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A simple, accurate, and robust reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the quantification of Baclofen in rat plasma. The method demonstrated high degree of linearity (r 2  = 0.9936) across a concentration range of 10-50 μg/mL. Precision, accuracy, limit of detection (LOD), limit of quantification (LOQ), and robustness were evaluated according to ICH guidelines. The LOD and LOQ were found to be 0.076197 and 0.23090 μg/mL, respectively. This method provides an efficient approach for Baclofen quantification in plasma, making it suitable for pharmacokinetic and bioavailability studies. The novelty of this study lies in its optimization for routine use in laboratories, ensuring reproducibility with minimal variations across different conditions and analysts., (© 2024 John Wiley & Sons Ltd.)

Peptides can operate as therapeutic agents that sit within a privileged space between small molecules and larger biologics. Despite examples of their potential to regulate receptors and modulate disease pathways, the development of peptides with drug-like properties remains a challenge. In the quest to optimize physicochemical parameters and improve target selectivity, unnatural amino acids (UAAs) have emerged as critical tools in peptide- and peptidomimetic-based drugs. The utility of UAAs is illustrated by clinically approved drugs such as methyldopa, baclofen, and gabapentin in addition to small drug molecules, for example, bortezomib and sitagliptin. In this Perspective, we outline the strategy and deployment of UAAs in FDA-approved drugs and their targets. We further describe the modulation of the physicochemical properties in peptides using UAAs. Finally, we elucidate how these improved pharmacological parameters and the role played by UAAs impact the progress of analogs in preclinical stages with an emphasis on the role played by UAAs.

As a gamma amino butyric acid-ergic agonist, Baclofen is often prescribed to adults and children for the treatment of severe spasticity that originates in the brain or spinal cord. Even after reviewing the literature extensively, no one has documented a method for estimating baclofen using microwave-assisted stability-indicating spectrofluorimetric techniques, despite the abundance of options for baclofen stability, assay, and bioanalysis. Organic solvents, which are typically necessary for current procedures but may be costly and toxic, have a severe effect on aquatic life and the environment. Using green solvents and 4-chloro-7-nitrobezofuran as a fluorescent probe, this work conducted a stability-indicating spectrofluorimetric estimate of baclofen. Through the use of a design-of-experiments technique, a reliable microwave-aided spectrofluorimetric method was developed, with little solvent consumption and time for sample analysis. Prior to conducting response surface analysis and optimizing important variables and responses, a fractional factorial design was used to screen method variables and responses. A central composite design was then employed for these purposes. This flexible spectrofluorimetric technique was used to assess baclofen concentrations in forced degraded samples and marketed formulations. For baclofen determination, the suggested spectrofluorimetric approach was found to be green, quick, easy to use, economical, and user-friendly., (© 2024 John Wiley & Sons Ltd.)

Enantioselective analysis of chiral drugs plays a significant role in chemistry, biology and pharmacology. Baclofen, an antispasmodic chiral drug, has been widely studied due to the obvious differences in toxicity and medical activity between enantiomers. Herein, a simple and efficient method for separation of baclofen enantiomers by capillary electrophoresis was established without complicated sample derivatization and expensive instruments. Then, the molecular modeling and density functional theory were used to simulate and investigate the chiral resolution mechanism of electrophoresis, the calculated intermolecular forces were directly presented by visualization softwares. Moreover, the theoretical and experimental electronic circular dichroism (ECD) spectra of ionized baclofen were compared, and the configuration of dominant enantiomer in the nonracemic mixture can be determined by ECD signal intensity, which was proportional to the electrophoresis peak area difference of the corresponding enantiomer excess experiments. In this way, the peak order identification and configuration quantification of baclofen enantiomers in electrophoretic separation were successfully achieved without relying on a single standard., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: This study aimed to formulate an orally disintegrating tablet (ODT) containing both baclofen and meloxicam together for treating osteoarthritis., Methods: Direct compression method was used to prepare ODTs using three types of co-processed excipients (Prosolv ODT G2 ® , F-melt ® , and Pharmaburst ® 500). ODTs were evaluated according to weight variation, thickness, friability, hardness, drug content, wetting time, in-vitro disintegration time, in-vitro dissolution test, and palatability. To enhance the in-vitro dissolution of meloxicam and palatability of ODT, a six sigma methodology was used, and an improvement phase was established where ODTs were prepared using lyophilization and levigation techniques. Finally, a pharmacokinetic study of the improved ODT was accomplished in comparison to the conventional oral tablet., Results: Pharmaburst-based formula (F4) showed the shortest wetting time and, consequently, the shortest disintegration time and the highest percentage of drug dissolved within 3 min compared to the other formulae. All the improved ODTs had a bitterness taste score vary from (0) palatable and (+1) tasteless. The current sigma level was 3.628 σ and 3.33 σ for palatability and solubility of ODT, respectively, which indicated the process was successfully improved compared with the previous sigma level of 2.342 σ of both processes. Pharmacokinetic study of the improved ODTs showed a significant decrease of T max to 120 and 30 min instead of 180 and 120 min for meloxicam and baclofen, respectively., Conclusion: ODTs were successfully improved using the six sigma methodology, the pharmacokinetic parameters of both drugs were enhanced due to rapid absorption through the oral mucosa., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Abdelmonem et al.)

For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake., (© 2020 Society for the Study of Addiction.)

The γ-aminobutyric acid (GABA) type B receptor (GABA B -R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA A receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABA B1 and GABA B2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.

