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178

Quantitative and Qualitative Determination of Counterfeit Drugs

determination method with 1H- NMR using maleic acid as the internal reference. The sample contained two APIs quantied to be 34.3±0.2 mg of vardenal and

7.2±0.1 mg of homosildenal. [7]

Lachenmeier et al., used a standardless methodology referred to as pulse length- based concentration determination (PULCON) with NMR to obtain the purity of reference materials, including ibandronic acid, amantadine, ambroxol, and lercanidipine. [17] They compared the results of their analysis with the direct determination method and with the reference values from HPLC analysis. For the NMR analysis via PULCON and the direct determination method, a 400 MHz NMR was employed. The direct determination method used two internal standards, 3,5- dinitrobenzoic acid and 2,3,4,5- tetracloronitrobenzene. [17]

The PULCON analysis utilized a reference standard from an electronic reference to access in vivo concentrations (ERETIC). [17] The ERETIC factor for the chloroform solutions were determined by adding ethylbenzene in CDCl3, while the factor for the aqueous solutions was determined by adding citric acid in D2O. Only a single calibration with the PULCON method was needed as it could be reused for multiple samples over an extended period. The reference samples analyzed were as follows: one sample each of ibandronic acid, amantadine HCl, ambroxol HCl, and lercanidipine, and four samples of medicinal products of ibandronic acid. Both types of NMR methods showed satisfactory purity values of all samples of ibandronic acid. The purity using the direct determination method of 1H- NMR was 93.6%– 96%, whereas with PULCON it was determined to be 94.8%– 99.6%. A t- test showed no signicant difference between the two methods and the values agreed with sample specications as well as with the reference values from HPLC. The authors also utilized the analysis of the three reference samples of amantadine HCl, ambroxol HCl, and lercanidipine to conrm the performance of the PULCON method. They concluded that the PULCON method was effective in checking the specications of commercial products. Additionally, it had the advantage, compared to direct method 1H- NMR, as to not needing multiple calibrations of the samples being evaluated. [17]

Abraham et al., utilized another unique method of NMR spectroscopy, known as TD- NMR to analyze for counterfeit drugs. [8] This method did not require the dissolving of samples in a deuterated solvent. Abraham determined the structures of four different monoclonal antibodies, CM- 1, CM- 2, CM- 3, and CM- 4 (Selleck Chemicals), and whether the drugs were diluted. They ran TD- NMR on samples at an initial concentration of 5 mg/ mL. By changing the concentration of the buffer mixed with the antibodies, it was possible to create thirteen variation sets of three buffered solutions. The relaxation times changed depending of the combination employed. It was observed that six samples had no API, and seven of them had lower concentrations than declared. [8]

Casagrande et al.,. analyzed eight monoclonal antibodies samples found on the Swiss market. [18] They prepared the samples by adding 10% D2O and ran a 600 MHz 1H- NMR via the direct determination method. The internal

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Using NMR Spectroscopy to Analyze Counterfeit Medications

179

reference used was a typical monoclonal antibody from the Roche internal spectral database. Two of the tested samples using showed the presence of excipients and no API. One contained hydroxyethyl starch and another benzyl alcohol. Three samples had low molecular weight API, while another had methylprednisolone, diclofenac, or gemcitabine. Additionally, three samples had the wrong biological altogether; being insulin, human serum albumin (HSA), or gelatin. [18]

Some other studies utilizing NMR to detect counterfeit drugs, were from JinLee [19], Maruyama [20], and Reepmeyer [21]. They employed 1H- NMR and 13CNMR to identify and quantify adulterants in counterfeit drugs, such as in dietary supplements, Saposhnikoviae radix (SA) herbal supplements, and OTC herbal aphrodisiacs, respectively. Similarly, Remaud et al., [22] utilized 13C- NMR to identify and quantify the contents of counterfeit aspirin and paracetamol.

