Identification of Synthetic Impurities and Their Significance in Natural Products Quality Control

To the Editor

Herbal remedies are widely sought after in developing countries for primary healthcare due to their cost-effectiveness, compatibility with the human body and minimal adverse effects. According to World Health Organization, 80% of the world's population still rely on traditional medicine as their primary health care. Most of the modern drugs in the market such as aspirin, digitoxin, morphine, and quinine are derived through the scientific validation of herbal medicines.

Nationally and internationally many of the pharmacopoeias and formularies had incorporated monographs for quality control of herbal species/extracts. These monograph analyses are based on herbal analytical/biological markers. Thus, these markers are gaining importance in the market as they are utilized to standardize and prove the chemical/Biological equivalence of herbal drugs. Thus, herbal drugs are adulterated with these analytical/biological markers for chemical and biological equivalence to match the regulatory requirements. Many of these herbal medicines/dietary supplements are sold in powder form, making them vulnerable to contamination with synthetic analogues. ¹ Unfortunately, in today's scenario, most herbal products have not been subjected to a drug approval process to demonstrate their safety and effectiveness.

Thus, there is an urge to define specific and novel analytical methods that can identify and quantify the presence of synthetic analogues in herbal medicines/dietary supplements which is evident through the literature for the analysis of herbal medicines for the presence of synthetic analogues.^2–4 It is essential to make a qualitative assessment and quantify the synthetic analogue's adulteration to sensitize the regulatory bodies and promote active vigilance on herbal formulations that are prone to adulteration with synthetic analogues.

Synthetic Analogues

The term “synthetic analogue” denotes a chemical compound that closely resembles a naturally occurring counterpart but exhibits slight differences in chemical structure, properties and functionality. These compounds are occasionally termed “designer drugs” due to their artificial modification derived from existing drugs. Within the realm of pharmacology, an analog can manifest as either a functional analogue or a structural analogue. A functional analogue possesses comparable physicochemical and pharmacological properties to the natural compound, while a structural analogue is characterized by a chemically altered structure in comparison to another compound. Exemplifying pharmacological analogues are morphine, heroin and fentanyl, all sharing the same mechanism of action as naturally occurring morphine, albeit with fentanyl exhibiting a distinct chemical structure from the other two. ⁵

Even though synthetic analogues have a similar biological effect, novel psychoactive substances containing synthetic cannabinoids are often regarded as powerful and hazardous, leading to significant adverse effects. For instance, they have been found to result in more severe neuropsychiatric side effects compared to their natural counterparts. Also, the impurities and related substances formed during the synthetic process may cause adverse effects. ⁶

Current Available Analytical Techniques and Their Limitations

Many methods were reported for the detection of adulteration, most of these techniques were capable of detecting the Active Pharmaceutical Ingredients and other drugs that are therapeutically similar to the natural phyto active constituents. A near-infrared spectroscopy method was developed and reported to rapidly identify illegal synthetic adulterants in herbal antidiabetic medicines. ⁷ A recent study carried out screened and quantified 14 synthetic antidiabetic adulterants in herbal pharmaceuticals utilizing high-performance liquid chromatography (HPLC) and other analytical techniques. ⁸ A very recent research work reported a simultaneous determination of selected antidiabetic pharmaceutical drugs as adulterants in herbal medicines sold in Kenya using liquid chromatography–tandem mass spectrometry (LC-MS/MS). ⁹

To overcome this barrier, the University of Georgia developed a test method using the radiocarbon dating technique to analyze curcumin products on the market to determine the percentage of synthetic curcumin (SC) versus natural curcumin (NC) or a combination of both. Currently, this approach is not in use due to its high expenditure, high-skilled labor, time consumption and lack of availability. ¹⁰ To support and enrich scientific knowledge, much simpler methods are required which can be utilized for routine analysis by the regulatory agencies.

In our recent study, a simple, rapid and cost-effective reverse-phase HPLC technique was developed for the isolation, identification, characterization and quantification of synthetic impurities present in SC. The same method was applied to the NC and the characterized impurities that were found in SC were not found in NC. The synthesis of SC involves the utilization of specific chemicals, solvents, reagents and intermediates that differ from those found in the extraction of NC. Thus, this innovative concept allows for the detection of adulteration in NC by SC using the developed analytical method for synthetic impurities. ⁴

In conclusion, the diversity of impurities in natural products diverges substantially from those encountered in synthetic chemicals or analogues, as influenced by factors such as the synthetic pathway, extraction techniques, raw materials, solvents and intermediate products.^4,11 Expanding upon this innovative paradigm, the development of pioneering analytical methodologies such as HPLC, LC-MS/MS, inductively coupled plasma mass spectrometry, high-resolution mass spectrometry and gas chromatography–mass spectrometry for the identification and characterization of impurities in synthetic chemicals or analogues emerges as an efficacious strategy for addressing issues related to natural product adulteration and ensuring quality control. This groundbreaking approach holds considerable promise across diverse domains, encompassing quality control in the analysis of natural drugs, food assessment and the anticipation of potential toxicities.