Efficiency of extraction and conversion of pseudoephedrine to methamphetamine from tamper-resistant and non-tamper-resistant formulations.

(TO ORDER EPHEDRINE PSEUDOEPHEDRINE, BMK, PMK, 4ANPP, APVP, MDMA, KETAMINE,ALPRAZOLAM POWDER, 2CB FLY, PROTONITAZENE AND OTHER NITAZENES, FENTANIL REPLACEMENTS FOR RESEARCH.

For best Privacy and encryption contacts below:

Signal:+919319668540, Zhohouabiotech@zohomail.com,zhohouabt@tuta.io

Abstract

Clandestine chemists have demonstrated an ability to convert commercially available pseudoephedrine formulations to methamphetamine. Some of these formulations have properties that manufacturers claim limit or block the extraction of pseudoephedrine and its direct conversion to methamphetamine. In this study, 3 commercially available pseudoephedrine formulations were evaluated for ease of extraction and conversion to methamphetamine using a common chemistry technique called the one-pot method that is frequently employed by clandestine chemists. Two marketed pseudoephedrine formulations with claimed tamper-resistant properties – Zephrex-D® and Nexafed® – were compared to Sunmark®, a comparator formulation of pseudoephedrine without tamper-resistant properties. Particle size reduction was conducted using 8 readily available tools; solubility was assessed using 2 common aqueous solutions and various reaction conditions (e.g., temperature, stirring); extractability was evaluated using 8 common organic solvents. The one-pot (single vessel) method commonly used in clandestine processes was employed; chemicals and equipment were purchased locally on the open market. Quantities and addition times of the chemicals used to carry out the procedure and the duration of the reaction were varied to determine the effect on methamphetamine yield. The procedure was appropriately scaled and conducted in a controlled environment to reduce risk and maximize yields. Pseudoephedrine and methamphetamine were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS). Standard quantitative procedures were used to determine the quantities of pseudoephedrine and methamphetamine recovered and produced, respectively. Particle size reduction resulted in some loss of material of each pseudoephedrine formulation; Zephrex-D tablets were broken down to a coarse material; Nexafed and Sunmark tablets were reduced to a fine powder. The solubility rates of intact and ground tablets varied by product; Zephrex-D was most resistant to solubilizing while Nexafed and Sunmark were comparable and dissolved completely, demonstrating no solubility-resistant properties. Conditions of the one-pot method were modified throughout the studies to increase methamphetamine yield. Using optimal parameters identified in these studies and allowing the reaction to proceed for 90 min, average percent conversions were similar for the 3 formulations: 43.3% for Zephrex-D, 46.4% for Nexafed, and 48.6% for Sunmark. The greatest conversion occurred with a 150 min reaction time and resulted in 44.8%–48.4% conversion of Zephrex-D, 54.1%–66.4% conversion of Nexafed, and 58.6%–71.8% conversion of Sunmark. This series of methodological evaluations demonstrated that clandestine chemists can readily produce similar yields of methamphetamine using pseudoephedrine products with and without claimed tamper-resistant technology.

Order ephedrine HCl, BP crystals powder Australia and EU warehouse/Buy pseudoephedrine HCl powder Australia and EU warehouse (TO ORDER EPHEDRINE PSEUDOEPHEDRINE, BMK, PMK, 4ANPP, APVP, MDMA, KETAMINE,ALPRAZOLAM POWDER, 2CB FLY, PROTONITAZENE AND OTHER NITAZENES, FENTANIL REPLACEMENTS FOR RESEARCH.

