1. Introduction
Curcuma longa L., or turmeric, is a perennial herb belonging to the family Zingiberaceae, commonly used in Asian food curries and dietary supplements [1]. The United States Pharmacopeia (USP) defines “curcuminoids” as the sum of curcumin (CUR), desmethoxycurcumin (DMC), and bisdesmethoxycurcumin (BMC) as a partially purified natural complex of diarylheptanoid derivatives isolated from turmeric [1,2,3]. The global curcumin market for turmeric and dietary supplements is estimated at USD 155 million in 2024 and is expected to reach USD 240.68 million by 2029 [4]. Several turmeric-based products (capsules, tablets, dairy products, functional foods, and raw rhizome powder) are available in the market. They are susceptible to occasional contamination and adulteration with different substances [1,5,6]. Turmeric-based products either mixed with or substituted by other Curcuma species, starches, synthetic curcuminoids, or dyes can potentially cause issues related to human health [7,8]. For instance, the consumption of turmeric products contaminated with a yellow azo dye, metanil yellow, has been linked to neurotoxicity, while turmeric contaminated with lead chromate is associated with lead poisoning [9,10].
The rhizome of C. longa is commonly used for the preparation of dietary supplements (DS), which comprises mainly 3–5% diarylheptanoids (curcuminoids), and ~6% turmeric oil [11,12]. Curcuminoids (orange-yellow color) are key active non-volatile components of rhizome, while CUR, DMC, and BMC are major curcuminoids. Volatile turmeric oil is responsible for the aromatic rhizome flavor that is rich in sesquiterpenes. The major and most representative components of sesquiterpenes are aryl-, α-, and β-turmerones [13,14,15,16]. Both volatile and non-volatile components of turmeric rhizome are known for their various pharmacological properties. It is thus essential to evaluate the phytochemical composition of turmeric rhizomes for the quality control of DS on the market. Although numerous studies have been published on determining the curcuminoid ratio, limited studies are available on volatile analysis, non-targeted analysis, keto-enol forms of bioactive curcuminoids under different pH conditions, and disintegration studies.
Fourier transform infrared (FTIR) and near-infrared (NIR) spectroscopy techniques are valuable tools in identifying adulterant substances in nutraceuticals, functional foods, and spices [17,18]. Spectroscopic data coupled with chemometric modeling are powerful tools for determining the authenticity of samples. Several studies have been published on analyzing turmeric dietary supplements using spectroscopy techniques. For example, Shannon et al. reported the correct identification of typical turmeric samples (100%) and spiked samples (98.8%) using FTIR coupled with chemometric analysis [17]. Similarly, Thangavel et al. used FT-NIR along with a multivariate analysis to determine the curcumin, starch, and moisture contents in turmeric samples [18].
Previously, our lab developed a rapidly targeted UHPLC-MS method for separating curcuminoids and three adulterants, metanil yellow, Sudan I, and Sudan red G [5]. We also reported the roles of different solvents such as water, milk (homogenized, 2% reduced fat, low fat, fat free, soy, almond, coconut, and milkadamia), and different proportions of aqueous ethanol mixtures on the extractability of curcuminoids from turmeric powder [19]. In this study, we initially investigated the application of spectral fingerprinting methods to differentiate between commercial turmeric DS samples, including eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3) available from commercial sources. Furthermore, we performed targeted and non-targeted analyses to identify the bioactive curcuminoid concentration, ratios, and volatile components. In addition, we also performed disintegration studies on limited samples and investigated the influence of acidic pH on curcuminoids. This information will be significant to regulatory agencies, pharmacologists, manufacturers, and consumers.
2. Materials and Methods
2.1. Solvents and Materials
LC-MS-grade reagents (methanol, acetonitrile, formic acid, and water) were purchased from Fisher Scientific (Pittsburgh, PA, USA). GC-grade hexane was purchased from Fisher Scientific (Pittsburgh, PA, USA). Disposable 15 mL polypropylene centrifuge tubes used to extract metabolites from turmeric were purchased from Thermo-Scientific (Waltham, MA, USA). LC and GC vials were purchased from Fisher Scientific (Pittsburgh, PA, USA). Disposable syringe and polyvinylidene difluoride (PVDF) syringe filters with a pore size of 0.45 µm were purchased from National Scientific Company (Duluth, GA, USA). The standard curcuminoid samples were purchased from Toronto Research Chemicals Inc., Toronto, Ontario, Canada. The ar-tumarone standard was purchased from PhytoLab GmbH & Co. KG, Vestenbergsgreuth, Germany.
2.2. Experimental Samples
Commercial turmeric DS samples, including eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3), were purchased from commercial online and local grocery stores. Dried rhizome samples and tablets were ground using a typical coffee Mill grinder (Model 550K-Black, Muller, Austria) purchased from Amazom.com (Seattle, Washington, USA). The capsules were opened, and the ground powder was used for analysis. The polymeric capsule coverings were discarded.
2.3. FT-IR and NIR Data Analysis of DS and Rhizome Samples
Fourier transform infrared (FT-IR) and near-infrared (NIR) spectral fingerprints of turmeric DS and rhizome samples were analyzed using a Nicolet iS50 FT-IR with OMNIC-32 software (Thermo-Scientific, Waltham, MA, USA). Fine ground powder samples were separately placed in 4 mL glass vials and mixed thoroughly, and individual vials were analyzed in triplicate. Diffuse reflectance NIR and FT-IR spectra were collected from the ranges of 10,000–4000 cm−1 and 4000–400 cm−1, respectively, at a resolution of 4 cm−1 using an integrating sphere and ATR crystal, respectively. The spectral data were converted to Excel format. InGaAs 2.6 µm and DTGS ATR detectors were used for NIR and IR analyses, respectively. The spectral data were converted to Excel format, and multivariate analysis was performed using Solo software (release 7.8.2, Metlab version 7.9.0.529, Eigenvector Research, Inc., Manson, WA, USA).
