BackgroundOral liquid solutions of the diuretic active ingredient furosemide (FUR) marketed across Europe do not comply with recent requirements for paediatric preparation owing to their ethanol content and, moreover, in some countries only tablet or injection dosage forms of furosemide are available.ObjectivesTo formulate extemporaneous paediatric ethanol-free solutions of FUR (2 mg/mL) with suitable solubility in the aqueous vehicle and an acceptable taste and to evaluate their stability under two different storage conditions during a 9-month study period.MethodsOur work presents two developed formulations of FUR ethanol-free paediatric oral solutions 2 mg/mL for easy extemporaneous compounding in a pharmacy. FUR solubility avoiding the use of ethanol was achieved using sodium hydroxide (formulation F1) or disodium hydrogen phosphate dodecahydrate (formulation F2). The preparations were stored at 25°C±3°C or at 40°C±0.5°C and protected from light. For FUR and preservative, methylparaben (MP), a stability assay was conducted by a high-performance liquid chromatography validated method and determination of pH stability.ResultsThe remaining FUR concentration was >90% of the initial concentration after 270 days in both formulations at both storage conditions, 25°C and 40°C. The concentration of MP decreased significantly in the formulation F2 stored at 40°C.ConclusionsBoth formulations were stable when stored at room temperature for up to 9 months; formulation F1 was stable even at 40°C. MP used as an antimicrobial agent fully satisfied the recommended criteria for preservative efficacy in oral preparations according to the European Pharmacopoeia 9.0 (5.1.3).
The application of eye drops from flexible dropper bottles fitted with different types of dropper tips is associated with the high variability of eye drop weights. The aim of this report was to investigate the simultaneous effect of three factors influencing the mean weight of drops dispensing from two plastic dropper tips. Using a designed experiment (Box-Behnken), the effect of the concentration of benzalkonium chloride solutions (BAC) in the range of 0-0.02%, the dispensing angle from 90 degrees to 30 degrees from horizontal, and the residual volume of liquid in the dropper bottle from 4 to 10 mL on the mean drop weights were examined. The significant effect of the increase in BAC concentration resulted in a linear decrease in drop weights for both of the dropper tips investigated. The significant effect of the dispensing angle was influenced by the dropper tip design. For the dropper tip A, the effect of the dropper tip tilt was described by the quadratic equation with a minimum, which corresponded to the dispensing angle equal to that of 48 degrees from horizontal. Below this angle, the increase in drop weights occurred due to the drop formation from the wetted external surface of the tip orifice. The linear decrease in drop weights in response to the decrease in dispensing angle was detected for the dropper tip B. The regression equations and the contour line plots obtained allowed the drop weights to be estimated for the actual combinations of both the BAC concentration and the dispensing angle. The effect of the residual volume was found to be non-significant. Based on the formula of Tate's law, the direct proportion between surface tension of a solution and the radius of the effective perimeter of a dropper tip can be used to estimate the theoretical maximal weight of drops at the dispensing angle of 90 degrees . Using the stalagmometric values of surface tension of the BAC solutions, the maximal drop weights were estimated for both of the dropper tips investigated. A comparison between the theoretical and the experimentally measured drop weights enabled the dropper tips behavior to be discussed by using Harkins and Brown correction factor F. The F-value of 0.74 noted for the dropper tip A differed from that of stalagmometer F-value (0.61) indicating a deviation from the simple drop formation process in answer to more complicated design of the dropper tip A. On the other hand, the F-value of 0.6 observed for the dropper tip B demonstrated the better consistency with stalagmometry. As a result, the dropper tip B with the linear decrease of drop weights in response to the increased concentration of BAC and the decreased dispensing angle without the adverse external drop formation could be recommended in real drop dispensing.
The utilization of co-processed excipients (CPEs) represents a novel approach to the preparation of orally disintegrating tablets by direct compression. Flow, consolidation, and compression properties of four lactose-based CPEs—Cellactose® 80, CombiLac®, MicroceLac® 100, and StarLac®—were investigated using different methods, including granulometry, powder rheometry, and tablet compaction under three pressures. Due to the similar composition and the same preparation technique (spray drying), the properties of CPEs and their compacts were generally comparable. The most pronounced differences were observed in flowability, undissolved fraction after 3 min and 24 h, energy of plastic deformation (E2), ejection force, consolidation behavior, and compact friability. Cellactose® 80 exhibited the most pronounced consolidation behavior, the lowest values of ejection force, and high friability of compacts. CombiLac® showed excellent flow properties but insufficient friability, except for compacts prepared at the highest compression pressure (182 MPa). MicroceLac® 100 displayed the poorest flow properties, lower ejection forces, and the best mechanical resistance of compacts. StarLac® showed excellent flow properties, the lowest amounts of undissolved fraction, the highest ejection force values, and the worst compact mechanical resistance. The obtained results revealed that higher compression pressures need to be used or further excipients have to be added to all tested materials in order to improve the friability and tensile strength of formed tablets, except for MicroceLac® 100.
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