Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

Stavroula Nanaki,Evangelos Karavas,Margaritis Kostoglou,Panagiotis Barmpalexis,Dimitrios Bikiaris,Rodanthi Maria Eleftheriou

doi:10.3390/sci1020048

Stavroula Nanaki, Evangelos Karavas + Show 4 more

Open Access

https://doi.org/10.3390/sci1020048

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Journal: Sci	Publication Date: Aug 15, 2019
Citations: 13	License type: CC BY 4.0

Affiliation: Pharmathen (Greece), Aristotle University of Thessaloniki

Abstract

In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus® (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 °C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism.

Highlights

Aprepitant (APT), with a chemical name of 5-(((2R,3S)-2-((1R)-1-(3,5-bis(trifluoromethyl) phenyl) ethoxy)-3-(4-fluorophenyl) – 4 morpholinyl) methyl) -1,2 -dihydro-3H -1,2,4 -triazol-3-one, is an antiemetic Active Pharmaceutical Ingredient (API) used for the treatment of chemotherapy induced emesis, nausea and vomiting as well as postoperative nausea and vomiting [1,2]
In the present study the thermal degradation profiles of APT, Poloxamer 188 and SOL were evaluated with the aid of Thermo-Gravimetric Analysis (TGA)
In the case of APT no mass loss is observed up to 246.6 ◦ C, while from that temperature up to 380.0 ◦ C a significant mass loss is observed followed by a second thermal degradation event from 380.0 ◦ C up to approximately

Summary

Introduction

Aprepitant (APT), with a chemical name of 5-(((2R,3S)-2-((1R)-1-(3,5-bis(trifluoromethyl) phenyl) ethoxy)-3-(4-fluorophenyl) – 4 morpholinyl) methyl) -1,2 -dihydro-3H -1,2,4 -triazol-3-one, is an antiemetic Active Pharmaceutical Ingredient (API) used for the treatment of chemotherapy induced emesis, nausea and vomiting as well as postoperative nausea and vomiting [1,2] It is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors with little or no affinity for serotonin. Sci 2019, 1, 48; doi:10.3390/sci1020048 www.mdpi.com/journal/sci (5-HT3), dopamine and corticosteroid receptors [3,4,5] It is a lipophilic compound supplied in the form of a white to off-white crystalline solid powder with pKa value of 9.7 within the pH range 2 to 12. APT is categorized as a BCS class IV drug with low aqueous solubility being the rate limiting step for API’s poor gastrointestinal absorption [6,11,12,13]

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