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J. People Plants Environ > Volume 26(6); 2023 > Article
Lee: Development and Validation of Dissolution Test Method for Herbal Medicine Containing Ginsenosides

ABSTRACT

Background and objective: This study aimed to develop a dissolution test method for quality control of commercial 40% ethanol extract of ginseng-containing dosage forms.
Methods: Through preliminary dissolution testing of the commercial dosage forms, suitable parameters for HPLC (high performance liquid chromatography) analysis were determined, including an injection volume of 50 μL and a dissolution time of 1 hour. Additionally, the stability testing of the solution enabled the selection of an appropriate dissolution medium, pH 4.0 buffer solution. Method validation was carried out using reference standard of eight ginsenosides (Rg1, Re, Rf, Rg2, Rb1, RC, Rb2, Rd), indicative components of ginseng, under the selected testing conditions. The evaluation of method validation encompassed specificity, accuracy, precision, and linearity as assessment criteria.
Results: The accuracy assessment revealed that the average recovery rates within a 95% confidence interval were appropriate for all ginsenosides, ranging from 98.25% to 101.17%. The precision evaluation, conducted at an intermediate concentration of 8 μg/mL (n = 6), demonstrated relative standard deviations of 0.25% to 1.08%, which met the criterion of being below 2%. The linearity assessment showed that the coefficient of determination (R2) values for all ginsenosides exceeded 0.999, indicating excellent linearity. The quantification limits ranged from 0.32 to 1.09 μg/mL, confirming their suitability for dissolution assessment of the respective formulation. Employing the selected dissolution test method, the dissolution profiles of most ginsenosides in the commercially available ginseng-containing dosage forms reached their maximum values within 60 minutes. No significant differences were observed in results beyond 120 minutes, confirming that a dissolution time of 60 minutes is appropriate for this dosage form.
Conclusion: The established method holds promise as a valuable tool for quality control of pharmaceuticals containing ginseng, including those previously unassessed, contributing to future applications in the pharmaceutical industry.

Introduction

Ginseng has long been recognized as one of the effective medicinal plants, and it is currently widely used as an ingredient in pharmaceuticals and health functional foods. Research on the efficacy of ginseng has been conducted by numerous researchers (Christensen, 2009). Various products containing ginseng are available on the market, with red ginseng, made by steaming and drying the ginseng roots using traditional methods, being the most popular product (In et al., 2006). This red ginseng exhibits unique characteristics, containing several distinct components such as Rg3, Rg5, and Rk1, which are not found in raw ginseng roots (Kim et al., 2000; Kwon et al., 2001), (Park et al., 2002a, 2002b). Research on the various biological activities of these compounds has been conducted and reported (Shin et al., 2006; Lee et al., 1997; Yue et al., 2006). Ginsenosides, a type of ginseng saponin, are the major constituents known to possess pharmacological and biological activities such as anti-diabetic and anti-tumor effects (Mochizuki et al., 1995; Chen et al., 2006), (Cho et al., 2006a, 2006b), (Han et al., 2006; Lee et al., 2006; Li et al., 2006; Wang et al., 2006; Xie et al., 2005; Yang et al., 2006). To date, over 30 different ginsenosides have been isolated and characterized, each demonstrating distinct pharmacological effects (Kim et al., 2000; Kwon et al., 2001). Ginsenosides can be categorized into two groups based on their aglycone moiety: 20(S)-protopanaxadiol (ginsenoside Rb1, Rb2, Rb3, Rc, Rd, and Rg3) and 20(S)-protopanaxatriol (ginsenoside Re, Rg1, Rg2, and Rh1) (Fig. 1) (Lau et al., 2004; Park et al., 2002; Shin et al., 2006). The Korean government has established official methods for standardizing the content of ginsenosides Rg1 and Rb1, which are marker compounds of ginseng, and particularly, the Ministry of Food and Drug Safety has mandated their determination as a combined quantity when assessing the content of unprocessed saponins (KATS, 2018). The analysis of ginsenosides has been attempted using various analytical instruments, including TLC (thin-layer chromatography), GC (gas chromatography), and HPLC. In the early 1980s, during the development of ginsenoside analysis by GC, direct analysis methods for ginsenoside trimethylsilyl derivatives were commonly employed (Fuzzati, 2004). To ensure the safe and effective management of pharmaceuticals containing natural products, stringent quality control is essential. In the case of orally administered dosage forms, issues related to manufacturing conditions and processes can restrict drug release and absorption, thereby limiting pharmacological activity. Therefore, it is necessary to evaluate specific parameters related to drug release (Ansel et al., 2000). Due to the pharmacological significance of drug release and absorption, dissolution testing is widely utilized for quality control of synthetic pharmaceuticals. However, there is a significant challenge in its broader application for the evaluation of pharmaceuticals containing natural products (Taglioli et al., 2001; Bempong and Houghton, 1992; Kressmann et al., 2002; Westerhoff et al., 2002; Sittichai et al., 2007; Kratz et al., 2008). The characteristics of pharmaceuticals containing natural products pose difficulties as they consist of diverse components from natural substances, making it challenging to establish a correlation between specific pharmacological activity tested in vitro and pharmacological activity within the body. Additionally, variations in the content of indicator substances based on the collection region and time of the raw medicinal plant material hinder the establishment of quantitative analytical methods. The metabolic processes undergone by individual components further complicate the demonstration of a practical association with pharmacological activity (Williamson, 2001). In this study, we aimed to establish a dissolution test method using reference standards for the major indicator substances found in ginseng-containing pharmaceuticals. This method would allow us to predict the in vivo absorption and efficacy of ginseng-containing pharmaceuticals. We conducted validation of this test method to provide a means for appropriately managing the quality and effectiveness of ginseng-containing pharmaceuticals. High-performance liquid chromatography (HPLC) was employed as the analytical instrument to evaluate the specificity, accuracy, precision, linearity, and solution stability of the analytical method. Our goal was to substantiate the proposed method.

