DEA Resources, Microgram Journal, Volume 1, January-June 2003-Information and Instructions for Microgram Journal

Desloratadine: The Reaction Byproduct of the Reduction
of Cold Tablets Containing Loratadine with Hydriodic Acid/Red Phosphorus

Shannon C. DiPari,* Jason A. Bordelon, and Harry F. Skinner
U.S. Department of Justice
Drug Enforcement Administration
Southwest Laboratory
2815 Scott Street
Vista, CA 92081
[email: Shannon.C.DiPari -at- usdoj.gov ]

[Reprinted with Permission from the Journal of the Clandestine Laboratory Investigating Chemists
Association 2005;15(1):4-11. Note that the original article did not contain an Abstract or Keyword list,
and those provided below are by the Editor. Note also that this version has been reformated to
Microgram Journal standards, and additionally has had minor errors corrected.]

ABSTRACT: Production of methamphetamine via hydriodic acid/red phosphorus reduction of over-the-counter pseudoephedrine products that contain other active co-ingredients will generate products that are contaminated with those co-ingredients and/or their reduction byproducts. In the case of pseudoephedrine products containing loratadine, the final product will contain desloratadine. Identification of desloratadine in methamphetamine therefore provides an indication of the commercial product used as the precursor in the synthesis.

KEYWORDS: Desloratadine, Loratadine, Pseudoephedrine, Methamphetamine, Hydriodic Acid, Red Phosphorus, Reduction, Trace Analysis, Impurity Profiling, Forensic Chemistry

Introduction

Clandestine methamphetamine laboratories are prevalent in the United States. One of the primary synthetic methods encountered is the reduction of ephedrine or pseudoephedrine with hydriodic acid/red phosphorus.¹ When first encountered and for many years thereafter, commercial hydriodic acid and red phosphorus were used in the reduction. In recent years, however, hydriodic acid and red phosphorus purchases have been restricted by law, forcing the clandestine laboratory operators to search for alternative sources. Red phosphorus is commonly obtained by the use of matchbooks and flares whereas hydriodic acid needs to be synthesized by the clandestine laboratory operator. The synthetic methods to generate hydriodic acid use iodine and either red phosphorus or other reactive phosphorous compounds such as hypophosphorous acid or phosphorous acid.²

Due to the increased restrictions on obtaining pure precursor ephedrine or pseudoephedrine, most clandestine laboratory operators are utilizing common cold tablet preparations.^3,4 These cold tablet preparations contain either ephedrine or pseudoephedrine, and often other ingredients such as cough suppressants, analgesics, expectorants, or antihistamines. Common co-ingredients include acetaminophen, brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, and triprolidine. When these compounds are present in the ephedrine/pseudoephedrine reduction mixtures, they will be carried through the reaction sequence unchanged, or will produce characteristic byproducts that are identifiable by GC/MS. ^5,6

The identification of these compounds or their byproducts in clandestinely produced methamphetamine can assist the analyst in determining which cold tablet preparation was used as the precursor source. The ratios of these byproducts relative to methamphetamine are usually very low in the final product. However, they can be easily extracted and identified.⁷ As new cold products become available on the market, clandestine laboratory operators will use them to obtain pseudoephedrine and manufacture methamphetamine. Any new co-products contained in these cold tablets have the potential to produce impurities not previously encountered by the forensic analyst. A recent example is tablets containing loratadine, which are already being used in methamphetamine production. Loratadine is the active ingredient in Claritin^®, which recently changed from a prescription to an over-the-counter medication.

Experimental

Reactions
Loratadine, red phosphorus and 30 mL of 57% hydriodic acid were refluxed (boiling point = 120 °C) in a round bottom flask fitted with a condenser. The reactions were monitored by removal of aliquots with subsequent analysis. The aliquots were sampled initially, once the mixture began to reflux, and then at every hour. The progress of each reaction was monitored as a decrease of the precursor and the formation of desloratadine. The progress was also monitored by detection of intermediates and byproducts.

Gas Chromatography
These analyses were performed using an Agilent Technologies 6890N Gas Chromatograph equipped with electronic pneumatic control and a flame ionization detector. A 10.0 m x 0.32 mm i.d. fused-silica capillary column coated with 0.52 μm DB-5 (Agilent Technologies) was employed. Hydrogen was the carrier gas, with an average linear velocity of 40 cm/sec (constant flow). The injection port and detector were maintained at 280 °C. The samples were extracted into ether, and one μL of each sample was injected in split mode (25:1). The oven temperature was programmed as follows: Initial temperature 130 °C, hold for 1.0 minute, then increase temperature 25 °C per minute to 280 °C, hold for 1.0 minute (total run time = 10.0 minutes).