2.4. Extraction and Analysis of Curcuminoids
Dietary supplements and turmeric rhizome powder (100 ± 0.2 mg) were extracted with 5 mL of 80% aqueous methanol under sonication (Advanced Sonic Processing Systems, Oxford, CT, USA) into 15 mL polypropylene centrifuge tubes for 30 min. Extracts were centrifuged at 1792× g for 15 min and filtered using 0.45 µm PVDF filter. The filtrate was transferred to 2 mL HPLC amber glass vials and analyzed by UHPLC-MS/MS analyses.
Ultraviolet–visible spectral analysis: Aliquots of methanolic extracts (100 µL) of DS and rhizomes were pipetted into a 96-well microplate reader (Molecular Devices, SPECTRAmax Plus 384, San Jose, CA, USA) equipped with a SoftMax Pro software version 5.2.0. The absorption intensity of the extracts and different concentrations of reference standards were collected at 420 nm.
UHPLC-DAD analysis of curcuminoids: UHPLC system (series 1290, Agilent Technologies, Santa Clara, CA, USA) consisting of a quaternary pump, autosampler, and diode array detector was used for curcuminoids analysis. Chromatographic separations were performed on C18 Agilent column (ZORBAX, Eclipse Plus, 2.1 × 50 mm, 1.8 µm, 1200 bar pressure limit, Agilent Technologies) using water (mobile phase A) and acetonitrile (mobile phase B) both acidified with 0.1% formic acid. The gradient program was set as follows: 35–50% phase B (0–11 min), and then 50–95% (11–12 min) and kept isocratic for 1 min, followed by 95–65% B (1 min) and kept isocratic for 3 min. The total run time was 16 min. The flow rate and the injection volume were maintained at 0.6 mL/min and 10 µL, respectively. Data were collected at 420 nm, and Open Lab Agilent software (M8301-61033, Agilent Technologies, Santa Clara, CA, USA) was used for data processing. Three standard curcuminoids (BMC, DMC, and CUR) were accurately weighed with an analytical balance and dissolved in methanol. The stock solution concentration was 100 μg/mL. Different concentrations (range of 0.8–50.0 µg/mL) were injected into the UHPLC-DAD, and calibration curves were prepared by plotting the peak area against the different concentrations.
2.5. GCMS Analysis of Hexane Extract
Extraction of non-polar compounds from dietary supplement and turmeric rhizome powder (100 ± 0.2 mg) was performed with 5 mL hexane. The solution mixture was sonicated for 15 min in a sonicator bath (Advanced Sonic Processing Systems, Oxford, CT, USA). Extracts were centrifuged at 1792× g for 15 min and filtered using a 0.45 µm PVDF filter. The filtrate was transferred to 2 mL amber color HPLC vials and analyzed by GC-MS.
GC-MS system performed the chromatographic separation of volatile compounds from hexane extracts from commercial dietary supplements and turmeric rhizomes (Agilent GC 6890, Santa Clara, CA, USA). An HP-5 MS capillary column 30 m in length with an internal diameter of 0.25 mm and a film thickness of 0.25 µm was used (Agilent, Santa Clara, CA, USA). The injection and mass transfer line temperatures were set at 260 °C and 250 °C, respectively. The amount injected into the GCMS system in spitless mode was 1 µL. Helium was used as a carrier gas at a flow rate of 1.0 mL/min. The temperature program was set as follows: the initial oven temperature was kept at 50 °C for 2 min and then gradually increased to 100 °C at a rate of 5 °C/min. The temperature was maintained at 100 °C for two additional minutes. The temperature again increased from 100 °C to 250 °C at the rate of 10 °C/min and held at 250 °C for two additional minutes. Total run time was 31 min. A single quadrupole mass spectrometer was operated at 70 eV with the electron ionization (EI) source kept at 260 °C. A total of 781 scans per second were recorded over the mass range of m/z 50–1000. The identification of volatile compounds was achieved using the mass spectra database of the National Institute of Standards and Technology (Ver. NIST MS search 2.0) and with data in the literature.
2.6. Untargeted Metabolomic Analysis
Extracts obtained from turmeric DS and dried rhizomes were analyzed with the Vanquish UHPLC system coupled with a diode array detector (DAD), charged aerosol detector (CAD), and an Exploris 240 mass high-resolution mass spectrometer (Thermo Scientific, Waltham, MA, USA). The UHPLC conditions for chromatographic separation are described in Section 2.7, except the injection volume was 5 µL. The ESI-MS conditions were as follows: the mass range was set in a range of 100–1000 m/z, and sheath gas, auxiliary, and sweep gas were set at 50, 10, and 1 (arbitrary units), respectively. Capillary and vaporizer temperatures were set at 320 °C and 350 °C, respectively, while spray voltage was set at 3.5 kV. The full scan mass spectra and data-dependent acquisition (DDA) events were acquired at a resolving power of 60,000. For MSn activation, an isolation width of 1 amu; a maximum ion injection time of 100 ms; stepped collision energy values of 30, 50, and 150 eV; and an activation time of 10 ms were used. High-resolution mass data were acquired in both positive and negative ionization modes. The software package Xcalibur 4.4 (Thermo Scientific, Waltham, MA, USA) was used to analyze the mass spectral data.