Additional studies that utilized quantitative NMR via an analytical method were by Holzgrabe [23], Malet- Martino [24], Schramek [25], and Kang [26]. Holzgrabe et al., utilized 500 MHz 1H- and 13C- NMR to analyze a sachet of 2.617 g anti- rheumatic drug purchased from Vietnam. [23] They found 33% acetaminophen, 10% sulfamethoxazole, 1.6% indomethacin, and <1% trimethoprim. Similarly, Malet- Martino et al., studied nine samples of dietary supplements (DS) from South Europe claiming to contain a mix of herbs and sugars. [24] By utilizing a 500 MHz 1H- NMR, four of the samples were identied to be adulterated with the sildenal analogue, propoxylphenylthiohydroxyhomosildenal (PP- THHS), one had thiosildenal (THIO), two had sildenal (SILD) and tetrahydropalmatine (THP), one had phentolamine (PHE), and one had osthole (OST). [24] Schramek et al., utilized the analytical method of 1H- NMR to quantify capsule samples of DS purchased from Germany. [25] Using 2D- 1H- NMR- COSY, it was determined that the samples contained two analogues of sildenal, piperazional, and isopiperazinonal in equal amounts. [25] Kang et al., similarly analyzed 23 samples of weight- loss compounds purchased from South Korea, by utilizing the analytical curve method on a 600 MHz via 1H- and 13C- NMR. [26] They found that ve out of 23 samples were adulterated; three of them contained levothyroxine, and one each of sennoside A, sennoside B, and phenolphthaleine. In addition, they found three unknown adulterants in one of the samples. [26]

Some other studies that analyzed DS utilizing quantitative NMR were by MaletMartino [27], Pauli [28], Lachenmeier [29], and Hakkarainen [30]. Malet- Martino et al., utilized a 500 MHz 1H- NMR to analyze 150 samples of sexual enhancement DS purchased online in France. [27] They found sildenal in 27 samples, tadalal in 19, vardenal in two, and ibanserin in four. [28] Similarly, Pauli et al., utilized

H- NMR on a 400 MHz instrument to analyze turmeric- containing DS samples purchased in Italy. [28] They found 4.8%– 7.4% of adulterant synthetic curcumin in the samples, which had been causing acute nonviral cholestatic hepatitis in 21 individuals in the country. [28] Lachenmeier et al., studied 16 DS samples

180

Quantitative and Qualitative Determination of Counterfeit Drugs

purchased online, utilizing 400 MHz 1H- NMR. [29] They found sibutramine in three samples, mesterolone in two as well as oxymetholone, monacolin K, vinpocetine, evodiamine, caffeine and testosterone propionate each in one sample. [29] Another study by Hakkarainen et al., studied three samples of grapefruit seed extract (GSE) purchased online in Sweden, by using the direct determination method of NMR. [30] They utilized 1H- and 13C- NMR on 300 MHz and 600 MHz broadband probe, and on 600 MHz cryogenic probe concurrently. They observed that all three samples had benzethonium in addition to glycerol and water. No authentic GSE was found in any of the samples.

Bogun et al., utilized direct determination method to analyze liquid methamphetamine samples obtained from clandestine labs in New Zealand. [31] They ran the analysis on a 40 MHz 1H- and 31P. They were able to identify and quantify between phosphorus- containing acids or the equivalent basic anion. [31] Similarly, Kaur et al., utilized 1H- and 31P- NMR on a 400 MHz instrument to analyze three samples of blister packs of miltefosine purchased in Bangladesh. [32] They observed that the samples had no APIs present. [32]

Quantitative studies are quite useful (see Table 7.1), however the actual practicality in the eld is limited because they require the utilization of high- eld NMR, which often have restrictions regarding cost and maintenance; particularly cryogenic exchange. Often, a qualitative analysis of a sample is sufcient to determine whether the API is present. Thus, low- eld and/ or benchtop NMR have become increasingly popular.

