PHILADELPHIA, Aug. 21, 2016 --The developing world is awash in substandard, degraded or falsified medications, which can either directly harm users or deprive them of needed treatment. And with internet sales of medications on the rise, people everywhere are increasingly at risk. So, a team of researchers has developed a simple, inexpensive paper-based device to screen suspicious medications.
The researchers will present their work today at the 252nd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features more than 9,000 presentations on a wide range of science topics. A brand-new video on the research is available at http://bit.ly/ACSfakedrugdetection.
"People who don't have access to the best-quality medicines also don't have as many resources to buy the analytical instrumentation to detect the quality problems," says Marya Lieberman, Ph.D. "Instead of a $30,000 instrument, we've developed a $1 paper card. We designed the card so it would be as easy and inexpensive to use as possible."
Medications can be compromised in many different ways. For example, they may be bulked up with fillers, or they can degrade because they are stored improperly. Identifying poor-quality medications is challenging, as inspectors may not know in advance what chemical adulterants or degradation products they need to look for. Plus, bad-quality medications may contain at least some of the active ingredient, so simply detecting the presence of the real medication isn't enough to rule out issues.
In this study, Lieberman of the University of Notre Dame, along with Hamline University undergraduate Sarah Bliese, developed a card to detect falsified or degraded antibiotics such as ciprofloxacin or ceftriaxone, both of which the World Health Organization lists as "essential." To screen for a variety of potential quality issues, the researchers included 12 lanes separated by wax barriers on the paper device. Each lane contained a different set of reagents to detect materials or functional groups found in active pharmaceutical ingredients, degradation products or common fillers.
To run a sample, the researchers crush a pill and rub the resulting powder across all 12 lanes, and then dip the bottom of the paper card in water for three minutes. The water wicks up the lanes, bringing reagents into contact with the powder. Colors are formed when the reagents interact with the pharmaceutical, filler or degradation product. The researchers then compare the color pattern from the sample with the color patterns obtained from high-quality pharmaceutical products. The comparison can be done by eye or with an image-analysis program on a smartphone.
Ceftriaxone is sensitive to heat and breaks down if storage temperatures climb too high. As an experiment, the researchers subjected ceftriaxone to high temperatures and ran the card test, simultaneously analyzing the degradation products via liquid chromatography-mass spectrometry. They verified that the colorimetric pattern for the degraded antibiotic was different from that of the correctly stored product. In addition to these tests on the pure active ingredient, Lieberman and Bliese analyzed dozens of real-world samples of ceftriaxone from Kenya and Uganda.
Unscrupulous makers of falsified medication sometimes add colorants containing toxic heavy metals to their products to make the illicit pills more closely resemble their legitimate counterparts, Bliese says. So, in a related project at Hamline University, Bliese and Deanna O'Donnell, Ph.D., are exploring whether a portable X-ray fluorescence spectroscopy device can scan pills for these substances.
In June, Lieberman and Bliese traveled to Kenya to test a new paper card which can detect substandard antibiotics. While Lieberman is currently focusing her work on the developing world, she says her cards could be applicable worldwide to perform, for example, the analysis of herbal medicines and nutritional supplements. "Sometimes those 'herbal products' are actually spiked with pharmaceuticals," she explains. "The paper test cards could be a defense against this." Bliese says her next project will be to develop a paper test card to help first responders identify drugs of abuse and differentiate them from household products or legitimate medicines.
A press conference on this topic will be held Monday, Aug. 22, at 9 a.m. Eastern time in the Pennsylvania Convention Center. Reporters may check in at Room 307 in person, or watch live on YouTube http://bit.ly/ACSlivephiladelphia. To ask questions online, sign in with a Google account.
Lieberman acknowledges funding from the US-AID Development Innovation Ventures program, the Bill & Melinda Gates Foundation and the Indiana Clinical and Translational Sciences Institute. Bliese acknowledges funding from the National Science Foundation REU program.
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Determining quality of antibiotics using paper analytical devices, high performance liquid chromatography, and portable X-ray fluorescence
The quality of antibiotics in the developing world is a growing concern, because poor-quality medicine can cause treatment failure, adverse drug effects, increased drug resistance, and reduce the confidence of consumers in the health care system of the society. Good quality medicines must meet pharmacopeia standards that describe the content and bioavailability of their active pharmaceutical ingredients (APIs). Medicines can fail to meet these standards for reasons including deliberate falsification, careless manufacturing, and degradation during storage. Lack of regulatory and technical capacity allows sub-standard pharmaceuticals to penetrate supply chains and reach patients. In unregulated markets inactive products have been repeatedly identified, and in some instances falsified products have caused clinical problems including renal failure, hepatitis, aconite poisoning, or intoxication with arsenic and mercury.
Ceftriaxone is an injectable antibiotic used to treat life-threatening infections and ciprofloxacin is a wide spectrum fluoroquinolone antibiotic. Both are listed by the World Health Organization (WHO) as essential medicines. We developed a way to detect falsified or degraded ceftriaxone using a paper analytical device (PAD). These paper devices contain 12 lanes, separated by hydrophobic wax barriers, with different reagents deposited on the lanes to detect APIs, degradation products, and fillers that might be used to adulterate falsified products.
Validation of the USP method for the analysis of ceftriaxone sodium, ceftriaxone injectable samples, ciprofloxacin hydrochloride, and ciprofloxacin extended-release samples was completed using High Performance Liquid Chromatography (HPLC). Samples of ceftriaxone were heated to simulate poor storage conditions and the rates of formation of different degradation products were tracked; the products were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Four degradation products were identified throughout the study; the retention times of these products were similar to those of acid hydrolysis products reported in the literature. In parallel with this high-tech instrumentation study, PADs were used to track the colorimetric responses during degradation. A set of ciprofloxacin samples collected by covert shoppers in Kenya were analyzed using HPLC for API concentration and portable X-ray fluorescence (pXRF) for the detection of heavy metals as a qualitative study.