Cocrystals Enhance Biopharmaceutical and Antimicrobial Properties of Norfloxacin.

A solvate cocrystal of the antimicrobial norfloxacin (NFX) was formed by using isonicotinamide (INA) as a coformer with the solvent evaporation technique. The cocrystal formation was confirmed by performing solid-state characterization techniques. We evaluated the dissolution under supersaturated conditions and also the solubility at the vertex of triphasic domain of cocrystal and NFX in both water and Fasted-State Simulated Intestinal Fluid (FaSSIF). The antimicrobial activity was evaluated using the microdilution technique. The cocrystal showed 1.8 times higher dissolution than NFX in water at 60 min and 1.3 times higher in FaSSIF at 180 min in the kinetic study. The cocrystal also had an increase in solubility of 8.38 times in water and 6.41 times in FaSSIF. The biopharmaceutical properties of NFX with cocrystallization improved antimicrobial action, as shown in the results of minimum inhibitory concentration (MIC) and inhibitory concentrations of 50% (IC50%) and 90% (IC90%). This paper presents, for the first time, a more in-depth analysis of the cocrystal of NFX-INA concerning its dissolution, solubility, and antimicrobial activity. In all these criteria, the cocrystal obtained better results compared to the pure drug.

Briquettes of acai seeds: characterization of the biomass and influence of the parameters of production temperature and pressure in the physical-mechanical and energy quality.

Agro-industries, leveraged by the high demand of acai products, promote environmental impact through the generation of wastes in several locals in Amazon. The use with bioenergetic purposes has capacity to mitigate these scenario. Thus, the aim of the study was to characterize the biomass of acai seeds and establish the technical parameters of temperature and pressure of work to the production of briquettes of physical, mechanical and thermal quality. Temperatures of 120, 140 and 160 °C; and pressures of 15, 20 and 25 MPa were studied. We analyzed the briquettes mechanical compressive strength, rate of water absorption, rate of volumetric expansion and energy and apparent density. To the characterization of in natura seeds, the proximate analysis, chemical composition (extractives, holocellulose and lignin contents), higher, lower and useful heating value were determined. The proximate analysis indicated biomass thermal resistance, potential to direct burning and conversion by thermochemical processes. The lignin content may increase briquettes compressive strength produced in high temperatures. It was observed that the temperature had more influence in the evaluated briquettes characteristics than the pressure. The compressive strength was greater in 160 °C and 15 MPa briquettes, indicating that the lignin works as binder in this temperature, however, with pressure improvement the resistance is not favored due to the limit of resistance to compaction. The rate of water absorption decreased with the pressure increase and the temperature statistically affected in 140 °C briquettes. We observed volumetric expansion values in consonance to other found in dense biofuels of the literature. Further, the apparent density and energy density were favored by pressure improvement and the temperature helped in the increase of the apparent density. Moreover, the produced briquettes presented gain in the apparent density regarding the in natura biomass and had energy density comparable to coal and adequate to co-firing in boilers.

Comparator product issues for biowaiver implementation: the case of Fluconazole

The aim of this work was to assess if the commercially available Fluconazole drug products (Reference, Generic and Similar) would meet the biowaiver criteria from Food and Drug Administration (FDA) and Brazilian Agency for Health Surveillance (ANVISA) agencies. All formulations were evaluated considering the dissolution profile carried out in Simulated Gastric Fluid (SGF) pH 1.2, Acetate Buffer (AB) pH 4.5 and Simulated Intestinal Fluid (SIF) pH 6.8. The results demonstrated that all formulations fulfilled the 85% of drug dissolved at 30 min criterion in SGF pH 1.2. However, in AB pH 4.5 and SIF pH 6.8, some formulations, including the comparator, did not achieve this dissolution percentage. The discrepant dissolution profiles also failed the ƒ2 similarity factor analysis, since none of the formulations showed values between 50 and 100 in the three dissolution media. Comparative dissolution profiles were not similar, considering that the main issues concerning the dissolution were evidenced for the comparator product. Hence, a revision in the regulatory norms in order to establish criteria to switch the comparator could result in an increased application of drugs based on biowaiver criteria

Obtaining Cocrystals by Reaction Crystallization Method: Pharmaceutical Applications.