7.4 QUALITATIVE NMR

Balayssac et al., used low- eld benchtop 1H- NMR to analyze counterfeit weight- loss DS purchased online. [33] Initially, they qualied and quantied 40 samples of DS and categorized them to build statistical models. The samples were grouped as nonadulterated, sibutramine- adulterated, phenolphthaleinadulterated, or adulterated with both sibutramine and phenolphthalein. Another 13 samples were purchased from the internet and analyzed to compare with the previous 40 samples. The samples were dissolved in 1 mL of deuterated methanol and a LF- 1H- NMR was run on a 60 MHz machine. Three of the samples were phenolphthalein- adulterated and another three were sibutramineadulterated. The remaining seven were classied as non- adulterated, not containing contaminants. [33]

Pagès et al., utilized benchtop cryogen- free LF- 1H- NMR, to detect and identify adulterants in sexual enhancement and weight- loss DS. [34] Eleven sexual enhancement and ve weight- loss samples were purchased from the internet claimed to be “100% natural”. The samples were initially run on a 500 MHz HF-

H- NMR. The adulterants, sildenal and tadalal, were identied in ten of the sexual enhancement and four weight- loss samples. These were also detected using a 60 MHz benchtop instrument, validating the accuracy of LF- benchtop NMR in detecting counterfeit drugs. [34]

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TABLE 7.1 Applications of qNMR spectroscopy for the analysis of counterfeit drugs

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181

Using NMR Spectroscopy to Analyze Counterfeit Medications

Technique/ Method Drug Location NMR (MHz)

Direct Anabolic Steroids Brazil 600

OTC creams/ ointments

with no API

Germany, Sweden,

Switzerland,

300

Pakistan, UK

ACEi China 500

Sertraline HCl,

Brazil 500

Alprazolam, Vitamin D3, Enalapril Maleate Paracetamol Brazil 500

Omeprazole Europe 600

Cialis® Germany, Syria,

India, China

Nuclei/ Experiment Adulterant Ref

H No API/ Less API/ peanut oil,

[10]

benzyl alcohol

H, 13C, 19F Dexamethasone 21- acetate,

[11] triamcinolone acetonide, unknown corticosteroid

H 1- [(2S,4R)- thio- 2- methylpropionyl-

[12] 5- d- ethanedicarboxylicacid]- lproline,

1- [(2S,4S)- thio- 2- methylpropionyl-

5- d- ethanedicarboxylicacid]- lproline

H Lower level of API [13]

H Para- aminophenol

H Propanol, acetone,

[14] dichloromethane, dibutyl phthalate

H- 1H- 2D-

No API, vardenal, homosildenal [7]

DOSY

181

(continued)

TABLE 7.1 (Continued) Applications of qNMR spectroscopy for the analysis of counterfeit drugs

182

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182

Technique/ Method Drug Location NMR (MHz)

mAbs Switzerland 600

Methamphetamine New Zealand 40 Grapefruit seed extract Sweeden 300, 600 Ibandronic acid,

Lab 400 PULCON, 1H No adulterants [17] amantadine, ambroxol, Lercanidipine

Miltefosine Bangladesh 400

Analytical Anabolic Steroids Brazil 600

Mix of herbs/ sugars South Europe 500

Anti- rheumatic Vietnam 500

DS Germany 500 Weight- loss compounds South Korea 600

Saposhnikoviae radix

Japan 600 herbal supplements

Nuclei/ Experiment Adulterant Ref

H No API, hydroxyethyl starch,

[18]

benzyl alcohol

H, 31P Piperazional, Isopiperazional [31]

H, 13C Benzethonium [30]

H, 31P No API [32]

H No API/ Less API/ peanut oil,

[10]

benzyl alcohol

H PP- THHS, THIO, SILD, THP,

[24]

PHE, OST

H, 13C Acetaminophen, sulfamethoxazole,

[23]

indomethacin, trimethoprim

H, 2D- COSY Piperazional, isopiperazional [25]

