My official title is Senior Research Chemist, Process Chemistry. I work for a company that partners with other pharmaceutical and biotech companies in bringing drugs to market. Discovering and testing drugs is a long and expensive process – 12-15 years, about a billion dollars.
Suppose a company want to develop a drug to treat a disease. Initially, they examine millions of molecules in basic biological tests. The results of these tests show whether a molecule affects part of a biological process involved in the disease. Building on these results, chemists design and make new molecules that may perform better in these initial tests. Several rounds of chemistry and biology provide more and more information about potential drug molecules. Eventually, a select few of these molecules are administered to animals. The animals are observed, then killed and autopsied. This informs more rounds of synthesis and testing go on.
It’s estimated that 90% of drug projects fail somewhere in these early stages. The 10% of successful projects will undergo clinical trials, the careful administration of drugs to humans and the observation of their effects. Three major phases of clinical trials are required to demonstrate the safety and efficacy of drugs before they can be considered for market. This is an expensive, risky, and highly regulated process, culminating in the submission of library-sized bodies of documentation to the FDA. The FDA reviews the material and provides a final verdict on whether or not a drug may be sold in the US. About 10% of drug candidates that enter the clinic will eventual be approved. Undertaking a drug discovery project means a 1% chance of success and lots of capital at risk.
In the early stages of drug research, where the focus is on basic biology, you can do most of the experimentation with 5-10 mg of the drug molecule. Figuring out how to make a molecule that’s never been made before is hard. This is the domain of a medicinal chemist. A medicinal chemist must first choose an appropriate starting material, a widely available molecule that usually bears some resemblance to the target product. The chemist will then design a series of chemical reactions that she anticipates will, step-by-step, turn the starting material into the target. A reaction is performed, the material is purified, the next reaction is tested. Medicinal chemists use general patterns of chemical reactivity to design a series of reactions – however, sometimes these reactions don’t work very well, or at all. Tweaks need to be made alternatives need to be tried. A skilled medicinal chemist may spend 30 minutes designing a way to make a molecule on paper, then take two months to make the planned chemistry work in the lab. Still, making 5-10 mg of a druglike molecule is usually achievable in that time frame. At this stage of things, how the molecule is made is not important. It is enough simply to make it.
Much further along in the discovery process, when doses of the compound are going to be administered to animals or humans (and maybe before), 5-10 mg of compound isn’t sufficient. You need grams of material, then kilograms. This is where a team of process chemists (like me!) comes in. The “how” of making the compound is now very important. Why not just do what the medicinal chemist did, only bigger? Many reasons. The medicinal chemist may have used ten reactions to make a molecule that could be made in five. These extra reactions generate lots of waste and cost money to run. Some of the reactions may have used expensive or toxic chemicals that we want to avoid. Sometimes chemical reactions that work well on small scales do not work as well with more material. Purifications that work well on a small scale may be impractical on large scales.
My goal as a process chemist is to figure out ways to make potential drug molecules with as little chemical material, time, effort, cost, and waste as possible. Often, this means designing and executing a scheme of chemical reactions completely different from what the medicinal chemist used. On a daily basis, my job centers on running and analyzing individual chemical reactions. I test different chemical reagents and their relative amounts, temperatures, concentrations, rates of addition, and many other variables. I use sophisticated instrumentation to analyze the individual components of a reaction. I strive to make individual reactions as high-yielding (yield = amount of material actually made/amount of material theoretically possible) as possible, with products as pure as possible. If I’m lucky, I get to think about how green and easy to perform a reaction is, but most of the time, it’s very hard even to get good yield and purity. Since the material from one reaction is used in the next, I typically work on two reactions at a time. Poor performance in one reaction can upset an overall scheme for making amolecule. Recently, my colleague and I have developed a route of making a molecule using four total reactions that previously required eight reactions to make. It is very satisfying to make large quantities of pure white powder!
The chemistry we develop may be passed along to engineers for further refinement. While I am an expert in what reactions to use and in what order, engineers are experts in chemical equipment and in the numerical details of, for example, heat transfer, filtration, and crystal growth. They work to develop chemical processes that can reliably be executed by medium-skilled technicians. Ultimately, the chemistry we develop may be used to manufacture pure drug products for market.
'via Blog this'