Determination of Flibanserin in Female Sexual Desire Enhancer Products by LC–MS/MS and Its Confirmation by LCMS-IT-TOF

In the world, many people experience sexual problems at some point in their lives. Women are disproportionately affected due to the lack of appropriate treatments in modern medicine, leading to most of them not receiving treatment or finding an appropriate solution. The research showed that one in every 10 women in the United States has some form of sexual dysfunction. (1) Flibanserin (FLB), an active substance that can be used especially in hypoactive sexual desire disorder (HSDD), has become a source of hope for many women with this problem.

FLB was initially developed as an antidepressant; however, due to FLB’s inability to demonstrate an antidepressant effect in the experiments, participants indicated heightened sexual desire as a side effect, suggesting the potential application of this substance in the treatment of HSDD. So the Food and Drug Administration (FDA) approved FLB again in 2015, but this time for the treatment of HSDD instead of depression. (2) According to the data obtained from the begonia, daisy and violet studies, 12.8% of those taking FLB experienced side effects such as drowsiness, 10.6% dizziness, 9.9% nausea and 7.1% fatigue. (3) Due to these side effects, it is recommended that FLB be taken before going to bed. Also, taking FLB with alcohol was avoided due to the risk of fainting and hypotension.

Although flibanserin (FLB) is one of the few active substances approved for the treatment of hypoactive sexual desire disorder, the number of available studies remains limited, as its approval by the FDA is relatively recent. The majority of published studies have focused on pharmaceutical quality control or bioanalytical applications, predominantly employing LC–MS/MS (4−10) and HPLC (4,11) techniques. These studies have investigated a wide range of sample matrices, including natural products such as beer, grape wine, and herbal tea, as well as biological samples (e.g., plasma and brain tissue) and pharmaceutical formulations such as Veroxeserin. In contrast, a study conducted in Poland reported the presence of FLB in certain herbal products, raising concerns regarding the unauthorized use of this compound. (7) This finding prompted questions about the potential presence of FLB in products marketed as female sexual desire enhancers in the Turkish market. Therefore, the present study aimed to determine FLB in various commercially available products obtained in Türkiye to assess the presence of FLB and to characterize their contents. Notably, it was observed that some products lacked manufacturer address information, despite regulatory requirements, and that the recommended usage instructions were concerning, particularly in light of the known side effects of FLB.

This study aimed to develop and validate a sensitive and reliable LC–MS/MS method for the determination of flibanserin (FLB) in commercial products collected from the Turkish market that are marketed as female sexual desire enhancers. The samples were additionally analyzed using an LC-MS-IT-TOF instrument to support the qualitative characterization of their contents. A further objective of this work was to investigate whether FLB is being inappropriately incorporated into over-the-counter products in a manner analogous to the illicit use of sildenafil in food products or dietary supplements. By screening products predominantly obtained through online sales channels, this study sought to assess the potential unauthorized presence of FLB and to highlight possible risks to women’s health associated with such unregulated practices. As a complementary aspect, the environmental and practical performance of the proposed analytical approach was evaluated using greenness, whiteness, and blueness assessment tools, including ComplexMoGAPI, AGREE, WAC, and BAGI.

2. Experimental Section

2.2. Instrumentation

The mass spectrometric studies were succeeded in an 8040 model MS/MS instrument connected to a Nexera XR Series LC (from Shimadzu); the whole system was composed with DGU-20A3R degasser, LC-20AD gradient pump, SIL-20AC autosampler, CBM-20A communications bus module, CTO-10ASVP column oven.

The LCMS-IT-TOF series liquid chromatography–high-resolution mass spectrometry instrument (Shimadzu) was used for structural characterization; the instrument consisted of the following modules: DGU-20A3 degasser, 2× LC-20AD gradient pump, SIL-20A autosampler, CTO-10ASVP column oven, CBM-20A communication module, and ion-trap and time-of-flight (IT-TOF) mass spectrometer. LCMS Solutions 3.80 software was used for setting instrumental parameters and spectrum integration.

3. Result and Discussion

3.1. Ionization Characteristics of Flibanserin

Although the LC–MS/MS system has some financial disadvantages, its ability to detect even very low concentrations makes it a suitable system for this study. Analyses were performed to determine the ionization type, and it was determined that FLB causes positive ionization. The daughter ions and collision energy observed under multiple reaction conditions using the electrospray ionization method are given in Table 2. The waiting time was determined to be 100 ms. Three daughter ions were detected, 161.05, 119.05, and 133.05 m/z. Their fragmentation paths are given in Figure 1. It is suggested that the daughter ion with the m/z value of 161.05 is fragmented by heterolytic fragmentation, the daughter ion with the m/z value of 133.05 is fragmented by heterolytic fragmentation and carbonyl release, and the ion with the m/z value of 119.05 is fragmented by McLafferty rearrangement and hydroxyl release. The product ions at m/z 161 and m/z 119 have been reported in previous studies, while the ion at m/z 133 is considered a transitional step and is formed in lower abundance than the other two. (4,6)

ACS Omega 2026, 11, 6, 10828–10836: Figure 1. Fragmentation paths of FLB in positive electrospray ionization mode.

