RESUMO
A simple, stability-indicating, chromatographic method of quantifying spironolactone (SPI) and its metabolite, canrenone (CAN), in the presence of excipients typical in dermatological formulations and skin matrices in studies of passive and iontophoretic permeation was proposed and validated here. SPI and CAN were separated using a reversed-phase column with a mobile phase of methanol-water (60:40, v/v) at a flow rate of 1.0 mL/min. Data were collected with a UV detector at 238 and 280 nm, with retention times of 6.2 and 7.9 min for SPI and CAN, respectively. The method was precise, accurate and linear (r2 > 0.99) in a concentration range of 1-30 µg/mL, and recovery rates of SPI and CAN from the different skin layers exceeded 85%. The method was not only sensitive (LOD of 0.05 and 0.375 µg/mL and LOQ of 0.157 and 1.139 µg/mL for SPI and CAN, respectively) but also selective against skin matrices and highly representative components of topical formulations. The method moreover demonstrated SPI's degradation in iontophoresis by applying Pt-AgCl electrodes and its continued drug stability using Ag-AgCl electrodes. Altogether, the method proved valuable for quantifying SPI and CAN and may be applied in developing and controlling the quality of dermatological products.
Assuntos
Canrenona/análise , Fármacos Dermatológicos/análise , Iontoforese/métodos , Pele/química , Espironolactona/análise , Animais , Canrenona/química , Canrenona/farmacocinética , Fármacos Dermatológicos/química , Fármacos Dermatológicos/farmacocinética , Estabilidade de Medicamentos , Excipientes , Limite de Detecção , Modelos Lineares , Nanopartículas , Reprodutibilidade dos Testes , Pele/metabolismo , Absorção Cutânea , Espironolactona/química , Espironolactona/farmacocinética , SuínosRESUMO
Spironolactone (SPR) is a poorly water-soluble drug widely used for the treatment of various diseases. The objective of this study was to carry out the preparation and solid-state characterization of SPR 1/3 hydrate. The solid form was generated by an unreported recrystallization process in acetone and characterized for the first time by a combination of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), equilibrium solubility, and an accelerated stability study. XRD, DSC, and TGA studies revealed that SPR 1/3 hydrated converts completely to form II after heating to 180°C. Solubility studies at 37°C showed that SPR 1/3 hydrate was statistically less soluble than SPR form II in all tested media and that SPR form II partially converts to SPR 1/3 hydrate in aqueous media. Accelerated stability studies demonstrated that both forms were physically and chemically stable up to 6 months (40°C/75% RH). We concluded that contamination of SPR 1/3 hydrate in SPR raw materials is undesirable. Taking this into account we recommend its polymorphic monitoring either in active pharmaceutical ingredients or commercial tablets by solid-state identification/quantification methods (XRD, DSC, TGA, and FTIR). Of these, XRD proved to be the most conclusive and accurate.
Assuntos
Espironolactona/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Pós/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Comprimidos/química , Água/química , Difração de Raios X/métodosRESUMO
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.
Assuntos
Baclofeno/química , Carvedilol/química , Hidroclorotiazida/química , Mercaptopurina/química , Metadona/química , Oseltamivir/química , Veículos Farmacêuticos/química , Fenobarbital/química , Propranolol/química , Sotalol/química , Espironolactona/química , Amido/química , Tacrolimo/química , Ácido Ursodesoxicólico/química , Vancomicina/química , Administração Oral , Baclofeno/administração & dosagem , Carvedilol/administração & dosagem , Composição de Medicamentos , Estabilidade de Medicamentos , Hidroclorotiazida/administração & dosagem , Concentração de Íons de Hidrogênio , Mercaptopurina/administração & dosagem , Metadona/administração & dosagem , Oseltamivir/administração & dosagem , Soluções Farmacêuticas , Fenobarbital/administração & dosagem , Propranolol/administração & dosagem , Pirazinamida/administração & dosagem , Sotalol/administração & dosagem , Espironolactona/administração & dosagem , Suspensões , Tacrolimo/administração & dosagem , Temperatura , Fatores de Tempo , Ácido Ursodesoxicólico/administração & dosagem , Vancomicina/administração & dosagemRESUMO
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.
