Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

Abstract

The amorphous form of a drug usually exhibits higher solubility, faster dissolution rate, and improved oral bioavailability in comparison to its crystalline forms. However, the amorphous forms are thermodynamically unstable and tend to transform into a more stable crystalline form, thus losing their advantages. In order to investigate and suppress the crystallization, it is vital to closely monitor the drug solids during the preparation, storage, and application processes. A list of advanced techniques—including optical microscopy, surface grating decay, solid-state nuclear magnetic resonance, broadband dielectric spectroscopy—have been applied to characterize the physicochemical properties of amorphous pharmaceutical solids, to provide in-depth understanding on the crystallization mechanism. This review briefly summarizes these characterization techniques and highlights their recent advances, so as to provide an up-to-date reference to the available tools in the development of amorphous drugs.

Indomethacin: The Interplay between Structural Relaxation, Viscous Flow and Crystal Growth

“…This correlation is widely discussed in the literature in terms of the Ediger’s decoupling parameter ξ [ 12 ]: where f p is the probability of the structural entity (newly attached to the crystal growth interface) remaining in the crystalline state, and ΔG lc is the difference between the Gibbs energies of the undercooled liquid and crystalline phases. The log(u kin )-log(η) dependence constructed using the literature data [ 54 , 55 ] is included in Figure S3 , giving the data yield ξ = 0.683–0.695 (depending on the evaluation method, as discussed therein), which is consistent with the reports utilizing, e.g., dielectric measurements [ 66 , 73 , 74 ]. In his original derivation of the decoupling parameter ξ [ 12 ], Ediger demonstrated the correlation between ξ and the kinetic fragility m (ξ decreases with increasing m).…”

Amorphous and Co-Amorphous Olanzapine Stability in Formulations Intended for Wet Granulation and Pelletization

“…Crystal engineering alters the intermolecular interactions responsible for holding the molecules together, affects the packing of the molecules and impacts the physical properties of solids (e.g., compressibility, solubility and dissolution rate) [ 9 , 10 , 11 ]. In this respect, the disarrangement of the crystalline structure of drugs by the production of their amorphous counterparts is regarded as one of the most promising strategies to enhance drug solubility and bioavailability [ 12 , 13 , 14 ]. In fact, amorphous materials, unlike their corresponding crystalline materials, possess high free energy, i.e., low enthalpy and high entropy [ 15 ], which positively affects properties such as solubility in water and dissolution rate [ 12 , 16 ].…”

New Development in Understanding Drug–Polymer Interactions in Pharmaceutical Amorphous Solid Dispersions from Solid-State Nuclear Magnetic Resonance

“…The identification and the understanding of the physical stability of ASDs remain a significant challenge and open exciting future perspectives for the design of ASDs stabilized by suitable and tunable API− polymer interactions. 10 Historically, thermal analysis methods, such as differential scanning calorimetry (DSC) and temperature-modulated DSC, have often been employed to elucidate API−polymer interactions in ASDs, which allows T g measurements from the miscibility of the various ASD components to be inferred. 11,12 One such approach is the Gordon−Taylor model 13 that estimates the T g of an ideal binary mixture (T g,mix ), where significant deviations between the predicted T g,mix and experimentally determined T g provide useful information about the interactions between the various constituents of the mixture and potentially repulsive interactions, which destabilize the system.…”

“…The formation of the drug–polymer intermolecular interactions, such as hydrogen bonding (H-bond), ionic forces, π–π, or electrostatic interactions, are well established as the most significant interactions capable of stabilizing dispersed systems by inhibiting recrystallization phenomena in the amorphous matrix and preventing competitive API–API or polymer–polymer intramolecular interactions. The identification and the understanding of the physical stability of ASDs remain a significant challenge and open exciting future perspectives for the design of ASDs stabilized by suitable and tunable API–polymer interactions …”

“…The identification and the understanding of the physical stability of ASDs remain a significant challenge and open exciting future perspectives for the design of ASDs stabilized by suitable and tunable API–polymer interactions. 10 …”