Baclofen is a centrally acting skeletal muscle relaxant approved by the US Food and Drug Administration (FDA) for the treatment of muscle spasticity, but the immediate release mode of administration and rapid absorption has been associated with adverse effects. The main objective of this study was to prepare modified release floating beads of baclofen in order to decrease the unwanted side effects. The beads were prepared using alginate and coated with Eudragit RS100, Eudragit L100 and cetyl alcohol. They were evaluated for their encapsulation efficiency, buoyance characteristics, morphology, and in vitro release. They have also been tested in vivo for their oral bioavailability and potential side effects. The prepared beads showed floating properties up to 12 h with different lag times ranging from 45.67 to 72.33 sec. Morphological evaluation using scanning electron microscopy (SEM) revealed that the coated beads show smooth with no pores or cracks surfaces. Real-time morphology of the beads during in vitro release testing was studied by the SEM. Optimized formulation of baclofen coated beads exhibited favorable mechanical properties, in addition, it provided extended baclofen release for up to 6 h. In addition, in vivo studies showed that the coated beads effectively decreased the hypotensive side effect associated with rapid plasma peaking from Baclofen® immediate-release tablets. In addition, there were significant differences between the values of C max , T max , and AUC 0-24 of optimized modified release baclofen floating formulations when compared to Baclofen® immediate-release tablets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study aimed to develop a novel oral drug delivery system for gastroretentive sustained drug release by using a capsular device. A capsular device that can control drug release rates from the inner immediate release (IR) tablet while floating in the gastric fluid was fabricated and printed by a fused deposition modeling 3D printer. A commercial IR tablet of baclofen was inserted into the capsular device. The structure of the capsular device was optimized by applying a design of experiment approach to achieve sustained release of a drug while maintaining sufficient buoyancy. The 2-level factorial design was used to identify the optimal sustained release with three control factors: size, number, and height of drug-releasing holes of the capsular device. The drug delivery system was buoyant for more than 24 h and the average time to reach 80% dissolution (T 80 ) was 1.7-6.7 h by varying the control factors. The effects of the different control factors on the response factor, T 80 , were predicted by using the equation of best fit. Finally, drug delivery systems with predetermined release rates were prepared with a mean prediction error ≤ 15.3%. This approach holds great promise to develop various controlled release drug delivery systems.

Intrathecal analgesia is a method using various molecules alone or in combination. Among these, a preparation of sufentanil-ropivacaine-baclofen is widely used. Instead of moving patients to the few expert centers taking charge of these specific preparations, it could be beneficial to transport syringes to peripheral centers who manage pump refills. The objective of this study was to determine the physicochemical compatibility and stability of a preparation of sufentanil, ropivacaine, and baclofen in polypropylene syringes. Drugs were mixed together at different concentrations and stored with light protection at 5°C ± 3°C and 25°C ± 2°C. The stabilities were determined by visual inspection, turbidity, pH measurement, and ultra-high-pressure liquid chromatography assay of drug concentrations. The concentrations of ropivacaine, baclofen, and sufentanil were stable after 7 days at 5°C ± 3°C and no degradation of product appeared. The drug mixtures were clear in appearance and no color change or precipitation was observed. Throughout this period, the absorbance and the pH value of samples remained stable. The preparations of sufentanil, baclofen, and ropivacaine remained stable for at least 7 days when stored in polypropylene syringes at 5°C ± 3°C., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Baclofen is a racemic mixture that is commonly used for the treatment for spasticity. However, the optimal dose and dosing interval to achieve effective cerebral spinal fluid (CSF) concentrations of baclofen are not known. Moreover, it is unclear if there are differences in the ability of R- or S-baclofen to cross the blood-brain barrier and achieve effective CSF concentrations. We have validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with improved selectivity and sensitivity for the simultaneous quantitation of R- and S-baclofen and metabolites in plasma and CSF. Protein precipitation by acetonitrile was utilized to obtain an acceptable recovery of the analytes. The detection and separation of analytes was achieved on a 48 °C-heated Crownpak CR(+) column (150 mm × 4.0 mm, 5μ) with elution using 0.4% formic acid (FA) in water and 0.4% FA in acetonitrile as the mobile phase running at a flow rate of 1.0 mL/min. Accurate quantitation was assured by using this MS/MS method with atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. Therefore, this method is enantioselective, accurate, precise, sensitive, reliable, and linear from 1 to 1500 ng/mL for baclofen and 2 to 4000 ng/mL for the metabolites. An additional method was developed to separate racemic baclofen 3-(4-chlorophenyl)-4 hydroxybutyric acid metabolites for individual concentration determination. Both validated methods were successfully applied to a clinical pharmacokinetic human plasma and CSF study evaluating the disposition of baclofen and metabolites.

The chiral separation of baclofen (Bac) was obtained by nano-liquid chromatography tandem mass spectrometry (nano-LC-MS/MS) using a 100 μm I.D. fused silica capillary column packed with silica particles chemically modified with vancomycin. Various experimental parameters, such as composition (buffer concentration, water content, organic modifier) and pH of the mobile phase and sample solvent were investigated for method optimization. In order to increase the sensitivity an on-column focusing procedure was applied. Acceptable separation of Bac enantiomers was obtained in less than 11 min eluting in isocratic mode, with 90:10 MeOH/water (v/v) containing 10 mM ammonium acetate at pH 4.5. These optimized experimental conditions were applied to the analysis of human plasma samples spiked with racemic mixture of Bac. The use of a Buckypaper disc as sorbent membrane allows one to recover both enantiomers with yields ≥ 65%. The method was fully validated, following the identification criteria of the European Commission Decision 2002/657/EC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An efficient, economic and high yielding method was described for the synthesis of baclofen (BAC) pharmacopoeial impurities (impurity A and impurity B) which can be used for gram-scale synthesis. Furthermore, a novel ecofriendly thin-layer chromatographic TLC-densitometric method was established and validated for the determination of BAC and its synthesized impurities. The developed TLC-densitometric method is based on the chromatographic separation using TLC plates (60 F 254 ) using a green mobile phase of ethyl acetate-methanol-ammonia solution, 33% (8:2:0.1, by volume) with UV scanning at 220 nm. The proposed method was validated with respect to International Conference on Harmonization guidelines. The validated method was successfully applied for determination of BAC in pure form and in its commercial dosage form. Additionally, the greenness profile of the developed method was evaluated and compared with those of the reported chromatographic methods. The developed method was found to be superior to the published methods, being environmentally benign., (© 2019 John Wiley & Sons, Ltd.)