For best Privacy and encryption contacts below:

Signal:+919319668540, Zhohouabiotech@zohomail.com,zhohouabt@tuta.io

1. Introduction

Methamphetamine is a Schedule II controlled substance that is highly addictive, widely abused, and relatively easy to produce using pseudoephedrine, a common decongestant medication, as a starting material. Typically, pseudoephedrine tablets are crushed and mixed with other easily obtained ingredients in a single vessel, usually an empty two-liter plastic soda container, initiating a chemical reaction that produces 1 to 3 grams of finished methamphetamine [1]. Called the one-pot method, this process for making methamphetamine also produces volatile and toxic gases and byproducts that pose serious environmental and safety risks . To address the growing methamphetamine threat, in 2005 the US Congress enacted the Combat Methamphetamine Epidemic Act (CMEA) that restricted daily and thirty-day sales of over-the-counter (OTC) pseudoephedrine products sold at retail. The CMEA required point of sale logbook systems to identify purchasers and record sales and retailers were required to place pseudoephedrine-containing products behind-the-counter (BTC) or in a locked cabinet, verify the identity of the purchaser and obtain the purchaser’s signature before completing a sale of pseudoephedrine or other precursor substance identified in the statute as a scheduled listed chemical product.

In addition to these requirements, the CMEA contained a provision permitting manufacturers of CMEA-regulated products to petition the Attorney General for an exemption from the aforementioned restrictions for products containing a regulated ingredient that cannot be used to make methamphetamine:

“EXEMPTIONS FOR CERTAIN PRODUCTS—Upon the application of a manufacturer of a scheduled listed chemical product, the Attorney General may by regulation provide that the product is exempt from the provisions of subsection (d) and paragraphs (1) and (2) of this subsection if the Attorney General determines that the product cannot be used in the illicit manufacture of methamphetamine”

Thus far, 2 pseudoephedrine-containing products claiming to have tamper-resistant formulations that prevent or inhibit the use of the products to make methamphetamine have entered the market. Nexafed® (Acura Pharmaceuticals) employs a patented polymer matrix technology known as Impede™ that in the presence of a solvent forms a thick gel designed to sequester the pseudoephedrine, thus limiting its extraction and conversion to methamphetamine [11,12]. The second product, called Zephrex-D (Westport Pharmaceuticals), uses a patented, lipid-based, technology known as Tarex® (Highland Pharmaceuticals, LLC). The manufacturer claims that this technology limits the extraction and conversion of pseudoephedrine to methamphetamine .

To investigate the subject of tamper-resistance in currently marketed pseudoephedrine products, we undertook a series of studies within a controlled laboratory environment to apply methods typically used by clandestine chemists to extract or convert pseudoephedrine tablets to methamphetamine using Nexafed, Zephrex-D, and Sunmark, a generic formulation of pseudoephedrine without claimed tamper-resistance. Phase 1 studies identified baseline conditions for pseudoephedrine extraction and conversion to methamphetamine using the one-pot reaction. In Phase 2 studies, one-pot reaction conditions were modified to increase methamphetamine production.

The first objective was to assess the ease or difficulty of extracting pseudoephedrine from Zephrex-D, Nexafed, and Sunmark tablets. The second objective was to evaluate the feasibility of converting pseudoephedrine directly (i.e., using ground tablets) and indirectly (i.e., using pseudoephedrine extracted from ground tablets) to methamphetamine using variations of posted recipes of the one-pot method. The third objective was to determine the yield and reproducibility of yield of methamphetamine using the one-pot method developed during these studies.

Detailed recipes for making methamphetamine from pseudoephedrine tablets using the single vessel or one-pot method are readily accessible on Internet sites. Most rely on basic chemistry principles to produce the finished product. Pseudoephedrine tablets are available in varying strengths (i.e., 30, 120, and 240 mg tablets) and package sizes (i.e., 10–20 tablets) and are sold at pharmacies and other retail outlets in accordance with the aforementioned provisions of the CMEA [11,15]

2. Materials and methods

Three marketed pseudoephedrine products, Zephrex-D Nasal Decongestant (pseudoephedrine HCl 30 mg), Nexafed Nasal Decongestant (pseudoephedrine HCl 30 mg), and Sunmark Nasal Decongestant Maximum Strength (pseudoephedrine HCl 30 mg) (McKesson) were selected for this series of experiments.2

