After 20 years of working in the pharmaceutical industry scouting active drugs in research to take to market, along with method transfer to the manufacturing site, I have learned that there is no such thing as “one-method-fits-all,” and we should always look outside the box to solve a challenge.
In research, where a limited number of samples are available, we must be careful and get the maximum amount of information to elucidate the structure the medicinal chemist has produced. A large part of this is checking the counterions to determine if they match the proposed compound structure. However, I have also used ion chromatography (IC) to determine the amount of sulfur, phosphorous, and halogen (anions) in the sample by combusting the “sample” with an oxygen flask, which is now usually done by combustion IC. The total content obtained is calculated back to the structural theoretical percentage in the compound.
If the drug is bioactive, it goes to the discovery stage. We learn how to streamline the process and improve the quality and yield. Many generic methods and walk-up systems are used to speed up the process.
Once it passes phase one testing, the focus is to learn more about the chemical process stage by stage, deep-diving into starting materials, intermediates, drug substances, their degradation products, and impurities. Often, degradation products and impurities are small molecules like small organic acids and amines, which are suitable for ion chromatography. We learned to start looking at the chemistry earlier and invest in understanding what will come downstream in the process. In this case, nitrite, nitrate and amines are very important to eradicate or minimize the nitrosamine impurities formation. Regulated by the International Council for Harmonisation guidelines (ICH) or regional pharmacopeia, toxic impurities like cyanide, hydrazine and certain transition metal species formed in the process — or in degradation — are limited and monitored.
In the later phases of drug development, the active ingredient is sent to pharmaceutical development to formulate into the administrated medicine. It could be a tablet, a capsule, an inhaler, or an intravenous injection. To do this, we look at excipients. They can be from various carbohydrates such as sucrose, lactose, starches, cellulose, and sugar alcohols (xylitol, sorbitol or mannitol) as in the FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). Then, there is a binding agent such as magnesium stearate.
If we are lucky to see the drug through to market, we transfer all the analytical methods to manufacturing. Therefore, those methods need to be reproducible and robust. So, the more automated, the better. Technology such as reagent-free ion chromatography (RFIC) — you just add water to generate eluent — makes the method transfer process much simpler. The key is to use the appropriate detection, like mass spectrometry to improve sensitivity, and intuitive software to enable quick learning to counter manufacturing staff turnover.
I hope my sharing how I spent my 20 years in the pharmaceutical industry helps you to better understand the vital role ion chromatography plays in drug development. If you have any questions or comments, please enter them below.
Additional Information
Website
Webinars:
- What can ion chromatography do for the pharma Industry?
- Determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation
- USP Modernization and ion chromatography – where are we now?
Application notes:
- Determination of Gentamicin and Related Impurities in Gentamicin Sulfate
- HPAE-PAD Determination of Cyclodextrins
- Determination of Sulfate Counter Ion and Anionic Impurities in Aminoglycoside Drug Substances by Ion Chromatography with Suppressed Conductivity Detection
- Identification of plastic additives in pharmaceutical packaging using a fully automated parallel extraction evaporator system and UHPLC-HRMS
Thermo Fisher Scientific
United States
