Amorphous Solid Dispersions of Polyphenols: Current State of the Art (Part I)

Abstract

Polyphenols have attracted considerable scientific interest over recent years due to their broad spectrum of biological activities, including antioxidant, cardioprotective, anti-inflammatory, antidiabetic, and anticancer properties. However, their practical application is often limited by unfavorable physicochemical characteristics, particularly low aqueous solubility. Consequently, amorphous solid dispersions (ASDs) have been extensively investigated as a formulation strategy to overcome these limitations. This article represents the first part of a two-part review and presents the current state of the art in amorphous solid dispersions of polyphenols. The available literature is systematically summarized with respect to the investigated polyphenolic compounds, the employed carriers (with particular emphasis on polymeric systems), the preparation methods, and the solid-state characterization techniques used to confirm amorphization. Both single-component systems and binary combinations of polyphenols reported in the literature are considered. The collected data are presented in tabular form and complemented by a heat map illustrating the frequency of reported polyphenol–carrier combinations. The aim of this review is to organize the available knowledge, identify the most extensively studied systems, and highlight research areas that remain underexplored. A detailed discussion of the pharmaceutical benefits and mechanistic aspects of polyphenols in ASD systems will be provided in Part II.

Introduction

Polyphenols are a diverse group of plant-derived bioactive compounds that are widely present in the human diet and have been associated with numerous health-promoting effects, including antioxidant [1,2,3,4], antidiabetic [5,6], anti-inflammatory [7,8], anticancer [9,10], cardioprotective [11], and neuroprotective [8,12] activities. Despite these promising biological properties, the practical application of polyphenols in functional foods and pharmaceutical formulations is often limited by their low oral bioavailability. The low bioavailability of many polyphenols primarily results from their poor aqueous solubility, which restricts dissolution and absorption in the gastrointestinal tract and consequently limits the attainment of therapeutically relevant concentrations in vivo [13,14,15]. According to the biopharmaceutical classification system (BCS), many polyphenols fall into classes characterized by low solubility, where improving dissolution behavior may directly enhance their permeability and overall bioavailability (Figure 1) [16].

Figure 1. Biopharmaceutical classification system (BCS).

To overcome these limitations, various formulation strategies, such as the use of cocrystals, liposomes, inclusion complexes, and nanofibers, have been explored to enhance the solubility and biological performance of polyphenols [17]. Among these approaches, the use of amorphous solid dispersions (ASDs) or co-amorphous solid dispersions (CAMs) has emerged as a particularly promising formulation strategy. ASDs are systems in which a poorly water-soluble compound, such as a polyphenol, is molecularly dispersed within a solid carrier matrix typically composed of hydrophilic polymers [18,19]. In contrast, CAMs are formed by combining the drug with one or more low-molecular-weight co-formers (e.g., amino acids, organic acids, or other small molecules) to create a homogeneous amorphous phase stabilized by intermolecular interactions [20,21,22,23,24,25,26,27,28]. The conversion of polyphenols into an amorphous state offers an increased apparent solubility and dissolution rate due to the higher free energy of the disordered solid form. However, the inherent thermodynamic instability of amorphous systems necessitates appropriate stabilization strategies, typically achieved through intermolecular interactions with a carrier matrix or co-former molecules that inhibit recrystallization. Numerous processing techniques have been developed to obtain stable ASDs and CAMs, many of which are already well established in the pharmaceutical and food industries (Figure 2) [29,30,31,32,33,34,35]. Polyphenols represent a pharmacologically relevant yet formulation-challenging subclass of poorly soluble bioactive compounds, which justifies a focused analysis of ASD strategies in this group.

Figure 2. Techniques used in the process of obtaining amorphous solid dispersion (ASDs) and co-amorphous solid dispersions (CAMs).

This review is divided into two parts. Part I focuses on the formulation design of ASDs and CAMs, providing an overview of the investigated compounds, the selection of polymeric carriers or co-formers, and the preparation techniques used to obtain amorphous systems. Particular attention is given to experimental design considerations, including factors that should be taken into account when selecting formulation components and processing methods. This section also discusses the analytical techniques used to confirm the amorphous state and to identify polyphenol–polymer or polyphenol–co-former interactions, as well as their role in stabilizing the amorphous phase and preventing recrystallization. Part II will address the biopharmaceutical performance of these systems, including the influence of carrier selection on the release profile of polyphenols from the matrix; pH-dependent dissolution behavior; and the outcomes of in vitro and in vivo studies evaluating improvements in solubility, bioavailability, and biological activity.

