Pseudoephedrine Products Research Articles

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

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.

Evaluation of pseudoephedrine pharmacy sales before and after mandatory recording requirements in Western Australia: a case study

BackgroundA community pharmacy real-time electronic recording program, ProjectSTOP, enables Australian community pharmacists to verify pseudoephedrine requests. In Western Australia the program was available for voluntary use from April 2007 and became mandatory November 2010. This case study explores the effectiveness of the program by reviewing the total requests for pseudoephedrine products, and the proportion of requests which were classified as ‘denied sales’ before and after mandatory implementation. Seasonal and annual trends in these measures are also evaluated.MethodsProjectSTOP data recordings for Western Australia pharmacies between 1 December 2007 and 28 February 2014 were analysed. Data included a de-identified pharmacy number and date of each pseudoephedrine product request. The total number of requests and sale classification (allowed, denied, safety, or not recorded) were calculated for each month/pharmacy. The potential influence of mandatory reporting using ProjectSTOP was investigated using a Regression Discontinuity Design. Correlations between sales from the same pharmacy were taken into account by classifying the pharmacy number as a random effect. The main effects of year (continuous variable), and season (categorical variable) were also included in the model.ResultsThere was a small but steady decline in the total requests for pseudoephedrine per month per 100,000 population (per pharmacy) from the time of mandatory reporting. The number of denied sales showed a steady increase up until mandatory reporting, after which it showed a significant decline over time. Total sales were heavily influenced by season, as expected (highest in winter, least in summer). The seasonal pattern was less pronounced for denied sales, which were highest in winter and similar across other seasons. The pattern over time for safety sales was similar to that for denied sales, with a clear change occurring around the time of mandatory reporting.ConclusionResults indicate a decrease in pseudoephedrine product requests in Western Australia community pharmacies. Findings suggest ProjectSTOP has been successful in addressing suspicious sales and potential diversion however ongoing data review is recommended.

The advent of a new pseudoephedrine product to combat methamphetamine abuse

Background: The personal and societal effects of methamphetamine abuse are well documented. The ease of accessibility to methamphetamine and the quality of the “high” it produces makes the drug highly desired by its abusers. Over time, many methamphetamine users will also become methamphetamine cooks, where pseudoephedrine in over-the-counter cold products is converted to methamphetamine through a simple, albeit extremely dangerous, process. New laws limiting access to these products have had limited success. No existing commercial pseudoephedrine products offer significant impediments to slow or limit the extraction and conversion of pseudoephedrine in clandestine methamphetamine laboratories. Objective and Methods: A new pseudoephedrine 30 mg tablet product using Impede technology (Nexafed®) to deter methamphetamine production has recently been introduced into the marketplace. Using methods designed to mimic clandestine laboratory processes, the ability of this product to disrupt extraction and conversion of pseudoephedrine to methamphetamine yet provide therapeutic effectiveness was evaluated. Results: Impede™ technology tablets limited the extraction and/or conversion of pseudoephedrine to methamphetamine when compared to a commercially marketed pseudoephedrine product (Sudafed®). Nexafed® tablets were also shown to be bioequivalent to the same control product, thus ensuring therapeutic equivalence. Conclusions: With the advent of new pseudoephedrine products in the marketplace with features to limit the extraction and conversion of pseudoephedrine to methamphetamine, new tools are now available to minimize the clandestine manufacture of the drug and potentially limit its social impact.

Assessing community pharmacist engagement in a policing partnership strategy to reduce the illicit diversion of pseudoephedrine products

The incidence of illicit diversion of pharmaceutical products is a worldwide problem associated with negative health consequences and with other crimes. The illicit diversion of pharmaceuticals containing the active ingredient pseudoephedrine is of concern, primarily due to the role this substance plays in the manufacture of synthetic illicit drugs such as methylamphetamine. There are a range of strategies employed to curb the problem of precursor diversion. Not least is the development of strategies involving front-line health professionals such as community pharmacists to play an important role in reducing the incidence of diversion. This study aimed to examine levels of pharmacist engagement in an intervention expected to decrease diversion of pseudoephedrine products from community pharmacies. The primary objective was to explore levels of community pharmacist engagement with the intervention and to explore their perceptions of intervention effectiveness. A survey instrument was developed to examine six main areas relating to the implementation, operation and outcomes of the intervention, in addition to the roles performed by community pharmacists in two Australian State jurisdictions. The respondent pharmacists were recruited through a combination of email and facsimile communications from the Pharmacy Guild of Australia and through an electronic pharmacy newsletter. Thirty percent of eligible community pharmacies in the study jurisdictions responded to the survey. The results of the survey highlight that in the absence of an alternative strategy to assist community pharmacists to reduce pseudoephedrine diversion, the majority of respondents were satisfied with the effectiveness of the police-pharmacy intervention. It was found that a pharmacist's positive perception of the role police played in the intervention strongly influenced their engagement in the strategy. Identifying the factors that significantly influence pharmacist engagement in this strategy has broader implications for other law enforcement-public health strategies. It is important for policy models to incorporate these significant elements in their design to enhance the implementation, operation and outcomes of prevention-type interventions.

