Amorphous Solid Dispersion Screening

Abstract

Finding the optimal form for drug development can involve a number of different screening activities, including a search for polymorphs, salts, cocrystals, and/or amorphous solid dispersions. High‐risk compounds will require special formulations that include amorphous solid dispersions. An amorphous dispersion screen is performed to find a suitable amorphous dispersion that exhibits acceptable properties. The screening performed in early development may focus on parameters such as solubility, supersaturation, short‐term physical and chemical stability, and animal bioavailability to get into early‐phase clinical trials quickly and establish proof of concept. Before starting an amorphous dispersion screen project, information on the active pharmaceutical ingredient (API) is needed. This may include chemical structure, solid form, physical stability, chemical stability, log P, hydrogen bond donors/acceptors, calculated solubility parameters, and known solubilities of the solid in various solvents/biorelevant media.

Drug–Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy

“…69 The knowledge of the 13 C assignment of both the drug and HPMC-AS polymer plays an important role in the identification of drug−polymer interactions in ASDs as this is largely based on the change in chemical shifts. 4,43 The 13 C assignments for the 13 C CP MAS NMR spectra of all ASDs, recorded at less than 1 day at RT/ambient RH, are based on the known spectra of HPMC-AS 69 and acetaminophen form I and II 68 (Table SI-2). In the spectra of the ASDs, signals assignable to the amorphous acetaminophen generally appear broader than in the crystalline form as expected from amorphization as the loss of crystallinity brings of a range of chemical environments present that are randomly distributed in the sample resulting in severe inhomogeneous line broadening.…”

“…This strategy can be adopted only as long as a supersaturated solution of amorphous API can be maintained in the aqueous medium over time. 4 Amorphous solid dispersions (ASDs) have been extensively used to stabilize supersaturated solution of APIs, resulting in a general increase for oral bioavailability of poorly soluble drugs. 5−7 An ASD can be defined as a dispersion of one or more APIs in a solid-state inert carrier, usually an amorphous polymer, 8 and can be prepared by a range of manufacturing processes, 9 including spray drying, 10 spray freeze drying, 11 hot melt extrusion.…”

“…22 These characteristics contribute to the stabilization of the ASD, which is due to the polymer's antiplasticizing effect, reducing molecular mobility of the amorphous API, and the formation of specific API−polymer interactions. 21 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 such dispersed systems 4 by inhibiting recrystallization phenomena in the amorphous matrix and preventing competitive API−API or polymer− polymer intramolecular interactions. Recently, the HPMC-AS polymer 23 has been widely used to prepare ASD due to its remarkable ability in stabilizing amorphous dispersions arising from the formation of strong API−HPMC-AS interactions.…”

“…30 DSC therefore allows to detect miscibility of individual components of an ASD, where the observation of a single Tg indicates miscibility between API and the polymer. 31 Gordon−Taylor's (GT) model 32 can be used to estimate the Tg of an ideal binary mixture (Tg mix ) with significant deviations between predicted Tg mix and experimentally determined Tg providing useful information about the interactions between the components in the mixture, 4,25,26 as the presence of API−API or API−polymer interactions can affect the Tg value of the system, while agreement suggests systems with the absence of specific drug−polymer interactions. Furthermore, access to ASD stability can be also obtained using thermodynamic modeling and short-to medium-term physical stabilities of several API−polymer blend ASDs.…”

Will the Drugs of the Future Be Small Molecules or Biological Drugs?

“…V současnosti se nejčastěji setkáváme s použitím pevných disperzí, které se v průmyslu připravují metodami sprejového sušení nebo extruze z taveniny. Pevné disperze se skládají z nejméně dvou komponentúčinné látky a nosiče (hydrofilního polymeru), přičemž nejvyšší rozpustnosti a tedy i biodostupnosti daného léčiva je dosaženo v případě, že účinná látka je molekulárně dispergována v polymeru 22,23 . Přítomnost polymeru zajišťuje jak vyšší fyzikální stabilitu ve srovnání s čistou amorfní formou, tak ovlivňuje uvolňování léčiva z polymerní matrice.…”