Research Methods

Materials

We purchased eight ginsenoside standard reference materials from Biopurify (Chengdu, China). Acetonitrile, used as the analytical solvent, was obtained from Honeywell (Charlotte, USA). Reagents including Sodium chloride, Acetic acid, Potassium phosphate monobasic were purchased from Daejung (Kyunggi, Korea), while Sodium acetate trihydrate and Sodium hydroxide were obtained from Samchun (Kyunggi, Korea). Hydrochloric acid was purchased from Duksan (Kyunggi, Korea). A commercial product, Gincosan capsule (Soho Flordis International Switzerland SA, Switzerland), was used for the dissolution evaluation.

Analytical equipments

For HPLC analysis, we employed the UltiMate 3000 system (Thermo SCIENTIFIC, Waltham, USA). The dissolution test apparatus used for the dissolution testing of ginseng-containing pharmaceuticals was the vision 8 elite (Hanson research, CA, USA).

Preliminary dissolution test

Preliminary dissolution tests to establish the dissolution test duration and assess the analytical suitability in each test medium were conducted according to the “Pharmacopoeial Standards for Pharmaceutical Equivalence Tests” issued by the Ministry of Food and Drug Safety. Three different dissolution media (pH 1.2, pH 4.0, pH 6.8) were used for these preliminary dissolution tests. The tests were performed using commercial formulations containing 40% ethanol-extracted ginseng, with three capsules maintained in 500 mL of dissolution fluid at 37 ± 0.5°C. The tests were conducted using the paddle method, rotating at 50 rpm. Sample solutions were collected at 5, 60, and 120 minutes, followed by filtration for subsequent analysis. The analysis of the sample solutions was performed under the conditions specified in the Korean Pharmacopoeia High-Performance Liquid Chromatography method, with a detection wavelength of 203 nm. The mobile phase conditions, as well as a 1.0 mL/min flow rate, were maintained with an Aegispak-F (C18 4.0 × 125 mm, 3 μm) column at 25°C, as indicated in Table 1.

Injection volume setting for HPLC analysis

To determine the injection volume that would yield suitable chromatograms for the HPLC analysis of the dissolution test samples, we established injection volumes of 10, 30, and 50 μL for a standard solution with a concentration of 1 μg/mL for each ginsenoside in the three dissolution media. We compared and evaluated the peak shape and quantification feasibility as a function of the injection volume. The analysis of the sample solutions was conducted under the conditions specified in the preliminary dissolution test.

