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Purpose: A simple and sensitive spectrophotometric method in visible region has been developed and validated for quantification of metaxalone (MET) and dabigatran etexilate mesylate (DAB) in their bulk and pharmaceutical dosage forms. Methods: The method is based on the oxidative coupling reaction of 3-methyl-2-benzothiazoline hydrazone (MBTH) with MET and DAB in the presence of ferric chloride to form green coloured chromogen with absorption maximum at 666 nm and 632 nm respectively. Results: Beer’s law is obeyed in concentration range of 4-20 and 1-6 μg/mL for MET and DAB respectively with correlation coefficient of 0.999. Limit of detection and quantification were 0.46 μg/mL and 1.518 μg/mL for MET and 0.0578 μg/mL and 0.298 μg/mL for DAB. When marketed formulations were analyzed, the results obtained by the proposed method were in good agreement with labelled amounts. The developed method was validated statistically as per ICH guidelines. Conclusion: The developed method is simple, sensitive, specific and can be successfully employed in routine analysis of MET and DAB pharmaceutical dosage forms.

Owing to know the complexity in reverse phase high performance liquid chromatography (RP-HPLC) method optimization; i.e., the selection of optimum combination of input variables for achieving the desired separation, a mathematical relationship between the experimental variables with the responses is to be established by response surface methodology. The paper aims to describe the use of the Box–Behnken experimental design to identify the significant variables effects influencing the separation of metaxalone (MTX) and its two base hydrolytic impurities (DP-1 and DP-2) in a stability indicating RP-HPLC method. Influence variables such as column temperature, buffer pH, and buffer concentration, each at three levels were screened for the desirability of responses like theoretical plates, resolution (MTX-DP-1), capacity factor of MTX, tailing factor at 10% (MTX), and analysis time (Rt of DP-2). A statistical program (Design Expert 8.0) was used to calculate and optimize the five responses simultaneously by means of a multiple response optimization algorithm. The optimum conditions are established including the robustness of the method using a Box–Behnken design, as part of the validation exercise. 10 mM phosphate buffer with pH 4.7 at 31°C column temperature was found to be the optimized condition to produce desirable responses. System suitability limits were defined based on the results of the robustness test. The RP-HPLC method was further validated with respect to linearity, range, precision, specificity, accuracy, limit of detection, and limit of quantification, according to the current regulatory requirements. The optimized method gives rapid and efficient separation with complete resolution between the three peaks, and represents an improvement over the existing reported methods.

The purpose of this study was to evaluate the effect of pH on the dissolution behavior of metaxalone in the marketed product Skelaxin tablets. The dissolution was evaluated using United States Pharmacopeia (USP) dissolution Apparatus 2 and 3 at pHs ranging from 1.5 to 7.4 Results from these studies show that the dissolution of this product is pH dependent. At low pH (simulated gastric fluid, pH 1.5), the dissolution of metaxalone from Skelaxin tablets, was less than 10% over 75 minutes; whereas, dissolution at pH 4.5 showed greater than 90% release in the same time period. These results were consistent for both Apparatus 2 and 3. This suggests that Skelaxin Tablets should be considered a delayed release dosage form.

Skeletal muscle relaxants (SMR) are commonly used drugs prescribed for the treatment of muscle spasm and discomfort. Although many have been in use for decades, physicians may be unaware of the accumulating evidence of their risks, benefits, safety and side effects. This review examines the efficacy, side effects, and safety of three commonly prescribed SMRs: metaxalone, cyclobenzaprine, and carisoprodol. All three appear to have equal efficacy, but their side effects vary considerably. Metaxalone has the fewest reports of side effects, and no reports of major safety issues. Cyclobenzaprine, closely related to the tricyclic antidepressants, causes the expected lethargy and anticholinergic side effects, and may have some toxicity in overdose and in combination with other substances. Carisoprodol raises the greatest concern. Reports in the literature suggest a significant potential for physical and psychological dependence perhaps suggesting a potential for misuse. It also has, perhaps, the greatest toxicity. A secondary goal of this review is to stimulate more discourse about these commonly used, but poorly understood compounds.

A simple Multicomponent Spectrophotometric method for simultaneous estimation of Metaxalone and Diclofenac Potassium in combined tablet dosage form had been proposed. Considering the absorption spectra of both analytes in the range of 220-350 nm in methanol, the four wavelengths of equal intervals of 40 nm were selected as 350 nm, 310 nm, 270 nm and 230 nm to produce calibration curves of mixture of analytes. The present method used inbuilt application of instrument (Shimadzu Pharm Spec 1700, UV spectrophotometer) to quantify Metaxalone and Diclofence potassium in formulation. The method had been validated in accordance with ICH guidelines for accuracy and precision.

