Researchers at the University of Warwick and Astra Zeneca have found a new way to use solid-state NMR equipment to crack the secrets of hydrogen atoms and thus spot unwanted polymorphs in pharmaceuticals.
Pharmaceuticals companies are constantly battling the problem of polymorphism in which an active drug can actually exist in more than one form or crystal structure which can cause the drug to act in very different ways. Now researchers at the University of Warwick and Astra Zeneca have devised a new method of using solid-state NMR (nuclear magnetic resonance) equipment to spot unwanted polymorphs that should be adopted as a routine tool by pharmaceutical companies.
NMR equipment is already used to detect polymorphism in pharmaceuticals. However the standard technique looks at the carbon 13C nuclei in the drugs by a method called cross-polarisation magic-angle spinning (CP MAS). This is a very insensitive technique as only 1 in 100 carbon nuclei are the 13C isotope. This means that 99 out of 100 carbon nuclei are a NMR-invisible form of carbon. Only one-dimensional spectra are routinely possible from such an experiment.
Researchers have long wished to be able to couple this carbon based solid–state NMR technique with one that looks at hydrogen nuclei. It has been possible to look at hydrogen when the sample is a solution (solution-state NMR) but this is not as easy in solid-state NMR as the extensive network of coupled together 1H nuclei leads to broad lines in the spectrum that are hard to tell apart. This makes it almost useless when you are examining a tablet. Tablets are also particularly difficult to examine as the active drug within the tablet is combined with a mixture of other filler compounds (excipients).
This breakthrough by the Warwick team opens up hydrogen nuclei to useful study by solid-state NMR which will bring immense benefits to the study of polymorphism in drugs and organic molecules in general. This is because hydrogen atoms are central to hydrogen bonding (as opposed to carbon atoms which "observe" from afar). Hydrogen bonding is often the driving force in determining how organic molecules do differ in their methods of "3D packing" forming polymorphs or pseudo-polymorphs (pseudo-polymorphism referring to crystal structures that differ through the inclusion or non inclusion of small molecules, eg with or without water). This new NMR technique can identify which pseudo polymorph of an active pharmaceutical is present in a complete tablet.
The research team led by Dr Steven Brown from the University of Warwick’s Department of Physics have exploited recent developments in NMR hardware and pulse sequence design allowing them to gain high-resolution 1H solid-state NMR spectra by a method called CRAMPS (combined rotation and multiple-pulse spectroscopy). By using this high-resolution two-dimensional 1H CRAMPS solid-state NMR they obtained a spectrum for a tablet formulation in less than 2 hours, which is equivalent to the time required for a good 13C CP MAS one dimensional spectrum.
Dr Steven Brown said: "This Hydrogen 1H solid-state NMR method gives powerful new insight that complements established Carbon 13C based techniques - this new approach should be adopted as a routine tool in pharmaceutical characterisation"
The research paper entitled "Distinguishing Anhydrous and Hydrous Forms of an Active Pharmaceutical Ingredient in a Tablet Formulation Using Solid-State NMR Spectroscopy" by John M. Griffin, Dave R. Martin, and Steven P. Brown has just been published in Angewandte Chemie Volume 119, Issue 42 , Pages 8182-8184
Source: University of Warwick
Related stories:
Warming up for Magnetic Resonance Imaging
Standard magnetic resonance imaging, MRI, is a superb diagnostic tool but one that suffers from low sensitivity, requiring patients to remain motionless for long periods of time inside noisy, claustrophobic machines. A promising new MRI method, much faster, more selective — able to distinguish even among specific target molecules — and many thousands of times more sensitive, has now been developed in the laboratory by researchers at the Department of Energy's Lawrence Berkeley National Laboratory and the University of California at Berkeley.
Scientists bring MRI/NMR to microreactors
In a significant step towards improving the design of future catalysts and catalytic reactors, especially for microfluidic “lab-on-a-chip” devices, researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory and the University of California at Berkeley, have successfully applied magnetic resonance imaging (MRI) to the study of gas-phase reactions on the microscale.
Researchers solve fuel-cell membrane structure conundrum
Fuel-cell cars are reaching commercial viability in today’s increasingly eco-conscious society, but despite their promise, even scientists have struggled to explain just how the fuel-cell’s central component – the proton exchange membrane – really works.
First finding of a metabolite in 1 sex only
Researchers at the University of Illinois at Chicago have discovered a chemical compound in male blue crabs that is not present in females -- the first time in any species that an entire enzyme system has been found to be activated in only one sex.
Big Magnets, Big Molecules
Magnets strong enough to stop a heart pacemaker, wreck credit cards and yank tools from your hands will be used to probe the structure of big molecules in a $14 million facility that will be unveiled Friday, Sept. 8 at the University of Utah.
Scientist uses form to explain function of key building blocks of life
UW-Madison biochemists have developed an approach that allows them to measure with unprecedented accuracy the strengths of hydrogen bonds in a protein. The scientists were then able to predict the function of different versions of the protein based on structural information, a novel outcome that was published recently in the Proceedings of the National Academy of Sciences.
Unlocking hydrogen's fuel potential
Hydrogen is being touted as the fuel of the future, a clean-burning, renewable and inexpensive replacement for petroleum. But a major stumbling block for hydrogen-powered vehicles is figuring out a way to carry enough hydrogen onboard to travel even moderate distances between refueling stops.
Meteorites Could Play a Key Role in Earth Life
University of Arizona scientists have discovered that
meteorites, particularly iron meteorites, may have been critical to the evolution of life on Earth.
Their research shows that meteorites easily could have provided more phosphorus than naturally occurs on Earth -- enough phosphorus to give rise to biomolecules which eventually assembled into living, replicating organisms.