Quantification of the active ingredient in a pharmaceutical topical gel formulation

Significance of the topic

Topical pharmaceutical formulations such as gels, creams and ointments pose analytical challenges because they often require laborious extraction and sample preparation for traditional assays. Rapid, non-destructive alternatives that reduce sample handling and analysis time are therefore valuable for routine quality control and formulation development. This study evaluates Fourier transform near-infrared (FT-NIR) transmission spectroscopy as a fast, minimally invasive method to quantify ketoprofen in a translucent carbopol-based gel matrix.

Objectives and study overview

• Assess the feasibility of FT-NIR transmission spectroscopy to quantify the active pharmaceutical ingredient (ketoprofen) in a clear carbopol gel without extensive sample preparation.
• Prepare a set of gels with defined ketoprofen loadings (0–8% w/w) and build chemometric calibration models to predict drug content.
• Evaluate model performance using cross-validation and independent check samples and report measurement precision and accuracy.

Methodology

• Formulation: Carbopol 980 gel base was prepared with propylene glycol, water and triethanolamine to produce a series of gels containing 0, 1, 2, 4, 6 and 8% (w/w) ketoprofen. A cosolvent of water and propylene glycol plus triethanolamine was used to dissolve the drug prior to mixing with the Carbopol stock.
• Sample handling: Gels were placed into 7 mm diameter disposable glass vials, centrifuged to remove entrapped air, and four aliquots per formulation were prepared to assess reproducibility.
• Spectral acquisition: Transmission-mode FT-NIR spectra were collected at ambient laboratory temperature using an Antaris FT-NIR Analyzer. Measurement parameters: 4000–10000 cm-1 spectral range, 4 cm-1 resolution, 64 co-added scans, approximately 47 seconds acquisition time, InGaAs detector.
• Chemometrics: Data preprocessing included multiplicative scatter correction and derivative treatments (Norris and Savitzky–Golay approaches). Both Stepwise Multiple Linear Regression (SMLR) and Partial Least Squares (PLS-I) algorithms were evaluated. A single-point SMLR model using the spectral feature near 8792 cm-1 (assigned to the second C–H overtone region of ketoprofen) was selected for its simplicity and interpretability. Model selection used press/PRESS plots and leave-one-level-out cross-validation to determine robustness.

Used instrumentation

• Thermo Scientific Antaris FT-NIR Analyzer with standard transmission module.
• InGaAs detector.
• Thermo Scientific TQ Analyst software for chemometric modeling (SMLR, PLS-I).
• Glass vials (7 mm diameter) for sample containment and centrifuge for degassing.

Main results and discussion

• Spectral features: Ketoprofen raw material displayed distinct NIR spectral bands. Second-derivative spectra of the formulated gels retained resolvable features that correlated with drug concentration, enabling quantitative modeling without extraction.
• Calibration details: The single-point SMLR calibration used the intensity at ~8792 cm-1. The calibration exhibited a correlation coefficient (R) of 0.9996 and a Root Mean Squared Error of Calibration (RMSEC) of 0.0775% ketoprofen (w/w).
• Validation: Leave-one-level-out cross-validation produced an RMSECV of 0.0990%, slightly higher than RMSEC as expected. Independent check samples (one sample each omitted from the 1%, 4%, and 6% levels) were predicted with small errors: 1.00% actual → 1.00% predicted (0% difference); 4.00% → 4.02% predicted (+0.55% relative difference); 6.00% → 5.98% predicted (−0.33% relative difference).
• Precision: Six replicate measurements of the 4% level yielded a %RSD of 0.10%, demonstrating excellent short-term repeatability for the transmission measurement in vials.
• Interpretation: The spectral region chosen corresponds to an overtone absorption of methylene/hydrocarbon moieties in ketoprofen, which remains detectable against the gel matrix background when derivative preprocessing and scatter correction are applied. The combination of a translucent gel matrix and transmission measurement geometry facilitated direct analysis without sample extraction.

Benefits and practical applications

• Non-destructive, rapid quantification of active ingredient in translucent topical gels with minimal sample handling.
• Elimination of time-consuming extraction steps reduces analysis time and potential sources of error associated with sample preparation.
• High accuracy and precision suitable for many routine QC tasks and formulation screening during development.
• Method simplicity: a single-wavelength (single-point) SMLR model can provide straightforward implementation for production or laboratory QC environments.

Future trends and potential applications

• Extension to other topical forms: Investigate applicability to cream and ointment matrices or more opaque gels by optimizing measurement geometry (e.g., reflectance vs transmission) and pathlength.
• Robustness across formulation variability: Expand calibration sets to include batch-to-batch variation, excipient level changes, and temperature effects to increase method generalizability.
• Advanced chemometrics: Explore full-spectrum multivariate models (PLS, support vector regression, or machine learning approaches) to handle more complex matrices or low-dose analytes.
• Inline and at-line monitoring: Adapt FT-NIR transmission/reflectance probes for process analytical technology (PAT) to monitor topical product mixing or filling in real time.
• Instrument evolution: Newer FT-NIR instrumentation with higher throughput and improved detectors can further reduce acquisition times and improve sensitivity.

Conclusions

FT-NIR transmission spectroscopy proved to be an effective, rapid and reproducible method for quantifying ketoprofen in a translucent carbopol gel without the need for extraction. The single-point SMLR calibration centered at ~8792 cm-1 delivered excellent linearity, low calibration and cross-validation errors, and strong agreement with independent check samples. Given its speed and minimal sample manipulation, FT-NIR is a practical alternative to traditional, labor-intensive assays for routine QC and formulation development of suitable topical gels.

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