PHARMACEUTICALS
100
80 60 40 20 0
100
80 60 40 20 0
Comparison of RMC / kg ( base 100 ) 100
Existing process
Comparison of COGS / kg ( Base 100 ) 100
Existing process
. . . • • -37
• ° / o
• • ••••
• • • • • • • • •
. . . -28 ° / o
••• ••••••••••••• that the usage of MeTHF would be beneficial with regards to the overall process efficiency and the environmental impact .
With these objectives identified , a process feasibility was performed and it revealed that MeTHF was a viable replacement to THF , providing similar impurity profile and conversion . The development was initiated with an emphasis on implementing a telescoping between the two steps and a focus on solvent and aqueous consumption reduction .
MeTHF was found to be compatible with both steps , the second step being initially performed under acidic conditions . After aqueous treatment , MeTHF could be recovered via distillation and reused in the same process . The quality of the solvent
63
Improved process
72
Improved process
was verified after several cycles and confirmed our assumptions .
The crude API is isolated by precipitation and filtration ; no filtration issue was identified at this stage . The isolated crude was then dissolved in MeOH and crystallised as its HCl salt . The purge study performed revealed a robust elimination of the process impurities at several stages of the process , providing the API in specification .
Demonstration at scale
Once established , the new process was demonstrated through a consistency study at 100 g scale to confirm the repeatability . The process improvement programme was performed in six months at our laboratories at Vizag , India , from the multi-disciplinary evaluation up to the confirmation of the new process robustness .
The yield of the isolated API was increased from 72 % to 83 %. Reducing the number of solvents used from five in the initial process to two after redevelopment , and eliminating a complex intermediate isolation without impacting the robustness of the process and the impurity profile of the final API streamlined the process .
The solvents used ( Me-THF and MeOH ) were chosen for their physicochemical properties but also taking account their environmental impact and ability to be recycled . The solvent recycling is established and an estimate of 80 % solvent recovery has been calculated .
Our standard procedures when developing new processes or during optimisations is to add atom efficiency and PMI as additional key metrics to cost of goods ( COGS ) to evaluate the impact on process efficiency .
The PMI was reduced by 75 %, meaning that the same quantity of API can be produced with this secondgeneration process using only 25 % of the total mass of material that was used in the first generation process , taking into account solvent recovery .
This is a great achievement in terms of environmental impact reduction but also on the improvement of process efficiency . The raw material cost and COGS have also been reduced by nearly 37 % and 28 % respectively , improving the cost-efficiency of the process and the viability of its production . ●
Jean-Baptiste Guillermin
HEAD OF TECHNICAL BUSINESS DEVELOPMENT
References : 1 : Chem . Soc . Rev ., 2012 , 41 , 1485 – 1498 2 : ACS Sustainable Chem . Eng . 2019 , 7 , 16937-16951 |
3 : Green Chem ., 2020 , 22 , 13 4 : Org . Process Res . Dev . 2022 , 26 , 3 , 480-49 |
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AXPLORA
jean-baptiste . guillermin @ axplora . com www . axplora . com
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