. Wood,et al.  The Process Development of a Scaleable Route to the PDE5 Inhibitor UK-357,903 , 2002 .

[13]  Joel M Hawkins,et al.  Flow Heck reactions using extremely low loadings of phosphine-free palladium acetate. , 2013, Organic letters.

[14]  Keith R Horspool,et al.  Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API. , 2010, Journal of pharmaceutical sciences.

[15]  Jukka Rantanen,et al.  Solid form screening--a review. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[16]  A. Klamt,et al.  COSMOquick: A Novel Interface for Fast σ-Profile Composition and Its Application to COSMO-RS Solvent Screening Using Multiple Reference Solvents , 2012 .

[17]  Nigel Greene,et al.  The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. , 2006, Regulatory toxicology and pharmacology : RTP.

[18]  D. Ende,et al.  A Calorimetric Investigation To Safely Scale-Up a Curtius Rearrangement of Acryloyl Azide , 1998 .

[19]  Y. Abramov,et al.  The Challenges of Developing an API Crystallization Process for a Complex Polymorphic and Highly Solvating System. Part I , 2009 .

[20]  Bryan M. Li,et al.  Telescoped Flow Process for the Syntheses of N-Aryl Pyrazoles , 2012 .

[21]  Teresa W. Makowski,et al.  Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin , 2014 .

[22]  Yang Liu,et al.  Route Designer: A Retrosynthetic Analysis Tool Utilizing Automated Retrosynthetic Rule Generation , 2009, J. Chem. Inf. Model..

[23]  G. L. Reid,et al.  Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development , 2015 .

[24]  Yuriy A. Abramov,et al.  Current Computational Approaches to Support Pharmaceutical Solid Form Selection , 2013 .

[25]  R. Vaidyanathan,et al.  Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib , 2014 .

[26]  Gargi Mukherjee,et al.  Polymorphs, Salts, and Cocrystals: What’s in a Name? , 2012 .

[27]  R. Woodward,et al.  Total Synthesis of (±)-Reserpine , 2022, Synfacts.

[28]  J. W. Mullin,et al.  Programmed cooling of batch crystallizers , 1971 .

[29]  Roger Nosal,et al.  API Quality by Design Example from the Torcetrapib Manufacturing Process , 2007, Journal of Pharmaceutical Innovation.

[30]  K. E. Price,et al.  Sonogashira Reactions with Propyne: Facile Synthesis of 4-Hydroxy-2-methylbenzofurans from Iodoresorcinols , 2010 .

[31]  E. Hansen,et al.  Development of a concise, asymmetric synthesis of a smoothened receptor (SMO) inhibitor: enzymatic transamination of a 4-piperidinone with dynamic kinetic resolution. , 2014, Organic letters.

[32]  K. Leeman,et al.  Synthesis of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted 2H-Pyranone via Dieckmann Cyclization of a β-Acetoxy Ester , 2014 .

[33]  Nicholas Murray Thomson,et al.  Chapter 4:Rapid Early Development of Potential Drug Candidates , 2011 .

[34]  Shu Yu,et al.  Development of Migita Couplings for the Manufacture of a 5‐Lipoxygenase Inhibitor , 2013 .

[35]  Wolfgang Beckmann,et al.  Seeding the Desired Polymorph: Background, Possibilities, Limitations, and Case Studies , 2000 .

[36]  D. Ende,et al.  Development and Application of Laboratory Tools To Predict Particle Properties upon Scale-Up in Agitated Filter-Dryers , 2013 .

[37]  A. Klamt,et al.  Rational coformer or solvent selection for pharmaceutical cocrystallization or desolvation. , 2012, Journal of pharmaceutical sciences.