Changing over-the-counter ephedrine and pseudoephedrine products to prescription only: Impacts on methamphetamine clandestine laboratory seizures

BackgroundClandestine laboratory operators commonly extract ephedrine and pseudoephedrine—precursor chemicals used to synthesize methamphetamine—from over-the-counter cold/allergy/sinus products. To prevent this activity, two states, Oregon in 07/2006 and Mississippi in 07/2010, implemented regulations classifying ephedrine and pseudoephedrine as Schedule III substances, making products containing them available by prescription only. Using simple pre-regulation versus post-regulation comparisons, reports claim that the regulations have substantially reduced clandestine laboratory seizures (an indicator of laboratory prevalence) in both states, motivating efforts to implement similar regulation nationally. This study uses ARIMA-intervention time-series analysis to more rigorously evaluate the regulations’ impacts on laboratory seizures. MethodsMonthly counts of methamphetamine clandestine laboratory seizures were extracted from the Clandestine Laboratory Seizure System (2000—early 2011) for Oregon, Mississippi and selected nearby states (for quasi-control). FindingsSeizures in Oregon and nearby western states largely bottomed out months before Oregon's regulation, and changed little thereafter. No significant impact for Oregon's regulation was found. Mississippi and nearby states generally had elevated seizures before Mississippi's regulation. Mississippi experienced a regulation-associated drop of 28.9 seizures (50.2%) in the series level (p<0.01), while nearby states exhibited no comparable decline. ConclusionsOregon's regulation encountered a floor effect, making any sizable impact infeasible. Mississippi, however, realized a substantial impact, suggesting that laboratories, if sufficiently extant, can be meaningfully impacted by prescription precursor regulation. It follows that national prescription precursor regulation would have little impact in western states with low indicated laboratory prevalence, but may be of significant use in regions facing higher indicated prevalence.

Pseudoephedrine Use Among US Children, 1999–2006: Results From the Slone Survey

Pseudoephedrine, a decongestant found in many cough-and-cold and allergy medications, has been associated with deaths and adverse events in young children; however, the absolute risks of pediatric pseudoephedrine use are difficult to assess because the number of children exposed on a population basis and typical patterns of use are unknown. In addition, use may be changing because of the Combat Methamphetamine Epidemic Act of 2005, which limited pseudoephedrine availability. We sought to describe the prevalence and patterns of pseudoephedrine use among US children and to assess any change since the 2005 law took effect. We analyzed data on pseudoephedrine use among 4267 children who were aged 0 to 17 years and enrolled from 1999 to 2006 in the Slone Survey, a national random-digit-dial telephone survey of medication use in the US population. Overall, 214 children took pseudoephedrine in a given week. Use was highest for children who were younger than 2 years. Sixteen children (7.5% of users) took >1 pseudoephedrine-containing product within the same week, including 6 children who were younger than 2 years. Of the pseudoephedrine products used, most were multiple-ingredient liquids (58.9%) and multiple-ingredient tablets (24.7%). Fifty-two children (25.0% of users) took pseudoephedrine for >1 week, including 7 children who were younger than 2 years. Use in 2006 (2.9%) was significantly lower than in 1999-2005 (5.2%). Pseudoephedrine exposure, mostly in the form of multiple-ingredient products, is common among US children, especially children who are younger than 2 years, who are at the highest risk for toxicity and for whom safe dosing recommendations are lacking. Concerning patterns of use include taking >1 pseudoephedrine-containing product concurrently and using pseudoephedrine for extended periods. Pediatric pseudoephedrine use seems to be declining since the institution of the 2005 Combat Methamphetamine Epidemic Act.