2.7. Disintegration Study of Selected Dietary Supplements
Dietary supplement disintegration was performed according to the USP 39 general chapters 2040 and 701 for immediate release DS forms [20,21,22]. Briefly, six capsules (DS-3 and DS-9) were individually immersed in the 0.05 M acetate buffer media, and six tablets (DS-8) were in the water and agitated media for 30 min. Tablets were immersed in water, and capsules with hard shells (gelatin or non-gelatin) were immersed in acetate buffer (pH 4.5 at 37 °C). Apparatus A was used for units <18 mm in length, and Apparatus B was used for units >18 mm in length (Vankel VK 100, Varian Inc., Cary, NC, USA). No disks were added to the disintegration tubes.
2.8. Impact of Acidic pH on Turmeric Dietary Supplement
Analysis of the curcuminoid profile from a single dietary supplement was performed to investigate the changes under acidic pH. This was achieved via a release study performed using 0.1 N HCl solution. Approximately, 250 ± 1 mL of 0.1 N HCl solution was taken from a 500 mL beaker placed on a Corning hot plate magnetic stirrer (PC-351, Corning, New York, NY, USA). A dietary supplement capsule was added, the stirring speed was set at ~60 rpm (dial setting between 1 and 2), and the temperature was maintained at 37 °C (dial setting just over 2) according to the manufacturer manual. The temperature of the bath was checked manually with a thermometer. Sample (1 mL) was collected at 0 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min. One milliliter of methanol (100%) was added to the collected sample, and the mixture was vortexed for 1 min and centrifuged. Samples were filtered through a 0.45 µm PVDF syringe filter before UHPLC analysis.
2.9. Data Processing
For quantification, the area of each curcuminoid was collected using the LC OpenLab program from Agilent Technologies (M8301-61033, Agilent Technologies, Santa Clara, CA, USA) was used to analyze and identify peaks in the chromatogram. Compound Discoverer (Version 3.3, Thermo Scientific, Waltham, MA, USA) program was used to collect the maximum features from the raw HRMS data. The workflow of the program to analyze the raw data includes the extraction of the MS spectrum, align retention time, the detection of compounds, group compounds, the deconvolution of the overlapping ions based on their isotope patterns (fill gaps), and the prediction of the composition using existing database search (mzCloud, Chemspider, and mzLogic) and in-house library search. The resulting areas of each sample were exported to Microsoft Excel 365 (Microsoft, Redmond, WA, USA) in triplicate for analysis.
2.10. Statistical Analysis
Principal component analysis (PCA) of curcuminoids and volatile compounds was performed using Pearson’s correlation method and one-way analysis of variance (ANOVA) with XLSTAT software (version 2023.2.0; Addinsoft, Paris, France). Tukey’s HSD test observed significant differences between means at a 5% probability level (p ≤ 0.05).
3. Results and Discussion
3.1. Principal Component Analysis of IR and NIR Spectral Fingerprints
FT-IR and NIR spectroscopy techniques are widely used in different research areas and industries due to their speed, high precision, and potential to perform a non-destructive analysis in a cost-effective manner. In the present study, we used FT-IR and NIR spectral data combined with PCA to understand the compositional differences between eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3) (Figure 1). A PCA of the FT-IR spectral data showed three distinct clusters. Cluster 1, which includes turmeric rhizomes (TR1-TR3) and DS-3; cluster 2, which includes DS-5 and DS-6; and cluster 3, which includes DS-1, DS-2, DS-4, DS-7, DS-8, DS-9, DS-10, DS-11, and DS-12. The first, second, and third principal components showed 90.2% of the total variation (Figure 1A). The PCA of the NIR spectral data also showed four clusters. TR1 and TR2 were clustered together with DS-6, while TR3 was clustered with DS-11. However, DS-1, DS-8, and DS-9 were clustered together and showed distinct separation from the other analyzed DS samples (2, 3, 4, 5, 6, 7, 10, 11, and 12). The first, second, and third principal components explained 91.8% of the total variation (Figure 1B).
These results demonstrate that DS and raw turmeric rhizomes were significantly influenced by the chemical composition and the capsule matrix used for dietary supplement formulation. In a published study, the authors used FT-IR spectral methods to identify turmeric samples adulterated with starch in commercially available turmeric powder [17]. Similarly, Kar et al. used the FT-NIR-PLSR (Fourier transform near-infrared–partial least square regression) model to determine adulteration in turmeric powder. They found that starch adulteration in commercial samples was in the range of 1–30% (w/w) [23]. In our study, IR and NIR showed significant differences in the clustering patterns between dietary supplements and rhizome samples. Hence, we performed UV–visible screening of all DS samples and three rhizome samples.
3.2. Ultraviolet–Visible (UV–Vis) Absorption Spectroscopy Screening and Targeted UHPLC-DAD Analysis of Curcuminoids from Dietary Supplements and Turmeric Rhizomes
The UV spectrum of curcuminoids showed absorption maximum at 420 nm due to the presence of chromophore 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in their chemical structure, which could be used as a screening tool to discriminate samples based on total curcuminoid contents. All DS samples were extracted uniformly with methanol and screened in triplicate at a fixed 420 nm wavelength in 96-well plates. The results show that the absorption maximum at 420 nm varied between 0.15 and 0.83 ODU. A calibration curve was constructed with the authentic curcuminoid standard. The concentrations were calculated based on the absorption maxima. The results were correlated with a detailed UHPLC-DAD analysis.
