kilomentor

Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation are proposed as a quantitative tool to rank the challenges of a process scale up.

Nature to be commanded must be obeyed.

In synthesis we talk about assembling, building or constructing a molecular structure. In an important aspect this is a misleading metaphor because we are comparing an activity in the nano-world to an activity in the macro world. Operating in the macroscopic world, as for example in building a house, we handle the pieces, we position the pieces, we join the pieces.

In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: to small to touch, to align or even to see.

In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc.. Then the chemist presents the proposed reaction partners, the proverbial A & B, to each other under the orchestrated conditions and A & B, spontaneously interact, as their nature dictates but we fervently hope, to the proverbial expected C & D.

How is this perspective different from the conventional one? According to the academic synthetic chemistry tradition, synthetic accomplishments are judged on the basis of the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts and other excipients are in the background (the attitude is that it can be done and will be done BUT these are not pertinent criteria to evaluate the quality of the synthesis).

From the perspective I am presenting here, the ruggedness is to be taken into account BUT the deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity is paramount.

Is there any particular value in this way of looking at the chemistry that surpasses the traditional way of looking at the chemical process as a series of chemical reactions with the separation of intermediates taken as an obvious technical work? My perspective emphasizes:

• The work involved in setting up and controlling the necessary reaction conditions.
• The work involved in quenching the reaction condition/then working up the reaction and finally isolating the desired product.

The value in this perspective is that in chemical synthesis, the money, manpower and resources consumed during the reaction step phase, while A & B are reacting with each other, is miniscule compared to the money, manpower and resources expended preparing for the reaction and recovering pure product from the reaction.

The clash of these perspectives leads to the question, “Which would I rather do- a four step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel or crystallized or distilled to give a adequate practical purity intermediate".

People have personal preferences and this is as it should be in a pluralistic society BUT I pick the second sequence and as the need for larger quantities and higher quality intensify, I increasingly prefer the second route.

Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy and scalability.

OK so what. How does this insight change our behavior in the synthetic laboratory, office or library?

We should evaluate or rate synthetic schemes using more criteria.:

1. Number of Chemical Steps
2. Isolated overall Yield
3. Yields of the Individual Steps.
4. Difficulty Rating for Each Reaction Mixture Separation
5. Number of Phase Shifts in the Synthetic Process
6. Intermediates that are Acids or Bases
7. Ease or Difficulty in reaching Practical Purity

How could we execute this rating? We could classify work-ups.

A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)

B. Product can be separated by crystallization of precipitation as filterable solid.

C. Product can be separated by atmospheric or vacuum distillation based on a projected difference in boiling points (based on molecular weights)

D. Product can be separated based on chemical reactivity (formation of reversible simply separable derivative, or destruction of contaminant by reaction)

E. Theproduct seems likely only to be separable in practical purity by chromatography.

Clearly as process chemists we want to face more A-C separations and fewer d-E type separations.

As Kilomentor presents more details of its distinctive strategy of pharmaceutical or chemical process development you will see how this drives the key decision process.

• Chemical Blogs / Login
• Start Your Chemical Blog
• Chemical Forum
• Article Finder
• Periodic Table
• Chemical News
• Unit Converters
• pH Calculator
• Balance Chemical Equation
• Calculate Molecular Weight

• Main
• archives
• Albums
• Links

• In Process Controls and Forensic Samples in Chemical Process Development
• Making a Good Recrystallization Process Step Better.
• Common Ground for Generic and Innovator Pharmaceutical Companies
• Biocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process Development
• Separation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.
• Sulfate Pharmaceutical Salts (reprint to remove comments)
• Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification
• Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.
• The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt
• Reiterating the Objective of the Kilomentor Blog
• The process vision: an integrating strategy in pharmaceutical process development
• Phosphate Pharmaceutical Salts : Chemical Process Development & Organic Synthesis
• Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperature
• Making the Hydrochloride Pharmaceutical Salt of Basic Drug Substances
• Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.

• General [63]

• RSS 0.90
• RSS 1.0
• RSS 2.0
• XML