A stability-indicating, reversed-phase HPLC method for quantification of assay and organic impurities in doxycycline hyclate bulk and parenteral dosage forms.

The aim of this study is to develop a stability-indicating, reversed-phase HPLC method for the quantification of assay and organic impurities (process and degradation) of doxycycline hyclate in a doxycycline injectable formulation. Both the active and dosage forms are officially present in the USP monograph, and assay and impurity methods are provided by separate UPLC techniques, which are highly sensitive to the flow rate and temperature, considering the quality control requirements and user-friendliness. A simple stability-indicating HPLC method with a shorter run time was developed for the simultaneous quantification of assay and impurity. The method was developed using HPLC with a gradient program and a reversed-phase Waters XBridge BEH C8 column (150 × 4.6 mm, 3.5 µm i.d.). Mobile phase A consisted of phosphate buffer (pH 8.5, 25 mM potassium phosphate, 2 mM ethylenediaminetetraacetic acid, and 0.5 ml of triethylamine). Mobile phase B consisted of methanol with a flow rate of 1.7 ml/min, a column temperature of 55°C, a UV wavelength of 270 nm, and an injection volume of 25 µl. Modern research represents a concomitant method for quantifying assay and organic impurities of doxycycline hyclate (active form) and doxycycline for injection (dosage form). The assay and impurity method were validated per United States Pharmacopeia (USP) 1225 and International Conference on Harmonization (ICH) guidelines. The retention time of doxycycline and degradation impurity, 4-epidoxycycline, was about 9.8 and 6.4 min, respectively. The linearity range of doxycycline and 4-epidoxycycline was 0.5-150 and 0.5-18 µg/ml, respectively. The percentage of recovery of doxycycline and 4-epidoxycycline was 98.7-100.6% and 88.0-112.0%. Validation of the analytical method demonstrated that the method is suitable, specific, linear, accurate, precise, rugged, and stability indicating for estimating the assay, known and degraded impurities of doxycycline, and doxycycline for injection.

Amphotericin B liposomal formulation: applicable preparation methods, challenges, and tips.

OBJECTIVE: This study was intended to explore and evaluate the appropriate methods for preparation of Amphotericin B (AmB) liposomes with acceptable characteristics. SIGNIFICANCE: This project provides pre-formulations for industrial manufacturing of liposomal AmB which confers improved properties, besides reduced toxicity compared with the plain drug. METHODS: At first, Solubility screening tests were performed, and in the following, three liposome preparation methods including ethanol injection, solvent evaporation, and solvent-free method were examined. In the following, the physicochemical characteristics of the prepared liposomes as well as size, size distribution, zeta potential (ZP), morphology, drug loading, loading capacity, physicochemical stability, and drug-lipid interaction studies were investigated. HPLC was applied for analyzing AmB. RESULTS: In all three methods, liposomes with acceptable characteristics were obtained. The size range of liposomes was 150.3 to 263.9 nm and polydispersity index ≤0.32. In morphologic evaluations, the liposomes have appeared as spherical and separate vesicles. A physical loading of AmB without specific interaction between components was achieved. The lyophilized powder in the solvent-free method was physicochemically stable for 6 months without changes in appearance; the remaining drug after 6-month storage at 25 °C and 60% RH, accounts for 91.5 ± 0.5% compared with the initial drug loaded in liposomes, and degradation pattern follows a linear order. CONCLUSION: As a result, AmB-loaded liposomes were prepared in three applicable methods. The solvent-free method can be considered the most economical and environmental-friendly.

Enhanced water-soluble derivative of PC407 as a novel potential COX-2 inhibitor injectable formulation.