The UHPLC-DAD analysis showed three major peaks: bisdemethoxycurcumin (BMC), demethoxycurcumin (DMC), and curcumin (CUR). The identification and quantification of each compound were confirmed with a mass spectroscopy analysis. The mass spectra obtained in negative ionization mode of peak eluting at a retention time (tR) of 8.56 min showed a molecular ion at m/z 307.0978 [M-H]−, and its major product ions at m/z 187.0627 were identified as BMC. Similarly, a peak eluting at tR 9.19 min displayed a molecular ion peak at m/z 337.1083 [M-H]−, and their product ions at m/z 217.0507, 173.0469, and 134.0360 were identified as DMC. The major peak (tR 9.82 min) with molecular mass at m/z 367.1188 [M-H]− and the product ions at m/z 217.0507 were identified as CUR. The presence of fragmentation ions at m/z 217.0507 in the mass spectra of DMC [M-H-120]− and CUR [M-H-150]− represents the presence of one or two methoxyl groups, respectively. Our findings are in good agreement with the previous literature [24,25].
A significant difference (p < 0.05) was observed in the levels of curcuminoids among the different dietary supplement and rhizome samples. The levels of individual and total curcuminoids in all samples are presented in Table 1. The concentration of total curcuminoids ranged between 1.4 ± 0.0 mg/100 mg (DS-3) and 69.8 ± 3.2 (DS-9) mg/100 mg on a dry weight basis. Curcumin was the most predominant curcuminoid in all samples. The levels of CUR were also significantly higher in DS-8 (31.0 ± 2.2 mg/100 mg DW) and DS-9 (51.2 ± 2.2 mg/100 g DW), while lower levels were observed in DS-3 (0.8 ± 0.0 mg/100 mg DW) and DS-10 (0.8 ± 0.1 mg/100 mg DW). The levels of DMC were higher than BMC in samples DS1-DS9 except for the two dietary supplement samples (DS10-DS11) and the three rhizomes (TR1-TR3). Interestingly, DS12 showed very similar amounts of BMC and DMC. The percentage ratio of the individual curcuminoids BMC, DMC, and CUR also varied remarkably, as shown in Figure S1, compared to the expected ratio (BMC:DMC:CUR ratio of 1:2:6) described in the literature [1,15,26]. In DS8, significantly higher levels of curcumin were present compared to DMC and BMC (31.0:5.6:1.3). However, in DS11, the ratio of CUR:DMC:BMC was 1.4:0.9:1.3. The variations observed in the total curcuminoid content and the ratios of the individual curcuminoids can be attributed to multiple factors, such as processing, variations in cultivars, growing locations, etc.
There was a high correlation (R2 = 0.99) between the UV–vis and UHPLC-DAD data analysis, suggesting that UV–vis spectroscopy can be used as a quick cost-effective screening tool for the determination of the curcuminoid content with a careful understanding of the other components present in the matrix. The limitation of the UV–vis spectroscopy screening method is that no ratio information on individual curcuminoids can be obtained. The presence of synthetic curcumin in the sample can be determined by comparing the curcumin-to-curcuminoid ratio and a threshold of 85.44% for the relative curcumin value calculated using USP and AOAC criteria [22]. In our study, no DS sample showed the presence of spiked curcumin (Table 1). In a recent study, You et al. showed that 5 supplements out of 14 samples showed the presence of synthetic curcumin [1].
A principal component analysis (PCA) was conducted to visualize curcuminoid concentrations among the analyzed samples. The principal component F1 elucidated 90.6% of the data variation and only differentiated curcuminoids on the F1 component. All the analyzed DS samples and turmeric rhizomes were also differentiated on F1 components except DS-11, which was explained by the F2 component. Overall, the PCA demonstrated 99.5% of the total variation in the first two PC components (Figure 2).
3.3. GCMS Analysis
Three prominent volatile compounds, ar-turmerone, turmerone, and curlone, were identified in all turmeric dietary supplements (DS) except DS-9 in which turmerone was not detected. A typical GCMS chromatogram of the three volatile compounds identified from the dietary supplements, ground turmeric, and rhizome is presented in Figure S2. The results demonstrate significant differences in the volatile compound levels among the DS and dried rhizome samples. Significantly higher levels (three times higher) of the three prominent volatile compounds were found in DS-11, while the lowest levels were observed in DS-9. No significant difference was observed among the turmeric rhizomes (Table 2).
Moreover, in the rhizome samples, we also identified α-curcumene, zingiberene, β-bisabolene, and β-sesquiphellandrene, which were absent in the DS samples. This can be attributed to processing and storage conditions which might result in a significant loss of volatile compounds. These findings are in good agreement with previous reports in which ar-turmerone was identified as a major sesquiterpenoid in turmeric dietary supplements [1,15]. In another report, higher levels of ar-turmerone were observed in dried turmeric rhizomes, but their content was lower than that in fresh rhizomes [27].