Cocrystals have gained attention in the pharmaceutical industry due to their ability to improve solubility, stability, in vitro dissolution rate, and bioavailability of poorly soluble drugs. Conceptually, cocrystals are multicomponent solids that contain two or more neutral molecules in stoichiometric amounts within the same crystal lattice. There are several techniques for obtaining cocrystals described in the literature; however, the focus of this article is the Reaction Crystallization Method (RCM). This method is based on the generation of a supersaturated solution with respect to the cocrystal, while this same solution is saturated or unsaturated with respect to the components of the cocrystal individually. The advantages of the RCM compared with other cocrystallization techniques include the ability to form cocrystals without crystallization of individual components, applicability to the development of in situ techniques for the screening of high quality cocrystals, possibility of large-scale production, and lower cost in both time and materials. An increasing number of scientific studies have demonstrated the use of RCM to synthesize cocrystals, mainly for drugs belonging to class II of the Biopharmaceutics Classification System. The promising results obtained by RCM have demonstrated the applicability of the method for obtaining pharmaceutical cocrystals that improve the biopharmaceutical characteristics of drugs.

In Vitro Dissolution Profile of Dapagliflozin: Development, Method Validation, and Analysis of Commercial Tablets.

Dapagliflozin was the first of its class (inhibitors of sodium-glucose cotransporter) to be approved in Europe, USA, and Brazil. As the drug was recently approved, there is the need for research on analytical methods, including dissolution studies for the quality evaluation and assurance of tablets. The dissolution methodology was developed with apparatus II (paddle) in 900 mL of medium (simulated gastric fluid, pH 1.2), temperature set at 37 ± 0.5°C, and stirring speed of 50 rpm. For the quantification, a spectrophotometric (λ = 224 nm) method was developed and validated. In validation studies, the method proved to be specific and linear in the range from 0.5 to 15 µg·mL-1 (r2 = 0.998). The precision showed results with RSD values lower than 2%. The recovery of 80.72, 98.47, and 119.41% proved the accuracy of the method. Through a systematic approach by applying Factorial 23, the robustness of the method was confirmed (p > 0.05). The studies of commercial tablets containing 5 or 10 mg demonstrated that they could be considered similar through f1, f2, and dissolution efficiency analyses. Also, the developed method can be used for the quality evaluation of dapagliflozin tablets and can be considered as a scientific basis for future official pharmacopoeial methods.

Inclusion complexes of hydrochlorothiazide and ß-cyclodextrin: Physicochemical characteristics, in vitro and in vivo studies.

Hydrochlorothiazide is a thiazide diuretic widely used in clinics to treat arterial hypertension. It is a class IV drug according to the Biopharmaceutical Classification System, that is, it presents low solubility and low permeability and, consequently, low absorption in the gastrointestinal tract. As a strategy to improve stability and biopharmaceutical properties of hydrochlorothiazide, the use of cyclodextrins to produce inclusion complexes, applying different methods, was investigated. In the phase solubility studies, ß-cyclodextrin was identified as the cyclodextrin which provided the most promising results in terms of the solubilization of the drug. The thermal analysis verified the interaction between hydrochlorothiazide and ß-cyclodextrin, indicating the formation of inclusion complexes, and the thermal stability varied according to the preparation technique. The physicochemical characterization showed that in the inclusion complexes obtained by co-evaporation, kneading followed by freeze-drying and kneading followed by spray-drying the hydrochlorothiazide complexation mostly occurred with different degrees of amorphization and the drug solubility was improved. These three inclusion complexes presented better in vitro characteristics and the inclusion complex obtained by kneading followed by freeze-drying increased the in vivo diuretic activity of the drug accompanied by significant effects on natriuresis, kaliuresis and chloriuresis. The inclusion complex formation was effective in improving the biopharmaceutical properties of hydrochlorothiazide and protecting the drug from hydrolysis. This paper describes an important alternative approach to the development of liquid pharmaceutical formulations to pediatric administration, a real need of the current pharmaceutical market.

Quantitative Analysis of Norfloxacin in ß-Cyclodextrin Inclusion Complexes--Development and Validation of a Stability-indicating HPLC Method.

The aim of this study was to develop and validate a simple liquid-chromatography method, with good accuracy, reproducibility and sensitivity, for the quantification of norfloxacin in ß-cyclodextrin inclusion complexes. In the method validation, the parameters evaluated were linearity, limits of detection and quantification, specificity, accuracy, precision and robustness. The stability-indication property of the method was evaluated through studies on the degradation under stress conditions. A method employing a simple mobile phase consisting of phosphate buffer (pH 3.0) and acetonitrile (86:14 v/v) was developed. Fluorescence detection was employed to minimize the influence of degradation products, due to its high sensitivity, selectivity and specificity. The method was specific, linear in the concentration range of 1 - 30 µg/mL, robust, precise and accurate. The proposed method was successfully applied in the determination of norfloxacin in inclusion complexes, thus aiding quality-control analysis in the future development of drug delivery systems.