PC407 is an effective COX-2 inhibitor in non-steroidal anti-inflammatory drug development but the poor solubility limits their usefulness. The aim of the study was to prepare and evaluate 4-oxo-4-[4-(5-(naphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamido]butyrate disodium, a derivative of PC407 with enhanced water solubility for injectable formulation. The prepared derivative displayed interesting high aqueous solubility (20.3 mg/mL, much superior to the parent compound PC407, 1.6 µg/mL) with confirmed in vivo analgesic activity. This derivative represents the profiles of prodrug and potential candidate of PC407 for the development of injectable COX-2 inhibitor due to extraordinary water solubility, low toxicity, and impressive analgesic activity.

Evaluating the 6-month formulation of paliperidone palmitate: a twice-yearly injectable treatment for schizophrenia in adults.

INTRODUCTION: Paliperidone Palmitate is the only antipsychotic that has been developed in three different intramuscular long-acting injectable (LAI) dosing regimen: monthly (PP1M), quarterly (PP3M), and from 2020 also twice-yearly (PP6M). The latter was approved for the maintenance treatment of adults with schizophrenia and clinically stabilized with PP1M or PP3M. AREAS COVERED: Data from studies evaluating efficacy in the maintenance treatment of schizophrenia with PP6M are reviewed. Since no post-marketing safety studies are currently available, data from spontaneous reporting system databases, FAERS and Eudravigilance, are analyzed and the reported treatment-emergent adverse events of PP6M are discussed. EXPERT OPINION: The efficacy of PP6M is comparable to that of PP3M in terms of relapses prevention in patients with schizophrenia previously stabilized on PP3M or PP1M. Also, the maintenance of clinical efficacy in the long term has been demonstrated. Data from pharmacovigilance analyses, as well as from phase 3 studies, show that PP6M is generally well tolerated, consistently with PP3M safety data. PP6M allows a longer dosing interval than any other LAI antipsychotics, potentially reducing nonadherence and disease relapses. In future, an increase in the prescription rates of PP6M is expected and real-world efficacy and tolerability studies will be conducted.

A comparison of recurrence rates after discontinuation of second-generation antipsychotic long-acting injectable versus corresponding oral antipsychotic in the maintenance treatment of bipolar disorder: A systematic review.

It has been previously reported that among patients with schizophrenia that long-acting injectable (LAI) antipsychotic formulations can delay time to relapse longer when compared to their oral equivalents when patients discontinue therapy. Unanswered is whether this same pattern would be observed for patients with bipolar disorder receiving maintenance treatment. A systematic review was undertaken to identify relevant studies of LAI antipsychotics in maintenance treatment of bipolar disorder, employing a placebo-controlled randomized withdrawal design, and where equivalent studies using the corresponding oral formulation were also available. We found five studies [one aripiprazole monohydrate once monthly (AOM) study, one oral aripiprazole (OARI) study, two 2 weeks risperidone-LAI (RIS-LAI) studies, and one oral paliperidone (OPAL) study]. Numerically lower recurrence rates at 2, 4, 6, 8, 12, 16, 20, and 26 weeks were observed when AOM was discontinued when compared with discontinuation from OARI. Numerically lower recurrence rates at 2, 4, 6, 8, and 16 weeks were observed when RIS-LAI was discontinued when compared with discontinuation from OPAL. These results can be interpreted as a substantial delay in time to recurrence with a LAI antipsychotics formulation compared to the oral equivalent when medication is discontinued in patients with mania who had been stabilized on LAI antipsychotics or corresponding oral antipsychotics.

Exploring novel and fast stability or sameness evaluation tool for different categories of injectable formulations.

