Physical Stability and Dissolution of Lumefantrine Amorphous Solid Dispersions Produced by Spray Anti-Solvent Precipitation.

Sonal V Bhujbal,Lynne S Taylor,Qi (Tony) Zhou,Dmitry Y Zemlyanov,Vaibhav Pathak

doi:10.1016/j.xphs.2020.12.033

Abstract

This study aims to develop amorphous solid dispersion (ASD) of lumefantrine with a cost-effective approach of spray anti-solvent precipitation. Four acidic polymers, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), poly(methacrylic acid–ethyl acrylate) (EL100) and cellulose acetate phthalate (CAP) were studied as excipients at various drug-polymer ratios. Of the studied polymers, satisfactory physical stability was demonstrated for HPMCP- and HPMCAS-based ASDs with no observed powder X-ray diffraction peaks for up to 3 months of storage at 40 °C/75% RH. HPMCP and HPMCAS ASDs also achieved greater drug release levels in the dissolution study than other polymers. The HPMCP-based ASDs with a drug:polymer ratio of 2:8 exhibited a maximum drug release of 140 μg/mL for up to 2 h, which is significantly higher than the currently marketed formulation of Coartem® (<80 ng/mL). Relatively, the CAP and EL100 ASDs indicated a higher water content and crystallized within a day when stored at 40 °C/75% RH. The choice of polymer, and the drug-polymer ratio played a crucial role in the solubility enhancement of lumefantrine. Our study indicates that the developed spray anti-solvent precipitation method could be an affordable approach for producing ASDs.

Highlights

Due to an increase in the number of therapeutic compounds characterized by poor aqueous solubility, formulation strategies for enhancing drug solubility are in demand
Since preliminary results showed that the hydroxypropylmethylcellulose phthalate (HPMCP)- and hydroxypropylmethylcellulose acetate succinate (HPMCAS)-based amorphous solid dispersion (ASD) had better stability over other polymers, additional drug-polymer ratios of 2:8 and 3:7 were prepared and further investigated for these two polymers
The physical stability of ASDs prepared with HPMCP, HPMCAS, and cellulose acetate phthalate (CAP) was further studied at the accelerated storage condition of 40 C/75% RH for three months

Summary

Introduction

Due to an increase in the number of therapeutic compounds characterized by poor aqueous solubility, formulation strategies for enhancing drug solubility are in demand. Some commonly-used strategies are amorphization, complexation, salt formation, and micellization.[1,2] Drug amorphization is popular because it enhances the drug solubility and dissolution rate and results in the generation of a supersaturated solution which creates higher flux across the intestinal membrane.[3] the amorphous state is thermodynamically unstable and may revert to the crystalline form. If this conversion is too rapid, the amorphous drug can lose its dissolution advantage, causing quality and efficacy issues. An amorphous drug is often formulated with a polymer to form an amorphous solid dispersion (ASD).[4,5]

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