PCA and HCA (Hierarchical Cluster Analysis) were conducted to visualize the variations in the volatile compounds among the DS and dried rhizome samples (Figure 3). The results show that the DS and dried rhizome samples were easily differentiated from each other. It was also observed that DS-11 had a high level of volatile compounds compared to all other samples. The volatile compounds ar-tumerone, tumerone, and curlone were differentiated based on component F1 only. All dried rhizome samples (TR1-TR3) and DS samples DS-3, DS-4, DS-5, DS-6, DS-8, DS-9, DS-11, and DS-12 were differentiated by principal component F1, while DS samples DS-1, DS-2, DS-7, and DS-10 were differentiated by F2. Overall, the first and second components explained 99.9% of the total variances.
3.4. Untargeted Metabolomics Analysis Using Compound Discoverer Software
An untargeted metabolism coupled with the Compound Discoverer software was used for the putative identification of untargeted metabolites. More than 400 metabolites were putatively identified using multiple databases such as mzCloud, ChemSpider, Metabolika, an in-house mass list, and other online available databases in positive and negative ionization modes. Among them, 32 metabolites were confirmed in positive ionization modes and 18 metabolites in negative ionization modes by MS/MS fragments and the available data in the literature (Table 3).
Keto-enol tautomerism is pH-dependent; the keto form is predominant in acidic or neutral conditions, while the enol form is dominant under basic conditions [28,29]. The published literature identified 89 curcuminoids, including keto-enol forms in turmeric, using a UHPLC-QTOF-MS/MS analysis [24]. The enol form of curcuminoids has a longer retention time than the keto form. Similar results were observed in our study; we identified three keto and three enol curcuminoid forms. We also identified piperine in DS-4, DS-7, and DS-9, while a prominent essential oil, ar-tumerone, was also found in all analyzed samples. The published literature revealed that piperine enhanced the bioavailability of curcumin by limiting the extent of curcumin glucuronidation by inhibiting the enzyme UDP-glucuronyltransferase in the liver [30,31]. They found a 97-fold enhancement in curcumin bioavailability compared to pure curcumin after 6 h of piperine administration [31]. Clinical studies also showed the effective role of the co-administration of curcumin and piperine in improving human health and protecting against non-fatty liver disease, type 2 diabetes mellitus, certain types of tumors, obesity, and other metabolic diseases [32,33,34,35].
A PCA was conducted to amplify and detect the subtle differences between DS and rhizomes based on identified metabolites (Figure 4). A PCA of mass data obtained in positive ionization mode showed a distinct separation of DS-4 and DS-7 from the other analyzed samples. The first (PC1), second (PC2), and third (PC3) principal components explained 61.7%, 19.8%, and 8.3% of the variance in positive ionization mode, respectively. The loading plots show that PCA differentiates according to the curcuminoid keto and enol isomeric forms, alpha-curcumene, and caryophyllene oxide in both the first and second principal components, while piperine and curcuminoids isomers are differentiated in PC3. Similarly, the results obtained from the PCA of the mass data obtained in negative ionization mode display separation among the rhizome and DS samples. PC1, PC2, and PC3 explain 85.9%, 9.7%, and 2.5% of the total variance in negative ionization mode.
3.5. Quantification Variability and Labeling
Accurate labeling of dietary supplements is important for regulatory compliance and consumers’ health. Our results demonstrate significant variation in the labeling accuracy of commercial products. The quantity of curcuminoids in DS-2, DS-4, and DS-9 were within 10% of the label range, while the detected amounts in DS-1, DS-5, and DS-8 (approximately 24.7%, 42.0%, and 72.0%, respectively) were significantly below the label claims. Interestingly, no claims on the total curcuminoid content were depicted in the labels of DS-3, DS-6, and DS-7. The rhizome samples, TR-1, TR-2, and TR-3, had curcuminoid contents according to the published literature or within the range of accepted values. Recently, You et al. 2022, reported variation in the label accuracy, and only 4 out of the 14 samples analyzed supported authentic label claims [1].
3.6. Disintegration Analysis on Limited Dietary Supplements and Effect on Curcuminoids in Acidic pH Conditions
The disintegration of tablets and capsules is the essential process for the determination of the release of active ingredients. According to the United States Pharmacopeia (USP), complete disintegration occurs when a tablet or capsule has disintegrated into a soft mass with no firm core and no residue remains on the screen of the test apparatus (except fragments of the insoluble coating or capsule shell) after 30 min [20,21,22]. Our results show that all the selected DS samples passed according to USP standards (Table 4).
We also investigated the effect of acidic pH on curcuminoids from a single dietary supplement capsule in 0.1 N HCl solution. Chromatograms and data were collected at 340 nm to observe the changes in the keto-enol forms of curcuminoids (Figure 5). The results demonstrate that the release of curcuminoids (keto and enol forms of BMC, DMC, and CUR) from the capsule increased with time until 90 min. After that, both forms showed a decrease in their levels until 120 min.
The published literature reports that the decomposition of curcuminoids is pH-dependent [36,37,38]. In acidic conditions, the decomposition of curcumin is lower (<20% decomposition after 1 h) compared to the basic–neutral solution [37,39,40]. The higher stability of curcuminoids in acidic conditions may be due to a conjugated diene structure. In a higher pH, the chemical structure was destroyed due to the removal of the proton group from the phenolic group. Puglisi and co-authors reported that the keto-enol tautomers of curcuminoids depend on the pH, solvent, and temperature [36]. In acidic conditions, curcuminoids act as proton donors and are mainly present in keto form [37]. The amount of keto-enol moiety plays a significant role in curcuminoids’ physicochemical properties and antioxidant activities [41]. The keto form is mainly responsible for curcuminoids’ strong antioxidant activity [36].