Gas Chromatography/Mass Spectrometry
The electron impact (EI) mass spectra were obtained using an Agilent Technologies Mass Spectrometer. The spectrometer was equipped with a 5973 mass selective detector and 6890N gas chromatograph. A 30.0 m x 0.25 mm i.d. fused-silica capillary column coated with 0.25 μm HP5-MS (Agilent Technologies) was employed. Helium was the carrier gas with an average linear velocity of 40 cm/sec (constant flow). The injection port and ion sources were set at 240°C and 180°C, respectively. One μL from each of the samples was injected in split mode (30:1). The oven temperature was programmed as follows: Initial temperature 100 °C for 1.0 minute, then increase temperature 20 °C per minute to 280 °C, hold for 10.0 minutes (total run time = 20 minutes). The mass spectrometer was scanned over an m/z range of 40 - 500. The transfer lines were maintained at 280 °C.

Infrared Spectrophotometry
The infrared spectra were obtained in potassium bromide on a Nicolet Magna 560 Fourier Transform Infrared (FTIR) Spectrophotometer. The infrared spectra were also obtained by attenuated total reflectance (ATR) on an Avatar 370 FTIR Spectrophotometer.

Results and Discussion

The intermediates and byproducts in the synthesis of methamphetamine utilizing ephedrine/pseudoephedrine via HI/red P are well documented. ^{1, 7-11} For example, if chlorpheniramine or 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrolidinopropane (commonly referred to as “reduced triprolidine”) are present in a methamphetamine sample, then the precursor source of the pseudoephedrine also certainly contained chlorpheniramine or triprolidine, respectively.⁵ Whenever a new compound shows up in the finished product, this indicates that a new, previously unused cold tablet preparation has probably been used as the precursor source.

Recently, a methamphetamine sample was analyzed in this laboratory and was found to contain a new compound not seen in previous exhibits. The compound was in very low concentration in comparison to the methamphetamine, indicating it was probably not added as a cutting agent. The gas chromatogram is shown in Figure 1. The compound eluted on the gas chromatograph in the same general area of other “byproduct amines” produced from the previously discussed pseudoephedrine pharmaceutical preparations.^5-7 The mass spectrum was easily obtained by employing an extraction technique to enhance these compounds.⁷ That is, the methamphetamine sample (50 to 100 mg) was dissolved in 2-3 mL of water and made pH 8/9 basic with sodium bicarbonate. The basic solution was then extracted with 2 mL of hexane. The majority of the methamphetamine remained in the aqueous solution and did not extract into the hexane. Neutrals and “byproduct amines” are enhanced over the methamphetamine and also over the most common cutting agent dimethylsulfone. The extracted solution was further enhanced by evaporating it to dryness on a hot plate at 90º C, using a stream of air for about two minutes. Phenyl-2-propanone, methamphetamine, and residual dimethylsulfone are more volatile and evaporate, leaving only the suspected “byproduct amine.” In the present case, after the compound was isolated, the mass spectrum was easily obtained. The mass spectrum of the compound gave a base peak of 280 amu and parent ion of 310 amu, as shown in Figure 2.

Fexofenadine	Cetirizine
Loratadine

Several new products containing pseudoephedrine and previously unreported antihistamines including fexofenadine, cetirizine, and loratadine are now commercially available. The molecular weights are as follows: Fexofenadine (mw: 501.7), cetirizine (mw: 388.9) and loratadine (mw: 382.9). A “D” at the end of the proprietary name of the antihistamine product denotes that the product also contains the decongestant pseudoephedrine. The ratio of fexofenadine HCl to pseudoephedrine HCl is 60:120 mg/tablet. The ratio of cetirizine HCl to pseudoephedrine HCl is 5:120 mg/tablet. The ratio of loratadine to pseudoephedrine sulfate is 5:120 or 10:240 mg/tablet. The loratadine containing product has recently been converted from a prescription to an over-the-counter product, making it much easier to obtain than the other two products. Based on the ratio of the “byproduct amine” to methamphetamine in the methamphetamine exhibits, and the mass spectrum of the new compound, the loratadine product with pseudoephedrine was suspected to be the source of the new byproduct. The structures of fexofenadine, cetirizine, and loratadine are shown above.

The chemical name of loratadine is ethyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptal[1,2-b]pyridine-11-ylidene-1-piperidine carboxylate. Loratadine is also known as 8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptal-[1,2-b]pyridine-11-ylidene-1-piperidine carboxylic acid ethyl ester. Based on the structure of loratadine, the reaction with HI was suspected to cleave the amide group and reduce the double bond. Both of these structural changes are consistent with the cleavage of the amide/ester groups and the reduction of the double bond, as previously observed with triprolidine.⁵ The expected products would have molecular weights of 310.8 and 312.8 amu, respectively.

Loratadine was obtained by extracting commercial tablets containing only loratadine as the active ingredient. The ground tablets were extracted with chloroform, recrystallized with acetonitrile/ether, and air-dried on a hot plate. The mass spectrum and infrared spectrum of the solid matched a standard of loratadine (USP Cat. #137020). The mass spectrum and infrared spectra (KBr and ATR) are shown in Figures 3 - 5.

