A novel solid formulation of a rivaroxaban eutectic using a hot melt extruder with improved thermal stability and dissolution profile†

Parth S. Shaligram, Ranjitsinh Pawar, Nagabhushan Shet and Rajesh G. Gonnade
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Abstract

The current work aims to enhance the solubility, dissolution rate and stability of the poorly water-soluble drug rivaroxaban (RXB) by preparing an amorphous solid dispersion (ASD) of its eutectic with mandelic acid (MA) as an acidic coformer. Eutectics generally have lower melting points compared to their constituents. Hence, they can be used to lower the processing temperature of the drug to prevent its thermal degradation under a hot melt extruder (HME). Six eutectics of RXB were prepared with various carboxylic acid coformers. The eutectic of RXB and MA (1 : 4, mol/mol), which had the lowest melting point, was selected for the HME process. A hydrophilic polymeric matrix was used to prepare the ASD of the selected eutectic. The resultant extruded filament was further subjected to solubility and dissolution studies. We could load up to 25% RXB–MA eutectic in the polymer matrix to yield a complete ASD of RXB–MA at a lower processing temperature of 110 °C. The ASD of the RXB–MA eutectic showed three times the drug release compared to pure RXB. The RXB–MA (1 : 4) eutectic lowered the HME process temperature, further enhancing the thermal stability, solubility and dissolution rate of RXB. The solubility and dissolution rate enhancement might favourably impact the drug's bioavailability.

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一种新型的利伐沙班共晶固体配方,采用热熔挤出机,具有更好的热稳定性和溶解谱†
本研究旨在通过制备一种非晶固体分散体(ASD)来提高难溶性药物利伐沙班(RXB)的溶解度、溶出速率和稳定性。与它们的组分相比,共晶通常具有较低的熔点。因此,它们可用于降低药物的加工温度,以防止其在热熔挤出机(HME)下的热降解。用不同的羧酸共构象制备了6种RXB共晶。选择熔点最低的RXB和MA共晶(1:4,mol/mol)进行HME工艺。采用亲水性聚合物基质制备了所选共晶的ASD。所得到的挤压长丝进一步进行了溶解度和溶解性研究。我们可以在聚合物基体中加载高达25%的RXB-MA共晶,在较低的110°C加工温度下产生完整的RXB-MA ASD。RXB - ma共晶的ASD释放量是纯RXB的3倍。RXB - ma(1:4)共晶降低了HME工艺温度,进一步提高了RXB的热稳定性、溶解度和溶解速率。溶解度和溶出率的提高可能有利于药物的生物利用度。
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