Stability test in buffer solutions

In the preliminary dissolution tests, while dissolution rates were observed at 5 minutes in the pH 1.2 dissolution medium, a significant decrease in dissolution rates for most ginsenosides was noted after 60 minutes. To assess the solution stability of ginsenosides at different pH levels, solution stability tests were conducted for each dissolution medium. Standard solutions of each of the eight ginsenosides were prepared to achieve a concentration of 10 μ g/mL and were diluted accordingly. These solutions were maintained at the dissolution test temperature of 37°C and injected in 50 μL aliquots at 4-hour intervals for a total duration of the dissolution test. This allowed for the assessment of the short-term solution stability in each dissolution medium.

Analytical validation

We accurately weighed 5 mg of each of the eight ginsenoside standard reference materials and placed them in 50 mL volumetric flasks. We prepared standard stock solutions with a concentration of 100 μg/mL by adjusting the volume to 30% acetonitrile and then diluted these stock solutions with 30% acetonitrile and pH 4.0 buffer, as shown in Fig. 2. This process was repeated three times to create calibration curves with standard solution concentrations of 1.5, 6, 8, 20, and 30 μg/mL for the method validation. Additionally, for precision evaluation, we prepared six solutions at the intermediate concentration of 8 μg/mL. The acetonitrile content in all standard solutions was adjusted to 9% of the final volume.

Dissolution test of commercial product

Based on the results of the preliminary dissolution tests and solution stability tests, we conducted dissolution testing according to the paddle method, as specification in the general test method of the Korean Pharmacopoeia. The dissolution test was carried out at 37°C in 500 mL of pH 4.0 dissolution medium, with paddle rotation at 50 rpm for 60 minutes. Sample solution collection was performed at 5, 10, 15, 30, 45, and 60 minutes after the start of dissolution. A 50 μL injection volume was used for sample analysis, and the dissolution rates of ginsenosides present in the commercial product were determined over time using the analytical method mentioned above.

Results and Discussion

Setting of dissolution time and injection volume

Based on the preliminary dissolution test results for setting the dissolution time, as shown in Fig. 3, it was determined that in the pH 1.2 dissolution medium, except for ginsenosides Rf and Rg2, no peaks were detected after 60 minutes. Therefore, it was concluded that the pH 1.2 dissolution medium was not suitable for conducting ginse-noside dissolution tests. Subsequently, solution stability tests were conducted for each dissolution medium to observe the changes in ginsenoside peaks over time. In the pH 4.0 and pH 6.8 dissolution media, detectable peaks were observed at 5, 60, and 120 minutes. However, it was noted that the pH 6.8 dissolution medium exhibited a higher standard deviation in overall dissolution rates compared to the pH 4.0 dissolution medium, suggesting potential issues with the precision of the test method. Additionally, considering the characteristics of capsule dosage forms, where the capsules dissolve rapidly, leading to drug release, pH 4.0 dissolution medium was deemed suitable for evaluating the dissolution rate of this dosage form for predicting drug absorption in the gastrointestinal tract. Furthermore, as there was no significant difference in dissolution rates between 60 and 120 minutes in both dissolution media, it was determined that a dissolution time of 60 minutes is appropriate.
For dissolution testing aimed at predicting drug absorption tendencies in the body, relatively low-concentration analyses are required compared to other quality control methods. Especially for ginseng-containing products, the low content of each marker compound, ginsenosides, necessitated research to establish an appropriate injection volume for analysis. Standard solutions of the eight ginsenosides were prepared in pH 1.2, pH 4.0, and pH 6.8 dissolution media at a concentration of 1 μg/mL, with injection volumes set at 10, 30, and 50 μL. According to the HPLC analysis results, as shown in Table 2, it was observed that in the pH 1.2 dissolution medium, all ginsenosides, except for Rf and Rg2, did not exhibit detectable peaks when injecting 10 μL. Even with increased injection volumes, a decrease in peak area with time was observed for Rd. Consequently, it was determined that six ginsenosides, excluding Rf and Rg2, had issues with solution stability under low pH conditions, rendering the pH 1.2 dissolution medium unsuitable for dissolution testing. In contrast, the pH 4.0 and pH 6.8 dissolution media showed relatively stable trends. When injecting 30 μL or more, detectable peaks for all ginsenosides were observed. Considering accuracy in quantitative analysis, an injection volume of 50 μL was chosen as the suitable injection volume for HPLC analysis, which would provide clearer insight into quality changes.

