# A new chromatographic approach for the simultaneous determination of tramadol, ibuprofen, and caffeine in a novel fixed-dose combination tablet: an integrated framework to analytical sustainability and multimodal analgesia

## TL;DR

A new HPLC method is developed to quickly and accurately measure tramadol, ibuprofen, and caffeine in a combined pain relief tablet.

## Contribution

The first HPLC method for simultaneous quantification of tramadol, ibuprofen, and caffeine in a fixed-dose combination tablet is developed and validated.

## Key findings

- The HPLC method achieved optimal separation within 8 minutes using a Zorbax SD-C8 column and specific mobile phase.
- The method showed high accuracy (100.42% to 100.82%) and precision (<2% RSD) for the three drugs.
- The method was evaluated for sustainability using multiple green analytical metrics.

## Abstract

Multimodal analgesia and rational polypharmacy have emerged as modern pain management strategies, offering synergistic pain relief while mitigating the adverse effects of high-dose monotherapy. A novel antinociceptive fixed-dose combination tablet containing tramadol, ibuprofen, and caffeine exemplifies this approach by integrating a centrally acting weak opioid tramadol, a peripherally acting nonsteroidal anti-inflammatory drugs ibuprofen, and a central nervous system stimulant adjuvant caffeine into a single formulation. In the present work, the first HPLC method for the concurrent quantification of tramadol, ibuprofen and caffeine in bulk powder and tablet dosage forms was developed and validated to support the quality control of this innovative multimodal analgesic fixed-dose combination. The optimal chromatographic separation was achieved using a Zorbax SD-C8 column (150 × 4.6 mm, 5 µm) as the stationary phase. The mobile phase was composed of acetonitrile: 0.01 M phosphate buffer pH 5.0 (35.0: 65.0, v/v), delivered at a flow rate of 1.0 mL/min with UV detection at 220.0 nm. The separation was achieved within 8.0 min, with linearity ranges of 1.0–45.0 μg/mL for tramadol, 1.0–25.0 μg/mL for ibuprofen, and 1.0–30.0 µg/mL for caffeine. The suggested method was validated according to the ICH guidelines and successfully utilized for the quantitative determination of tramadol, ibuprofen and caffeine in bulk powder, laboratory-prepared mixtures and pharmaceutical formulation. The proposed method exhibited outstanding performance for determination of the three cited drugs, characterized by high accuracy (ranging from 100.42% to 100.82%) and excellent precision (< 2% RSD). The sustainability profile of the method was assessed using the Analytical eco-scale, Analytical GREEnness metric, Green analytical procedure index, Blue Applicability Grade Index, White analytical chemistry, and Violet Innovation Grade Index to evaluate the sustainability, applicability, and innovative potential of the proposed method. The method combines analytical rigor, operational simplicity, and sustainable design, setting a new benchmark for analytical support of rational polypharmacy products.

The online version contains supplementary material available at 10.1186/s13065-025-01688-8.