Medical Devices; Clinical Chemistry and Clinical Toxicology Devices; Classification of the Meprobamate Test System. Final order.

The Food and Drug Administration (FDA or we) is classifying the meprobamate test system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the meprobamate test system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

Photochemical degradation of atenolol, carbamazepine, meprobamate, phenytoin and primidone in wastewater effluents.

The photochemical degradation of five pharmaceuticals was examined in two secondary wastewater effluents. The compounds, which included atenolol, carbamazepine, meprobamate, phenytoin and primidone, were evaluated for both direct and sensitized photolysis. In the two wastewaters, direct photolysis did not lead to significant compound degradation; however, sensitized photolysis was an important removal pathway for the five pharmaceuticals. Upon solar irradiation, hydroxyl radical (HO) was quantified using the hydroxylation of benzene and singlet oxygen ((1)O2) formation was monitored following the degradation of furfuryl alcohol. Degradation via sensitized photolysis was observed following five-day exposures for atenolol (69-91%), carbamazepine (67-98%), meprobamate (16-52%), phenytoin (44-85%), and primidone (34-88%). Varying removal is likely a result of the differences in reactivity with transient oxidants. Averaged steady state HO concentrations ranged from 1.2 to 4.0×10(-16)M, whereas the concentrations of (1)O2 were 6.0-7.6×10(-14)M. Partial removal due to presence of HO indicates it was not the major sink for most compounds examined. Other transient oxidants, such as (1)O2 and triplet state effluent organic matter, are likely to play important roles in fates of these compounds.

A rapid quantitative method of carisoprodol and meprobamate by liquid chromatography-tandem mass spectrometry.

The identification and quantitation of carisoprodol (Soma) and its chief metabolite meprobamate, which is also a clinically prescribed drug, remains a challenge for forensic toxicology laboratories. Carisoprodol and meprobamate are notable for their widespread use as muscle relaxants and their frequent identification in the blood of impaired drivers. Routine screening is possible in both an acidic/neutral pH screen and a traditional basic screen. An improvement in directed testing quantitations was desirable over the current options of an underivatized acidic/neutral extraction or a basic screen, neither of which used ideal internal standards. A new method was developed that utilized a simple protein precipitation, deuterated internal standards and a short 2-min isocratic liquid chromatography separation, followed by multiple reaction monitoring with tandem mass spectrometry. The linear quantitative range for carisoprodol was determined to be 1-35mg/L and for meprobamate was 0.5-50mg/L. The method was validated for specificity and selectivity, matrix effects, and accuracy and precision.

Attenuation of contaminants of emerging concern during surface-spreading aquifer recharge.

The attenuation of a diverse suite of contaminants of emerging concern (CECs) and bulk water quality changes was evaluated at a surface-spreading aquifer recharge operation across a detailed subsurface profile (9 locations), representing both short- and long-travel times (10 h to 60 days). Seventeen CECs were detected in the recharge basin and the concentrations of all were reduced during soil aquifer treatment (SAT), with 11 of the target compounds attenuated by >80% after 60 days of travel time. Select CECs (atenolol, gemfibrozil, N,N-diethly-3-methylbenzamide, meprobamate, tris(2-chloroethyl)phosphate, and primidone) and bulk water organic-carbon measurements (total organic carbon, biodegradable organic carbon, size-exclusion chromatography and fluorescence excitation-emission matrices) were identified as monitoring parameters that can be used to assess SAT performance at surface-spreading operations.

Identification, isolation, characterization and response factor determination of process-related impurity in meprobamate drug substance.

This paper describes identification and characterization of a process-related impurity of meprobamate drug substance observed in HPLC-UV method. Forced degradation studies were carried out under acidic, basic, oxidation, light and thermal conditions to assess the nature of the impurity. The pure impurity was obtained by preparative LC isolation and analyzed by NMR and mass. Structural elucidation by spectral data and formation of this impurity were discussed in detail. The structure of the process-related impurity was established as carbamic acid-2-carbamoyloxymethyl-2-methyl-pent-3-enyl ester (olefin). Also, the relative response factor, linearity, detection limit (DL), quantitation limit (QL) and recovery were determined for meprobamate and the impurity. Good linearity was obtained for the impurity over the concentration range of 0.03-0.20% (w/w) with the coefficient of determination (r(2)) of 0.999. The DL and QL of olefin impurity were 0.0003 and 0.001% (w/w), respectively. The isolated impurity was co-injected with meprobamate sample to confirm the retention time in HPLC.

Stability-indicating HPLC method for the determination of impurities in meprobamate with refractive index detection.

