Recent Advances in Understanding the Micro- and Nanoscale Phenomena of Amorphous Solid Dispersions

Abstract

Many pharmaceutical drugs in the marketplace and discovery pipeline suffer from poor aqueous solubility, thereby limiting their effectiveness for oral delivery. The use of an amorphous solid dispersion (ASD), a mixture of an active pharmaceutical ingredient and a polymer excipient, greatly enhances the aqueous dissolution performance of a drug without the need for chemical modification. Although this method is versatile and scalable, deficient understanding of the interactions between drugs and polymers inhibits ASD rational design. This current Review details recent progress in understanding the mechanisms that control ASD performance. In the solid-state, the use of high-resolution theoretical, computational, and experimental tools resolved the influence of drug/polymer phase behavior and dynamics on stability during storage. During dissolution in aqueous media, novel characterization methods revealed that ASDs can form complex nanostructures, which maintain and improve supersaturation of the drug. The studies discussed here illustrate that nanoscale phenomena, which have been directly observed and quantified, strongly affect the stability and bioavailability of ASD systems, and provide a promising direction for optimizing drug/polymer formulations.

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

“…However, they can function as drug reservoirs that maintain a supersaturated concentration that drives absorption. These nanoparticles can also reduce the tendency to crystallize by inhibiting drug nucleation due to specific polymer-drug intermolecular interactions [42].…”

Drug-Rich Phases Induced by Amorphous Solid Dispersion: Arbitrary or Intentional Goal in Oral Drug Delivery?

“…In the ASD system, different amorphous polymeric or small molecular excipients are utilized to stabilize the amorphous drug during the storage as well as to enhance the solubility and dissolution rate of the drug in solution [21][22][23][24]. While amorphous drug molecules are considered to be homogeneously dispersed within the excipients in an ideal ASD system, an amorphous-amorphous phase separation (AAPS) phenomenon is often observed during the manufacturing or storage due to the imperfect miscibility of drug and excipients [29,[75][76][77].…”

“…Amorphous solid dispersions (ASDs) are, in general, homogeneous dispersions of amorphous drug molecules within a solid excipient [20]. To overcome the instability of amorphous drugs caused by the high free energy, certain polymers are utilized as the antiplasticizer and/or the stabilizer to maintain the amorphous structure of the drug molecules during storage [21][22][23]. Polymers can increase formulation stability through various mechanisms such as the physical barrier, configurational entropy, molecular mobility, chemical potential, glass transition temperature and drug-polymer interaction [24].…”

Mechanism and Improved Dissolution of Glycyrrhetinic Acid Solid Dispersion by Alkalizers

“…SEM, DSC, XPRD, FTIR, Raman, XPS, and a molecular model were used to perform solid-state characterizations and to study the dissolution mechanism of the TSDs. Among the known technologies, amorphous solid dispersions have become one of the most effective methods of enhancing the solubility and gastrointestinal absorption of poorly soluble drugs [18][19][20]. Hot melt extrusion technology has been widely adopted because it offers continuous control and because it is solvent free and less time consuming.…”