3.7. Comparison of the Method with Data in the Literature

The analytical methods developed for FLB analysis in the literature were summarized in Table 5. The methods could be divided into two parts: quality control and bioanalytical purposes. It was obvious that all the instrumentation systems used for bioanalytical analyses presented so far were LC–MS/MS. The methods developed for quality control analyses were based on analysis with HPLC and LC–MS/MS. Apart from these, there are two other high-throughput methods that were developed for various purposes. However, these two methods have significant disadvantages, such as requiring experience and mastery for routine analyses. (17,18) Poplawska et al. were created to analyze both FLB and tadalafil at the same time in herbal products using an LC system along with PDA, MS, and a charged aerosol detector, just like the method that was developed. (7) They also characterized herbal preparations with LCMS-IT-TOF. Compared to their method, our method has advantages such as a working range that was approximately 100 times and LOQ was 0.5 times lower. Also, they characterized 9 compounds in herbal products with high-resolution mass spectrometry studies. Our method used high-resolution mass spectrometry to characterize all samples from 9 different market brands in detail. In addition, starting from sample collection to final analysis, the principles of less environmental harm and efficient and sustainable analytical method development were considered and evaluated with 4 different metric tools, which is another originality of the our article. Moreover, this study encourages other researchers to focus on such synthetic products and assess their impact on public health. In certain societies, these products hold a peculiar appeal: their sale remains hidden, yet their use is widespread. As a result, the table already presents a detailed comparison of all the methods developed so far. (19)

ACS Omega 2026, 11, 6, 10828–10836 - Table 5. Comparison with Previous Studies.webp

4. Conclusion

Due to the lack of the drug treatment for hypoactive sexual desire disorder in women and the feeling of shame or hesitation stemming from cultural reasons. People in many countries do not think about or try to seek medical help for this issue. This situation not only complicates the diagnosis of such diseases but also exposes those affected to potential harm. Many women who cannot get medical help or access treatments like flibanserin and bremelanotide, which are available in only a few countries, often seek other options. In this case, products marketed as sexual desire enhancers for women are based on taking advantage of people’s helplessness. When marketing such products, the following is stated: “If you want to make a sweet surprise for your partner without him knowing, it will be enough to drop 7–8 drops into her drink and wait for half an hour.” Beyond the fact that such statements could lead women to take these products against their will, marketing them in this way encouraging people to use them and making it seem normal is also wrong.

FLB was licensed by the United States Food and Drug Administration as the only medication for the treatment of female sexual interest/arousal disorder of any degree. (11) The current LC–MS/MS method is a novel, simple, and time-saving analytical method for the determination of FLB with a low quantification limit. The method was fully validated and used to determine FLB in samples that were bought as a solution to the treatment of female sexual desire enhancement. It has been shown that some of the products did not include content information. In addition, it has also been determined that the manufacturer’s address was present in some products while not others. As a result of the analysis, in some products had low concentration of FLB, which was not enough to make an effect. When the same samples were given to LCMS-IT-TOF to characterization, it was shown that the contents of the product did not match with that given in the lists on their boxes, and they included substances like caffeine, lactose, and citric acid, which have no effect on the disease., Finally, analyzing products like this in detail and identifying any substances that may threaten human health is an important point in terms of public health, especially considering that patients using such products do not have any other solution in Türkiye or in the other countries.

In the present study, a comprehensive screening of 15 finished products was conducted, making it one of the most extensive surveys of commercially available formulations reported in the literature to date. Owing to the nanogram-per-milliliter-level LOQ achieved with the developed LC–MS/MS method, the method offers not only a highly sensitive approach for the analysis of finished products but also a potential alternative for plasma and urine analyses in future bioanalytical applications. Furthermore, the method is distinguished by its strong ecological profile, demonstrated through multiple green analytical chemistry assessment tools, underscoring its suitability as an environmentally conscious analytical approach. Although the proposed method demonstrated favorable greenness, whiteness, and blueness characteristics, further enhancements in environmental performance may be achieved in future studies through the implementation of miniaturized or low-flow LC systems and the integration of automated sample preparation, which could reduce energy consumption and improve overall sustainability.

Overall, the analytical strategy presented herein provides a robust and versatile platform that can be effectively utilized across pharmaceutical quality control laboratories, food and dietary supplement testing facilities, and a wide range of academic research settings. This study therefore represents a valuable contribution to the field by combining comprehensive product surveillance with a highly sensitive, validated, and sustainability-oriented analytical methodology.