Green and sustainable metrics: Charting the course for green-by-design small molecule API synthesis

The use of designer surfactants to facilitate chemical transformations in water is a prime example for the knowledge transfer from academia to industry. Accordingly, chemistry in aqueous media aided by surfactants has emerged as a viable alternative to the use of organic solvents as part of the effort to transform chemical manufacturing into a green art. While classical metrics indicate tremendous savings on waste generation, a more exhaustive analysis including the intrinsic carbon footprint of such surfactants has never been conducted. The present work addresses this topic and outlines this analysis as part of a case study on the example of a widely known and applied working-horse of surfactant chemistry, TPGS-750-M. Meanwhile, the fate of the employed water is considered, and a holistic comparison to organic solvents is drawn. The key for a streamlined assessment is the reflected use of proper metrics, clearly pointing out a nonzero carbon footprint of such chemistries in aqueous media, though the techniques range at the greener end of the scale of reaction media.

Section: Saving Precious Metals By Means Of Surfactantsmentioning

confidence: 99%

API Syntheses in Aqueous Media: Assessing the Environmental Footprint en route from Academic Discovery to Industrial Applications as “Green Opportunity” for Process Chemistry

Fleck

Roschangar

Haydl

2023

“…Recent advances in the biocatalytic retrosynthetic toolbox have transformed the way in which pharmaceutical process development organizations conceive of novel synthetic routes. , While this generally applies to a wide variety of therapeutically relevant molecules, this is particularly true for drug candidates with significant structural similarity to naturally occurring biomolecules such as proteins, peptides, and nucleosides. The increasing occurrence of these complex molecules also brings to the forefront a responsibility in the pharmaceutical industry for companies to focus on the development of more efficient, sustainable, green chemistries . Our company and others in the industry have recently demonstrated novel bond disconnections leveraging a diverse biocatalytic toolbox for a number of important drug candidates, including islatravir, molnupiravir, , uprifosbuvir, belzutifan, and several statins such as atorvastatin , and simvastatin .…”

Section: Introductionmentioning

confidence: 99%

Automated End-to-End Workflow for Volumetric Mass-Transfer Coefficient (k_La) Characterization in Small-Molecule Pharmaceutical Development

Mattern,

Grosser

2023

Biocatalytic aerobic oxidations have recently emerged in the small-molecule pharmaceutical industry as a selective and green alternative to traditional chemocatalyzed oxidations that rely on transition-metal-based oxidants. Engineering aspects, such as mass transfer and reactor design, play a key role in determining the adoption and success of such biocatalytic aerobic oxidations; therefore, a detailed understanding and characterization of mass transfer at various process scales become a critical component of reaction development. Traditional mass-transfer characterization techniques are tedious to execute for a large number of processing conditions and reactor configurations and require careful experimental planning and data capture to ensure accurate regression of the volumetric mass-transfer coefficient, k L a. A custom-automated reactor characterization workflow has been developed to surmount these challenges and enable rapid design space characterization of mass transfer in reactors spanning the laboratory to production scales. Custom data compression and processing scripts paired with automated parameter regression enable rapid data processing and regression of experimental k L a values. Furthermore, a detailed analysis of system lag and error was conducted to enable more accurate modeling of system start-up during k L a experiments. This workflow has been leveraged to build a database of more than 2000 unique processing conditions in small-molecule centric, traditional batch chemistry reactors spanning laboratory development through manufacturing. This database allows scientists to quickly determine suitable processing conditions with a known k L a and mass-transfer performance, lowering the barriers to adoption and enabling rapid biocatalytic aerobic oxidation reaction development and scale-up.

“…Further purity upgrade of the filtered dry cake was achieved via a hot slurry in MeOH, affording 1 with 98.6–99.3% purity and a 76–84% overall isolated yield. Due to the requirement of two additional solid isolations, the process mass intensity (PMI) for the clinical supply process to access 1 was as high as 75 …”

Section: Introductionmentioning

confidence: 99%

“…Due to the requirement of two additional solid isolations, the process mass intensity (PMI) for the clinical supply process to access 1 was as high as 75. 5 Despite the relative simplicity of the active pharmaceutical ingredient (API) step, significant improvement was required to address some issues in the original process. The issues included:…”

Section: ■ Introductionmentioning

confidence: 99%

Leveraging Synergistic Solubility in the Development of a Direct Isolation Process for Nemtabrutinib

Chen

Iuzzolino

Burgess

et al. 2023

We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton's Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Significant improvements on process efficiency were achieved by a direct isolation process leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness improvements on impurity control, an efficient, practical, and scalable synthesis of nemtabrutinib was developed.