Will the correct structure please stand up? … Part 1

Many organic chemists—if not all—check to see if a synthetic reaction is complete via TLC and LC/MS and/or 1H NMR. At the same time, the chemists are using the analytical data to verify that the final product is what they intended on making. In some cases, LC/MS and 1H NMR do not adequately distinguish one potential product from another. It then becomes a question of identifying a technique(s) that can clearly verify the correct product.

The chemical structures shown below (3-methyl-5-(pyridin-2-yloxy)pyridine and 5'-methyl-2H-1,3'-bipyridin-2-one) are two possible products for a synthetic reaction. They have an identical formula weight (FW) and a nearly identical MS and 1H NMR (not shown). What other experiments can a chemist/spectroscopist propose that will assist in identifying the correct structure and thus distinguish the ester from the carbonyl product?

 

I would like to give a special thanks to David C. Adams for proposing the idea.

Will the correct structure please stand up? … Part 1

Many organic chemists—if not all—check to see if a synthetic reaction is complete via TLC and LC/MS and/or 1H NMR. At the same time, the chemists are using the analytical data to verify that the final product is what they intended on making. In some cases, LC/MS and 1H NMR do not adequately distinguish one potential product from another. It then becomes a question of identifying a technique(s) that can clearly verify the correct product.

The chemical structures shown below (3-methyl-5-(pyridin-2-yloxy)pyridine and 5'-methyl-2H-1,3'-bipyridin-2-one) are two possible products for a synthetic reaction. They have an identical formula weight (FW) and a nearly identical MS and 1H NMR (not shown). What other experiments can a chemist/spectroscopist propose that will assist in identifying the correct structure and thus distinguish the ester from the carbonyl product?

 

I would like to give a special thanks to David C. Adams for proposing the idea.

The Stages behind Developing a New Drug in Industry … Part 5

In this final installment of the series on Drug Development, we examine stage 4 and the effort involved in Drug Manufacturing and Process. The 4th stage begins with a large scale production of the new drug, followed by formulation studies and then ending with regulatory reviews of the entire process before the drug can be marketed and sold.

The new drug is batched produced through a scale-up synthesis of the active drug component. At this point, new impurities may surface and thus warrant further investigations into its toxicity effects. Each impurity must be identified, elucidated, re-synthesized and re-tested to ensure all safety precautions were taken.

On the formulation side, further studies are done to ensure that the active drug ingredient and its impurities are combined with an excipient that is compatible and that the dosage upon intake is consistent. In addition, stress tests are performed on the mixture to check for any harmful degradation products that may occur during storage. These studies tend to overlap with the Drug Trials set in stage 3.

For good measures, all the analyses and tests are scrutinized by a team of internal and external experts. They verify that all the correct procedures were applied and the data is consistent with what is intended to be sold.

The Stages behind Developing a New Drug in Industry … Part 5

In this final installment of the series on Drug Development, we examine stage 4 and the effort involved in Drug Manufacturing and Process. The 4th stage begins with a large scale production of the new drug, followed by formulation studies and then ending with regulatory reviews of the entire process before the drug can be marketed and sold.

The new drug is batched produced through a scale-up synthesis of the active drug component. At this point, new impurities may surface and thus warrant further investigations into its toxicity effects. Each impurity must be identified, elucidated, re-synthesized and re-tested to ensure all safety precautions were taken.

On the formulation side, further studies are done to ensure that the active drug ingredient and its impurities are combined with an excipient that is compatible and that the dosage upon intake is consistent. In addition, stress tests are performed on the mixture to check for any harmful degradation products that may occur during storage. These studies tend to overlap with the Drug Trials set in stage 3.

For good measures, all the analyses and tests are scrutinized by a team of internal and external experts. They verify that all the correct procedures were applied and the data is consistent with what is intended to be sold.

The Stages behind Developing a New Drug in Industry … Part 4

Drug Trials commence with in vitro and in vivo experiments on nonhuman subjects and observing the effects of the candidate drug(s). These are commonly referred to as the pre-clinical trials. Once safe and effective thresholds have been set, the candidate drug(s) can be administered to human subjects and thus begin the clinical trials. The clinical trials are divided into various Phases I, II, III, IV.

In a concerted effort, preformulation studies look at the candidate’s solubility, stability, crystal properties, etc. to optimize the method of delivery. As testing nears completion (or soon after the Drug Design stage is complete), an application for a new drug is submitted to an internal regulatory board and a patent is filed.

The Stages behind Developing a New Drug in Industry … Part 4

Drug Trials commence with in vitro and in vivo experiments on nonhuman subjects and observing the effects of the candidate drug(s). These are commonly referred to as the pre-clinical trials. Once safe and effective thresholds have been set, the candidate drug(s) can be administered to human subjects and thus begin the clinical trials. The clinical trials are divided into various Phases I, II, III, IV.

In a concerted effort, preformulation studies look at the candidate’s solubility, stability, crystal properties, etc. to optimize the method of delivery. As testing nears completion (or soon after the Drug Design stage is complete), an application for a new drug is submitted to an internal regulatory board and a patent is filed.

The Stages behind Developing a New Drug in Industry … Part 3

The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.

In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.

The Stages behind Developing a New Drug in Industry … Part 3

The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.

In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.