Hot-Melt Extrusion as an Advantageous Technology to Obtain Effervescent Drug Products.

Ana Luiza Lima,Juliano A Chaker,Ludmila A G Pinho,Marcilio Cunha-Filho,Livia L Sa-Barreto,Ricardo Neves Marreto,Guilherme M Gelfuso,Tais Gratieri

doi:10.3390/pharmaceutics12080779

Ana Luiza Lima, Juliano A Chaker + Show 6 more

Open Access

https://doi.org/10.3390/pharmaceutics12080779

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Abstract

Here, we assessed the feasibility of hot-melt extrusion (HME) to obtain effervescent drug products for the first time. For this, a combined mixture design was employed using paracetamol as a model drug. Extrudates were obtained under reduced torque (up to 0.3 Nm) at 100 °C to preserve the stability of the effervescent salts. Formulations showed vigorous and rapid effervescent disintegration (<3 min), adequate flow characteristics, and complete solubilization of paracetamol instantly after the effervescent reaction. Formulations containing PVPVA in the concentration range of 15–20% m/m were demonstrated to be sensitive to accelerated aging conditions, undergoing marked microstructural changes, since the capture of water led to the agglomeration and loss of their functional characteristics. HPMC matrices, in contrast, proved to be resistant to storage conditions in high relative humidity, showing superior performance to controls, including the commercial product. Moreover, the combined mixture design allowed us to identify significant interactions between the polymeric materials and the disintegrating agents, showing the formulation regions in which the responses are kept within the required levels. In conclusion, this study demonstrates that HME can bring important benefits to the elaboration of effervescent drug products, simplifying the production process and obtaining formulations with improved characteristics, such as faster disintegration, higher drug solubilization, and better stability.

Highlights

Effervescent drug products frequently contain an organic acid source and a hydrogen carbonate salt in their composition, which, in an aqueous medium, react vigorously releasing gas [1,2]
Several hydrophilic thermoplastic polymers commonly used in hot-melt extrusion (HME) combined with effervescent components were tested in the usual extrusion conditions of each material
TEC was selected for being a versatile plasticizer agent for several HME polymers [34]

Summary

Introduction

Effervescent drug products frequently contain an organic acid source and a hydrogen carbonate salt in their composition, which, in an aqueous medium, react vigorously releasing gas [1,2]. These preparations are hybrids between a solid dosage form, for manufacture and commercialization purposes, and a liquid dosage form, for administration. The traditional approach of effervescence is still one of the most efficient and elegant alternatives to facilitate the intake of high drug doses, increase drug release and absorption, and improve taste-masking [1,3,4]. The high hygroscopicity of the effervescent components can cause a rapid moisture intake, leading to hydrolysis processes that compromise drug stability. Strict control of the production area is mandatory, including manufacturing conditions of low temperatures and relative humidity, together with the use of hermetic packaging [8]

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