Investigation of ß-cyclodextrin-norfloxacin inclusion complexes. Part 1. Preparation, physicochemical and microbiological characterization.

INTRODUCTION: Drugs classified as class IV by the Biopharmaceutical Classification System present significant problems in relation to effective oral administration. In the case of antibiotics, the subsequently high doses required can enhance the emergence of microorganism resistance and lead to a low rate of patient treatment adherence. OBJECTIVE: In an attempt to improve physicochemical properties and microbiological activity of norfloxacin, the aim of this study was to investigate different methods (coevaporation, kneading followed by freeze-drying or spray-drying) to obtain complexes of norfloxacin and different cyclodextrins. METHODS: Guest-host interactions were investigated through a complete physical-chemical characterization and the dissolution profile and microbiological activity were determined. RESULTS: The formation of a complex of norfloxacin and ß-cyclodextrin (1:1), obtained by kneading followed by freeze drying, led to increased drug solubility, which could maximize the oral drug absorption. CONCLUSION: Moreover, the microbiological activity was enhanced by around 23.3%, demonstrating that the complex formed could represent an efficient drug delivery system.

Investigation of ß-cyclodextrin-norfloxacin inclusion complexes. Part 2. Inclusion mode and stability studies.

INTRODUCTION: Norfloxacin (NFX) is a broad spectrum antibiotic with low solubility and permeability, which is unstable on exposure to light and humidity. OBJECTIVE: In this study, the mode of NFX inclusion into ß-cyclodextrin complexes was evaluated and a complete physical, chemical and microbiological stability study of the inclusion complexes was carried out. METHODS: Potentiometric titrations were performed to evaluate changes in the pKa of the NFX molecule due to the formation of an inclusion complex and NMR analysis demonstrated that the NFX molecule is included in the ß-cyclodextrin cavity. RESULTS: Inclusion complexes obtained by kneading followed by freeze-drying showed improved NFX stability compared with the isolated drug or the physical mixture. This method was effective in terms of protecting the drug from photodegradation and also avoiding hydrolysis. Differences between NFX and the complexes could be evidenced by thermal analysis, infrared spectroscopy and x-ray powder diffraction as well as by determining the solubility and drug content. The antimicrobial potency was also preserved on applying the promising method of kneading. CONCLUSION: The satisfactory stability indicates that the NFX/ß-cyclodextrin complexes could be useful as an alternative to the existing NFX drug formulation.

Formulation development and stability studies of norfloxacin extended-release matrix tablets.

The aim of this research was to develop a new hydrophilic matrix system containing norfloxacin (NFX). Extended-release tablets are usually intended for once-a-day administration with benefits to the patient and lower discontinuation of the therapy. Formulations were developed with hydroxypropylmethylcellulose or poly(ethylene oxide) as hydrophilic polymers, with different molecular weights (MWs) and concentrations (20 and 30%). The tablets were found to be stable (6 months at 40 ± 2°C and 75 ± 5% relative humidity), and the film-coating process is recommended to avoid NFX photodegradation. The dissolution profiles demonstrated an extended-release of NFX for all developed formulations. Dissolution curves analyzed using the Korsmeyer exponential equation showed that drug release was controlled by both drug diffusion and polymer relaxation or erosion mechanisms. A more erosion controlled system was obtained for the formulations containing lower MW and amount of polymer. With the increase in both MW and amount of polymer in the formulation, the gel layer became stronger, and the dissolution was more drug-diffusion dependent. Formulations containing intermediate MW polymers or high concentration (30%) of low MW polymers demonstrated a combination of extended and complete in vitro drug release. This way, these formulations could provide an increased bioavailability in vivo.

Physicochemical and microbiological stability studies of extemporaneous antihypertensive pediatric suspensions for hospital use.