Methamphetamine suppression and route of administration: precursor regulation impacts on snorting, smoking, swallowing and injecting

The route of drug administration affects risk for dependence and medical harm. This study examines whether routes used by methamphetamine treatment participants were impacted by a major drug suppression policy-federal regulation of the methamphetamine precursor chemicals ephedrine and pseudoephedrine. Autoregressive-integrated moving average (ARIMA) intervention time-series analysis. California (1992-2004). Ephedrine single-ingredient products regulation, implemented August 1995; ephedrine with other active medicinal ingredients regulation, implemented October 1996; pseudoephedrine products regulation, implemented October 1997. Monthly counts of non-coerced methamphetamine treatment admissions reporting snorting, smoking, swallowing or injecting. Findings After rising sharply, snorting, smoking, swallowing and injecting admissions dropped 50%, 43%, 26% and 26%, respectively, when the 1995 regulation was implemented. Snorting also dropped 38% at the time of the 1997 regulation. Snorting, swallowing and injecting remained at lower levels to the end of the study period. Smoking resurged (40%) at the time of the 1996 regulation and continued rising. Precursor regulation was associated with changes in the administration of methamphetamine. Injecting, the route with the greatest health risk, entered a long-term reduction. So, too, did snorting and swallowing, two routes with lower risk for dependence. In contrast, smoking, which has a relatively high risk for dependence, dropped, then rebounded and entered a long-term rise. A possible explanation is that injecting, snorting and swallowing were largely linked with US domestic methamphetamine production, which has yet to recover from the regulations. While Mexican production, which was impacted only temporarily by the regulations and has supplanted domestic production, may have helped to diffuse smoking, a route with which it is historically correlated.

Reporting Purchasers of Pseudoephedrine Products to Police: New Zealand Community Pharmacists' Experiences

ABSTRACTBackgroundPseudoephedrine is the precursor of choice for the illicit manufacture of methamphetamine, much of which is obtained through purchases of pseudoephedrine products from community pharmacies.AimTo investigate issues surrounding data collection by community pharmacists in New Zealand on purchasers of pseudoephedrine products and its provision to police.MethodQuestionnaires were mailed to a random sample of 50% of community pharmacies in New Zealand, with a second mailing to non‐responders.ResultsThere was a response rate of 63%. 95% of pharmacists limited the quantity of pseudoephedrine products sold on each occasion. 45% asked for identification from all purchasers. Requesting/collecting identification resulted in various problems such as dealing with aggressive customers, and requiring time to attend court cases as a result of data provided to police. A major issue identified was the lack of feedback from police on information that had been provided. Nonetheless, there was support amongst pharmacists to continue to collect this information.ConclusionAlthough there were a number of problems encountered by pharmacists, many of these can be overcome.

Perceptions about behind-the-counter availability of pseudoephedrine

Recent federal legislation has mandated pharmacies to move pseudoephedrine products behind the counter. [1][1]–[3][2] We undertook a qualitative study that explored perceptions about this new policy in hopes of identifying strategies to maximize its desired effect. Ninety participants completed a

Separation of Fexofenadine, Pseudoephedrine, Potential Impurities, and Degradation Products Using Ion Interaction Chromatography

Ion interaction chromatography has been demonstrated to be a viable separation scheme for a wide variety of small molecules. This separation mechanism has been shown to be effective for a complex mixture of analytes that range from uncharged to positively and/or negatively charged. The analytes present in fexofenadine‐D tablets are either uncharged or cationic. Therefore, if a single HPLC method is to be used for this difficult separation, a dual mechanistic system must be present so that the charged and neutral components are retained and separated. An ion interaction liquid chromatographic system that contains an anionic surfactant, such as sodium dodecyl sulfate (SDS), meets both of these requirements: a reversed stationary phase for a hydrophobic analyte and a fixed anionic charge site for a positively charged analyte. The effect that each mobile phase parameter may have on this complex separation was found to be crucial. These variables were studied and include: concentration of SDS, ionic strength, pH, concentration of phosphoric acid, concentration of organic modifier, column temperature, and different gradients. The results obtained in this study and the optimized separation is discussed.