4. Conclusions
Spectroscopy techniques, including FTIR, NIR, LC-MS, GCMS, MS-spectral database/literature search, and chemometric treatment, enabled us to establish the significant variability in turmeric dietary supplements and rhizomes. Quantitation and the proportions of three curcuminoids (BMC, DMC, and CUR) and three prominent volatile compounds (ar-turmerone, turmerone, and curlone) showed significant variations in their levels among the different DS samples and rhizomes. The dietary supplements DS-2, DS-4, and DS-9 were within the 10% range of the label claim. No adulteration of the dietary supplements with synthetic dyes was observed. All the selected DS samples passed the disintegration analysis test. A release study of DS samples in an acidic solution showed that curcuminoids were present in keto-enol forms, and their levels initially increased until 90 min and then decreased. Overall, to accurately evaluate the role of bioactive curcuminoids in turmeric, it is essential to analyze and understand the bioactivities of different isomeric forms. This will enable researchers to assess the role of curcuminoids as it relates to health and nutrition.
Conceptualization, D.L.L.; methodology, J.S., F.S.T., and D.L.L.; formal analysis, J.S.; investigation, J.S., F.S.T., and D.L.L.; resources, D.L.L.; data curation, J.S., F.S.T., and D.L.L.; writing—original draft preparation, J.S.; writing—review and editing, J.S., F.S.T., and D.L.L.; supervision, D.L.L. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
The original contributions presented in the study are included in the article/
The authors thank Samina Shami for her help in preparing the samples for chromatographic analysis. The authors thank Karen Andrews for her help in contracting disintegration studies. The authors thank Karen Andrew, Gusev Pavel, and Deepesh Pandey for their critical feedback.
The authors declare no conflicts of interest.
Footnotes
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Enlarge this image.Figure 1. Principal component analysis of infrared (A) and near-infrared (B) spectral data obtained from different dietary supplements, powdered turmeric, and ground turmeric rhizome. Commercial turmeric DS samples included eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3).
Enlarge this image.Figure 2. Principal component analysis of bisdemethoxycurcumin (BMC), demethoxycurcumin (DMC), and curcumin (CUR) obtained from different dietary supplements (eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8)), powdered turmeric (DS-10-DS-12), and ground turmeric rhizomes (TR-1, TR-2, and TR-3).
Enlarge this image.Figure 3. Principal component analysis and Hierarchical Cluster Analysis of volatile compounds (ar-tumerone, tumerone, and curlone) obtained from commercial turmeric DS samples: eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3).
Enlarge this image.Figure 4. PCA of untargeted metabolite high-resolution mass data of different dietary supplements, powdered turmeric, and ground turmeric rhizomes. Commercial turmeric DS samples included eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3).
Enlarge this image.Figure 5. HPLC chromatograms (wavelength 340 nm) and release study of three curcuminoids (bisdesmethoxycurcumin (BMC), desmethoxycurcumin (DMC), and curcumin (CUR)) in turmeric dietary supplement (capsule) in 0.1 N HCl solution.
Levels of Bis-desmethoxycurcumin (BMC), desmethoxycurcumin (DMC), and curcumin (CUR) in different dietary supplements, powdered turmeric, and ground turmeric rhizome analyzed by GCMS. Commercial turmeric DS samples included eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3). Label claims regarding the amount of curcuminoids present in the dietary supplement. Data represent mean ± SE and mg/100 mg. Presence of synthetic curcumin was speculated according to percentage of curcumin to total curcuminoid was found to be more than 85.44%.
