Article pubs.acs.org/crystal
Use of a Plasticizer for Physical Stability Prediction of Amorphous Solid Dispersions Michelle H. Fung and Raj Suryanarayanan* Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States S Supporting Information *
ABSTRACT: Utilizing glycerol as a plasticizer, an accelerated physical stability testing method of amorphous solid dispersions (ASDs) was developed. The influence of glycerol concentration on the glass transition temperature and αrelaxation time (a measure of molecular mobility) of amorphous ketoconazole, celecoxib, and the solid dispersions of each prepared with polyvinylpyrrolidone was investigated. By temperature scaling (Tg/T), the effects of glycerol concentration and temperature on the relaxation time were simultaneously evaluated. Glycerol, in a concentration dependent manner, accelerated crystallization in all of the systems without affecting the fragility. In celecoxib-PVP ASDs, the drug crystallization was well coupled to molecular mobility and was essentially unaltered at glycerol concentrations up to 2% w/w. The acceleration in crystallization brought about by glycerol expedited the determination of the coupling between molecular mobility and crystallization. As a result, we were able to predict the physical stability of the unplasticized ASD. This approach is especially useful for ASDs with high polymer content where drug crystallization is extremely slow at the relevant storage temperature.
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INTRODUCTION
G (T ) =
Amorphous solid dispersion (ASD) is a popular formulation strategy for improving the oral bioavailability of poorly watersoluble APIs.1−3 However, recrystallization of amorphous API during storage or dissolution would eliminate the solubility advantage of amorphous pharmaceuticals and lead to product failure. Accelerated studies conducted under elevated temperature and water vapor pressure cannot be reliable predictors of stability under relevant storage conditions. The goal of this study was to develop an “accelerated method” to evaluate the physical stability of drugs in ASDs. In these systems, molecular mobility provides an avenue to assess physical stability. While there are several tools to evaluate mobility, a unique advantage of dynamic dielectric spectroscopy (DES) is that it can simultaneously characterize different modes of molecular motions, over a wide temperature range. More importantly, the potential coupling between mobility and physical stability provides an avenue to predict crystallization behavior from mobility measurements. The coupling between mobility and crystallization was built on the idea that drug crystallization rate at a crystal−melt interface, G(T), can be estimated from the temperature dependence of translational molecular diffusion, D(T), and the thermodynamic driving force for nucleation, f(T).4 G(T ) = D(T ) ·f (T )
(2)
Furthermore, because of the similar temperature dependence of η and the rotational motions measured by DES, crystallization rate, G(T), can be approximated by the following expression, G (T ) ∝
f (T ) τα(T )
(3)
where τα(T) is the temperature dependence of α-relaxation time measured by DES. However, the Stokes−Einstein equation, relating translational diffusion to viscosity, breaks down over the temperature range of Tg to 1.2 Tg.5 The decoupling between translational diffusion and viscosity can be expressed as follows: D(T ) ∝
1 η (T ) ξ
(4)
where ξ is the decoupling factor. The relationship between crystallization and relaxation times can be described by
G (T ) ∝
(1)
Since it can be difficult to measure translational molecular diffusion, D(T) is often approximated by the temperature dependence of the viscosity, η(T) resulting in eq 2. © 2017 American Chemical Society
f (T ) η(T )
f (T ) τα M(T )
(5)
Received: May 2, 2017 Revised: June 13, 2017 Published: June 23, 2017 4315
DOI: 10.1021/acs.cgd.7b00625 Cryst. Growth Des. 2017, 17, 4315−4325
Crystal Growth & Design
Article
where M is the coupling coefficient and indicates the coupling between crystallization and molecule mobility. Equation 5, when represented in terms of crystallization time, tc, yields eq 6.
tc(T ) ∝
τα M(T ) f (T )
dispersions and accelerate drug crystallization, and (ii) the coupling between mobility and crystallization will be unaffected at modest plasticizer concentrations (up to ∼10% w/w). If our hypotheses are valid, the physical stability of unplasticized ASDs can be reliably predicted from studies of plasticized systems.
(6)
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Over a narrow temperature range (∼20 °C), the relationship between crystallization time (tc) and molecular mobility (τα) can be expressed by eq 7, providing an avenue to obtain the coupling coefficient (M). log tc = M log τα + A
EXPERIMENTAL SECTION
Materials. Ketoconazole (C26H28Cl2N4O4; purity >98%) was a gift from Laborate Pharmaceuticals (Haryana, India). Celecoxib (C17H14F3N3O2S; form III) was purchased from Aarti Drugs Ltd. (Maharashtra, India). Polyvinylpyrrolidone (Kollidon K12, BASF, Ludwigshafen, Germany) was dried at 110 °C for 1 h prior to use. Glycerol was purchased from Fisher Scientific (Waltham, MA). Ketoconazole (KTZ) is a weakly basic BCS Class II compound, while celecoxib (COX) is weakly acidic. Preparation of Amorphous Samples. Melt-Quenched Amorphous Drugs. Crystalline COX and KTZ were heated to 175 and 165 °C, respectively, held for 30 s, and cooled rapidly in liquid nitrogen. The quench-cooled materials were then gently ground using a mortar and pestle, passed through 190 mesh (90 μm) sieve, and stored at −20 °C in desiccators containing anhydrous calcium sulfate until further use. Sample preparation and handling were conducted in a glovebox at