Pediatric population is a sensitive sector of the healthcare and pharmaceutical field with additional needs compared to the adult population. Extemporaneous formulations for children are generally prepared by manipulating adult formulations, but medication errors can result in suboptimal efficacy and with significant safety concerns. The aim of proposed project was to explore a 3D printing technology for the development of customized minicaplets of baclofen for the pediatric population. Based on results of 3-point bend test, polyvinyl alcohol (PVA) with sorbitol (10% w/w) were selected for preparation of baclofen loaded filaments using hot melt extrusion (HME). Effect of dimension, infill percentage and infill pattern on dose, disintegration time and release profile were investigated. Characteristic crystalline peaks of baclofen were absent in DSC thermograms and XRD pattern of filament and minicaplets. Minicaplets printed in diamond (fast) infill pattern with 100% infill showed higher disintegration time (38 mins) compared to linear, sharkfill and hexagonal pattern. 3 2 full factorial orthogonal design suggested that baclofen release (D50 and D85) was marginally affected by infill percentage but significantly affected by caplet dimension (p < 0.05). Thus, low cost FDM 3D printing technique can be a promising alternative for preparation of dose and release customized pediatric dosage forms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Compounded liquid medication is frequently required in children to allow easy dose adjustment and overcome swallowing difficulties. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients baclofen 2.0 mg/mL, carvedilol 5.0 mg/mL, hydrochlorothiazide 2.0 mg/mL, mercaptopurine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, phenobarbital 9.0 mg/mL and 15.0 mg/mL, propranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, pyrazinamide 100.0 mg/mL, spironolactone 2.0 mg/mL and 2.5 mg/mL, sotalol hydrochloride 5.0 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursodeoxycholic acid 20.0 mg/mL, and vancomycin hydrochloride 25.0 mg/mL. Suspensions were compounded with raw powders, except for mercaptopurine, pyrazinamide, and sotalol hydrochloride, which were made from commercial tablets. Stability was assessed by measuring the percentage recovery at 0 (baseline), 60 days, and 90 days after compounding for suspensions made with raw powders, which were stored at 2ÅãC to 8ÅãC. The stability of tablets, which were stored at 2ÅãC to 8ÅãC and 20ÅãC to 25ÅãC, was assessed by measuring the percentage recovery at 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by ultraviolet high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions in the conditions tested. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Populations, protonation constants and octanol-water partition coefficients were determined and assigned specifically to fast interconverting individual conformers, exemplified in baclofen and pregabalin, the GABA-related drug molecules of biaxial, double rotations. Rotamer statuses along both axes in water and octanol were elucidated from 1 H NMR vicinal coupling constants. Conformer abundances were obtained by the appropriate combination of the rotamer populations in the two adjacent moieties in the molecule. The bulky aromatic group in baclofen versus the aliphatic side chain of pregabalin explains why baclofen exists mainly in trans-trans conformeric form, throughout the pH range, unlike pregabalin that has no any highly dominant form. Characteristically enough, for pregabalin, the lipophilicity of the conformers is primarily influenced by the conformation state. Conformers in gauche state are of higher lipophilicity. The conformers of the two compounds were ranked by their membrane-influx and -outflow propensities., (Copyright © 2018. Published by Elsevier B.V.)

The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABA B receptor ligand-directed nanoparticles consisting of baclofen functionalized trimethyl chitosan (Bac-TMC) as polymeric carriers, tripolyphosphate (TPP) as ionic crosslinker, and siSurvivin as therapeutic genes, were designed to enhance the survivin gene silencing. GABA B receptor agonist baclofen (Bac) was initially introduced into TMC as a novel ligand. This Bac-TMC/TPP nanoparticles increased the uptake of survivin siRNA through the interaction with GABA B receptor, further resulted in efficient cell apoptosis and gene silencing. For siRNA-loaded nanoparticles pulmonary delivery, mannitol was utilized for it delivery into pressurized metered dose inhalers (pMDI). The fine particle fractions of this formulation was (45.39±2.99)% indicating the appropriate deep lung deposition. These results revealed that this pMDI formulation containing Bac-TMC/TPP nanoparticles would be a promising siRNA delivery system for lung cancer treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A new method for the direct conversion of 4-pentenylsulfonamides to 2-formylpyrrolidines and a 2-ketopyrrolidine has been developed. This transformation occurs via aerobic copper-catalyzed alkene aminooxygenation where molecular oxygen serves as both oxidant and oxygen source. The 2-formylpyrrolidines can further undergo oxidative carbon-carbon bond cleavage in situ upon addition of DABCO, providing 2-pyrrolidinones. These transformations have been demonstrated for a range of 4-pentenylsulfonamides. 4-Pentenylalcohols also undergo oxidative cyclization to form γ-lactones predominantly. The reaction is chemoselective, oxidizing one alkene in the presence of others, and is compatible with several functional groups. Application of these reactions to the formal syntheses of baclofen and (+)-monomorine was demonstrated.