H, 13C Levothyroxine, sennoside A &

[26] B, phenolphthaleine, unknown compounds

H, 13C Xanthalin [20]

Quantitative and Qualitative Determination of Counterfeit Drugs

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183

Megaton South Korea 600 OTC herbal aphrodisiacs US 500 Sexual enhancers France 500

H, 13C Acetylvardenal [19]

H, 13C thiohydroxyhomosildenal [21]

H Sildenal, tadalal, vardenal,

[27] ibanserin, testosterone, phentholamine, yohimbine, icariin

Turmeric- containing DS Italy 400 DS Germany 400

H Syncumin [28]

H Sibutramine, mesterolone,

[29] oxymetholone, monacolin K, vincopocetine, evodiamine, caffeine, testosterone propionate, kavalactones, dehydro- epi- androsterone

Comparative Anabolic Steroids Brazil 600

H No API/ Less API/ peanut oil,

[10] benzyl alcohol

Polarization

Transfer

Ibuprofen, naproxen Belgium, France,

Portugal, UK,

75, 100

C, 2H, 1H,

INEPT

Fingerprint of manufacture [15]

Ibuprofen US, UK, Belgium,

600

France, Portugal

TD mAbs Lab 20

NMR: nuclear magnetic resonance, OTC: over‑ the‑ counter, ACEi: angiotensin‑ converting‑ enzyme inhibitor, API: active pharmaceutical ingredient, DOSY: diffusion ordered spectroscopy, mAbs- monoclonal antibodies, PULCON: pulse length‑ based concentration, PP- THHS: propoxylphenyl‑ thiohydroxyhomosildenal, THIO: thiosildenal, SILD: sildenal, THP: tetrahydropalmatine, PHE: phentolamine, OST: osthole, INEPT: intense nuclei enhanced polarization transfer, DEPT: distortionless enhancement by polarization transfer, DS: dietary supplements, TD: Time‑ domain

C, DEPT,

Fingerprint of manufacture [16]

INEPT

H None/ less API [8]

Using NMR Spectroscopy to Analyze Counterfeit Medications

183

184

Quantitative and Qualitative Determination of Counterfeit Drugs

Wilczyńki et al., utilized qualitative LF- 1H- NMR relaxometry to verify the authenticity of a 100mg sample of “Viagra” purchased on the black market in Poland, by comparing it to original Viagra. [35] The authors observed biexponential relaxation, hence two components were present in the counterfeit product, while the original Viagra had a single- exponential relaxation process. As a result, the authors concluded that LF- 1H- NMR relaxometry was useful to identify counterfeit drugs. [35]

Some other qualitative studies have utilized high- eld (HF) 1H- NMR to identify counterfeit drugs. Kesanakurti et al., analyzed 24 samples of Sarsaparilla, a popular natural health product, purchased in Canada. [36] Included were one sample each of Decalepis hamiltoni, Smilax ofcinalis, and Smilax oranata; ve of Hemidesmus indicus; seven each of Smilax aris tolochiifolia and Pteridium aquilinum; and two of Sarsaparilla root. The samples were analyzed in triplicate on a 600 MHz instrument. The authors were able to identify and group the samples into four taxonomically distant groups of Sarsaparilla. [36]

Rodomonte et al., utilized HF- NMR on both 1H and 13C nuclei on a 400 MHz instrument to analyze 16 in- lab synthesized analogs of sildenal, thiosildenal, and acetilsildenal. [37] The synthesized samples included sildenal, homosildenal, hydroxysildenal, dimethylsildenal, piperidinosildenal, pyrrolidinosildenal, morpholinosildenal, diethylaminosildenal, thiosildenal, thiohomosildenal, thiohydroxyhomosildenal, thiodimethylsildenal, noracetilsildenal, acetilsildenal, hydroxyacetilsildenal, dimethylacetilsildenal, and morpholinoacetilsilddenal. They aimed to create a reference for future analysis of counterfeit drugs. Using HF- NMR they found which signals of the samples were predictive of adulterants. Of the 16 synthetic samples, 14 were already reported in the literature. Pyrrolidinosildenal was novel, while diethylaminosildenal was previously cited, but never as an adulterant. [37]