The purpose of this study is to develop and validate a simple, sensitive, and robust high-performance liquid chromagraphic (HPLC) method for the determination of impurities ca. 2-methyl-2-propyl-1,3-propane diol (MP0) and 2-hydroxymethyl-2-methyl pentyl carbamate (MP1) in meprobamate (MEP) drug substance with refractive index (RI) detection. This method utilizes a Zorbax Eclipse XDB C(18) HPLC column, a mobile phase of 80:20 (v/v) 10 mM KH(2)PO(4),-acetonitrile, respectively. The stability-indicating capability of the method has been established by performing stress studies under acidic, basic, oxidation, light, humidity, and thermal conditions. The major degradation products of acid and base hydrolysis are identified as MP0 and MP1. The recovery data obtained for impurities are between 96.0-109.8%. The detection and quantitation limits of this method ranges from 0.009 to 0.017 mg/mL and 0.029 to 0.055 mg/mL, respectively. The relative standard deviation (RSD) for the area at QL is less than 6.1%. Good linearity (r(2) > 0.99) and precision (RSD < 2.2%) have been obtained for MEP, MP0, and MP1. This method has been applied successfully to determine the content of impurities in MEP bulk drug.

Quantitative analysis of carisoprodol and meprobamate in whole blood using benzylcarbamate and deuterated meprobamate as internal standards.

Carisoprodol and meprobamate are frequently encountered drugs in impaired driving casework. Deuterated internal standards, although preferred, were not available until recently. Earlier published studies report the use of a variety of non-deuterated internal standards, many of which lack the chemical and physical similarities that are desired for quantitative analysis. Carisoprodol and meprobamate were determined in whole blood using solid-phase extraction and gas chromatography-mass spectrometry with benzylcarbamate and meprobamate-d(7) as internal standards. When benzylcarbamate was used as internal standard, the linear ranges for carisoprodol and meprobamate were 0-20 mg/L and 0-40 mg/L, respectively. The linear range increased to 100 mg/L when meprobamate-d(7) was used. Limits of detection for carisoprodol and meprobamate were 0.2 and 0.4 mg/L, respectively, regardless of the internal standard selection. The limit of quantitation for both drugs using either internal standard was 0.4 mg/L. Accuracies using benzylcarbamate and meprobamate-d(7) were 100-106% and 91-100%, respectively. Corresponding values for precision indicated intra-assay coefficients of variation of 2.6-4.3% for benzylcarbamate and 1.0-2.3% for meprobamate-d(7). No carryover was evident at 100 mg/L, the highest concentration tested, and no interferences were observed. Results indicated that either benzylcarbamate or meprobamate-d(7) is a suitable internal standard for quantitative determination of carisoprodol or meprobamate from whole blood.

Carisoprodol-mediated modulation of GABAA receptors: in vitro and in vivo studies.

Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate, a controlled substance that produces sedation via GABA(A) receptors (GABA(A)Rs). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABA(A)R function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human alpha1beta2gamma2 GABA(A)R function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric rho1 GABA or glycine alpha1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol.

Improved solid-state NMR quantifications of active principles in pharmaceutical formulations.

The facility of implementation reached by solid-state nuclear magnetic resonance (ssNMR) spectroscopy makes this technique increasingly popular in pharmaceutical sciences, and more specifically for the dosage of active principles in pharmaceutical formulations, since about 80% of the formulations currently available on the market are present in the solid form. In this case, analysis by MAS NMR allows faster and simplified protocols, as a solubilization step is not required. However, the specificity of the ssNMR experiments should be explicitly taken into account when designing an accurate measurement procedure. In this work we show that, by using a combination of external concentration referencing and a properly designed sample preparation optimized for quantitative determinations, quantification of active principles in pharmaceutical formulations can be performed with both speed and precision. The method is illustrated by reinvestigating the dosage of Meprobamate, an anxiolytic agent typically prescribed in case of anxiety or muscular soreness, present in a commercial formulation (Equanil). Specifically, with respect to previously proposed analytical protocols, the procedure outlined here allows fast quantification with excellent precision.

Simultaneous determination of carisoprodol and meprobamate in human hair using solid-phase extraction and gas chromatography/mass spectrometry of the trimethylsilyl derivatives.

Carisoprodol (CSP) is a musculoskeletal relaxant whose active metabolite is meprobamate (MPB). This drug has recently been noticed to be abused as an inexpensive alternative to illicit drugs in Korea. A method using solid-phase extraction (SPE) and gas chromatography/mass spectrometry (GC/MS) was developed for the determination of CSP and MPB in human hair. Hair samples (30 mg) were washed with distilled water and acetone, cut into small fragments (<1 mm), incubated in 1.0 M HCl overnight at 50 degrees C, and then adjusted to pH 6.5. The drugs were extracted from the resulting hydrolyzed solutions using a SPE column. The eluents were evaporated to dryness, then derivatized using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) at 120 degrees C for 30 min. The derivatized extract (1 microL) was injected into the GC/MS system. Recoveries were in the range of 91.5-93.1% for CSP and 85.5-93.0% for MPB. The linear ranges were 0.5-10.0 ng/mg for both CSP and MPB with good correlation coefficients (r(2) = 0.995). The intra-day precision and accuracy ranged from 1.5 to 9.3% and -17.5 to 3.6%, respectively, and the inter-day precision and accuracy ranged from 3.9 to 6.2% and -15.0 to -3.9%, respectively. The limits of detection for CSP and MPB were 0.13 and 0.12 ng/mg, respectively. The applicability of the method was proven by analyzing a hair sample from an authentic abuser.