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see a part of Table 1. here: Reported polyphenol-based ASDs: compounds, carriers, preparation methods, and solid-state characterization.

Carrier	Method	Identification	References
APIGENIN
Soluplus	scCO2	XRPD FT-IR	[36]
Pluronic F-68 Pluronic F-127	Ball milling	XRPD TG DSC SEM FT-IR	[37]
Pluronic F-127	Spray drying	XRPD DSC SEM FT-IR	[38]
BAICALEIN
Nicotinamide	Solvent evaporation	XRPD DSC SEM FT-IR PLM	[39]
Histidine	Solvent evaporation	XRPD DSC FT-IR	[40]
PVP VA 64 Eudragit E PO	HME	XRPD DSC FT-IR	[41]
BUTEIN
PVP K30 PVP K30/poloxamer 407	Solvent evaporation	DLS XRPD DSC	[42]
CHRYSIN
Plasdone® S630	Solvent evaporation	XRPD	[43]
Brij®L4	Solvent evaporation	XRPD DSC SEM	[44]
CURCUMIN
Eudragit E PO	HME	XRPD DSC FT-IR	[45]
Eudragit/PVP, Eudragit/HPMC	Solvent evaporation	XRPD FT-IR	[46]
HPC SDS	Vibrational ball milling	XRPD DSC FT-IR	[47]
Eudragit RSPO Eudragit RLPO	HME	DSC XRPD	[48]
COS	Ball milling	DSC XRPD	[49]
PVP K30	Solvent evaporation	DSC IR XRPD Raman SEM NMR	[50]
HPMC	Solution mixing method	DSC SEM	[51]
HPMC Eudragit E100	Solvent evaporation	PLM	[52]
HPMC E5 Eudragit E100	Solvent evaporation	Raman Raman imaging IR Fluorescence DLS
PEG 6000 PVP K30 Eudragit E PO PVP K30/Eudragit E PO Eudragit E PO + HPMC E50	Solvent evaporation	Raman Raman imaging IR	[53]
PVP K30	Solvent evaporation	DSC XRPD	[54]
α-glucosyl stevia PVP K30	Freeze drying	DSC XRPD	[55]
Eudragit E PO	Solvent evaporation	DSC XRPD	[56]
Eudragit E PO	Solution mixing	DSC XRPD FT-IR 1H NMR	[57]
Eudragit E PO	Spray drying Rotary evaporation	DSC XRPD	[58]
HPMC/lecithin/isomalt	Hot-melt extrusion	XRPD DSC	[59]
Eudragit E100 HPMC E5	Solvent evaporation Cryo-milling	XRPD DSC UV-Vis IR	[60]
HPMCAS CMCAB CAAdP	Spray drying	XRPD DSC FT-IR	[61]
HPMC-AS	Freeze drying	XRPD DSC SEM PLM TEM	[62]
PVP	Spray drying	DSC XRPD	[63]
CURCUMIN-HESPERETIN
PVP K30/phosphatidylcholine	HME	DSC XRPD FT-IR	[64]
HPMC HPC PVP K30	Quench cooling	XRPD DSC Raman FT-IR NMR	[65]
CURCUMIN-PIPERINE
PVP VA64	HME	DSC XRPD FT-IR	[31]
DAIDZEIN
PVP K90	Spray drying	XRPD DSC SEM	[66]
DIOSMIN
Soluplus	Spray drying	XRPD DSC SEM FT-IR	[67]
ELLAGIC ACID
CMCAB CAAdP HPMCAS PVP CAAdP/PVP	Spray drying Co-precipitation Solvent evaporation	XRPD MDSC IR NMR	[68]
EPIGALLOCATECHIN GALLATE
PMCAS HPMCP Soluplus Cellulose acetate	Freeze drying	XRPD SEM PLM TG DSC	[69]
*FERULIC ACID (complete amorphization was not obtained)**
HPMC Soluplus PVP VA64 PVP K30 PEG 6000	Kneading Solvent evaporation	XRPD FT-IR SEM DSC	[70]
PVA PVA/PVP K10	Electrospinning	XRPD	[71]
PVP K30 PEG 6000 Poloxamer 188	Spray drying	SEM XRPD TGA IR	[72]

Rosiak, N.; Ignacyk, M.; Kryszak, A.; Piontek, J.; Cielecka-Piontek, J. Amorphous Solid Dispersions of Polyphenols: Current State of the Art (Part I). Pharmaceuticals 2026, 19, 598. https://doi.org/10.3390/ph19040598