The establishment of drug product stability and sameness is the heart of generic formulation development. For regulatory filing, various instrumental methods are used on a case basis to establish the generic and innovator product sameness in multiple aspects. Here in the present study, we explored the applicability of the Time-correlated single photon counting (TCS-PC) technique as a fast, reliable, and nondestructive method for establishing the sameness of three different categories of injectable formulations, namely, Amphotericin B liposome for injection, enoxaparin injection, and iron sucrose injection. All three category formulations were evaluated in their native and artificially induced post degradation state to identify the discrimination power of the used instrumental techniques. The degradation of materials were confirmed by high performance liquid chromatography (HPLC). Based on the product category, pre and post-degradation samples were evaluated by selective instrumental methods like differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), fluorescence spectroscopy, particle size analysis by dynamic light scattering (DLS), small angle X-ray scattering (SAXS), Raman spectroscopy, inductively coupled plasma optical-emission spectrometry (ICP-OES) and circular dichroism study. All pre and post-degradation samples were further analyzed by TCS-PC. We observed that, TCS-PC can identify the differences between the initial and post degradation samples in very less time with promising discrimination power across the different injectable formulation types. Thus TCS-PC can be used as a fast and promising stability or sameness evaluation tool for different injectable drug products.

Approaches for estimating the clinical starting dose of new dosage forms: An example of a long-acting injectable formulation of finasteride.

In our previous study, a long-acting injectable (LAI) formulation of finasteride was prepared as a new dosage form of PROPECIA®, and in vivo pharmacokinetics (PKs)-pharmacodynamics (PDs) was evaluated in beagle dogs. The resulting PK-PD profiles of the formulation showed pharmacological effects and achievability for monthly delivery. In this study, a first-in-human (FIH) dose of the LAI formulation loaded with finasteride was predicted. The three approaches were used for estimating a FIH dose of the LAI formulation: (1) No observed adverse effect level (NOAEL)-based approach; (2) Pharmacokinetically-guided approach; (3) Pharmacokinetic/pharmacodynamic model-based approach. The advantage, assumptions, limitations, and estimated FIH dose from each approach was discussed and compared since there is no consensus on the best approach. For the prediction of clinical exposures and estimation of FIH doses, the clinical PK-PD parameters were allometrically scaled from the nonclinical data, extracted from reported clinical studies, or fixed from published literature. The starting dose range of the LAI formulation (as finasteride) was estimated to be 16.80-81.06 mg from the three approaches, and the PK/PD model-based approach suggests the most optimal starting dose (16.80 mg) of the LAI formulation. The approaches for estimating starting doses presented in the study could be used as a basis for an Investigational New Drug (IND) application of new dosage forms.

Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model.

Background: Previous studies have proven that Purinostat Mesylate (PM) is a new HDAC inhibitor and exhibits significant antitumor efficacy. However, the clinical application of PM was greatly limited by its poor solubility in water and low bioavailability.Objective:To increase the solubility of PM through pharmaceutical research, and prepare it into an injection that meets the needs of intravenous use to promote its clinical application.MethodsThe prepared PM/HP-ß-CD inclusion complex was studied by computer simulation, fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H-NMR spectroscopy), and scanning electron microscopy (SEM). Then, the antitumor effects of PM/HP-ß-CD inclusion complex were studied by in vitro cytotoxicity assay, apoptosis assay, pharmacokinetic study and in vivo antitumor assay.Results:Phase Solubility Analysis revealed that PM and HP-ß-CD were compatible and the solubility of PM increased almost 220 times, to 2.02 mg/mL. The interaction mechanism studies revealed that PM could be embedded into the cavity of HP-ß-CD through the side of the aminobenzene ring. Cell viability and apoptosis assays showed that PM/HP-ß-CD complex maintained the good anti-cancer activity of PM, and PM/HP-ß-CD complex has a better anti-tumor effect and lower toxicity than LBH589 and Hyper-CVAD/RTX in vivo. All the results suggest that HP-ß-CD can solve the problem of PM administration and provide a way for clinical application of PM.Conclusions: In this study, an injectable formulation of PM in HP-ß-CD (10% w/v) was prepared to improve its water solubility. Our research provides a way for clinical administration of PM, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related hematologic malignancies in China and the USA.KEY MESSAGESWe developed a preparation of Purinostat Mesylate that can be administered intravenously, reducing the toxicity associated with oral administration.This preparation has an outstanding therapeutic effect on SU-DHL-6 xenograft tumour, indicating its clinical value, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related haematologic malignancies in China and the USA.