Assuntos
Anti-Hipertensivos/administração & dosagem , Furosemida/administração & dosagem , Hidroclorotiazida/administração & dosagem , Espironolactona/administração & dosagem , Anti-Hipertensivos/química , Brasil , Criança , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Contaminação de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Furosemida/química , Hospitais Universitários , Humanos , Hidroclorotiazida/química , Tamanho da Partícula , Pediatria , Espironolactona/química , Suspensões , Temperatura , TempoRESUMO
Spironolactone is a drug derived from sterols that exhibits an incomplete oral absorption due to its low water solubility and slow dissolution rate. In this study, formulations of spironolactone with four disintegrants named as croscarmellose sodium, crospovidone, sodium starch glycolate and microcrystalline cellulose II (MCCII) were conducted. The effect of those disintegrants on the tensile strength, disintegration time and dissolution rate of spironolactone-based compacts was evaluated using a factorial design with three categorical factors (filler, lubricant, and disintegrant). The swelling values, water uptake and water sorption studies of these disintegrants all suggested that MCCII compacts disintegrate by a wicking mechanism similar to that of crospovidone, whereas a swelling mechanism was dominant for sodium starch glycolate and croscarmellose sodium. The disintegration time of MCCII and sodium starch glycolate remained unchanged with magnesium stearate. However, this lubricant delayed the disintegration time of crospovidone and croscarmellose sodium. MCCII presented the fastest disintegration time independent of the medium and lubricant employed. The water sorption ratio and swelling values determined sodium starch glycolate followed by croscarmellose sodium as the largest swelling materials, whereas crospovidone and MCCII where the least swelling disintegrants. The swelling property of sodium starch glycolate and croscarmellose sodium was strongly affected by the medium pH. The disintegration time of spironolactone compacts was faster when starch was used as a filler due to the formation of soft compacts. In this case, the type of filler employed rather than the disintegrant had a major effect on the disintegration and dissolution times of spironolactone.
Assuntos
Carboximetilcelulose Sódica/química , Celulose/química , Povidona/química , Espironolactona/química , Amido/análogos & derivados , Absorção , Química Farmacêutica/métodos , Excipientes/química , Solubilidade , Amido/química , Resistência à Tração , Água/químicaAssuntos
Humanos , Antagonistas de Androgênios/classificação , Antagonistas de Androgênios/farmacologia , Acetato de Ciproterona/química , Acetato de Ciproterona/farmacologia , Finasterida/química , Finasterida/farmacologia , Flutamida/química , Flutamida/farmacologia , Espironolactona/química , Espironolactona/farmacologiaRESUMO
Type I corticosteroid receptors were determined in cytosol from hippocampus (HIPPO) and amygdala (AMYG), using [3H]aldosterone (ALDO), [3H]dexamethasone (DEX) or the mineralocorticoid antagonist [3H]ZK 91587 as ligands. Incubations with the first two compounds also contained the pure glucocorticoid RU 28362 to block type II receptors. Binding of the three ligands was comparable in cytosol from HIPPO and it was slightly higher for [3H]DEX in AMYG. However, after heat-induced receptor transformation, binding to DNA-cellulose was observed for [3H]ALDO-receptor complex obtained from HIPPO or AMYG, whereas it was negligible for [3H]ZK 91587. Receptors charged with [3H]DEX or [3H]ALDO showed similar retention on DNA-cellulose columns in the case of the AMYG, while binding to the polynucleotide was higher for [3H]ALDO in the HIPPO. Finally, only [3H]ALDO was taken up to a significant extent in purified cell nuclei prepared from slices of HIPPO and AMYG previously incubated with the three ligands. It is concluded that binding of a natural agonist steroid may be a prerequisite for type I receptor transformation and translocation from the cytoplasm into the nuclear fraction. DEX binding to type I receptors resembles a partial agonist with antagonist properties, whereas antagonists such as ZK 91587 are bound and retained in cytoplasm, without further translocation.