A stability indicating reverse phase HPLC method was developed for the determination of metaxalone, a skeletal muscle relaxant, present in bulk and its pharmaceutical formulations using gliclazide as the internal standard (I.S). A hypersil ODS C18 column (250 × 4.6 mm, packed with 5 micron) in an isocratic mode with mobile phase Acetonitrile: phosphate buffer 3.6 (50:50%v/v) was used at a flow rate of 0.8 mL/ min and effluent was monitored at 225 nm. The assay exhibited a linear dynamic range of 0.6-100 µg/mL. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The retention times were 5.13 min and 9.08 min for metaxalone and IS respectively. The extraction recovery of metaxalone from pharmaceutical dosage form (tablets) was >97% and the calibration curve was linear (r2= 0.999) over the entire linear range. The method had an accuracy of >98% and LOD and LOQ of 0.2 µg/mL and 0.6 µg/mL respectively. The specificity of the proposed method was performed whereby metaxalone undergoes different stress conditions like oxidation, reduction, photolysis, acid and alkaline hydrolysis.

Few data exist on potentially adverse metaxalone (Skelaxin®) ingestions in adults. All metaxalone ingestions involving patients aged ≥20 years during 2000-2006 were retrieved from Texas poison control centers. Exclusion criteria were lack of follow-up or multiple substance ingestion. Cases were analyzed for selected demographic and clinical factors. Of the 142 patients, 66.2% were female. Dose ingested was reported for 61 patients. Of those cases with a reported dose, distribution by management site was 29.5% on-site, 59.0% already at/en route to health care facility, and 11.5% referred to health care facility. Final medical outcome was ‘no effect’ for 50.8% cases, ‘minor effect’ for 31.1%, and ‘moderate effect’ for 18.0%. The more common adverse clinical effects reported were drowsiness (27.9%), tachycardia (6.6%), agitation (6.6%), nausea (4.9%), dizziness (4.9%), slurred speech (4.9%), and tremor (4.9%). A moderate medical outcome occurred in 13.6% of ingestions of ≤2400 mg and 20.5% of ingestions of >2400 mg. Management involved a health care facility in 18.2% of ingestions of ≤2400 mg and 100.0% of ingestions of >2400 mg. This study found that adult ingestions of higher doses of metaxalone, particularly >2400 mg, were associated with more serious medical outcomes and were managed at health care facilities. This study also proposes triage guidelines for when ingestions can be safely managed at home.

A rapid and simple high pressure liquid chromatography method with mass spectrometry detection was developed and validated for the determination of phenytoin in human plasma. Metaxalone was used as internal standard. The sample preparation involves a rapid and simple procedure based on liquid-liquid extraction. Analysis was performed in less than 3.0 minutes in isocratic mode on a reversed phase C18column (5μ; 50 × 4.6 mm) using a mobile phase composed of acetonitrile-buffer 2 mM ammonium acetate (80:20v/v), pH of buffer adjusted to 3.4 using formic acid, at 0.4 mL min-1 flow rate. The calibration curves were linear in the measured range between 101.2 ng mL-1and 5060.0 ng mL-1. The validated lowest limit of quantification was 101.2 ng mL-1for phenytoin. The mean relative recovery for drug and Internal standard was found to be 78.33% and 77.04%, respectively. The described method has the advantage of being rapid and easy and it could be applied in therapeutic monitoring of these drugs in human plasma.

The presence of acute or chronic muscle pain and muscle spasm is a common finding in the treatment of craniomandibular disorders. A review of the literature on the centrally acting oral skeletal muscle relaxants is presented to assist the practitioner in treating CMD. The pharmacology, pharmacokinetics, metabolism, adverse reactions and available dosage forms of the skeletal muscle relaxants are discussed. The agents reviewed are carisoprodol, methocarbamol, chlorphenesin carbamate, metaxalone, chloroxazone, orphenadrine citrate, diazepam, and cyclobenzaprine. Their mechanisms are not well defined. Most act via selective inhibition of polysynaptic pathways in the central nervous system. Most evidence for their efficacy is based on subjective responses and there is question as to the adequacy of the clinical studies to date. Based on the data all of the relaxants (possibly excepting diazepam) are better than placebo based on subjective analyses. Although combinations with analgesics provide better symptom relief, no superiority over analgesics exists. No skeletal relaxant has been shown to be superior over any other oral relaxant. Based on recent clinical suspicions, further study of multiple pharmacologic effects of newer agents is indicated.

