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The cycle of a molecule from merely a structure on paper to a proven drug sold in the market is technically divided into 4 different Phases which can be further classified under – Discovery (Research), Development (Process Optimization) & Commercialization (Sales and Marketing).

The first of these three criteria which is “Research” – consumes the highest amount of time in the entire drug life cycle, and is very tedious. As we all know, for “Research” establishing the “Proof of Concept” is most important because until this is done everything else is in vain. Therefore, while doing R&D saving time over cost makes the most sense.

As a result, the biggest focus of a “discovery” chemist is always onHow’ to make the designed molecules quickly so that they can be biologically evaluated. And in this quest a “discovery” chemist often overlooks parameters like cost and operational feasibility of their selected ROS (route of synthesis) at commercial scale. However, discovery chemists are not to be blamed since Priorities Define Actions!

Having said that, this opens up a new avenue for the process chemists to exhibit their skills of re-producing the same chemistry more efficiently, because now for a molecule to covert itself from merely a “Discovery Hit” to an “Active Pharmaceutical Ingredient” (API) it has to undergo several tests, requiring its continuous supply at large. Which is why “Development i.e. Process Optimization”, the second stage of the Drug Discovery process, is extremely important and inevitable.

For any synthesis, a good process chemist often focuses on the following important parameters:

  • Length of Synthesis
    • Shorter the route the larger can be the manufacturing efficiency!
  • Safety
    • Obviously there is no better alternative to a safer approach!
  • Environmental Friendliness
    • Lesser the effluent, cleaner is the environment – no one would ever want to discover a drug to live longer in a world which has nothing but pollution!
  • Cost Effectiveness
    • There is no point in having a drug if no one can afford to buy it!
  • Consistency
    • Unreliable parameters can never be scaled up!

Length of Synthesis

For Discovery, ROS are often designed to address analogue synthesis i.e. diversification of a common Scaffold (which in majority of cases is the pharmacophore) towards a late synthetic stage – hence larger focus is given to effective preparation of the scaffold rather than the target molecule itself. Therefore, the first thing a good process chemist does is to have a thorough review of the med-chem. synthetic route whilst aiming to reorder, reduce and/or modify the plausible synthetic steps. Reduction in number of synthetic steps has direct and huge impact on the overall yields, hence is well thought after.

An indirect way to reduce the length of synthesis is also to develop “One Pot Synthesis” since it avoids isolation of the in-situ stages and minimizes the handling loss.

Another indirect way to boost the overall yield is considering a “convergent” synthetic approach v/s a “linear” synthetic route. It has been mathematically proved (table below) that even for a linear synthetic sequence having excellent isolated yields for each synthetic steps, if one is able to design the route in such a way that several key intermediates are independently synthesized and combined at a late stage than one can find a large upside in the final isolated yields.

scaleup

 

 

 

 

 

Safety

Hazard is directly proportionate to scale. For example, using 10 liter of t-buli in a 100 liter reactor assembly is obviously very risky as compared to using it at 10 mL scale in 50 mL RBF within a confined fume hood set up. Therefore, while evaluating and defining a scalable ROS, a process chemist always thinks of plant safety. A wise process chemist never starts investing efforts on developing a ROS which is not closely reviewed and discussed with a chemical engineer at the plant. All potential “Safety Hazards” are minutely discussed and eliminated by having alternate synthetic routes/ chemical reagents/mechanical processes.

Environmental Friendliness

Solvents (or other similar media) play a vital role in chemical synthesis and in isolation and purification processes. However, when it comes to commercial production it becomes very important to appropriately select solvents and/or media which are less toxic hence safer to use, and more environmental friendly

Few ways by which a process chemist addresses the above requirements are as follows:

  • Use of greener reaction media (ionic liquids)
  • Replacing column chromatography and other similar tedious purification methods by less solvent and time consuming techniques like crystallization, solid precipitation, solvent trituration, to name a few.
  • Use of greener technologies like Biocatalysis, Flow chemistry and the like.

Recycling of the reaction/purification solvents, reaction catalysts among others, is an indirect way of addressing EHS needs and also saves cost.

Cost Effectiveness

This parameter is extensively explored since it directly impacts commercially viability. All thoughts which are capable of achieving the following targets are constantly reviewed and persuaded.

  • Replacement of a costly reagent with a cheaper and a greener chemical without effecting the overall yields
  • Identifying reaction conditions/mechanical processes which can avoid higher temperature and pressure (energy consumption) but have the same output

Consistency

Variable results eat up the profit margins hence they are never good for commercial sale up. Therefore, once a scalable ROS is identified – a process chemist works hard to make it robust, and he/she does this by meticulously recording all the important reaction parameters/observations like addition sequence, frothing, exothermicity, color change, precipitation of solids, formation of gummy reaction mass and so on – repeating the reaction(s) multiple number of times to identify result deviation(s), and finally optimizing each criteria until consistent reproducibility is observed.

It is needless to mention that all the observations pertaining work up, purification and isolation processes should also be neatly recorded and checked for their consistency – this includes the buffer used for quenching, volume of organic solvent used for extraction, ratio of solvent system used for crystallization, to name a few.

Chemistry is all about observations and a chemist who not only has good observation skills but also follows good documentation practices can make a difference!

Well Known Literature Examples of Process Optimization:

1. AZD0530 (SRC Kinase Inhibitor)*

Lab Synthesis

Optimized Scalable ROS

AZD0530 ROS Comparison

AZD0530 ROS comparison

 

 

 

 

 

 

 

2. Lu AA26778*

Lab Synthesis

Optimized Scalable ROS#

Lu AA26778 ROS Comparison

Lu AA26778 ROS comparison

 

 

 

 

 

 

 

 

 

3. Olaparib (PARP Inhibitors)*

Lab Synthesis

Optimized Scalable ROS

Olaparib ROS Comparison

Olaparib ROS comparison
 
 
 
 
 
 
About o2h:

Founded in 2005, o2h Discovery has an integrated drug discovery platform operating from our state-of-the-art research center in India and The Mill SciTech Park, Cambridge, UK. We have the in-house capability to execute hit-lead-optimisation programmes leading into patent and IND filing from our state-of-the-art biotechnology incubator with expertise in discovery chemistry, biology, pharmacology and the on-going project management of pre-clinical development. 

o2h Discovery has developed and launched its proprietary application AI Chemistry in the CloudTM which is the world’s first app to revolutionise the project management of external drug discovery programmes. The app enables communication between various scientific stakeholders essential to successful project advancement – leading to faster decision making. 

o2h Discovery has a proven track record of successfully delivering several medicinal chemistry drug discovery projects and subsequently has developed proficient troubleshooting skills. The o2h team is highly experienced and have worked on various scaleup and process optimization projects for some of the existing collaborators. 

The DNA of o2h is centered around the nurturing of its people, values and culture, it reflects in the way we work with each other, as well as our collaborators and partners. 

We are now open to inquiries from the larger market including API, Research Intermediates, Research Scaffolds, among others.

To discuss about your Chemistry project, please get in touch with Tejas at tejas@o2h.com