Stability test in dissolution media

It was observed that in the pH 1.2 dissolution medium, the peak areas of all ginsenosides, except for Rg2, significantly decreased with time. Consequently, dissolution stability tests were conducted for all dissolution media. As shown in Fig. 4, in the pH 1.2 dissolution medium, it was observed that the peak areas of all ginsenosides, except for Rg2, decreased with time, and after 24 hours, the peaks of all ginsenosides, except for Rg2 and Rf, were no longer detected. This phenomenon is attributed to the conversion of protopanaxadiol-type ginsenosides, particularly under acidic conditions, into other ginsenosides such as Rg3. Protopanaxadiol-type ginsenosides include ginsenosides Rb1, Rb2, Rc, and Rd, which have hydroxyl groups attached to C-3, C-12, and C-20, while protopanaxatriol-type ginsenosides, including ginsenosides Re, Rg1, Rg2, and Rf, have hydroxyl groups attached to C-3, C-6, C-12, and C-20. The ring portion of ginsenosides is relatively chemically stable, whereas both the sugar and side chain portions are susceptible to chemical reactions. Acid-catalyzed hydrolysis is known to occur readily at the sugar hydroxyl groups and side chains, making acidic conditions unsuitable for the dissolution test of ginsenosides.
The dissolution stability tests in pH 4.0 and pH 6.8 dissolution media exhibited relatively stable results. Even after 24 hours, no significant changes in peak areas were observed when compared to the initial analysis. However, as shown in Fig. 5, the pH 6.8 dissolution medium displayed an increase in the baseline of chromatograms and non-specific internal pressure fluctuations over time. This phenomenon is likely due to differences in solubility associated with excipients or other components in the dosage form at varying pH levels. The elevation of the baseline may adversely affect the precision of the analytical method during method validation. Therefore, pH 4.0 dissolution medium was deemed the most suitable for the dissolution test.

Analytical validation

The selected test method, determined through preliminary testing, underwent method validation for specificity, linearity, precision, and accuracy. As evident from Fig. 5, it can be observed that six peaks, excluding Rg1 and Re, were completely separated, while the peaks of Rg1 and Re were in close proximity. To assess specificity, resolution values between these peaks were determined. The selected test conditions included identical analytical parameters, an injection volume of 50 μL, and the use of a pH 4.0 buffer solution for dissolution testing.
The results of the specificity evaluation, as shown in Table 3, revealed that the resolution between ginsenosides Rg1 and Re exceeded 1.5. This finding confirmed compliance with the validation criteria set by the Ministry of Food and Drug Safety (MFDS), indicating that the method is suitable. Linearity and the evaluation of the quantitation limit (LOQ) were demonstrated as follows: Table 4 illustrates that the coefficient of determination (R2) exceeded 0.999 for all ginsenosides, satisfying the validation test criteria. The LOQ values, derived from the slope of the calibration curve and the standard deviation of the response, indicated a maximum of 1.09 μg/mL for ginsenoside Re, demonstrating its suitability for the analysis of dissolution test samples.
In terms of accuracy, as shown in Table 5, the average recovery rates for all ginsenosides at various concentrations fell within the 95% confidence intervals, providing evidence of method suitability and accuracy.
Precision was evaluated through six repeated tests at the intermediate concentration of 8 μg/mL. As indicated in Table 6, the standard deviation of the recovery rate for all ginsenosides was found to be below 2%, confirming compliance with the criteria. Even for Rd, which exhibited the highest standard deviation of 1.08, it was well within the 2% criterion, representing approximately 54% relative to the standard. This demonstrates that precise results can be achieved for the analysis of all ginsenosides.

Dissolution test of commercial product

Following the established dissolution testing method through method validation, dissolution tests were conducted on commercially available products. The dissolution rates were calculated as a percentage relative to the content of each ginsenoside, which was determined through quantitative analysis. As shown in Fig. 6, it was observed that all ginsenosides exhibited a dissolution rate of 90% or higher within 60 minutes.
In accordance with the guidelines for setting dissolution specifications for oral pharmaceuticals established by the Korea National Institute of Food and Drug Safety Evaluation, it is recommended that for general (non-controlled release) formulations, conditions should be selected to ensure an appropriate dissolution rate within one hour, as excessively rapid dissolution rates over time can compromise the discriminative power in comparing drug release profiles. Therefore, the conditions used in this study, namely a pH 4.0 dissolution medium and a rotation speed of 50 rpm for dissolution testing, were found to be in compliance with these guidelines.

