Microfibrous Solid Dispersions of Poorly Water-Soluble Drugs Produced via Centrifugal Spinning: Unexpected Dissolution Behavior on Recrystallization.

Stefania Marano,Susan A. Barker,Ali Rajabi-Siahboomi,Abil E. Aliev,Duncan Q. M. Craig,Bahijja T. Raimi-Abraham,Shahrzad Missaghi

doi:10.1021/acs.molpharmaceut.6b01126

Abstract

Temperature-controlled, solvent-free centrifugal spinning may be used as a means of rapid production of amorphous solid dispersions in the form of drug-loaded sucrose microfibers. However, due to the high content of amorphous sucrose in the formulations, such microfibers may be highly hygroscopic and unstable on storage. In this study, we explore both the effects of water uptake of the microfibers and the consequences of deliberate recrystallization for the associated dissolution profiles. The stability of sucrose microfibers loaded with three selected BCS class II model drugs (itraconazole (ITZ), olanzapine (OLZ), and piroxicam (PRX)) was investigated under four different relative humidity conditions (11, 33, 53, and 75% RH) at 25 °C for 8 months, particularly focusing on the effect of the highest level of moisture (75% RH) on the morphology, size, drug distribution, physical state, and dissolution performance of microfibers. While all samples were stable at 11% RH, at 33% RH the ITZ-sucrose system showed greater resistance against devitrification compared to the OLZ- and PRX-sucrose systems. For all three samples, the freshly prepared microfibers showed enhanced dissolution and supersaturation compared to the drug alone and physical mixes; surprisingly, the dissolution advantage was largely maintained or even enhanced (in the case of ITZ) following the moisture-induced recrystallization under 75% RH. Therefore, this study suggests that the moisture-induced recrystallization process may result in considerable dissolution enhancement compared to the drug alone, while overcoming the physical stability risks associated with the amorphous state.

Highlights

The drug dissolution performance of BCS class II drugs is pivotal for attaining suitable oral absorption from the gastrointestinal tract, with associated therapeutic benefit
Amorphous OLZ−, PRX−, and ITZ−sucrose microfibers with 10% (w/w) drug loading were successfully prepared using the operating conditions summarized in Table 1, these being chosen on the basis of melting (Tm) and degradation (Tdeg) temperature values of each component and their corresponding physical mixtures
Temperature-controlled centrifugal spinning is a promising approach for a large scale manufacture of fully amorphous sucrose-based solid dispersions with enhanced dissolution performance for BCS Class II drugs

Summary

Introduction

The drug dissolution performance of BCS class II drugs is pivotal for attaining suitable oral absorption from the gastrointestinal tract, with associated therapeutic benefit. The incorporation of this class of drugs into fully amorphous solid dispersions represents a well-known and efficient technology to address low bioavailability resulting from poor water-solubility.[1] Amorphous materials lack the ordered molecular lattice of crystalline materials, the strength of intermolecular interactions is lower than in crystalline solids. The higher free energy state of amorphous drugs can lead to increased rates of dissolution and apparent solubility (often up to several orders of magnitude) and, in turn, higher bioavailability.[2−5]

Objectives

Methods

Results

Conclusion