Similarly, Hasegawa et al., utilized 1H- and 13C- NMR to identify the DS “khaki powder”, marketed for tonic effect, purchased online. [38] They dissolved the sample in DMSO- d6 and ran the NMR on an 800 MHz instrument. They were able to detect tadalal in the sample which was further conrmed by HPLC and MS. [38]

Goda et al., tested herbal supplements, by utilizing 1H- and 13C- NMR on samples mixed dried plants purchased online in Japan. [39] They were able to detect the presence of a cannabimimetic phenyl- acetyl indole in the samples, which was conrmed utilizing MS. [39]

Additional experiments provided more clarity and identity of samples utilizing HF- 2D- NMR. For example, Venâncio et al., utilized 2D- DOSY- NMR to identify a sample of an anti- inammatory drug sold illegally in Brazil. [40] Using a 400 MHz NMR, they found ranitidine and a mixture of orphenadrine citrate, piroxicam, and dexamethasone in the samples. Similarly, Fernández et al., analyzed 16 tablets of artesunate, an antimalarial drug purchased in Cambodia utilizing 2D- DOSY-

H- NMR on a 500 MHz instrument. [41] They determined that only six of the

samples were genuine, while the remaining ten containing the wrong API, such as

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185

Using NMR Spectroscopy to Analyze Counterfeit Medications

185

acetaminophen, and/ or excipients were starch, lactose, sucrose, dextrin, or stearate. Additionally, Rebiere et al., utilized 2D- NMR on a 500 MHz instrument to analyze sixteen suspicious samples of so- called Viagra obtained from India, Syria, and China. [42] They found adulterants such as, sildenal citrate as the API as well as polyethylene glycol instead of lactose and triacetin as the excipients. [42] Likewise, Esteve- Turrillas et al., utilized 2D- DOSY- NMR on a sample of ketamine purchased online. [43] They found the presence of 3’,4’- methylenedioxy- 2,2dibromobutyrophenone, which they conrmed via IR and GC/ MS. [43] Similarly, Göker et al., utilized the same method to analyze two cans of 150 mL each of energy drinks purchased in Turkey. [44] They found the presence of propoxyphenyl which they veried using IR and MS. [44] Overall, the use of NMR to qualitatively identify counterfeits has been shown to be an effective, but costly, approach (see Table 7.2).

7.5 CONCLUSION

NMR spectroscopy is an effective approach for detecting and quantifying both the APIs and impurities in counterfeit drugs. Different methods, such as quantitative and qualitative NMR, have been utilized each with their own inherent advantages and disadvantages (see Table 7.3). Compared to other techniques, NMR is faster, nondestructive, and is able to identify and quantify APIs. Conversely, NMR is costly and often requires highly trained technicians to operate and interpret the data.

Of the quantitative NMR approaches, the direct determination method was effective as it did not require the need for reference standards. This is especially useful when these standards are not readily available, such as with new drugs. PULCON was particularly unique in not needing multiple calibrations of samples being analyzed, while TD- NMR did not need the sample to be dissolved in a deuterated solvent. Utilizing polarization transfer methods such as DEPT and INEPT, it was possible to determine a ngerprint for different manufacturers so that the origin of the drug could be identied. Despite these advantages, there are some setbacks to the quantitative analysis and NMR in general. NMR instruments are often big and expensive, as well as costly to maintain. Additionally, they can be complex to operate, and with HF- NMR require a cryogenic exchange.

Of the qualitative analysis, the benchtop and LF- NMR were effective for rapid screening to identify the components of counterfeit drugs. These studies utilize much simpler and less expensive NMR machines that require less space and complexity to operate. However, they are not as precise and may not be able to identify all compounds.

