Solution characterization of solid dispersions

SDs are designed so that upon dissolution the drug becomes supersaturated in the gastrointestinal fluid, thereby driving rapid absorption of drug into the blood stream.

Supersaturation, 𝑆, is defined as:

𝑆 = 𝐶

𝐶_K\]^ (1.8)

𝐶 is the concentration of drug is the supersaturated solution and 𝐶_K\]^ is the solubility of the thermodynamically stable crystal. SDs achieve supersaturation because the drug in the formulation exists as a glass, which has a higher apparent solubility relative to the crystal.

Although true equilibrium between glassy drug and drug dissolved in solution cannot exist because the glass is not the lowest free-energy state, a metastable partitioning of drug between the two phases is still obtained. The apparent solubility of the glassy drug, 𝐶_{@_`^^},

may be estimated by: various drugs),¹² Δ𝐺_@→K is the free energy different between glassy and crystalline drug,

∆𝐻_< is the enthalpy of fusion of crystalline drug, 𝑇_* is the melting temperature of crystalline drug, 𝑇 is temperature, and 𝑅 is the universal gas constant. Because 𝐶_{@_`^^}is significantly larger than 𝐶_K\]^, SDs can achieve large values of 𝑆.^12,13,14 Supersaturation, however, also induces crystallization of drug, so an optimal excipient for an API needs to

simultaneously stabilize glassy drug and inhibit crystallization. This stability of these phases affects not only the behavior of drug and polymer in aqueous solution, but also the release of both species from SD particles. The following sections discuss the physics and characterization of these stages of SD dissolution.

1.2.3.1 Dissolution of drug and polymer from SD particles

The release of drug from an SD particle is a fairly complex process. When an SD particle is submerged in aqueous solvent, it imbibes water molecules. Unlike the dissolution kinetics of particles of pure drug, which is limited by the diffusion and convection of the drug in water, the dissolution kinetics of SDs is controlled by both drug mass transfer and dissolution of the polymer matrix. Polymer dissolution, illustrated in Figure 1.7 for a slab of hydrophilic glassy polymer, occurs in three stages. (i) Water penetration causes the polymer to simultaneously swell and devitrify. The gel-water interface (front S) moves outward, while the gel-glassy polymer interface (front R) moves inward. (ii) Polymer chains begin to disentangle at the gel-water interface and dissolve into solution when the water concentration in the swollen polymer exceeds a critical concentration. The rate of disentanglement is affected by both molecular weight and the reptation time of the polymer chains. Both fronts S and R retreat towards the center of the film. (iii) Polymer chains at the gel-water interface continue to disentangle and dissolve after the glassy core disappears. Front S continues to move inward until all the polymer is dissolved.⁹²

Figure 1.7. Schematic of the dissolution of a slab of hydrophilic glassy polymer. (A) Slab before immersion in solvent. L is the initial thickness. (B) Initial swelling of polymer. Solvent swelling causes the gel-solvent interface to move outwards (front S), while devitrification leads to the gel-glassy polymer interface to move inwards (front R).

(C) Disentanglement of polymer from gel-solvent interface. Both fronts S and R move inwards. (D) Depletion of glassy polymer. Front S moves inward until all polymer dissolves. Adapted with permission from Narasimhan, B.; Peppas, N. A. J. Pharm. Sci.

1997, 86, 297–304. Copyright Wiley Periodicals and the American Pharmacists Association.⁹²

The coupled rates of dissolution for drug and polymer influence the ultimate dissolution profile of the drug. Faster dissolution of polymer relative to drug may also cause enrichment of drug at the dissolution interface and, consequently, crystallization.⁹³ Furthermore, high drug loadings decrease the dissolution rate of SDs.^94,95,96 Although several mathematical models have been developed for predicting the dissolution rate of drug from polymer matrices,92,97,98,99 the influence of drug:polymer interactions on the dissolution rate is not fully understood.

1.2.3.2 Phase behavior of SDs during dissolution

For SD formulations that target a concentration of drug above the crystalline solubility, release of drug from SD particles during dissolution will cause the solution to

be supersaturated. However, studies of the phase behavior of drug and polymer in supersaturated solutions were rare until the late 2000’s. In 2008 and 2009, Curatolo et al.

published two studies focused on HPMCAS SDs. To rationalize the performance of HPMCAS as an excipient, the authors claimed the polymer formed nanosized aggregates with drug. They hypothesized that these aggregates replenished the concentration of fully dissolved drug in solution. In spite of the claims by the authors, these two publications did not include any characterization of the structures in the dissolution media.^41,42

In 2012, Taylor et al. developed a new assay for characterizing SD dissolution media using UV extinction. By irradiating the sample with UV light at a non-absorbing wavelength and measuring light transmission, they discovered the formation of structures in the dissolution media for a variety of SD systems.100,101,102,103,104 UV extinction, however, could not distinguish between amorphous structures and crystalline structures.

To complement these studies, Taylor et al. developed a fluorescence spectroscopy assay for characterizing SD dissolution. This technique involves the addition of a fluorophore that interacts with amorphous drug (but not crystalline drug) in the dissolution media. By simultaneously monitoring both light transmission through the solution and the emission spectra of the sample, they determined that many SD systems formed amorphous drug-rich nanodroplets.They observed that these nanodroplets only formed when the concentration of drug in solution surpassed the glassy drug solubility (Figure 1.8).101,105,106 In agreement with the claims by Curatolo et al., Taylor proposed that these nanodroplets serve as reservoirs that maintain the concentration of fully dissolved drug. The stability of the nanodroplets was contingent on the drug:polymer pairing and the structures typically coarsened over time. Furthermore, drug was removed from solution by crystallization, which led to accelerated depletion of the nanodroplets.¹⁶ Although polymers are recognized as necessary for inhibiting nanodroplet coalescence and drug crystallization, their interaction with drug during dissolution is still not well understood. Additional studies are needed to resolve this mechanism.

Figure 1.8. UV extinction and fluorescence data for glassy phenylbutazone in phosphate-buffered saline. When the concentration of the drug exceeded ~ 50 µg/mL, UV extinction detected the formation of structure, while fluorescence confirmed the structure was amorphous. Based on the data, the authors concluded the drug formed amorphous nanodroplets in solution. Adapted with permission Almeida e Sousa, L.;

Reutzel-Edens, S. M.; Stephenson, G. A.; Taylor, L. S. Mol. Pharm. 2015, 12, 484–495.

Copyright American Chemical Society.¹⁰⁵