2.1. Phase 1: particle size reduction and solubility of study products

The first step in determining the ease of extractability of pseudoephedrine from study products was to reduce their particle size. Physical and mechanical techniques using 8 ordinary household tools were used to reduce study product tablets to smaller particle sizes (via grinding, cutting, etc.) to assess the resilience of the formulations and to determine the most ideal particle size reduction procedure to facilitate drug solubility. To account for any loss of material during the reduction procedure and accurately calculate weight recovery, the study products were weighed before and after particle size reduction; these weights were then used in the recovery calculations.

The next step included determining the pseudoephedrine solubility profile. Samples of intact and ground study product were dissolved in water and a commercially available 40% ethanol product under various conditions (e.g., temperature, stirring) and for variable amounts of time. Aliquots were collected and analyzed, in triplicate, by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The concentration of pseudoephedrine in the samples was determined relative to a calibration curve and supported with quality control samples. The percent solubility of pseudoephedrine from the dissolved study product was determined.

2.2. Phase 1: Bi-phasic extraction of pseudoephedrine from study products

Following a particle size reduction procedure, 2 tablets of each study product were added to a basic aqueous solution contained in a separatory funnel followed by the addition of an organic solvent. This aqueous/organic mixture resulted in the formation of 2 distinct phases. Eight solvents (3 laboratory grade, 5 commercial grade) were tested for their ability to extract pseudoephedrine from the study products; extractions were conducted in duplicate. The aqueous/organic phases were mixed and layers allowed to separate. The pseudoephedrine-containing organic layer was removed from the funnel and an aliquot was collected for dilution and quantitative analysis. The amount of pseudoephedrine in the solvent layer was quantified by LC–MS/MS. A series of separate experiments were conducted in which the pseudoephedrine was quantified after evaporation and reconstitution steps.

2.3. Pseudoephedrine to methamphetamine conversion: one-pot method

When conducting pseudoephedrine to methamphetamine conversion reactions, individual clandestine chemists vary reaction components and conditions to influence yield of methamphetamine from starting materials. As a result, there is no standardized process or definitive set of parameters for this reaction. The one-pot method refers to the chemical reactions, conducted in a single vessel, which are used by clandestine chemists to generate methamphetamine from pseudoephedrine-containing formulations. These studies were based on methodology commonly used by members of the clandestine drug synthesis community.

The one-pot method was performed in 2 ways in this study; the first included conducting the reaction on ground tablets (direct one-pot method), while the second used material collected after grinding and extracting pseudoephedrine from tablets into an organic solvent (indirect one-pot method). Furthermore, reaction conditions were evaluated in 2 phases. Phase 1 assessed solubility and extraction of pseudoephedrine from study products and conversion of pseudoephedrine to methamphetamine using direct and indirect one-pot method conditions. Phase 2 assessed the yield of one-pot reactions after subsequent optimization of reaction conditions identified in Phase 1. Comparative solubility, extraction, and one-pot methodologies were performed replicating clandestine processes, including the use of common household devices and supplies that were purchased from local retail stores, but with a rigorous scientific approach. All conditions were scaled appropriately for the safety of analysts and controlled to limit the rate of reaction and enhance the yield of methamphetamine.

In Phase1, experimental conditions were varied to determine the ratios of reagents (e.g., number of lithium strips from batteries; amount of water) and reaction time for the direct and indirect one-pot conversion of study products to methamphetamine. Conversion reactions were conducted in duplicate. The resulting solvent layer was quantitatively analyzed by LC–MS/MS to determine the methamphetamine yield under various conditions. The final reaction conditions resulted in yields of approximately 62% (direct one-pot) and 50% (indirect one-pot) methamphetamine.

