Rational excipient selection for co-amorphous formulations

Abstract

For almost two decades there has been intense debate about whether the amorphous solid state form could resolve the solubility problems and subsequent bioavailability issues of many small molecule drugs. Since the amorphous form is a high energy and unstable state of solid matter, any material in that form requires stabilization. Areas covered: This review examines the technologies being exploited to stabilize the amorphous state in co-amorphous formulations. The review emphasizes the importance of the appropriate selection criteria of stabilizing excipient and focuses on the mechanisms of stabilization. Expert opinion: An extensive literature review has revealed that the current research seeking to achieve stabilization of an amorphous form tends to be conducted on a case-by-case basis. This kind of approach is very inefficient since it can rarely be transferred to other cases. The greatest weakness in the selection of stabilizing excipient for co-amorphous formulations is that modern computational tools have rarely been utilized as a predictive tool in the selection of the excipient. It is evident that more research needs to be done to study larger datasets with modern in silico tools, chemometrics and advanced statistical tools to achieve a more predictive, and systematic approach for the screening of stabilizing excipients to be incorporated into co-amorphous formulations.

Permeability of glibenclamide through a PAMPA membrane: The effect of co-amorphization

“…4b-d.). These observations can be considered to be directly related to the strength and amount of stabilizing intermolecular interactions between the formulation components [4]. In GBC-ARG-mixtures, the peak shifts in observed FTIR were indicative of strong interactions (Fig.…”

“…an amino acid) or two active drug compounds have been shown to represent interesting candidates for combination therapy (drug-drug) or more general formulation options (drug-excipient). These approaches been found to enhance the dissolution properties of poorlysoluble drugs compared to their crystalline counterparts or individual amorphous forms, and to stabilize them in an amorphous form [2][3][4][5]. Often dissolution studies investigating co-amorphous systems have been conducted under sink conditions, but in order to investigate their supersaturation-abilities, non-sink dissolution testing is important.…”

Coamorphous Active Pharmaceutical Ingredient–Small Molecule Mixtures: Considerations in the Choice of Coformers for Enhancing Dissolution and Oral Bioavailability

“…The relatively few coamorphous design strategies that have been reported in essence mirror those taken to design pharmaceutical cocrystals. 65 For example, in silico miscibility prediction approaches (e.g., conductor-like screening model for real solvents) based on calculating mixing or excess enthalpy have recently been used to rationally select suitable cocrystal formers, 66 as well as to assess the ability of solvents to form solvates. 67 Molecular electrostatic potential surface calculations 68 that describe intermolecular interaction sites based on hydrogen bond donor/acceptor pairing energies in the gas phase have extended this approach beyond the individual hydrogen-bonding motifs to include as a summation all the hydrogen-bonding interactions in the solid state.…”

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

“…They are classified as a soliddispersion subtype of glass solutions, with the other forms of glass solutions being polymer-or mesoporous silica-based (Dengale et al, 2016). Combinations of either an active molecule and an excipient (e.g.an amino acid) or two active drug compounds have been shown to enhance the dissolution properties of poorly-soluble drugs and stabilize the amorphous form of both components (Löbmann et al, 2013a;Korhonen et al, 2017). Our review article "Emerging trends in the stabilization of amorphous drugs", covering the literature before 2013, was the first review presenting achievements of the co-amorphous approach by that time, with future prospects also being discussed (Laitinen et al, 2013).…”

“…Our review article "Emerging trends in the stabilization of amorphous drugs", covering the literature before 2013, was the first review presenting achievements of the co-amorphous approach by that time, with future prospects also being discussed (Laitinen et al, 2013). In that review, the research in this field was anticipated to grow and this indeed has happened as reflected by the number of co-amorphous combinations reported today (50 different drug-excipient combinations in various molar ratios, Korhonen et al 2017) and review articles about this topic (five according to PubMed search: Chavan et al, 2016;Dengale et al, 2016;Grohganz et al, 2014;Korhonen et al, 2017;Laitinen et al, 2013). In a recent review by Chavan et al (2016), formulation perspectives and different aspects in the development of co-amorphous formulations as drug products were reviewed.…”