Fluoride has been shown to be effective at preventing tooth decay and supporting remineralization of tooth enamel [1,2]. Aside from the fluorination of drinking water, milk, or salt, fluoride can also be encountered as a topical fluoride supplement such as fluoride tablets, toothpastes, mouthwashes, or gels [2,3]. However, its efficacy highly depends on concentration and dosage, which is also crucial to avoid overdosage and fluorosis [2].
Analytical methods, including ion chromatography (IC), are used to ensure that fluoride tablets meet the quality standards as given by the United States Pharmacopeia and National Formulary (USP-NF).
IC with suppressed conductivity detection has been approved by the USP as a validated method to quantify fluoride content in sodium fluoride tablets [4]. Using the Metrosep A Supp 16 - 250/4.0 column and applying a hydroxide eluent provides the required separation of fluoride and acetate. The qualification was performed according to USP General Chapters [5–7] and met all acceptance criteria from the USP Monograph «Sodium Fluoride Tablets» [4].
The system suitability solution and the standard solutions are prepared from a USP Sodium Fluoride RS certified standard by dilution with ultrapure water (UPW). The system suitability solution contains 2.0 µg/mL sodium fluoride (NaF) and 1.0 µg/mL of sodium acetate. The standard solutions contain 2.0 µg/mL NaF.
Samples were prepared from ground sodium fluoride tablets. A 0.215 g portion of the powder was accurately weighed and transferred into a 1000 mL volumetric flask. The flask was subsequently filled up to the mark with UPW.
To ensure complete dissolution, the mixture underwent ultrasonic agitation for 10 minutes. The resulting solution was then subjected to filtration using a 0.2 µm pore size membrane filter. The filtered solution was diluted 1:10 with UPW to achieve a final concentration of 2.0 µg/mL NaF.
Samples and standard solutions were injected directly into the IC using an 858 Professional Sample Processor (Figure 1).
Fluoride was separated from acetate by applying a binary potassium hydroxide gradient (Tables 1 and 2) and using the Metrosep A Supp 16 column (L91) followed by chemically suppressed conductivity detection.
Table 1. Requirements for the IC method as per USP Monograph «Sodium Fluoride Tablets» [4].
| Column with L91 packing | Metrosep A Supp 16 - 250/4.0 |
|---|---|
| Flow rate | 1.0 mL/min |
| Eluent | A: 100 mmol/L Potassium hydroxide B: Ultrapure water |
| Temperature | 40 °C |
| Injection volume | 20 μL |
| Detection | Suppressed conductivity |
Table 2. Binary gradient program for USP Monograph «Sodium Fluoride Tablets» [4].
| Time (minutes) | Eluent A (%) | Eluent B (%) |
|---|---|---|
| 0.0 | 15 | 85 |
| 7.0 | 15 | 85 |
| 8.0 | 80 | 20 |
| 15.0 | 80 | 20 |
| 15.1 | 15 | 85 |
| 25.0 | 15 | 85 |
The IC method presented for fluoride determination in sodium fluoride tablets was qualified according to the general requirements of USP and the USP Monograph «Sodium Fluoride Tablets» [4–7].
The appropriate separation of fluoride and acetate on the A Supp 16 column was achieved by applying a hydroxide gradient (Table 3). The chromatogram is shown in Figure 2.
The relative retention times (rG, unadjusted) for fluoride and acetate are 1.0 and 1.3, respectively. These unitless values are automatically calculated with the MagIC Net software by applying the following formula:
rG = relative retention time, unadjusted
tRi = retention time peak of interest
tRst = retention time peak of reference peak (peak corresponding to the substance to be examined, sodium fluoride)
Table 3 shows that the system suitability criteria are met, including resolution, tailing factor, and relative standard error (RSD) of multiple standard injections [4].
Table 3. System suitability test requirements and results from the study.
| Parameter | Actual | USP requirement | Status |
|---|---|---|---|
| Resolution fluoride/acetate | 3.7 | NLT 1.5 | Pass |
| Tailing factor for fluoride | 1.4 | NMT 2.0 | Pass |
| RSD fluoride (%, n=5) | 0.4 | NMT 2.0 | Pass |
The calibration for the sample analysis was performed using a single standard at 2.0 μg/mL NaF injected six times. The sample was analyzed in duplicate and fulfilled the respective USP validation criteria as shown in Table 4.
Table 4. Sample test showing the calculated percentage of the labeled amount of sodium fluoride (NaF) in the used tablets reached in the analysis.
| Parameter | Actual | USP requirement | Status |
|---|---|---|---|
| Fluoride sample [%] | 99.4 | 90–110 | Pass |
Ion chromatography (IC) has successfully passed the qualification tests for quantifying the fluoride content in pharmaceutical tablets, in full compliance with the USP Monograph «Sodium Fluoride Tablets». The qualification was conducted in accordance with the guidelines set by the USP.
Regarding system suitability and sample analysis, the IC method passed all predefined acceptance criteria including resolution, tailing factor, and the relative standard deviation for repeated standard injections as well as for the sample result. Consequently, ion chromatography has qualified as a reliable and highly automated method for fluoride quantification in pharmaceutical compounds, offering both user-friendliness and accurate results.
- Pollick, H. The Role of Fluoride in the Prevention of Tooth Decay. Pediatric Clinics of North America 2018, 65 (5), 923–940. https://doi.org/10.1016/j.pcl.2018.05.014.
- Yeung, C. A. A Systematic Review of the Efficacy and Safety of Fluoridation. Evid Based Dent 2008, 9 (2), 39–43. https://doi.org/10.1038/sj.ebd.6400578.
- ADA Science & Research Institute, LLC. Fluoride: Topical and Systemic Supplements. Department of Scientific Information, Evidence Synthesis & Translation Research, ADA Science & Research Institute, LLC. 2023.
- U. S. Pharmacopeia/National Formulary. USP Monographs, Sodium Fluoride Tablets; USP/NF, Rockville, MD, USA.
- U. S. Pharmacopeia/National Formulary. <621> Chromatography. In General Chapter; USP/NF, Rockville, MD, USA.
- U. S. Pharmacopeia/National Formulary. General Chapter, <1065> Ion Chromatography; USP-NF: Rockville, MD, USA, 2023. https://doi.usp.org/USPNF/USPNF_M897_01_01.html.
- U. S. Pharmacopeia/National Formulary. General Chapter, <1225> Validation of Compendial Procedures; USP-NF: Rockville, MD, USA, 2023. https://doi.org/10.31003/USPNF_M99945_04_01.
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