Conclusion

Through this study, an appropriate dissolution testing method for ginseng-containing pharmaceuticals, widely used for disease prevention and treatment, was established and its suitability was demonstrated through method validation. While most herbal medicines containing pharmaceuticals are generally subject to quality control based on the content criteria of marker substances, the importance of quality control related to the prediction of the in vivo absorption of each marker substance is increasing. If the dissolution rate of each marker substance is adopted as a criterion for quality control through in vitro dissolution testing, it is expected to contribute to safer and consistent pharmaceutical quality control. Furthermore, it is anticipated that this approach can serve as a basis for quality control requirements when these pharmaceuticals are exported abroad.

Fig. 1
Chemical structure of ginsenosides.
ksppe-2023-26-6-793f1.jpg
Fig. 2
Schematic diagram of analytical method validation.
ksppe-2023-26-6-793f2.jpg
Fig. 3
Preliminary dissolution test results for dissolution time configuration in pH 1.2 buffer (A), pH 4.0 buffer (B) and pH 6.8 buffer (C).
ksppe-2023-26-6-793f3.jpg
Fig. 4
Solution stability test result of ginsenosides in various pH buffer solutions.
ksppe-2023-26-6-793f4.jpg
Fig. 5
Results of chromatographic changes in dissolution testing over time in various pH buffer solutions.
ksppe-2023-26-6-793f5.jpg
Fig. 6
Dissolution test result of commercial product in pH 4.0 buffer
ksppe-2023-26-6-793f6.jpg
Table 1
Gradient condition of HPLC mobile phase
Time (min) Mobile phase A* (vol. %) Mobile phase B** (vol. %)
0 – 18 80 20
18 – 23 80 → 74 20 → 26
23 – 25 74 → 73.5 26 → 26.5
25 – 38 73.5 → 72 26.5 → 28
38 – 61 72 → 68 28 → 32
61 – 65 68 → 80 32 → 20
65 – 75 80 20

* A : Distilled water,

** B : Acetonitrile

Table 2
Peak detection in chromatogram of ginsenosides according to injection volume
Ginsenosides pH 1.2 buffer pH 4.0 buffer pH 6.8 buffer



Injection volume Injection volume Injection volume



10 μl 30 μl 50 μl 10 μl 30 μl 50 μl 10 μl 30 μl 50 μl
Rg1 X X X O O O O O O
Re X X X O O O O O O
Rf O O O O O O O O O
Rg2 O O O O O O O O O
Rb1 X X X X O O O O O
Rc X X X O O O O O O
Rb2 X X X X O O O O O
Rd X O O O O O X O O
Table 3
Resolution value between ginsenoside Rg1 and Re
Conc. (μg/mL) Avg. resolution
1.5 1.99
6 1.95
8 1.94
20 1.93
30 1.94
Table 4
Results of linearity and limit of quantitation using calibration curves
Evaluation factor Rg1 Re RF Rg2 Rb1 Rc Rb2 Rd
R2 0.9999 0.9999 0.9999 0.9999 0.9999 0.9999 0.9999 0.9999
LOQ (μg/mL) 0.60 1.09 0.57 0.44 0.32 0.59 0.55 0.58
Table 5
Accuracy evaluation results at the 95% confidence interval
Ginsenosides Conc.(ppm) Avg. recovery (%) 95% confidence interval (%)
Rg1 1.5 99.13 98.07 – 101.26
8 99.92
30 99.95

Re 1.5 101.17 98.86 – 101.72
8 99.70
30 99.99

Rf 1.5 99.75 99.09 – 100.72
8 100.07
30 99.90

Rg2 1.5 99.17 98.97 – 100.44
8 100.04
30 99.91

Rb1 1.5 100.50 99.07 – 101.16
8 99.80
30 100.05

Rc 1.5 104.77 97.65 – 105.11
8 99.23
30 100.14

Rb2 1.5 98.25 96.54 – 102.50
8 100.32
30 99.99

Rd 1.5 98.95 95.97 – 103.18
8 99.72
30 100.05
Table 6
Precision evaluation results at 8 μg/mL concentration
Ginsenosides Conc. (μg/mL) Recovery RSD (%) (spec. < 2%)
Rg1 8 0.32
Re 0.32
Rf 0.25
Rg2 0.51
Rb1 0.38
Rc 1.02
Rb2 0.82
Rd 1.08

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