Analytical methods for the detection and characterization of unapproved phosphodiesterase type 5 inhibitors (PDE-5i) used in adulteration of dietary supplements- a review.

This article is an up-to-date review of 112 unapproved phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in sexual enhancement dietary supplements and other products from 2003 to July 2023. Seventy-five of these unapproved PDE-5i are analogues of sildenafil (67%), followed by 26 analogues of tadalafil (23%), 9 analogues of vardenafil (8%) and 2 other type of compounds (2%). The products have been formulated in various packaging, primarily in capsule, tablet, and powder forms.

Analysis of N-nitrosodimethylamine in metformin hydrochloride products by high-resolution accurate mass gas chromatography mass spectrometry.

Rationale: The high resolving power of the Orbitrap mass spectrometer in a high-resolution accurate mass gas chromatography (HRAM-GC-MS) system provides greater selectivity and sensitivity for the identification and quantification of volatile analytes at low parts per billion (ppb) levels. Hence, it can be applied for the analysis of pharmaceutical impurities like N-nitrosodimethylamine (NDMA) in metformin hydrochloride products (METs).

Methods: Different METs extracted by a dichloromethane/aqueous system were analyzed by HRAM-GC-MS under softer electron ionization (EI) at 30 eV.

Isolation and characterization of N-phenyl propoxyphenyl carbodenafil from an illegal coffee powder product.

A new carbodenafil-like compound, N-phenyl propoxyphenyl carbodenafil has been identified from an illegal coffee powder product. It was isolated using a semi-preparative liquid chromatography column. The presence of a propoxy group at the aryl alkyl ether moiety, and the direct bonding of a phenyl group to piperazine ring have been unambiguously characterized by ultra-violet (UV), Fourier transform infrared (FTIR), high-resolution mass spectrometry (HRMS) and nuclear magnet resonance (NMR) analysis.

Isolation and characterization of N-hydroxyethyl dithio-desethyl carbodenafil from a health supplement.

A new phosphodiesterase type-5 inhibitor (PDE-5i) with thiocarbonyl and thiolactam skeleton has been identified. The unknown compound has very similar properties like dithio-desmethyl carbodenafil, which was detected alongside during the screening process. It has been isolated by a semi-preparative high performance liquid chromatography tandem ultra-violet detector (HPLC-UV).

Elucidation of the absolute configuration of a tadalafil analogue found as adulterant in a health supplement by mass spectrometry, chiroptical methods and NMR spectroscopy.

The chirality of a dipropylaminopretadalafil stereoisomer isolated from a health supplement has been studied. Under high resolution mass spectrometry (HRMS) study, this unknown compound seems to be one of the trans configuration tadalafil analogues i.e.

A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements.

To date, there are 80 synthetic PDE-5i found as adulterants in dietary supplements. Analogues of sildenafil remain as the top list with 50 (62%) and are followed by analogues of tadalafil, 21 (26%), analogues of vardenafil, 7 (9%) and others, 2 (3%). The sildenafil group can be sub-categorized into sulphonamide-bonded (24, 48%), acetyl-bonded (11, 22%), carbonyl or thiocarbonyl-bonded (8, 16%) and other types (7, 14%) based on the functional group linked to pyrazolopyrimidine-one moieties.

Isolation and characterization of a novel dithio-carbodenafil analogue from a health supplement.

A novel dithio-carbodenafil compound was isolated and identified from a health supplement. The structure of the unknown compound has been characterized using LC-UV, Fourier Transform Infrared (FTIR), high-resolution mass spectrometry, 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. It has been revealed as 3,5-dimethylpiperazinyl dithio-desmethylcarbodenafil as a result of two additional methyl groups on the piperazine ring.

Isolation and characterization of a tadalafil analogue, N-cyclopentyl nortadalafil in health supplement.

A tadalafil analogue was detected for the first time during the screening of a health supplement for undeclared sexual enhancement drugs. The compound had been isolated and purified by preparative high-pressure liquid chromatography (HPLC). Its chemical structure was elucidated using high-resolution mass spectrometry (HRMS), electrospray ionization tandem mass spectrometry (ESI-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy.

Analysis of 40 weight loss compounds adulterated in health supplements by liquid chromatography quadrupole linear ion trap mass spectrometry.