Extemporaneous suspensions of the antihypertensive agents furosemide, spironolactone and hydrochlorothiazide for pediatric use have been prepared at University Hospital (Federal University of Santa Catarina - Brazil). The aim of this work was to investigate the physicochemical and microbiological stability of these suspensions over the estimated shelf-life period of seven days and, if necessary, to optimize the formulations by improving the chemical stability. The pediatric suspensions were prepared using drug raw material and were stored at 25 ± 2°C and 5 ± 3°C. Chemical stability was evaluated by HPLC assay of the suspensions for drug content. Physical stability was evaluated by sedimentation volume, redispersibility, particle size, and zeta potential. Viable bacterial and fungal contaminations were assessed according to the official compendium. Furosemide and spironolactone suspensions as prepared herein can be stored for 7 days. However, the hydrochlorothiazide suspension formulation at pH 6.5 demonstrated poor chemical stability and was optimized by adjusting the pH to 3.3 where the drug exhibited acceptable stability. The optimized formulation demonstrated to be stable over the required period of 7 days.

Assembled modules technology for site-specific prolonged delivery of norfloxacin.

The aim of this research was to design and study norfloxacin (NFX) release in floating conditions from compressed hydrophilic matrices of hydroxypropylmethylcellulose (HPMC) or poly(ethylene oxide) (PEO). Module assembling technology for drug delivery system manufacturing was used. Two differently cylindrical base curved matrix/modules, identified as female and male, were assembled in void configuration by friction interlocking their concave bases obtaining a floating release system. Drug release and floatation behavior of this assembly was investigated. Due to the higher surface area exposed to the release medium, faster release was observed for individual modules compared to their assembled configuration, independently on the polymer used and concentration. The release curves analyzed using the Korsmeyer exponential equation and Peppas & Sahlin binomial equation showed that the drug release was controlled both by drug diffusion and polymer relaxation or erosion mechanisms. However, convective transport was predominant with PEO and at low content of polymers. NFX release from PEO polymeric matrix was more erosion dependent than HPMC. The assembled systems were able to float in vitro for up to 240min, indicating that this drug delivery system of norfloxacin could provide gastro-retentive site-specific release for increasing norfloxacin bioavailability.

A high-throughput liquid chromatography tandem mass spectrometry method for the comparative determination of fluticasone propionate by reversed-phase liquid chromatography and capillary electrophoresis methods in pharmaceutical nasal sprays.

A simple, specific, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the analysis of fluticasone propionate (FP) in pharmaceutical formulations was developed and validated using deflazacort as internal standard (IS). The LC-MS/MS method was carried out on a C8 column (50 mm) with a mobile phase consisted of methanol : water (95 : 5, v/v) 100 mM formic acid-50 mM ammonium acetate (90 : 5 : 5, v/v/v). The mass spectrometry method was performed employing positive atmospheric pressure chemical ionization technique, operating in multiple reaction monitoring mode. The chromatographic separation was obtained within 1.5 min and it was linear in the concentration range of 10-1000 ng mL(-1). Moreover, method validation demonstrates acceptable results for the specificity, accuracy, precision and robustness. The proposed method was successfully applied for the quantitative analysis of FP nasal sprays and the results were compared to validated liquid chromatography and capillary electrophoresis methods with photodiode array detectors showing non-significant difference (P > 0.05).

Simultaneous liquid chromatographic determination of ezetimibe and simvastatin in pharmaceutical products.

A reversed-phase liquid chromatographic (LC) method was developed and validated for the simultaneous determination of ezetimibe and simvastatin in pharmaceutical dosage forms. The LC method was carried out on a Synergi fusion C18 column (150 mm x 4.6 mm id) maintained at 45 degrees C. The mobile phase consisted of phosphate buffer 0.03 M, pH 4.5-acetonitrile (35 + 65, v/v) run at a flow rate of 0.6 mL/min, and detection was made using a photodiode array detector at 234 nm. The chromatographic separation was obtained within 15.0 min, and calibration graphs were linear in the concentration range of 0.5-200 microg/mL. Validation parameters such as specificity, linearity, precision, accuracy, and robustness were evaluated, giving results within the acceptable range for both compounds. Moreover, the proposed method was successfully applied for the routine quality control analysis of pharmaceutical products.

Validation of the anti-factor Xa assay for the potency assessment of enoxaparin in pharmaceutical formulations.

Enoxaparin is a low-molecular weight heparin used clinically for the prevention and treatment of venous and arterial thrombosis. An anti-factor Xa assay was used to evaluate the potency of the final drug preparation. Method validation investigated parameters such as the range, linearity (r2 = 0.9971), precision, accuracy, and robustness; the biological assay incorporated a chromogenic endpoint and detection at 405 nm. The method yielded good results with a quantitation limit of 0.037 IU/mL and a detection limit of 0.011 IU/mL. The results demonstrated the validity of the anti-factor Xa assay for the determination of enoxaparin.