Enantioseparation and mechanism study on baclofen by capillary electrophoresis and molecular modeling.

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.

Formulation and Evaluation of Baclofen-Meloxicam Orally Disintegrating Tablets (ODTs) Using Co-Processed Excipients and Improvement of ODTs Performance Using Six Sigma Method.

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 Tmax 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.

Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side.

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.

Formulation and evaluation of baclofen liposome vesicles using lecithin / Formulación y evaluación de vesículas de liposomas de baclofeno usando lecitina

INTRODUCTION: The main aim of present study was to prepare and characterize liposomal formulation of baclofen to improve the effectiveness of the topically applied formulation. METHOD: For the preparation of liposomes, different ratio of lecithin, cholesterol and ethanol were taken but ratio of drug and stearic acid were kept constant and prepared by ethanol injection method. Liposomes were characterized for vesicle size, vesicle shape, entrapment efficiency, in vitro studies, stability studies and in vivo studies. RESULTS: The average particle size of formulated liposome was in the range of 3.98 ± 0.45-4.24 ± 0.65 mim and small unilamellar vesicles with spherical in shape observed. Entrapment efficiency of optimized formulation was 58.67 ± 0.81 %. The maximum % cumulative drug release behaviours were 67.66 ± 5.32 % after 10 h. formulation stored in 4 ± 2 °C temperature shows better stability (64.19 ± 0.26) compared to elevated temperature. Swiss albino mice were used for the in vivo study and exhibit muscle relaxant activity in terms of no. of falls from rota rod apparatus (p value = 0.001). CONCLUSIONS: Baclofen loaded liposomal formulation have shown skeletal muscle relaxant activity in mice suggesting delivery of baclofen from liposomes in the therapeutic range

INTRODUCTION: the use of specific rules to correctly identify ingredients used in cosmetics was essential for their control. This paper analyses the complex process to adapt the INCI terminology between the 1960s and the 1990s. METHOD: analysis of the legislation published in Spain on the control of cosmetic products between the 1940s and the 1990s, focusing on cosmetic's registers and terminologies and nomenclatures used to identify their ingredients. Printed Primary sources, and periodical press have also been consulted. Primary sources have been discussed and contextualized with the help of more recent history of science publications. Results and CONCLUSIONS: The adoption of precise cosmetic nomenclature or terminology was required by health authorities registering these products, as well as for the labelling to inform consumer. The sanitary regulation of cosmetic products was very lax until the development of this industry and its market in Spain in the 1960s. The consolidation of the dermopharmaceutical sector occurred in the 1970s, in part due to the efforts of various pharmaceutical sectors. The gradual introduction of international cosmetic nomenclatures culminated in the 1990s with the official introduction of the INCI terminology in Spain

The GABAB Receptor-Structure, Ligand Binding and Drug Development.

The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA 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 GABAB1 and GABAB2 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.

3D-Printed Gastroretentive Sustained Release Drug Delivery System by Applying Design of Experiment Approach.

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 (T80) was 1.7-6.7 h by varying the control factors. The effects of the different control factors on the response factor, T80, 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.

Design, characterization and in vivo evaluation of modified release baclofen floating coated beads.

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 Cmax, Tmax, and AUC0-24 of optimized modified release baclofen floating formulations when compared to Baclofen® immediate-release tablets.

Physicochemical Stability of Ternary Mixtures of Sufentanil, Baclofen, and Ropivacaine in Polypropylene Syringes for Intrathecal Analgesia.

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.

Simultaneous Quantitation of S(+)- and R(-)-Baclofen and Its Metabolite in Human Plasma and Cerebrospinal Fluid using LC-APCI-MS/MS: An Application for Clinical Studies.

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.

Nano-liquid chromatography for enantiomers separation of baclofen by using vancomycin silica stationary phase.

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.

Baclofen impurities: Facile synthesis and novel environmentally benign chromatographic method for their simultaneous determination in baclofen.

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 F254 ) 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.

Application of 3D printing technology and quality by design approach for development of age-appropriate pediatric formulation of baclofen.

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. 32 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.

Compatibility of Baclofen, Carvedilol, Hydrochlorothiazide, Mercaptopurine, Methadone Hydrochloride, Oseltamivir Phosphate, Phenobarbital, Propranolol Hydrochloride, Pyrazinamide, Sotalol Hydrochloride, Spironolactone, Tacrolimus Monohydrate, Ursodeoxycholic Acid, and Vancomycin Hydrochloride Oral Suspensions Compounded with SyrSpend SF pH4.

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.

Population, basicity and partition of short-lived conformers. Characterization of baclofen and pregabalin, the biaxial, doubly rotating drug molecules.

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 1H 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.

GABAB receptor ligand-directed trimethyl chitosan/tripolyphosphate nanoparticles and their pMDI formulation for survivin siRNA pulmonary delivery.

The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABAB 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. GABAB 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 GABAB 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.

Stability of Acetazolamide, Baclofen, Dipyridamole, Mebeverine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4.

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.

Direct Synthesis of 2-Formylpyrrolidines, 2-Pyrrolidinones and 2-Dihydrofuranones via Aerobic Copper-Catalyzed Aminooxygenation and Dioxygenation of 4-Pentenylsulfonamides and 4-Pentenylalcohols.

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.

Development and Application of a High-Performance Liquid Chromatography Stability-Indicating Assay for Beyond-Use Date Determination of Compounded Topical Gels Containing Multiple Active Drugs.

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.

Baclofen Solution for Low-Volume Therapeutic Delivery.

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.

Enantioresolution of (RS)-baclofen by liquid chromatography: A review.

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.