Triboluminescence at Purdue

Researchers create triboluminescence instrument to rapidly test whether drugs contain trace crystallinity

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WEST LAFAYETTE, Ind.—Purdue University researchers have developed instrumentation that can quickly, accurately and inexpensively determine whether new pharmaceutical formulations have trace crystallinity—a factor that can negatively impact a drug’s stability and bioavailability. The instrument is based off of triboluminescence, and works by measuring light emitted when a pharmaceutical powder is crushed.
“Any light that is measured is directly proportional to how much crystallinity is in the formulation,” explained Casey Smith, a graduate student in Purdue’s Department of Chemistry.
The solid form of an active pharmaceutical ingredient profoundly influences the proportion of the drug that can enter and effect the body. Many drug candidates have low aqueous solubility, which leads to lower bioavailability. If a drug doesn’t dissolve in a timely manner, it can pass through a patient’s body before it has had time to take effect. One method used to overcome this problem is to bind the drug to a polymer to create an amorphous solid dispersion.
“New drugs that are coming out are increasingly larger and more hydrophobic,” says Garth Simpson, a professor of chemistry at Purdue University. “If crystallinity is detected, there’s a good chance that it won’t dissolve in a time frame required to be bioavailable and efficacious.”
“Trace crystallinity can affect drug stability by providing nucleation sites for the active pharmaceutical ingredient (API) to crystalize and grow. The effect of trace crystallinity on bioavailability depends on the specific system. In some cases, a small amount of crystallinity does little to inhibit the efficacy of the administered dose of the drug, but can significantly lower the shelf life. While in other cases, trace crystallinity can promote crystal formation upon dissolution in the gut (for an oral formulation),” he continues.
“Triboluminescence (TL) is the emission of light upon the mechanical disruption of a crystal. The piezoelectric effect is the main contributor to the mechanism of TL, in which sudden displacements of the lattice produce rapid changes in capacitance across the crystal,” Simpson tells DDNews. “For large enough changes in potential, plasma generation through dielectric breakdown of the surrounding air produces light. The piezoelectric requirement makes TL selective to the crystalline fraction of the sample. The low symmetry inherent in many drug molecules promotes the formation of piezoelectric crystals, providing high selectivity.”
The triboluminescence instrument is designed to provide rapid screening of amorphous solid dispersions. The instrument can detect crystallinity in levels as low as 140 parts per million. It is an electro-mechanical device that uses a solenoid to strike powder on a microscope slide, created in collaboration with the Department of Chemistry’s Jonathan Amy Instrumentation Facility. A photo multiplier tube beneath the slide measures the optical radiation resulting from the triboluminescence of the compound, and a motor moves the microscope slide down the line to probe new areas of the powder.
The instrument was made to enable analysis of materials in real-time during production using relatively simple and compact measurements, Simpson explains, and the measurement is based on striking a powdered sample with a impactor to correlate the emitted light to the crystalline fraction.
“This simple capability complements more information-rich, but larger and more complex, methods such as second harmonic generation microscopy (SHG) for quantifying trace crystallinity within nominally amorphous formulations,” he adds. “SHG is the up-conversion of light where two photons of a lower energy area converted into one photon of higher energy. It requires noncentrosymmetric crystals, which is similar to the symmetry requirements of TL. SHG is a powerful technique for trace crystallinity detection, but is complicated and costly due to the use of a femtosecond laser and the more involved optical setup and software. The TL instrument is meant to be a compact, robust method for simple ‘green light/red light’ initial screening.”
Scott Griffin, a Purdue chemistry graduate student, notes that this technique would be more likely used for prescreening off an assembly line in a factory where they’re making the drugs, saying, “If they get a positive outcome from the sample, then they can send it off for more rigorous testing.”
Griffin and Smith, both students in Simpson’s lab, were the lead authors in a paper on triboluminescence published in the peer-reviewed journal Analytical Chemistry, which included researchers from Merck & Co.
“TL measurements can inform pipelines for synthesis and manufacturing, providing early-stage detection of potentially problematic materials. Because the lower limit of detection is so much lower than alternative benchtop approaches, the speed with which assessments can be made can enable identification of problems and implementation of corrections earlier than alternative approaches. We wanted to have something that would be a simple yes or no assessment that could be done on site. If something fails, it can be taken to a more advanced instrument to get a better sense of quantitative characterization,” Simpson points out, noting that a triboluminescence instrument could also be used to quickly determine whether changes in the way a drug is produced can cause crystallinity.
Simpson mentions that there is still work to be done. The researchers want to be able to do similar crystallinity testing in slurries, and are working on a flow cell to accomplish that.
“[F]or a lot of these drug cocktails, when you put it into water it starts out in an amorphous state, but can spontaneously crystallize. We want tools that can characterize and measure that process,” he concludes. Researchers are also trying to get a sense for what fraction of drug molecules and drug compounds are likely to be amenable to triboluminescence analysis.

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