The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Background: Commercial baclofen formulations used with infusion pumps are available at therapeutic concentrations of 0.5-2.0 mg/mL. However, patients who receive higher daily doses of baclofen may benefit from products with greater baclofen concentrations since their refill frequency would be reduced (up to a maximum of 180 days). We evaluated baclofen solubility, baclofen 3 mg/mL intrathecal (IT) formulation stability, and chemical and physical compatibility with Medtronic SynchroMed ® II and Codman Medstream ® programmable IT infusion pumps., Methods: For solubility evaluations, baclofen powder was dissolved into isotonic saline and tested at 5°C, 25°C, and 40°C. To demonstrate drug product stability, both physical and chemical stability attributes of baclofen 3 mg/mL in prefilled syringes were evaluated over 36 months with storage at 25°C. For a simulated in-use stability (compatibility) study, a 3 mg/mL baclofen IT formulation was placed in SynchroMed II and Codman Medstream pumps at 37ºC for study durations, and evaluated at different flow rates. Pump effluent was collected at various times and analyzed by high-performance liquid chromatography for baclofen content. On completion of the in-use stability study, pumps exposed to baclofen 3 mg/mL were dissected and visually evaluated for signs of deterioration., Results: Baclofen solubility was found to be 3.2 mg/mL at 5°C, 3.6 mg/mL at 25°C, and 3.9 mg/mL at 40°C. During the 36-month stability study of prefilled syringes stored at 25°C, baclofen content remained unchanged and no precipitation was observed. The simulated in-use pump study performed at 37ºC showed that a baclofen 3 mg/mL IT formulation was stable at different flow rates and throughout different expected residence times for both pump models. Components from both pumps exhibited no noticeable deterioration after exposure to the 3 mg/mL formulation., Conclusion: Baclofen 3 mg/mL IT formulation was stable during long-term storage at 25°C and remained stable under conditions matching those encountered in clinical practice (37°C)., (© 2016 International Neuromodulation Society.)

Objectives: Baclofen is a zwitterion molecule where increased ions in the excipient increase the solubility. We developed baclofen in a stable solution similar to cerebrospinal fluid (CSF) without bicarbonate and proteins to improve the solubility of the baclofen and to reduce the potential toxicity to the central nervous system (CNS) and subarachnoid space. The objective is to develop a solution of baclofen wherein baclofen is solubilized in a multivalent physiological ion solution such as artificial cerebrospinal fluid (aCSF) at a concentration from 2 mg/cc to 10 mg/cc., Methods: First, to determine the solubility of Baclofen in aCSF, solubility was determined at six different pH levels at 37°C, by the addition of aCSF to a known amount of Baclofen. The final concentrations were confirmed by high performance liquid chromatography (HPLC) analysis. Second, the stability of Baclofen at 4 mg/cc investigated in a test manufacturing batch utilizing standard methods of production of 1500 20 cc vials inverted for 18 months at 25°C at 60% humidity. The stability and purity of the baclofen was verified at 18 months by HPLC analysis., Results: Baclofen was initially soluble between pH of 6-8 above 7 mg/cc but fell back to 6.3-5.8 mg/cc level with time. Baclofen produced in vials with inversion were noted to be stable at 4 mg/cc at 18 months with less than 2% breakdown of the baclofen in solution., Conclusion: Baclofen is much more soluble in artificial CSF than normal saline. The artificial CSF may also be less toxic to the subarachnoid space than saline., (© 2016 International Neuromodulation Society.)

Topical gels compounded by pharmacists are important clinical tools for the management of pain. Nevertheless, there is often a dearth of information about the chemical stability of drugs included in these topical formulations, complicating the assignment of beyond-use dating. The purpose of this study was to develop a high-performance liquid chromatography photodiode array-based stability-indicating assay that could simultaneously resolve six drugs (amitriptyline, baclofen, clonidine, gabapentin, ketoprofen, lidocaine) commonly included in topical gels for pain management and their potential degradation products. Furthermore, this method was applied to the determination of beyond-use dating of combinations of these drugs prepared in commonly utilized bases (Lipobase, Lipoderm, Pluronic organogel). Gabapentin was determined to be the least stable component in all formulations tested. Measured stability ranged between 7 to 49 days depending on the base and other active drugs present in the formulation. In the absence of gabapentin, baclofen was the next least stable component, lasting for 120 days, regardless of the type of formulating base used., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Baclofen is a commonly used racemic drug and has a simple chemical structure in terms of the presence of only one stereogenic center. Since the desirable pharmacological effect is in only one enantiomer, several possibilities exist for the other enantiomer for evaluation of the disposition of the racemic mixture of the drug. This calls for the development of enantioselective analytical methodology. This review summarizes and evaluates different methods of enantioseparation of (RS)-baclofen using both direct and indirect approaches, application of certain chiral reagents and chiral stationary phases (though very expensive). Methods of separation of diastereomers of (RS)-baclofen prepared with different chiral derivatizing reagents (under microwave irradiation at ease and in less time) on reversed-phase achiral columns or via a ligand exchange approach providing high-sensitivity detection by the relatively less expensive methods of TLC and HPLC are discussed. The methods may be helpful for determination of enantiomers in biological samples and in pharmaceutical formulations for control of enantiomeric purity and can be practiced both in analytical laboratories and industry for routine analysis and R&D activities., (Copyright © 2016 John Wiley & Sons, Ltd.)

