Effect of Storage Humidity on Physical Stability of Spray-Dried Naproxen Amorphous Solid Dispersions with Polyvinylpyrrolidone: Two Fluid Nozzle vs. Three Fluid Nozzle.

Sonal V Bhujbal,Eric J Munson,Lynne S Taylor,Yongchao Su,Alex-Anthony Cavallaro,Vaibhav Pathak,Dmitry Y Zemlyanov,Qi Tony Zhou

doi:10.3390/pharmaceutics13071074

Abstract

In a spray drying operation, a two-fluid nozzle (2FN) with a single channel is commonly used for atomizing the feed solution. However, the less commonly used three-fluid nozzle (3FN) has two separate channels, which allow spray drying of materials in two incompatible solution systems. Although amorphous solid dispersions (ASDs) prepared using a 3FN have been reported to deliver comparable drug dissolution performance relative to those prepared using a 2FN, few studies have systematically examined the effect of 3FN on the physical stability. Therefore, the goal of this work is to systematically study the physical stability of ASDs that are spray-dried using a 3FN compared to those prepared using the traditional 2FN. For the 2FN, a single solution of naproxen and polyvinylpyrrolidone (PVP) was prepared in a mixture of acetone and water at a 1:1 volume ratio because 2FN allows for only one solution inlet. For the 3FN, naproxen and PVP were dissolved individually in acetone and water, respectively, because 3FN allows simultaneous entry of two solutions. Upon storage of the formulated ASDs at different humidity levels (25%, 55% and 75% RH), naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. 3FN ASDs crystallized after 5 days of storage at all conditions, whereas 2FN ASDs did not crystallize even at 55% RH for two months. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymers as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. When only acetone was used as a solvent to prepare drug-polymer solutions for 3FN, the formulated ASD was found to be stable for >3 months of storage (at 75% RH), which suggests that instability of the 3FN ASD was due to the insufficient mixing of water and acetone solutions. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.

Highlights

Dissolution and absorption are essential for oral dosage forms to be effective, but a majority of new drug candidates (>90%) belong to Biopharmaceutics Classification System (BCS) class II or IV with poor water solubility [1]
Spray drying has increasingly been applied for manufacturing amorphous solid dispersions (ASDs) over the last decade, for thermo-sensitive drugs that cannot withstand high-temperature methods such as hot-melt extrusion [9]
PXRD was used to test the conversion of crystalline naproxen into its amorphous form, to confirm the successful formation of ASDs

Summary

Introduction

Dissolution and absorption are essential for oral dosage forms to be effective, but a majority of new drug candidates (>90%) belong to Biopharmaceutics Classification System (BCS) class II or IV with poor water solubility [1]. To improve solubility or dissolution of such drugs, several formulation techniques have been developed, such as amorphous solid dispersions, microemulsions, co-crystals, nanoparticles, salt formation, and cyclodextrin complexation [2,3]. Since a majority of small-molecule drugs are physically unstable in amorphous form, an ASD is used to prevent crystallization. Spray drying has increasingly been applied for manufacturing ASDs over the last decade, for thermo-sensitive drugs that cannot withstand high-temperature methods such as hot-melt extrusion [9]. The technique involves atomizing a feed solution of drug and polymer followed by its rapid drying to particles in the amorphous form [9]. Spray drying is a continuous process with scale-up capability [10] It is currently employed in the manufacture of several commercial

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