| Group | BMC (mg/100 mg) | DMC (mg/100 mg) | CUR (mg/100 mg) | Total Curcuminoids (mg/100 mg) | Curcumin-Total Curcuminoid Ratio (%) | Amount per Serving | Label Claim/Serving (mg) | Calculated Total Curcuminoid Content (mg/Serving) | Sample Type/Description | Label Claim in % (mg/Serving) |
|---|---|---|---|---|---|---|---|---|---|---|
| DS-1 | 1.1 ± 0.1 | 3.2 ± 0.4 | 12.9 ± 2.4 | 17.4 ± 2.9 | 74.8 | 1 capsule | 500 | 123.5 | Capsule/turmeric extract rhizome | 24.7 |
| DS-2 | 0.6 ± 0.0 | 1.2 ± 0.0 | 4.7 ± 0.12 | 6.5 ± 0.2 | 72.3 | 1 capsule | 47.5 | 44.6 | Capsule/turmeric extract rhizome and powder | 94 |
| DS-3 | 0.2 ± 0.0 | 0.9 ± 0.0 | 0.8 ± 0.0 | 1.4 ± 0.0 | 61.4 | 2 capsules | n.a. | 23.0 | Capsule/turmeric powder | No label claim |
| DS-4 | 0.9 ± 0.0 | 1.4 ± 0.0 | 5.5 ± 0.1 | 7.8 ± 0.2 | 70.1 | 3 capsules | 150 | 164.1 | Capsule/turmeric extract rhizome and bioperine | 109 |
| DS-5 | 0.6 ± 0.0 | 1.6 ± 0.1 | 5.8 ± 0.5 | 8.0 ± 0.7 | 73.0 | 2 capsules | 180 to 220 | 84.1 | Capsule/turmeric extract rhizome | 42 |
| DS-6 | 0.4 ± 0.0 | 1.3 ± 0.0 | 6.2 ± 0.2 | 7.9 ± 0.2 | 77.5 | 2 capsules | n.a. | 75.8 | Capsule/turmeric rhizome extrcat (Phytosome) | No label claim |
| DS-7 | 0.8 ± 0.0 | 1.3 ± 0.1 | 5.13 ± 0.3 | 7.3 ± 0.4 | 70.5 | 2 capsules | n.a. | 104.3 | Capsule/turmeric extract rhizome and bioperine | No label claim |
| DS-8 | 1.3 ± 0.1 | 5.6 ± 0.3 | 31.0 ± 2.2 | 37.9 ± 2.5 | 81.8 | 1 tablet | 475 | 345.9 | Tablet/turmeric extract rhizome | 72 |
| DS-9 | 4.3 ± 0.4 | 14.3 ± 0.7 | 51.2 ± 2.2 | 69.8 ± 3.2 | 73.4 | 2 capsules | 950 | 945.7 | Capsule/turmeric extract rhizome and bioperine | 99 |
| DS-10 | 0.5 ± 0.0 | 0.4 ± 0.0 | 0.8 ± 0.1 | 1.7 ± 0.1 | 45.8 | n.a. | n.a. | n.a. | Powder | n.a. |
| DS-11 | 1.3 ± 0.0 | 0.9 ± 0.0 | 1.4 ± 0.0 | 3.6 ± 0.1 | 37.8 | n.a. | n.a. | n.a. | Powder | n.a. |
| DS-12 | 0.7 ± 0.0 | 0.7 ± 0.0 | 1.7 ± 0.0 | 3.2 ± 0.1 | 52.9 | n.a. | n.a. | n.a. | Powder | n.a. |
| TR-1 | 1.1 ± 0.1 | 0.9 ± 0.0 | 1.8 ± 0.1 | 3.8 ± 0.2 | 47.6 | n.a. | n.a. | n.a. | Rhizome | n.a. |
| TR-2 | 1.0 ± 0.1 | 0.8 ± 0.0 | 1.7 ± 0.1 | 3.6 ± 0.2 | 47.3 | n.a. | n.a. | n.a. | Rhizome | n.a. |
| TR-3 | 1.0 ± 0.1 | 0.8 ± 0.0 | 1.8 ± 0.1 | 3.6 ± 0.2 | 49.8 | n.a. | n.a. | n.a. | Rhizome | n.a. |
Levels of volatile compounds in hexane extracts of different dietary supplements, powdered turmeric, and ground turmeric rhizomes analyzed by GCMS. Commercial turmeric DS samples included eight capsules (DS-1-DS-7 and DS-9), one tablet (DS-8), three ground turmeric samples (DS-10-DS-12), and three ground turmeric rhizomes (TR-1, TR-2, and TR-3). Data represent mean ± SD (standard deviation) and mg/100 mg.
| Group | ar-Tumerone | Tumerone | Curlone |
|---|---|---|---|
| DS-1 | 0.83 ± 0.24 | 0.45 ± 0.05 | 0.63 ± 0.09 |
| DS-2 | 0.92 ± 0.19 | 0.49 ± 0.04 | 0.60 ± 0.02 |
| DS-3 | 0.6 ± 0.01 | 0.62 ± 0.01 | 0.53 ± 0.00 |
| DS-4 | 0.73 ± 0.10 | 0.94 ± 0.16 | 0.73 ± 0.10 |
| DS-5 | 0.32 ± 0.00 | 0.32 ± 0.00 | 0.32 ± 0.01 |
| DS-6 | 0.33 ± 0.00 | 0.32 ± 0.00 | 0.33 ± 0.00 |
| DS-7 | 1.00 ± 0.01 | 0.58 ± 0.02 | 0.66 ± 0.03 |
| DS-8 | 0.33 ± 0.00 | 0.32 ± 0.00 | 0.33 ± 0.01 |
| DS-9 | 0.39 ± 0.00 | nd ± nd | 0.34 ± 0.00 |
| DS-10 | 0.47 ± 0.01 | 0.76 ± 0.04 | 0.53 ± 0.02 |
| DS-11 | 3.12 ± 0.82 | 3.70 ± 1.54 | 2.29 ± 0.39 |
| DS-12 | 0.68 ± 0.08 | 0.38 ± 0.02 | 0.47 ± 0.03 |
| TR-1 | 0.65 ± 0.08 | 0.38 ± 0.02 | 0.44 ± 0.01 |
| TR-2 | 0.72 ± 0.10 | 0.41 ± 0.02 | 0.47 ± 0.12 |
| TR-3 | 0.57 ± 0.09 | 0.36 ± 0.01 | 0.41 ± 0.03 |
Putative identification of untargeted metabolites in turmeric supplements and roots using UHPLC-HRMS data analysis acquired in positive and negative ionization modes.