The isolated loratadine was refluxed with the same ratio of hydriodic acid and red phosphorus often used in methamphetamine manufacture, and the reaction monitored by gas chromatography. The retention times for the reaction product and loratadine were 7.12 and 9.24 minutes, respectively. The reaction product formed as soon the reaction mixture was heated. The gas chromatograph retention time and the mass spectrum of this reaction product are the same as the unknown compound encountered in the methamphetamine exhibits. Loratadine was also refluxed with only hydrochloric acid, and this mixture produced the same reaction product.

The unknown compound had to be an acid cleaved amide product with no reduction of the double bond, since hydrochloric acid is not capable of reducing the double bond. The identity of the unknown compound is 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptal[1,2-b]pyridine-11-ylidene-1-piperidine, or more simply desloratadine. The identity was confirmed by comparison with extracted desloratadine from pharmaceutical tablets containing desloratadine. The methamphetamine precursor therefore had to be tablets containing loratadine and pseudoephedrine, since commercial tablets containing desloratadine do not contain pseudoephedrine. The mass spectrum for desloratadine is shown in Figure 6. The structure of desloratadine is shown below.

Desloratadine

The main byproduct formed when manufacturing methamphetamine using loratadine-containing pseudoephedrine tablets is desloratadine. However, in some of the methamphetamine samples containing desloratadine another “byproduct amine” was also detected. The compound elutes just after desloratadine. The mass spectrometer total ion chromatogram is shown in Figure 7. This compound has a base peak of 82 amu with an ion at 267 amu and a suspected parent peak of 310 amu. The mass spectrum is shown in Figure 8. This compound has not yet been identified, and will be addressed in future studies.

Conclusions

Use of cold tablet preparations as the source of pseudoephedrine has presented challenges in the identification of the trace amounts of the “byproduct amines” in methamphetamine samples. These challenges will continue as new pharmaceutical combinations with pseudoephedrine are made available. The identification of these byproducts in clandestinely produced methamphetamine can help analysts in determining which cold tablet preparations were used as the precursor source, and to link specific exhibits and cases, or both.

References

1. Skinner HF. Methamphetamine synthesis via hydriodic acid/red phosphorus reduction of ephedrine. Forensic Science International 1990;48:123.

2. Skinner HF. Identification and quantitation of hydriodic acid manufactured from iodine, red phosphorus, and water. Microgram 1995;28(11):349.

3. The Chemical Diversion and Trafficking Act of 1988. Anti-Drug Abuse Amendments Act of 1988, Subtitle A.

4. Drug Enforcement Administration, Statistical Reports, 1996.

5. Oulton SR, Skinner HF. Reaction byproducts of common cold tablet ingredients via hydriodic acid/red phosphorus. Journal of the Clandestine Laboratory Investigating Chemists Association 1999;9(4):21.

6. Melgoza L. Impurities in methamphetamine manufactured from over-the-counter pseudoephedrine tablet preparations. Journal of the Clandestine Laboratory Investigating Chemists Association 1999;9(2-3):21.

7. Martinez FS, Jacobs J L, Skinner HF. Extraction of reaction by-products of common cold tablet ingredients via hydriodic acid reduction. Journal of the Clandestine Laboratory Investigating Chemists Association 2003;13(1):13.

8. Lekskulchai V, Carter K, Poklis A, Soine W. GC/MS analysis of methamphetamine impurities: Reactivity of (+)- or (-)-chloroephedrine and cis and trans-1,2-dimethyl-3-phenylaziridine. Journal of Analytical Toxicology 2000;24:602.

9. Lurie IS, Bailey CG, Anex DS, Bethea MJ, McKibben TD, Casale JF. Profiling of impurities in illicit methamphetamine by high-performance liquid chromatography and capillary electrochromatography. Journal of Chromatography 2000;870:53.

10. Noggle FT, Clark CR, DeRuiter J. Characterization of methamphetamine and synthetic byproducts in clandestine samples: A case report. Microgram 1994;27:253.

11. Windahl KL, McTigue MJ, Pearson JR, Pratt SJ, Rowe JE, Sear EM. Investigation of the impurities found in methamphetamine synthesized from pseudoephedrine by reduction with hydriodic acid and red phosphorus. Forensic Science International 1995;76(2):97.

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Figure 1. Gas Chromatogram of a Methamphetamine Sample Containing Dimethylsulfone and the Unknown “Byproduct Amine.” Retention times: Dimethylsulfone: 0.579 Minutes; Methamphetamine: 1.289 Minutes; and Unknown “Byproduct Amine”: 7.122 Minutes.

Figure 1. Gas Chromatogram of a Methamphetamine Sample Containing Dimethylsulfone and the Unknown “Byproduct Amine.” Retention times: Dimethylsulfone: 0.579 Minutes; Methamphetamine: 1.289 Minutes; and Unknown “Byproduct Amine”: 7.122 Minutes.

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Figure 2. Mass Spectrum of the Previously Unseen “Byproduct Amine.”