Separation of racemic mixture of (RS)-bupropion, (RS)-baclofen and (RS)-etodolac, commonly marketed racemic drugs, has been achieved by modifying the conventional ligand exchange approach. The Cu(II) complexes were first prepared with a few l-amino acids, namely, l-proline, l-histidine, l-phenylalanine and l-tryptophan, and to these was introduced a mixture of the enantiomer pair of (RS)-bupropion, or (RS)-baclofen or (RS)-etodolac. As a result, formation of a pair of diastereomeric complexes occurred by 'chiral ligand exchange' via the competition between the chelating l-amino acid and each of the two enantiomers from a given pair. The diastereomeric mixture formed in the pre-column process was loaded onto HPLC column. Thus, both the phases during chromatographic separation process were achiral (i.e. neither the stationary phase had any chiral structural feature of its own nor did the mobile phase have any chiral additive). Separation of diastereomers was successful using a C 18 column and a binary mixture of MeCN and TEAP buffer of pH 4.0 (60:40, v/v) as mobile phase at a flow rate of 1 mL/min and UV detection at 230 nm for (RS)-Bup, 220 nm for (RS)-Bac and 223 nm for (RS)-Etd. Baseline separation of the two enantiomers was obtained with a resolution of 6.63 in <15 min. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Bisphenol A (BPA) is an estrogen-mimicking chemical that can be selectively detected in water using a chemical sensor based on molecularly imprinted polymers (MIPs). However, the utility of BPA-MIPs in sensor applications is limited by the presence of non-specific binding sites. This study explored a dual approach to eliminating these sites: optimizing the molar ratio of the template (bisphenol A) to functional monomer (methacrylic acid) to cross-linker (ethylene glycol dimethacrylate), and esterifying the carboxylic acid residues outside of specific binding sites by treatment with diazomethane. The binding selectivity of treated MIPs and non-treated MIPs for BPA and several potential interferents was compared by capillary electrophoresis with ultraviolet detection. Baclofen, diclofenac and metformin were demonstrated to be good model interferents to test all MIPs for selective binding of BPA. Treated MIPs demonstrated a significant decrease in binding of the interferents while offering high selectivity toward BPA. These results demonstrate that conventional optimization of the molar ratio, together with advanced esterification of non-specific binding sites, effectively minimizes the residual binding of interferents with MIPs to facilitate BPA sensing., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

An efficient asymmetric total synthesis of (S)-baclofen was accomplished via a one-pot operation from commercially available materials using sequential reactions, such as aldol condensation of acetaldehyde, diphenylprolinol silyl ether mediated asymmetric Michael reaction of nitromethane, Kraus-Pinnick oxidation, and Raney Ni reduction. Highly enantioenriched baclofen was obtained in one pot with a good yield over four reactions.

The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake. One area implicated in drug abuse is the nucleus accumbens shell (NACsh).The current study sought to define the role of the NACsh in the enantioselective effects of baclofen on binge-like ethanol consumption by directly microinjecting each enantiomer into the structure. Following bilateral cannulation of the NACsh, C57Bl/6J mice were given 5 days of access to ethanol or saccharin for 2h, 3h into the dark cycle. On Day 5 mice were given an injection of aCSF, 0.02 R(+)-, 0.04R(+)-, 0.08 S(-)-, or 0.16 S(-)-baclofen (μg/side dissolved in 200nl of aCSF). It was found that the R(+)-baclofen dose-dependently decreased ethanol consumption, whereas the high S(-)-baclofen dose increased ethanol consumption, compared to the aCSF group. Saccharin consumption was not affected. These results further confirm that GABAB receptors and the NACsh shell are integral in mediating ethanol intake. They also demonstrate that baclofen displays bidirectional, enantioselective effects which are important when considering therapeutic uses of the drug., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Continuous infusion of intrathecal baclofen (ITB), via implanted pump, is a powerful tool in the management of severe spasticity in neurological disorders. The advantages of ITB therapy are that it is non-destructive, reversible, and programmable, allowing for neuromodulation. Patients reported significant subjective improvements and decreases in muscle tone after baclofen injection, but excessive doses of ITB resulted in motor weakness. Few complications and adverse effects were reported. ITB therapy appears to be a promising treatment to improve residual motor control in patients with severe spasticity.

The objective of the present study was to fabricate and evaluate a multiparticulate oral gastroretentive dosage form of baclofen characterized by a central large cavity (hollow core) promoting unmitigated floatation with practical applications to alleviate the signs and symptoms of spasticity and muscular rigidity. Solvent diffusion and evaporation procedure were applied to prepare floating microspheres with a central large cavity using various combinations of ethylcellulose (release retardant) and HPMC K4M (release modifier) dissolved in a mixture of dichloromethane and methanol (2:1). The obtained microspheres (700-1000 µm) exhibit excellent floating ability (86 ± 2.00%) and release characteristics with entrapment efficiency of 95.2 ± 0.32%. Microspheres fabricated with ethylcellulose to HPMC K4M in the ratio 8.5:1.5 released 98.67% of the entrapped drug in 12 h. Muscle relaxation caused by baclofen microspheres impairs the rotarod performance for more than 12 h. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate- labeled microspheres was no less than 10 h. The buoyant baclofen microspheres provide a promising gastroretentive drug delivery system to deliver baclofen in spastic patients with a sustained release rate.

In the paper infrared (IR) spectroscopy and multivariate exploration techniques: principal component analysis (PCA) and cluster analysis (CA) were applied as supportive methods for the detection of physicochemical incompatibilities between baclofen and excipients. In the course of research, the most useful rotational strategy in PCA proved to be varimax normalized, while in CA Ward's hierarchical agglomeration with Euclidean distance measure enabled to yield the most interpretable results. Chemometrical calculations confirmed the suitability of PCA and CA as the auxiliary methods for interpretation of infrared spectra in order to recognize whether compatibilities or incompatibilities between active substance and excipients occur. On the basis of IR spectra and the results of PCA and CA it was possible to demonstrate that the presence of lactose, β-cyclodextrin and meglumine in binary mixtures produce interactions with baclofen. The results were verified using differential scanning calorimetry, differential thermal analysis, thermogravimetry/differential thermogravimetry and X-ray powder diffraction analyses., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Baclofen is a structural analogue of γ-aminobutyric acid (GABA) that has been used for the treatment of spasticity since 1977. This study describes a simple and sensitive LC/MS/MS assay for the quantification of baclofen in rat plasma, urine, as well as various tissue samples. The assay utilized a simple protein precipitation and achieved lower limit of quantification (LLOQ) of 0.25ng/mL for rat plasma and brain samples and 2ng/mL for rat urine, liver and kidney samples. The assay was validated to demonstrate the specificity, linearity, recovery, LLOQ, accuracy, precision, and stability by using matrix matched quality control samples. There is no endogenous or exogenous peaks interfering with the analytes and matrix effects were minimized by optimized separation condition. The assay was linear over a concentration range of 0.25-500ng/mL for rat plasma and brain tissue, and 2-5000ng/mL for rat urine, kidney and liver with correlation coefficients >0.999. The mean intra- and inter-day assay accuracies were 94.6-104.6 and 96.0-103.6%, respectively. The mean intra- and inter-day precisions were 5.71 and 5.70%, respectively. The developed assay was successfully applied to a pharmacokinetic study and examined urinary excretion and tissue distribution of baclofen in rats following intravenous and oral administration., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS)., Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3(2) factorial design was done using Polyox WSR 303 (X1) and HPMC K4M (X2) as independent variables and cumulative percentage drug released at 6 h (Q6h) as dependent variable., Results: Optimized formulation showed floating lag time of 4-5 s, floated for more than 12 h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6 h. In vivo pharmacokinetic studies in rabbits showed Cmax of 189.96 ± 13.04 ng/mL and Tmax of 4 ± 0.35 h for GFDDS. The difference for AUC(0-T) and AUC(0-∞) between the test and reference formulation was statistically significant (p > 0.05). AUC(0-T) and AUC(0-∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively., Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bioavailability of baclofen.