| S.No. | Compound | Formula | tR (min) | m/z [M] | [M + H]+ | [M + H]− |
|---|---|---|---|---|---|---|
| 1 | Choline | C5 H13 N O | 0.858 | 103.09975 | 104.10657 | - |
| 2 | Maltose | C12 H22 O11 | 0.861 | 342.11619 | 343.1234 | - |
| 3 | L-Glutamic acid | C5 H9 N O4 | 0.862 | 147.05323 | 148.0605 | - |
| 4 | Sucrose | C12 H22 O11 | 0.867 | 342.1177 | - | 341.11 |
| 5 | Isocitric acid | C6 H8 O7 | 1.107 | 192.02784 | - | 191.021 |
| 6 | Chlorogenic acid | C16 H18 O9 | 1.15 | 354.09705 | - | 353.09 |
| 7 | Leucine | C6 H13 N O2 | 1.164 | 131.09468 | 132.10196 | - |
| 8 | Ferulic acid | C10 H10 O4 | 1.395 | 194.05877 | - | 193.052 |
| 9 | 4-Hydroxybenzaldehyde | C7 H6 O2 | 1.489 | 122.03714 | - | 121.03 |
| 10 | Nonanedioic acid | C9 H16 O4 | 1.523 | 188.10561 | - | 187.098 |
| 11 | BMC (keto) | C19 H16 O4 | 3.043 | 308.10492 | 309.11218 | 307.099 |
| 12 | DMC (keto) | C20 H18 O5 | 3.349 | 338.1155 | 339.1153 | 337.11 |
| 13 | Curcumin (keto) | C21 H20 O6 | 3.643 | 368.12601 | 369.13325 | 367.12 |
| 14 | 6,8,10,12-pentadecatetraenal | C15 H22 O | 7.65 | 218.16704 | 219.1743 | - |
| 15 | L-(-)-Carvone | C10 H14 O | 8.643 | 150.10453 | 151.1118 | - |
| 16 | p-tert-Butylbenzoic acid | C11 H14 O2 | 8.652 | 178.09939 | 179.1066 | - |
| 17 | Piperine | C17 H19 N O3 | 8.84 | 285.13644 | 286.1437 | - |
| 18 | BMC (enol) | C19 H16 O4 | 8.688 | 308.10482 | 309.11209 | 307.1 |
| 19 | 4-Hydroxybenzaldehyde | C7 H6 O2 | 8.782 | 122.03685 | - | 121.03 |
| 20 | DMC (enol) | C20 H18 O5 | 9.333 | 338.11535 | 339.1153 | 337.108 |
| 21 | 4-Hydroxybenzaldehyde | C7 H6 O2 | 9.397 | 122.03686 | - | 121.03 |
| 22 | Hydrocinnamic acid | C9 H10 O2 | 9.95 | 150.06832 | - | 149.061 |
| 23 | Curcumin (enol) | C21 H20 O6 | 9.965 | 368.12585 | 369.1258 | 367.119 |
| 24 | 2,4-Dimethylbenzaldehyde | C9 H10 O | 11.803 | 134.07321 | 135.0804 | - |
| 25 | (+)-ar-turmerone | C15 H20 O | 12.059 | 216.15139 | 217.1586 | - |
| 26 | Lysophosphatidyl ethanolamine LPE (18:2) | C24 H40 N5 O3 P | 13.587 | 477.28561 | 478.2928 | - |
| 27 | Lysophosphatidylcholine (LPC (18:2) | C27 H46 N5 O3 P | 13.606 | 519.33253 | 520.3398 | - |
| 28 | N-stearoyl glutamic acid | C23 H43 N O5 | 13.705 | 413.3142 | - | 412.307 |
| 29 | Hexadecanamide | C16 H33 N O | 13.725 | 255.25621 | 256.2634 | - |
| 30 | Tetrahydroxycurcumin | C30 H40 O2 | 13.861 | 432.3029 | 433.3101 | - |
| 31 | Poly-L-aspartic acid | C4 H7 N O4 | 13.87 | 133.03755 | 134.0448 | - |
| 32 | 6-Prenylchrysoeriol | C21 H20 O6 | 13.902 | 368.12608 | - | 367.119 |
| 33 | Linoleyl hydroxamic acid | C18 H33 N O2 | 13.967 | 295.25111 | 296.2583 | - |
| 34 | Octa-2,4,6-triynoic acid | C4 H11 N4 P | 14.051 | 146.07184 | 147.1168 | - |
| 35 | Alpha-curcumene | C15 H22 | 14.065 | 202.17208 | 203.1793 | - |
| 36 | Didesmethyl tocotrienol | C25 H36 O2 | 14.263 | 368.27154 | 369.2788 | - |
| 37 | LysophosphatidylinositolLPI (16:0) | C37 H40 N4 O2 | 14.382 | 572.31415 | 573.3214 | - |
| 38 | (-)-Caryophyllene oxide | C15 H24 O | 14.451 | 220.18267 | 221.1899 | - |
| 39 | Alpha-Farnesene | C15 H24 | 14.513 | 204.18777 | 205.19504 | - |
| 40 | Phenol, 4-cyclohexyl- | C12 H16 O | 14.581 | 176.12014 | 177.1273 | - |
| 41 | 4-Phenyl Cyclohexane | C12 H14 | 14.902 | 158.10962 | 159.1169 | - |
Disintegration study on three selected turmeric dietary supplements (DS-3, 8, and 9) performed according to USP 39 general chapters 2040 and 701 for immediate-release DS forms.
| Sample | Form | Test Solution Used for Agitation | Temp °C Start | Temp °C Stop | Length of Agitation Time (Minutes) | Num of Pills Disintegrated | Test Result |
|---|---|---|---|---|---|---|---|
| DS-3 | hard-shell capsule | 0.05 M Acetate Buffer | 35.6 | 35.9 | <30 | 6 | Pass |
| DS-8 | tablet | Water | 36.5 | 36.3 | <30 | 6 | Pass |
| DS-9 | hard-shell capsule | 0.05 M Acetate Buffer | 36.6 | 36.6 | <30 | 6 | Pass |
Supplementary Materials
The following supporting information can be downloaded at
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