Development of paediatric dosage forms of furosemide using the problem structuring method of morphological analysis
The lack of age-appropriate (paediatric) authorised medicines is a long-standing problem amongst regulatory authorities, patients, parents and prescribers. This is driven by the paucity of information on clinical efficacy, deficiency in safety data (i.e. biopharmaceutics) and the lack of quality information such as palatability and acceptability data in children. To counteract this deficiency bespoke, unlicensed formulations are formulated by contract manufacturers, hospitals and dispensing pharmacists using a variety of ‘recipes’ and differing manufacturing protocols. In this work, Morphological Analysis as a problem structuring method is deployed using key stakeholders of the problem complex. This method, developed from operational research and design thinking sectors, has the ability to structure and parameterise a complex problem to isolate a smaller subset of an internally consistent solution space for the design of experiments. Hence, Morphological Analysis is used experimentally to decide which pharmaceutical dosage forms of furosemide would be selected as a solution space for paediatric patients with low cardiac output syndrome. Morphological Analysis application resulted in the selection of two different dosage forms for further work (Microemulsion oral liquid dosage form and an Orodispersible Mini-tablet). The furosemide microemulsion formulation was developed using ternary phase diagrams to isolate the efficient self-emulsification regions. A range of experimental techniques and instruments were used to characterise the system such as HPLC, phase stability studies, droplet size determination, surface tension measurement, drug-excipient compatibility studies using FTIR and NMR, viscosity determination, thermodynamic stability assessment and determination of shelf-life via accelerated and long-term stability studies. The optimum composition of the furosemide microemulsion consisted of: MCT Oil 14%, Labrasol 60%-Transcutol-HP 20% (3:1) and Water 6%. A furosemide oro-dispersible mini-tablet formulation (ODMT) was also developed and analysed for quality assessment. The development approach for ODMT used factorial design at two levels with four factors. Pre-formulation studies included drug-excipient compatibility assessment using differential scanning calorimetry and powder flowability evaluation using angle of repose and Hausner’s ratio techniques. For that, sixteen batches of ODMTs were manufactured using a Manesty F3 tablet press; Post-compression testing and characterisation processes were performed and this involved testing for weight variation, hardness assessment, friability, in vitro disintegration, wetting time, drug content analysis, dissolution time and stability of ODMTs under ICH conditions. The optimum composition of furosemide ODMT was found to be (ludiflash excipient + 0.6% magnesium stearate lubricant + 1mg/tablet furosemide API) with 10 minutes mixing time at value 19 compression force.
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