Impacts of federal precursor chemical regulations on methamphetamine arrests

The US government regulated precursor chemicals, ephedrine and pseudoephedrine, multiple times to limit methamphetamine production/availability and thus methamphetamine problems. Research has found that the regulations reduced methamphetamine hospital admissions, but authors have argued that other problems were unaffected. This study examines whether the regulations impacted methamphetamine arrests. ARIMA-intervention time-series analysis with control series. California (1982-2001). Dependent variable series: monthly methamphetamine arrests. Control series: monthly marijuana arrests and cocaine/heroin arrests. Bulk powder ephedrine and pseudoephedrine: regulated November 1989. Products containing ephedrine as the single active medicinal ingredient: regulated August 1995. Pseudoephedrine products: regulated October 1997. Large-scale producers used ephedrine and pseudoephedrine in these forms. Ephedrine combined with other active medicinal ingredients (e.g. various cold medicines)-used mainly by small-scale producers: regulated October 1996. The regulation targeting small-scale producers (1996) had no significant impact. In contrast, methamphetamine arrests stopped rising and dropped 31% to 45% each of the three times precursor chemicals used by large-scale producers were regulated. Within 3 years of the bulk powder regulation (1989) and again within 2 years of the ephedrine single ingredient regulation (1995), arrests fully rebounded. During the 4 years following the last regulation (pseudoephedrine products, 1997) arrests only partially rebounded. These effects parallel those reported on hospital admissions. The control series were generally unaffected. Precursor regulations targeting large-scale producers impacted methamphetamine arrests, a criminal justice problem, much as they impacted the public health problem of methamphetamine hospital admissions. Ongoing research is needed to determine whether these problems eventually fully rebound from the last regulation.

Impacts of federal ephedrine and pseudoephedrine regulations on methamphetamine-related hospital admissions.

To determine whether the federal regulation of ephedrine and pseudoephedrine, precursors used in illicit methamphetamine production, reduced methamphetamine-related acute care hospital admissions. ARIMA-intervention time-series analysis. California (1983-2000), Arizona and Nevada (1991-2000), USA. Monthly counts of methamphetamine-related acute care hospital admissions. Bulk powder ephedrine and pseudoephedrine: regulated November 1989. Products containing ephedrine as the single active medicinal ingredient: regulated August 1995. Products containing pseudoephedrine: regulated October 1997. Large-scale producers used ephedrine and pseudoephedrine in these forms. Ephedrine combined with other active medicinal ingredients (e.g. various cold medicines), used mainly by small-scale producers: regulated October 1996. In California, the bulk powder regulation stopped a 7-year rise in admissions (1983-89) and reduced them by 35% (P < 0.01). The single ingredient ephedrine regulation stopped a 4-year rise (1992-95) in California, Arizona and Nevada, with 48% (P < 0.01), 71% (P < 0.01) and 52% (P < 0.01) reductions, respectively. The pseudoephedrine products regulation stopped a 2-year rise (1996-97) in California, Arizona and Nevada, with 38% (P < 0.01), 41% (P < 0.05) and 61% (P < 0.01) reductions, respectively. Admissions rose at the end of the study period but were still well below peak 1990s levels. The regulation of ephedrine combined with other active medicinal ingredients had no significant impact in any of the three states. Regulations targeting precursors used by large-scale producers reduced admissions substantially during the study period. However, the regulation of precursors used primarily by small-scale producers had little, if any, effect.

Application of NONMEM to routine bioavailability data

Although NONMEM has been proposed as a modeling tool for sparse data sets, little work has described its application to pharmacokinetic data which is also amenable to typical evaluations. An analysis was performed with NONMEM using plasma concentration data obtained during the development of liquid and capsule extended-release (ER) pseudoephedrine products. A total of four studies (single dose and steady-state studies for both the liquid and capsule formulations) were evaluated, each with an immediate-release (IR) control, and consisting of 18 to 20 subjects. NONMEM analyses provided additional information which could not be obtained through traditional means. Specifically, NONMEM provided not only estimates of residual error from single dose and steady-state studies but also a stochastic measure of bioinequivalence and dose-dumping. It permitted hypothesis testing in the same process as pharmacokinetic parameter estimation, such as contrasting absorption rates from capsule and suspension ER products. A less biased estimate of absorption rate was obtainable for ER formulations by utilizing IR runs. Finally, these NONMEM runs confirmed that, even when data are plentiful and amenable to two-stage analyses, NONMEM provides estimates that may in fact be more meaningful and less susceptible to assay or residual variability. Fundamental differences between population and two-stage approaches are discussed.