Opportunities and challenges of physiologically based pharmacokinetic modeling in drug delivery.

Physiologically based pharmacokinetic (PBPK) modeling is an important in silico tool to bridge drug properties and in vivo PK behaviors during drug development. Over the recent decade, the PBPK method has been largely applied to drug delivery systems (DDS), including oral, inhaled, transdermal, ophthalmic, and complex injectable products. The related therapeutic agents have included small-molecule drugs, therapeutic proteins, nucleic acids, and even cells. Simulation results have provided important insights into PK behaviors of new dosage forms, which strongly support drug regulation. In this review, we comprehensively summarize recent progress in PBPK applications in drug delivery, which shows large opportunities for facilitating drug development. In addition, we discuss the challenges of applying this methodology from a practical viewpoint.

Evaluating Non-Conventional Chitosan Sources for Controlled Release of Risperidone.

In this work, two chitosan samples from cuttlebone and squid pen are produced and characterized. We studied the formation of thermoresponsive hydrogels with ß-glycerol phosphate and found proper formulations that form the hydrogels at 37 °C. Gel formation depended on the chitosan source being possible to produce the thermoresponsive hydrogels at chitosan concentration of 1% with cuttlebone chitosan but 1.5% was needed for squid pen. For the first time, these non-commercial chitosan sources have been used in combination with ß-glycerol phosphate to prepare risperidone formulations for controlled drug delivery. Three types of formulations for risperidone-controlled release have been developed, in-situ gelling formulations, hydrogels and xerogels. The release profiles show that in-situ gelling formulations and particularly hydrogels allow an extended control release of risperidone while xerogels are not appropriate formulations for this end since risperidone was completely released in 48 h.

The industrial design, translation, and development strategies for long-acting peptide delivery.

INTRODUCTION: Peptides are widely recognized as therapeutic agents in the treatment of a wide range of diseases, such as cancer and diabetes. However, their use has been limited by their short half-life, due to significant metabolism by exo- and endo-peptidases as well as their inherent poor physical and chemical stability. Research with the aim of improving their half-life in the body and thus improving patient compliance (by decreasing the frequency of injections) has gained significant attention. AREAS COVERED: This review outlines the current landscape and industrial approaches to achieve extended peptide exposure and reduce dosing frequency. Emphasis is placed on identifying challenges in drug product manufacturing and desirable critical quality attributes that are essential for activity and safety, providing insights into chemistry and design aspects impacting peptide release, and summarizing important considerations for CMC developability assessments of sustained release peptide drugs. EXPERT OPINION: Bring the patient and disease perspective early into development. Substantial advances have been made in the field of sustained delivery of peptides despite their complexity. The article will also highlight considerations for early-stage product design and development, providing an industrial perspective on risk mitigation in developing sustained release peptide drug products.

Surface analysis of sequential semi-solvent vapor impact (SAVI) for studying microstructural arrangements of poly(lactide-co-glycolide) microparticles.

Biodegradable poly(lactide-co-glycolide) (PLGA) microparticles have been used as long-acting injectable (LAI) drug delivery systems for more than three decades. Despite extensive use, few tools have been available to examine and compare the three-dimensional (3D) structures of microparticles prepared using different compositions and processing parameters, all collectively affecting drug release kinetics. Surface analysis after sequential semi-solvent impact (SASSI) was conducted by exposing PLGA microparticles to different semi-solvent in the liquid phase. The use of semi-solvent liquids presented practical experimental difficulties, particularly in observing the same microparticles before and after exposure to semi-solvents. The difficulties were overcome by using a new sequential semi-solvent vapor (SSV) method to examine the morphological changes of the same microparticles. The SASSI method based on SSV is called surface analysis of semi-solvent vapor impact (SAVI). Semi-solvents are the solvents that dissolve PLGA polymers depending on the polymer's lactide:glycolide (L:G) ratio. A sequence of semi-solvents was used to dissolve portions of PLGA microparticles in an L:G ratio-dependent manner, thus revealing different structures depending on how microparticles were prepared. Exposing PLGA microparticles to semi-solvents in the vapor phase demonstrated significant advantages over using semi-solvents in the liquid phase, such as in control of exposure conditions, access to imaging, decreasing the time for sequential exposure of semi-solvents, and using the same microparticles. The SSV approach for morphological analysis provides another tool to enhance our understanding of the microstructural arrangement of PLGA polymers. It will improve our comprehensive understanding of the factors controlling drug release from LAI formulations based on PLGA polymers.