NMR is a powerful technology effective in identifying and quantifying potential counterfeit drugs, as well as creating a ngerprint to nd their origin. Hence, it contributes to overcoming the illegal drug market and controlling the general public health threat.

TABLE 7.2 Applications of qualitative NMR spectroscopy for the analysis of counterfeit drugs

186

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186

Technique/ Method Drug Location

LF Weight loss DS Internet 60 LF- relaxometry Viagra Poland 40 Benchtop LF Sexual enhancement &

Internet 60

NMR (MHz)

Nuclei/ Experiment Adulterant Ref

H Sibutramine, phenolphthalein, both [33]

H Sildenal citrate [35]

H Sildenal, tadalal [34]

weight- loss DS

HF Sarsaparilla Canada 600

H Distant taxonomical groups of

[36]

Sarsaparilla

HF Analogs of sildenal,

thiosildenal, &

Lab 400

H, 13C Pyrrolidinosildenal,

diethylaminosildenal

[37]

acetilsildenal

HF “khaki powder” DS Internet 800

H, 13C Tadalal [38] HF Herbal supplements Japan 600, 1501H, 13C Phenyl- acetyl indole [39] HF Anti- inammatory Brazil 400

H, 2D- DOSY Ranitidine, orphenadrine citrate,

[40]

piroxicam, dexamethasone

HF Artesunate Cambodia 500

H, 2D- DOSY Acetaminophen, starch, lactose,

[41]

sucrose, dextrin, stearate HF Viagra® India, Syria, China 500 HF Ketamine Internet 300, 751H, 13C, DEPT,

H, 2D- DOSY Sildenal citrate, polyethylene glycol [42]

2D- DOSY

3’,4’- methylenedioxy- 2,2-

dibromobutyrophenone

[43]

HF Energy drink Turkey 400, 1001H, 13C, 2D- DOSY Propoxyphenyl [44]

LF: low‑ eld, HF: high‑ eld, NMR: nuclear magnetic resonance, DS: dietary supplements, DEPT: distortionless enhancement by polarization transfer, DOSY: diffusion ordered spectroscopy, mAbs: monoclonal antibodies

Quantitative and Qualitative Determination of Counterfeit Drugs

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187

Using NMR Spectroscopy to Analyze Counterfeit Medications

TABLE 7.3

187

Advantages and disadvantages of qualitative and quantitative NMR

NMR Method Advantages Disadvantages

Quantitative • Faster analysis compared to other

techniques that require separation

• Nondestructive

• Signal intensity depends directly on the number of protons and their concentration

• Identies and quanties API

• Determination of concentration of components in mixtures

• Direct determination NMR is effective when reference standards are not available

• PULCON does not need multiple calibrations of samples

• TD- NMR effective in more complex compounds and mixes of drugs in solid states; does not need a deuterated solvent

• 2D gives more precise information about the components

• DEPT and INEPT are useful in determining the ngerprint of manufacturers

Qualitative • Non- destructive

• Often sufcient to determine if the API is present

• Rapid screening, quick sample preparation, rapid spectral recording

• HF- NMR provides a more precise structure of the molecules

• Benchtop and LF- NMR are more simple and less expensive

HF: high‑ eld, LF: low‑ eld, DEPT: distortionless enhancement by polarization transfer, INEPT: intense nuclei enhanced polarization transfer, TD: Time‑ domain, PULCON: pulse length‑ based concentration, NMR: nuclear magnetic resonance

• Expensive to maintain

• Complex to operate

• Requires cryogens

• Larger in size; takes up space

• Only applied to components with known chemical structure

• Components need to be soluble in deuterated solvent

• Often requires high resolution NMR machines

• HF- NMR is more expensive and complex to operate

• Benchtop and LF- NMR have less precision; may not be able to identify all compounds

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