We produced (S)-4-cyano-3-(4-chlorophenyl)-butyrate by highly stereoselective biocatalyst in this study. A nitrilase-producing strain, named Gibberella intermedia WX12, was isolated by 3-(4-chlorophenyl)-glutaronitrile as substrate in the screening with phenol-sodium hypochlorite method. The fermentation conditions and catalytic properties of this strain were investigated. The preferred carbon and nitrogen sources for nitrilase production were lactose (30 g/L) and peptone (20 g/L). After being cultivated for 96 h, the cells were collected for use in biotransformation. The hydrolysis of 3-(4-chlorophenyl)-glutaronitrile was performed at 30 degrees C in phosphate buffer (pH 8.0, 50 mmol/L) for 24 h to give (S)-4-cyano-3-(4-chlorophenyl)-butyric acid with 90% yield and > 99% of ee, which can be used for the synthesis of (R)- and (S)-baclofen. The configuration of product was determined by chemically converting it to baclofen and comparison with the authentic sample by chiral HPLC analysis.

The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with monosubstituted allyl substrates was realized for the first time to provide corresponding products in high yields with excellent regio- and enantioselectivities. The protocol was applied to the enantioselective synthesis of (R)-baclofen and (R)-rolipram.

New salts of baclofen (4-amino-3-(para-chlorophenyl)-butyric acid) and its compositions with organic carbonic acids (citric, succinic, malic, oxalic, nicotinic, glutamic acids and glycine) exhibited neuroprotective and anticonvulsive effects. They reduced the intensity of the convulsive syndrome and postconvulsive psychoneurological disorders in animals exposed to the maximum electroshock and electroconvulsive shock. Analogs of baclofen containing citrate and to a lesser extent those containing glutamate and glycine were significantly more active than the initial substance.

Enantioresolution of (R,S)-baclofen was accomplished using a newly synthesized set of three chiral derivatizing reagents (CDRs) having amines [(S)-(-)-α,4-dimethylbenzylamine, (-)-cis-myrtanylamine and (R)-(-)-1-cyclohexylethylamine] as chiral auxiliaries in cyanuric chloride and another set of five CDRs having amino acids (L-Leu, D-Phg, L-Val, L-Met and L-Ala) as chiral auxiliaries. These eight CDRs were used for synthesis of diastereomers of (R,S)-baclofen under microwave irradiation. The diastereomers were separated on a reversed-phase C(18) column using mixtures of methanol with aqueous trifluoroacetic acid with UV detection at 230 nm. Chromatographic data obtained for the two sets of diastereomers were compared among themselves and among the two groups. The method was validated for limit of detection, linearity, accuracy and precision., (Copyright © 2011 John Wiley & Sons, Ltd.)

Studies are constantly being conducted on the elaboration of efficient methods to confirm the compatibility of active pharmaceutical ingredients (APIs) and excipients, since medicinal products, apart from their APIs, also contain numerous excipients that not only have important functions in pharmaceutical preparations but can also initiate or participate in interactions with drug substances, which eventually lead to a decline in drug quality. With this in mind, research was undertaken to evaluate two of the most often applied pattern recognition methods, hierarchical cluster analysis (HCA) and principal component analysis (PCA), as supporting techniques in the identification of potential physicochemical interactions that may occur during the preformulation of solid dosage forms. The investigation performed with the use of baclofen and selected excipients has shown that with thermogravimetric analysis, HCA and PCA fulfill their role as supporting techniques in the interpretation of the data obtained. Based on these methods, it is possible to detect incompatibilities between baclofen and excipients, and the data obtained concur strongly with the results of differential scanning calorimetry and IR spectrometry analyses.