Injectable niclosamide nanohybrid as an anti-SARS-CoV-2 strategy.

COVID-19 is a rapidly evolving emergency, which necessitates scientific community to come up with novel formulations that could find quick relief to the millions affected around the globe. Remdesivir being the only injectable drug by FDA for COVID-19, it initially showed promising results, however, later on failed to retain its claims, hence rejected by the WHO. Therefore, it is important to develop injectable formulation that are effective and affordable. Here in this work, we formulated poly ethylene glycol (PEG) coated bovine serum albumin (BSA) stabilized Niclosamide (NIC) nanoparticles (NPs) (∼BSA-NIC-PEG NPs) as an effective injectable formulation. Here, serum albumin mediated strategy was proposed as an effective strategy to specifically target SARS-CoV-2, the virus that causes COVID-19. The in-vitro results showed that the developed readily water dispersible formulation with a particle size <120 nm size were well stable even after 3 weeks. Even though the in-vitro studies showed promising results, the in-vivo pharmaco-kinetic (PK) study in rats demands the need of conducting further experiments to specifically target the SARS-CoV-2 in the virus infected model. We expect that this present formulation would be highly preferred for targeting hypoalbuminemia conditions, which was often reported in elderly COVID-19 patients. Such studies are on the way to summarize its potential applications in the near future.

Pharmacokinetic-pharmacodynamic modeling approach for dose prediction of the optimal long-acting injectable formulation of finasteride.

A controlled drug release formulation based on the subcutaneous injection of poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with finasteride was prepared and evaluated for monthly delivery. After selection of biodegradable polymer and polymer-to-finasteride ratio, the formulation was characterized. Scanning electron microscopy (SEM) and laser-light particle size analysis were used to examine the morphology, surface structure, and particle size. High­performance liquid chromatography (HPLC) was used to determine the drug loading, while liquid chromatography with tandem mass spectrometry (LC-MS/MS) was employed to analyze plasma finasteride concentrations. Results showed that the PLGA microspheres were spherical and of an appropriate size. The formulation stably releases the drug from the microspheres and the release sustained for a month without burst release, which was the desired duration. In vivo pharmacokinetic-pharmacodynamic (PK-PD) studies were conducted in beagle dogs through the administration of PROPECIA® (as a reference drug) per oral and subcutaneous injection of the long-acting injectable microsphere formulation (LAIF) loaded with five different doses of finasteride. From the acquired plasma data, PK-PD models for both PROPECIA®-administered group and LAIFs-injected groups were developed and validated. PK-PD profiles of both groups were predicted for up to one month. The predicted PK-PD profile of all LAIFs showed the achievability of monthly delivery and pharmacological effects without burst release, compared to the simulated PK-PD profile of PROPECIA®. According to the predicted PK-PD profiles, the formulation loaded with 16.8 mg of finasteride was determined to be the optimal dose. The data obtained from the PK-PD model could be used as the basis for the estimation of a first-in-human dose of the formulation.

Dry fabrication of poly(dl-lactide-co-glycolide) microspheres incorporating a medium molecular drug by a ball mill method.