In Phase 2, reaction parameters selected in Phase 1 were modified further to identify an optimized method to increase yield and consistency of yield of methamphetamine for the direct one-pot method. Modifications included the relative proportions of ingredients and duration of reaction. Two direct one-pot time-studies (150 min and 180 min) were conducted to determine the optimal reaction time which produced the greatest yield of methamphetamine since the reaction is known to convert methamphetamine to 1-(1′4′-cyclohexadienyl)-2-methylaminopropane (CMP) if allowed to proceed for excessive amounts of time [16] (Fig. 1). A reaction end point of 150 min was selected for the final method parameters in subsequent studies; study products were analyzed in triplicate.

1. 
   

2.4. Instrumental analysis

Quantitative analyses of samples were performed using a triple quadrupole LC–MS/MS system (Agilent 1100 series LC, Waters® Quattro Micro MS). Standard chromatographic and mass spectrometric methodologies were used to analyze the samples. Data acquisition and processing methods were developed to identify and quantitate pseudoephedrine and methamphetamine using isotopically-labeled internal standards. Commercially available reagents were purchased from local retail stores for use in solubility, extraction, and conversion experiments.

Certified reference materials were used for developing calibration and quality control (QC) samples for pseudoephedrine and methamphetamine quantitation. QC samples were analyzed throughout the duration of analytical runs to ensure acceptable instrument performance.

2.5. Calculations

Standard quantitative procedures were used to generate calibration curves from certified reference material. Quantitation of study samples was performed by comparison to the calibration curve responses allowing for quantitation of pseudoephedrine and methamphetamine. This means of quantitation was applied to all processes used throughout the study. The relative percent recovery of pseudoephedrine and production of methamphetamine was based on the theoretical values for 100% recovery/production in solution.

3. Results

3.1. Phase 1: particle size reduction of study products

All of the tools used resulted in reduction in size of the original tablets. Percent weight and active pharmaceutical ingredient (API) recovery varied by product and was dependent on the means of particle size reduction. A food grade processor was selected to reduce the particle size for use in subsequent studies based on ease of use and consistency of particle size produced for the 3 study products. Zephrex-D tablets were broken down to a coarser material relative to Nexafed and Sunmark tablets, both of which were reduced to a fine powder.

3.2. Phase 1: solubility of study products

Under certain experimental conditions (e.g., time, temperature, solvent) using intact and ground study products (aliquots analyzed in triplicate by LC–MS/MS), Zephrex-D tablets were most resistant to being solubilized. In general, the solubility profile of Nexafed tablets was more similar to the non-tamper resistant Sunmark tablets than to Zephrex-D tablets. There were few conditions which supported similarly high (>70%) pseudoephedrine recoveries from all 3 study products. After as little as 30 min, Sunmark tablets were easily and readily dissolved (≥60%), regardless of other experimental conditions (eg, temperature, stirring), exhibiting weak solubility-resistant properties.

3.3. Phase 1: Bi-phasic extraction of pseudoephedrine from study products

Eight common organic solvents (commercial and laboratory grade) were evaluated for their ability to preferentially extract pseudoephedrine from the study products as a preliminary step in its conversion to methamphetamine (extractions conducted in duplicate). Two laboratory grade solvents (Solvents A and B) were identified as optimal solvents for use in these experiments based on pseudoephedrine recovery . Solvent A was selected as the extraction solvent since recovery was slightly higher for Zephrex-D and Nexafed and this solvent was more easily evaporated.

Order ephedrine HCl, BP crystals powder Australia and EU warehouse/Buy pseudoephedrine HCl powder Australia and EU warehouse.

(TO ORDER EPHEDRINE PSEUDOEPHEDRINE, BMK, PMK, 4ANPP, APVP, MDMA, KETAMINE,ALPRAZOLAM POWDER, 2CB FLY, PROTONITAZENE AND OTHER NITAZENES, FENTANIL REPLACEMENTS FOR RESEARCH.

For best Privacy and encryption contacts below:

Signal:+919319668540, 

Zhohouabiotech@zohomail.com,

zhohouabt@tuta.io