Objective: To compare the quality of intrathecal baclofen obtained from a national compounding pharmacy (AnazaoHealth) with the manufactured product (Lioresal) with regard to accuracy and precision of baclofen concentration, and the content of the baclofen degradation product, 4-(4-chlorophenyl)-2-pyrrolidinone (PYR)., Design: Samples of baclofen used for refilling intrathecal pumps were placed in 1.2-mL silicone gasket-sealed cryogenic vials and stored at or lower than -25°C. Each sample was a different lot number (Lioresal) or prescription number (AnazaoHealth). The laboratory was blinded to the source of the solutions. Coupled with electrospray ionization-mass spectrometry analyte confirmation, quantitation of baclofen and PYR in each sample was performed in duplicate by using high-performance liquid chromatography with ultraviolet detection via a photodiode array detector., Setting: Outpatient clinic., Participants: Patients with intrathecal baclofen pumps., Main Outcome Measures: Accuracy and precision of baclofen concentration, and concentration of PYR., Results: The difference of mean concentrations from expected concentrations of 500 and 2000 μg/mL were significantly greater for samples from AnazaoHealth compared with Lioresal. Values are shown as mean (± standard error), with n the number samples, for AnazaoHealth compared with Lioresal: (537.1 ± 6.7 μg/mL [n = 8] versus 515.6 ± 0.82 μg/mL [n = 5]; P = .034, respectively) and (2211.4 ± 21.6 μg/mL [n = 12] versus 2055.3 ± 8.7 μg/mL [n = 4]; P = .004, respectively). AnazaoHealth samples with expected concentration of 4000 μg/mL were 3987.7 ± 79.9 μg/mL, n = 7. All 9 Lioresal samples were within 5% of the expected concentration. Of 27 AnazaoHealth samples, 22 were more than 5%, and 8 were more than 10% different from the expected concentration. No PYR was detected in any sample from AnazaoHealth. All samples of Lioresal contained PYR, but all solutions contained less PYR than 1% of the baclofen concentration., Conclusions: Lioresal was more accurate in concentration and more precise among batches than compounded intrathecal baclofen but had higher levels of PYR., (Copyright © 2012 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Baclofen exhibits insufficient CNS-availability when dosed systemically. Hence, prodrug candidates (methyl, ethyl, 1-propyl, 2-propyl and butyl 4-(tert-butoxycarbonyl amino)-3-(4-chlorophenyl) butanoate) were synthesized aiming at CNS-levels appropriate for the treatment of spastic disorders. The characterization of some biopharmaceutically highly relevant physicochemical properties (LogP and aqueous solubility) and the evaluation of biophase levels represent one important component of the project. The overall research aim was to generate an HPLC optimized method using DryLab, a simulation software for the optimization of a RP-HPLC method, which was optimized using a simulation software (DryLab), for the simultaneous determination of baclofen and ten synthesized prodrug candidates. The chromatographic resolution predicted and obtained via the simulation is Rs >1.5 for all baclofen derivatives, as well as, with parent baclofen. The method was used to assay the prodrugs and determine their purities, solubility and lipophilicity parameters. The designed analytical method also permits the tracking of the new prodrug candidates' hydrolysis in vitro and in vivo. The determined physicochemical properties indicate for some of the compounds that they might be suitable for CNS-targeting which was exemplified by the detection of significant baclofen levels in rat brain tissues following an i.p. dose of ethyl carbamate (vs. ethyl ester, for which only traces of baclofen were detected)., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Structure-activity studies have led to a discovery of 3-(4-pyridyl)methyl ether derivative 9d that has 25- to 50-fold greater functional potency than R-baclofen at human and rodent GABA(B) receptors in vitro. Mouse hypothermia studies confirm that this compound crosses the blood-brain barrier and is approximately 50-fold more potent after systemic administration., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Intrathecal baclofen administration is the reference treatment for spasticity of spinal or cerebral origin, but the risk of infection or catheter dysfunctions are important limits. To explore the possibility of alternative administration routes, we studied a new preparation comprising solid lipid nanoparticles (SLN) incorporating baclofen (baclofen-SLN). We used SLN because they are able to give a sustained release and to target the CNS. Wistar rats were injected intraperitoneally with baclofen-SLN or baclofen solution (baclofen-sol group) at increasing dosages. At different times up to 4 h, efficacy was tested by the H-reflex and two scales evaluating sedation and motor symptoms due to spinal lesions. Rats were killed and baclofen concentration determined in blood and tissues. Physiological solution or unloaded SLN was used as controls. After baclofen-SLN injection, the effect, consisting in a greater and earlier reduction of the H/M ratio than baclofen-sol group and controls, was statistically significant from a dose of 5 mg/kg and was inversely correlated with dose. Clinical effect of baclofen-SLN on both the behavioral scales was greater than that of baclofen-sol and lasted until 4th hour. Compared with baclofen-sol, baclofen-SLN produced significantly higher drug concentrations in plasma from 2nd hour until 4th hour with a linear decrement and in the brain at all times. In conclusion, our study demonstrated the efficacy of a novel formulation of baclofen, which exploits the advantages of SLN preparations. However, for clinical purposes, high baclofen concentrations in brain tissue and sedation may be unwanted effects, requiring further studies and optimization of dosages., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Intellectual disability (ID; mental retardation) is considered an immutable condition. Current medical practices are aimed at relieving symptoms and not at altering the underlying cognitive deficits. Scientific advancements from the past decade have led to the exciting possibility that ID may now be treatable. Moreover, pharmaceutical therapies targeting the most common form of inherited ID, Fragile X syndrome (FXS), may become the new benchmark for central nervous system (CNS) drug discovery: seeking cures for neurodevelopmental disorders.

STX209 (arbaclofen) is a γ-amino butyric acid type B (GABA(B)) receptor agonist from Seaside Therapeutics currently in clinical trials for autism spectrum disorders (ASD). The company has initiated a phase 2b study after positive results from a phase 2a trial, announced September 2010 (http://www.seasidetherapeutics.com/sites/default/files/STX209&#95;ASD&#95;P2b Trial&#95;Initiation%206%2021%202011%20Final.pdf).

Baclofen, an antispasmodic agent that acts as a GABA(B) agonist, resembles phenylalanine in structure and has been reported to be a substrate of the large amino acid transporter 1 (LAT-1). The objective of this study was to investigate the absorption of baclofen across the nasal mucosa both in vitro and in vivo. Baclofen transport was measured across excised bovine olfactory and respiratory mucosae to investigate site-specific uptake of baclofen, and the intranasal bioavailability of R- and S-baclofen was determined in rats. Increasing flux with increasing baclofen donor concentration and the absence of polarized transport was observed in vitro, and similar distribution profiles were observed for both enantiomers following intranasal administration in rats. The absence of stereospecificity in nasal absorption indicates limited involvement of the amino acid or other transporters in the nasal absorption of baclofen., (Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association)

An efficient rhodium/diene-catalyzed asymmetric addition of arylboronic acids to α,β-unsaturated γ-lactams has been developed. The power of this methodology is further demonstrated by the concise synthesis of (R)-baclofen and (R)-rolipram.