Poly(dl-lactide-co-glycolide) acid (PLGA) microspheres is a useful carrier for controlled drug release. However, the organic solvents used in their conventional manufacturing process may affect the chemical structure of a macromolecular drug. Thus, we investigated the applicability of a dry fabrication method for PLGA microspheres. Cyanocobalamin (MW = 1,355) (VB12) was used as a model drug, and it formed agglomerates under mild conditions with powdered PLGA in a generic ball milling system. Light and scanning electron microscopy showed the formation of PLGA microspheres and few agglomerates. The obtained microspheres had the particle size injectable as suspensions, namely smaller than 150 µm specified for subcutaneous and intramuscular injections by the Japanese Pharmacopoeia. The observed and theoretical drug contents were consistent. PLGA microspheres fabricated using a combination of small (ϕ3 mm) and large (ϕ10 mm) balls showed low initial burst of cyanocobalamin release in vitro. The in vitro drug release profile was equivalent with that of the microspheres fabricated by a conventional oil-in-water emulsion solvent evaporation method, while the drug release profile was influenced by the brand of the PLGA used. To prevent drug loss during fabrication, the dry fabrication method using a ball mill should be applied to prepare PLGA microspheres containing a medium macromolecular drug.

Long-acting injectable donepezil microspheres: Formulation development and evaluation.

Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect were developed, aimed at reducing dosing frequency and adverse effects and improving patient adherence. The spherical and monodispersed DNP-loaded microspheres were precisely fabricated by the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®) based on micro-electromechanical systems (MEMS) and microfluidic technology. The types of polymers and end-groups, the drug/polymer ratio (DPR), and the routes of administration for DNP were studied to ensure an effective concentration and desired duration. Laser-light particle size analysis and scanning electron microscopy were used to characterization. Also, non-clinical animal models of beagle dogs are used to optimize DNP formulations and evaluate their pharmacokinetic properties. The PK results showed that the DPR was a critical factor in determining the exposure level and duration of DNR release. Furthermore, the lactide ratio, which varied depending upon the type of polymer, determined the hydrophobic interaction and was also an important factor affecting the desired DNP release. Since DNP shows a large inter-species variation between dogs and humans, PK modeling and simulation of the reference drug (i.e., Aricept®) and DNP-loaded microspheres were used for formulation development to overcome and interpret these variations. In addition, the developed PK model was extrapolated to humans using the estimated PK parameter and published clinical pharmacology data for DNP. The predicted PK profile of the DNP-loaded microsphere in humans showed that the formulation with PLGA 7525A and the DPR of 1/9 could maintain drug concentration for a month and could control initial burst release. The data obtained from the study could be used as scientific evidence for decision-making in future formulation development.

Controlled release of a model hydrophilic high molecular weight compound from injectable non-lamellar liquid crystal formulations containing different types of phospholipids.

Skin offers an easily accessible and convenient site for the administration of drugs. Therefore, the development of injectable formulations with controlled drug release properties are now expected to deliver middle- and large-size biomolecules. In the present study, formulations mainly composed of a novel polyol ester with an isoprenoid side chain; mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE), that was capable of forming a non-lamellar liquid crystal (NLLC), were prepared with different types of phospholipid. Then, factors that affected the release of a model entrapped drug, fluorescein-isothiocyanate dextran (FD-4, M.W. 4,000), from the MGE formulations were analyzed with multi-regression analysis. In addition, self-assembly of the NLLC structure was investigated using small-angle X-ray scattering analysis after contacting the MGE formulations with water. NLLC-forming ability of the formulations after s.c. injection into rats was also confirmed using microscopic observations. FD-4 concentrations in blood were determined after s.c. injection of the MGE formulations. The injectable MGE formulations successfully constructed NLLC structures to form a sponge-like gel after contact with water in vitro and in vivo (in rats) as well. In in vitro conditions, the amount of FD-4 released from the formulations was altered by changing the type and concentration of phospholipid in the MGE formulations and can be expressed with parameters such as MGE content and interplanar spacing of the NLLC. A significantly sustained FD-4 level in the blood was observed after s.c. injection of the formulations. These results suggested that injectable MGE formulations may have the potential to achieve controlled release profiles of drugs after s.c. injection.