In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) with scheduled multiple reaction monitoring (MRM) enhanced product ion (EPI) method was developed for simultaneous determination of 40 compounds with weight loss effect, including bisacodyl, phenolphthalein, and sibutramine and its metabolites, etc. They might be adulterated in health supplements to get prominent weight loss effect. The samples were analyzed using a Q-Trap 5500 coupled with high performance liquid chromatography (HPLC) and a CORTECS ultra performance liquid chromatography (UPLC) C18 column (100 mm x 2.

Analysis of 32 toxic natural substances in herbal products by liquid chromatography quadrupole linear ion trap mass spectrometry.

In this study, an LC-MS/MS EPI method was developed for simultaneous determination of 32 toxic natural substances in herbal products. The analytes include aconite alkaloids, lobelia alkaloids, solanaceous alkaloids, digitalis steroid glycosides, strychnine, tetrahydropalmatine etc. They werecommonly used in herbal products.

Application of Orbitrap-mass spectrometry to differentiate isomeric sildenafil- and thiosildenafil-like analogues used for the adulteration of dietary supplements.

Two groups of isomeric phosphodiestrase-type 5 inhibitors (PDE-5), consisting of four sildenafil- and three thiosildenafil-like analogues, have been successfully differentiated using high-resolution MS/MS. The optimised MS/MS data obtained from each compound were used to build a database with the aid of mass processing software. Isomeric compounds with very close chromatographic separation like dimethylsildenafil and homosildenafil could be distinguished by their unique fingerprint fragment ions in the MS/MS database.

Structural elucidation of propoxyphenyl isobutyl aildenafil, adulterant in a health supplement using high-resolution Orbitrap mass spectrometry.

A new sildenafil analogue, propoxyphenyl isobutyl aildenafil has been found in trace quantity from one health supplement. It has been purified by preparative high performance liquid chromatography (HPLC). The structural elucidation of this compound has been carried out using high-resolution Orbitrap mass spectrometry under two fragmentation modes, namely High energy Collision Dissolution (HCD) and Collision Induced Dissolution (CID).

Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges.

The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature.

Structural elucidation of a new sildenafil analogue using high-resolution Orbitrap mass spectrometry.

Rationale: One new phosphodiesterase type 5 (PDE-V) inhibitor, propoxyphenyl homohydroxysildenafil (PP-HHS), has been isolated from one health supplement, and analyzed using high-resolution Orbitrap mass spectrometry. High-resolution mass spectrometry (HRMS) is useful to elucidate unknown substances at low concentrations.

Methods: Two isolated compounds, propoxyphenyl thiohomohydroxysildenafil (PP-THHS) and propoxyphenyl homohydroxysildenafil (PP-HHS), were infused into the Thermo Fischer Scientific LTQ Orbitrap XL™ hybrid FTMS system at a flow rate of 3 μL per min.

Partial conversion of methanol to formaldehyde in the gas chromatography injection port and reactivity with amines.

The partial conversion of methanol (MeOH) to formaldehyde (HCHO) in the gas chromatograph (GC) injection port was studied. The presence of formaldehyde in the injection port can result in reaction with injected analytes, especially primary and secondary amines. A systematic study of this problem was undertaken using norephedrine and ephedrine as probe analytes, and experiments involving varying inlet temperature, comparisons among solvents and solvent mixtures, isotopic labeling, and formaldehyde spiking.

Isolation and characterization of propoxyphenyl linked sildenafil and thiosildenafil analogues in health supplements.

Two new phosphodiesterase-5 inhibitors (PDE-5) which consist of one sildenafil analogue and one thiosildenafil analogue have been found in heath supplements. The structural properties of these analogues have been elucidated by NMR, high resolution MS, MS(2), UV and IR spectroscopy. The sildenafil analogue is very similar to aildenafil and the thiosildenafil analogue is similar to thioaildenafil, except the ethoxy group bonded to phenyl ring is replaced by a propoxy group.

Isolation and structural elucidation of flibanserin as an adulterant in a health supplement used for female sexual performance enhancement.

A health supplement used for female sexual performance enhancement was sent to Health Sciences Authority of Singapore for testing. An unknown compound was detected and isolated from the health supplement and its structure was elucidated using LC-DAD, LC-FTMS, NMR and IR. The detected compound was identified to be flibanserin, a non-hormonal treatment developed for pre-menopausal woman with hypoactive sexual desire disorder (HSDD).