Background and Objectives: To minimize the frequency that intrathecal pumps require refilling, drugs are custom compounded at very high concentrations. Unfortunately, the baricity of these custom solutions is unknown, which is problematic, given baricity's importance in determining the spread of intrathecally administered drugs. Consequently, we measured the density and calculated the baricity of clinically relevant concentrations of multiple drugs used for intrathecal infusion., Methods: Morphine, clonidine, bupivacaine, and baclofen were weighed to within 0.0001 g and diluted in volumetric flasks to produce solutions of known concentrations (morphine 1, 10, 25, and 50 mg/mL; clonidine 0.05, 0.5, 1, and 3 mg/mL; bupivacaine 2.5, 5, 10, and 20 mg/mL; baclofen 1, 1.5, 2, and 4 mg/mL). The densities of the solutions were measured at 37°C using the mechanical oscillation method. A "best-fit" curve was calculated for plots of concentration versus density for each drug., Results: All prepared solutions of clonidine and baclofen were hypobaric. Higher concentrations of morphine and bupivacaine were hyperbaric, whereas lower concentrations were hypobaric. The relationship between concentration and density is linear for morphine (r > 0.99) and bupivacaine (r > 0.99) and logarithmic for baclofen (r = 0.96) and clonidine (r = 0.98)., Conclusions: This is the first study to examine the relationship between concentration and density for custom drug concentrations commonly used in implanted intrathecal pumps. We calculated an equation that defines the relationship between concentration and density for each drug. Using these equations, clinicians can calculate the density of any solution made from the drugs studied here.

Four dichloro-s-triazine (DCT) and five monochloro-s-triazine (MCT) chiral derivatizing reagents (CDRs) were synthesized by incorporating amino acid amide moieties as chiral auxiliaries in trichloro-s-triazine and its 6-methoxy derivative, respectively. Another MCT reagent was synthesized by substitution of two chlorine atoms with two different amino acid amides in trichloro-s-triazine. These reagents were used for synthesis of diastereomers of (R,S)-baclofen under microwave irradiation (i.e. 60 s at 85% power using DCT reagents and 90 s at 85% power using MCT reagents). The diastereomers were separated on a reversed-phase C18 column using mixtures of methanol with aqueous trifluoroacetic acid (TFA) with UV detection at 230 nm. The separation behavior in terms of retention times and resolutions obtained for the two sets of diastereomers prepared with DCT and MCT reagents were compared among themselves and among the two groups. Longer retention times and better resolutions were observed with DCT reagents as compared to MCT reagents. The calibration curves were linear for both (R)- and (S)-baclofen in the concentration range 50-500 μg/ml. The average regression was 0.999 for both (R)- and (S)-baclofen. The RSD for (R)-baclofen was 0.40-0.86% for intra-day precision and 0.60-1.40% for inter-day precision and these values for (S)-baclofen were 0.52-0.75% and 0.64-1.32%, respectively. The recovery was 97.2-98.9% for (R)- and 97.0-98.9% for (S)-baclofen. The limit of detection was 1.63 ng/ml and 1.52 ng/ml for (R)- and (S)-baclofen, respectively., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A rapid method for the simultaneous analysis of R-(-)-, S-(+)-baclofen and impurity A, (4RS)-4-(4-chlorophenyl) pyrrolidin-2-one, by electrokinetic chromatography was established. The optimized condition was in 100mM sodium borate buffer (pH 9.9) containing 18mM alpha-cyclodextrin (CD) and 1% (v/v) ACN using a fused-silica capillary dynamically coated with polyethylene oxide (PEO), with an effective length of 56cm and an inner diameter of 50microm, hydrodynamic injection at 50mbar for 6s, temperature of 45 degrees C, applied voltage of 27kV and UV detection at 220nm. Baseline separation of all analytes was achieved within 9min (R(s)>2.7) with the migration order of impurity A, S-(+)- and R-(-)-baclofen. The method showed good linearity (r(2)>0.999 in a range of 5-50microg/mL for impurity A and 50-500microg/mL for baclofen enantiomers), precision (%RSDs<3.37%) and recoveries (100.3% for R-(-)-baclofen, 101.6% for S-(+)-baclofen and 96.1% for impurity A). Detection and quantitation limits were 10 and 30microg/mL for both enantiomers, and 2 and 5microg/mL for the impurity, respectively. The method was efficient for the determination of baclofen enantiomers and impurity A in pharmaceutical raw material and formulations due to its reliability, speed and simplicity.

Objective: To assess the differences between commercial and pharmacy-compounded preparations of baclofen for intrathecal administration., Design: Random sample., Setting: Pharmacies in the United States advertising compounded intrathecal baclofen preparation., Participants: Not applicable., Interventions: Intrathecal baclofen (ITB) samples were collected from 1 Food and Drug Administration-approved commercial source and 6 compounding pharmacies. An independent analysis of drug concentration and density was conducted. Information regarding ordering process, manufacturing, packaging, storage, and expiration was collected., Main Outcome Measure: Comparison of concentration and density variations., Results: Twenty-nine ITB samples in concentrations of 2000, 3000, 4000, 5000, and 6000 microg/mL were analyzed. Over 40% of compounded samples were more than 5% above or below labeled concentration. Twenty-two percent of compounded samples were more than 10% above or below labeled concentration. The only samples with no concentration deviation and consistent drug density were the commercially available, noncompounded products., Conclusions: Compounding pharmacies have variable practices in the provision of ITB. A high incidence of concentration inaccuracy existed. The use of compounded ITB may result in unintended dose alterations. Variable clinical efficacy, or life-threatening overdose or withdrawal may occur in patients who are sensitive to slight dose fluctuations. Given the variability of these compounded ITB samples, informed consent to use these products and understanding of potential side effects should be reviewed with patients.