A simple, rapid, sensitive, and selective liquid chromatography-tandem mass spectrometry (MS) method was developed and validated for the quantification of metaxalone, a skeletal muscle relaxant, in human plasma using galantamine as internal standard (IS). Following liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a reverse phase C18 column and analyzed by MS in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 222/161 for metaxalone and m/z 288/213 for the IS. The assay exhibited a linear dynamic range of 50-5000 microg/L for metaxalone in human plasma. The lower limit of quantification was 50 microg/L with a relative standard deviation of less than 10%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 2.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability, or bioequivalence studies.

Metaxalone (Met), a drug for treatment of pain and stiffness due to muscular injuries, was covalently linked to poly(ethylene glycols) (PEG) via a chloroacetyl chloride spacer. The average weight molecular weights used for PEG are 4000, 6000 and 10,000, respectively, and the procedure of chemical modification for PEGs was conducted by a two-step protocol: (1) synthesis of N-chloroacetyl-metaxalone; (2) synthesis of PEG(4000)-Met, PEG(6000)-Met and PEG(10000)-Met. The controlled drug release studies were performed in buffer solutions with pH values equal to 1.1, 7.4 and 10.0. The results demonstrate that, in the same condition, the rate of hydrolysis for PEG(10000)-Met is the slowest among three prodrugs, and more amount of metaxalone can be detected releasing from prodrug matrices at the presence of alpha-chymotrypsin in a buffer solution with pH 8.0. It was also found that these novel prodrugs can effectively improve the metaxalone's pharmacokinetics, and furthermore can markedly increase its half-life period.

The case history and toxicological findings of a fatal multi-drug overdose involving metaxalone (Skelaxin) are presented. Gas-liquid chromatography with flame-ionization detection and gas chromatography-mass spectrometry were used to determine the following drug concentrations (mg/L) in aortic blood: 19 mg/L metaxalone; 190 mg/L acetaminophen; 0.28 mg/L hydrocodone; and < 0.1 mg/L diazepam, nordiazepam, amitriptyline, and nortriptyline. The following concentrations of metaxalone were reported in alternate specimens: 17 mg/L in femoral blood; 44 mg/L in bile; 70 mg/kg in liver; 7 mg/L in urine; 202 mg/kg in gastric contents; and 14 mg/L in vitreous humor. These concentrations were determined using both direct extraction and the method of standard addition. The quantitative results obtained by both procedures were in good agreement. Because of the limited information published on metaxalone toxicity, the pathologist assigned the manner and cause of death as accidental acute hydrocodone intoxication. Four additional cases in which metaxalone was present were analyzed for comparison. Two cases were probable drug-related deaths and had metaxalone aorta blood concentrations of 18 and 11 mg/L. The other two cases had therapeutic metaxalone concentrations in the aortic blood of < 0.75 and 2.1 mg/L.

A possible cocrystal formation between metaxalone and short-chain dicarboxylic acids (HOOC-(CH2)n-COOH, n=0-3) was quickly investigated using a solvent-assisted grinding approach. Differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) microspectroscopy, and powder X-ray diffraction (PXRD) were used to verify the cocrystal formation between metaxalone and each dicarboxylic acid. A solvent evaporation method was used to prepare the standard cocrystal. The cocrystal formation was also estimated by using a one-step simultaneous DSC-FTIR microspectroscopy. The present study indicates that only n=2 of short-chain dicarboxylic acids such as succinic acid, fumaric acid and maleic acid could form a cocrystal with metaxalone. Both solvent-assisted grinding technique and solvent evaporation method were successfully applied to prepare the metaxalone cocrystal with n=2 of short-chain dicarboxylic acids. Moreover, this cocrystal formation was also easily screened and estimated using a unique DSC-FTIR microspectroscopy in real time. Acknowledgement This work was supported by National Science Council, Taipei, Taiwan, ROC (NSC 100-2320-B- 264-001-MY3).

A 29-year old female with a history of depression was found dead in a hotel room. The death scene investigation found empty pill bottles and an empty liter bottle of wine. Metaxalone, a centrally acting muscle relaxant, along with citalopram, ethanol, and chlorpheniramine were identified in the postmortem samples and quantitated by gas chromatography-mass spectrometry. The concentration of metaxalone in femoral vein blood was 39 mg/L. The heart blood concentration was 54 mg/L. Femoral vein blood concentrations of citalopram and chlorpheniramine were 0.77 mg/L and 0.04 mg/L, respectively. Ethanol levels were 0.13 g/dL in vitreous and 0.08 g/dL in heart blood. Other tissue samples were also analyzed. The authors consider the metaxalone concentrations toxic and potentially fatal. The citalopram concentrations were lower than those reported in fatal cases for this drug alone. Death was ascribed to polydrug abuse/overdose with metaxalone a major contributor. This represents the first reported case to our knowledge in which a metaxalone overdose significantly contributed to death.