Rapid Detection of the Low Dose API in Xanax Using Surface-Enhanced Raman Spectroscopy for Anti-Counterfeiting Purposes

Significance of the Topic

Counterfeit prescription drugs represent a growing threat to patient safety and public health. In recent years, fake Xanax tablets containing the potent opioid fentanyl have been linked to multiple overdoses. Traditional handheld Raman spectroscopy often fails to detect low-dose APIs on pill surfaces, creating a need for a more sensitive field-deployable method. Surface-enhanced Raman spectroscopy (SERS) offers the potential to identify trace amounts of active ingredients rapidly and non-destructively, making it an effective tool against pharmaceutical counterfeiting.

Objectives and Study Overview

The primary aim of this work was to develop and validate a SERS-based approach for on-site detection of the low-dose API alprazolam (<0.2 % w/w) in commercial Xanax tablets using a handheld Raman spectrometer. A secondary objective was to demonstrate the method’s ability to distinguish fentanyl, which is often substituted in fake capsules. By establishing characteristic SERS signatures and employing a spectral correlation algorithm, the method provides a rapid anti-counterfeiting screening workflow.

Methodology and Instrumentation

Sample Preparation and Measurement Workflow:

• Approximately 30 mg of a 0.25 mg alprazolam Xanax tablet was dissolved in 0.5 mL acetone.
• A paper-based SERS substrate was immersed for ~30 s to capture the dissolved compounds.
• The substrate was inserted into the handheld Raman analyzer and spectra were recorded at three distinct spots (integration time 15–30 s each).

Instrumentation:

• TacticID GP Plus handheld Raman spectrometer with 785 nm laser excitation
• TacticID N Plus handheld Raman spectrometer
• TacPac adapter for SERS substrates
• Onboard spectral library and correlation (HQI) software

Key Results and Discussion

• Direct Raman spectra of Xanax pills revealed only excipient peaks (lactose, cellulose, starch, magnesium stearate) and no alprazolam signatures.
• SERS spectra from authentic Xanax exhibited clear alprazolam peaks at 688, 1000, 1132, 1160, 1312, 1380, 1484, 1568 and 1592 cm⁻¹, despite the API being <0.20 % w/w.
• Excipient materials showed negligible SERS response, confirming high selectivity for the target API.
• Fentanyl samples produced distinct SERS peaks (e.g., strong band at 1000 cm⁻¹) but lacked alprazolam-specific features, enabling reliable discrimination.
• Spectral matching using Hit Quality Index (HQI) yielded average values of 91.0 for alprazolam in Xanax and 82.3 for fentanyl, with no false positives from excipients.

Benefits and Practical Applications of the Method

• Rapid, non-destructive in-field screening of tablets without sample compromise.
• High sensitivity for low-dose APIs, overcoming limitations of conventional Raman.
• Simple sample preparation suitable for law enforcement and customs officers.
• Integrated spectral library and correlation software for real-time decision support.
• Capability to detect and differentiate dangerous adulterants such as fentanyl.

Future Trends and Potential Applications

• Expansion of SERS substrate chemistries to broaden analyte coverage.
• Integration of AI-driven spectral interpretation for automated threat alerts.
• Real-time library updates and cloud connectivity for emerging counterfeit signatures.
• Application to quality control in pharmaceutical manufacturing and supply chain verification.
• Development of multiplexed portable devices combining SERS with complementary techniques.

Conclusion

A handheld SERS approach has been successfully demonstrated to detect and confirm the presence of trace alprazolam in Xanax tablets and to identify fentanyl substitutions. The method delivers rapid, selective, and non-destructive analysis in the field, providing a valuable tool for law enforcement and the pharmaceutical industry in the fight against counterfeit medications.

References

• U.S. Food and Drug Administration. Counterfeit Medicine. http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/CounterfeitMedicine/
• Addiction Resource. The Dangers of Fentanyl. https://addictionresource.com/drugs/the-dangers-of-fentanyl/
• U.S. Drug Enforcement Administration. Counterfeit Prescription Pills. https://www.dea.gov/docs/Counterfeit%20Prescription%20Pills.pdf
• Xanax Official Site. https://www.xanax.com/
• National Institute on Drug Abuse. Drugs of Abuse: Fentanyl. https://www.drugabuse.gov/drugs-abuse/fentanyl