Process analytical technologies and injectable drug products: Is there a future?

Parametric release was the first subset of real time release testing (RTRT), applied to terminally sterilised injectable drug products. The objective was to offer the industry an alternative to the time and money consuming sterility testing, without compromising the sterility of the products. The rationale was that quality cannot be tested into products, instead it must be planned (the principle of quality by design, QbD). This can be implemented by setting appropriate in-process controls supported on process analytical technologies (PAT). Two of the most versatile and promising PAT tools are the near infrared spectroscopy (NIRS) and the Raman spectroscopy. However, their application to injectable drug product development and manufacturing has been scarce. This review has the objective to provide a framework for the practical implementation of the QbD approach to injectable formulations, including application of diverse risk assessment and factorial design tools. Finally, the actual application of PAT, namely NIRS and Raman spectroscopy, to injectable drug product analysis is addressed.

Development of a dispersive liquid-liquid microextraction technique for the extraction and spectrofluorimetric determination of fluoxetine in pharmaceutical formulations and human urine.

PURPOSE: Fluoxetine is the most prescribed antidepressant drug worldwide. In this work, a new dispersive liquid-liquid microextraction (DLLME) method combined with spectrofluorimetry has been developed for the extraction and determination of FLX in pharmaceutical formulations and human urine. METHODS: For FLX determination, the pH of a 10 mL of sample solution containing FLX, was adjusted to 11.0. Then, 800 µL of ethanol containing 100 µL of chloroform was injected rapidly into the sample solution. A cloudy solution was formed and FLX extracted into the fine droplets of chloroform. After centrifugation, the extraction solvent was sedimented and supernatant aqueous phase was readily decanted. The remained organic phase was diluted with ethanol and its fluorescence was measured at 292±3 nm after excitation at 234±3 nm. RESULTS: Some important parameters influencing microextraction efficiency were investigated. Under the optimum extraction conditions, a linear calibration curve in the range of 10 to 800 ng/mL with a correlation coefficient of r(2) = 0.9993 was obtained. Limit of detection (LOD) and limit of quantification (LOQ) were found to be 2.78 and 9.28 ng/mL, respectively. The relative standard deviations (RSDs) were less than 4%. Average recoveries for spiked samples were 93-104%. CONCLUSION: The proposed method gives a very rapid, simple, sensitive, wide dynamic range and low-cost procedure for the determination of FLX.

Desarrollo tecnológico de succinilcolina infantil 100 mg, inyectable en solución / Technological development of 100 mg infant succinylcoline, injectable in a solution

Objetivo: desarrollar una nueva formulación inyectable en solución acuosa de succinilcolina, para uso pediátrico. Métodos: se utiliza la materia prima cloruro de succinilcolina con demostrada calidad para el diseño de la formulación. Fueron ensayadas tres variantes de formulación, durante seis meses, a una temperatura de 25±2 oC y una humedad relativa de 60±5 por ciento, se analiza la influencia de los componentes y el envase sobre el contenido del fármaco. Resultados: la formulación envasada en bulbos 6R, sin agentes preservantes, se selecciona como la mejor variante. Los tres lotes a escala de laboratorio cumplieron con los parámetros de calidad establecidos y se realizó el escalado piloto. Conclusiones: se comprobó la factibilidad del desarrollo del inyectable en solución de succinilcolina infantil 100mg(AU)

Objective: to develop a new injectable formulation in aqueos solution of succinylcoline for pediatric uses. Methods: the raw material for the formulation was succinylcoline chloride with proven quality for this design. Three variants of formulation were tested for six months at a temperature of 25±2 oC and relative humidity of 60±5 percent. The influence of the components and of the packing on the contents of the drug was analyzed. Results: the formulation packed in flasks 6R with no preserving agent was chosen as the best. Three batches at lab scale met the set quality parameters and also a pilot scale-up was performed. Conclusions: the feasibility of the development of an injectable product in 100mg infant succinylcoline solution(AU)