A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery.

Georgia Tsakiridou,Christos Reppas,Lida Kalantzi,Martin Kuentz

doi:10.3390/pharmaceutics11120625

Abstract

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients.

Highlights

In recent years, the pharmaceutical industry is pursuing less druggable targets, with characteristics such as increased size and flexibility [1,2]
Such experiments can be run via a design of experiment (DoE) setup, where samples are tested over time regarding the lack of phase separation and/or active pharmaceutical ingredients (APIs) crystallinity [63]
Adequate miscibility between API and stabilizing polymer is a prerequisite for successful formulation of amorphous solid dispersions (ASD)

Summary

Introduction

The pharmaceutical industry is pursuing less druggable targets, with characteristics such as increased size and flexibility [1,2]. Most APIs have a molecular weight of 300–400 g/mol, but the projection is that the pharmaceutical industry will be dealing with relatively bigger APIs (>500 g/mol) in the future [1]. This general shift in API characteristics has spurred an interest in enhanced oral formulation technologies of such molecules [3,4,5], with amorphous solid dispersions (ASD) as a key approach to improve apparent solubility and oral bioavailability of APIs with the above-mentioned characteristics [6,7,8]. Relevant evaluations are based on the miscibility characteristics of the drug with the polymer [14]

Methods

Discussion

Conclusion