Comparative evaluation of ternary amorphous solid dispersions: Identifying optimal excipient systems for enhancing drug solubility

Abstract

The limited aqueous solubility of numerous active pharmaceutical ingredients (APIs) remains a major barrier to achieving optimal oral bioavailability, therapeutic efficacy, and clinical translation. Amorphous solid dispersion (ASD) systems have emerged as a leading strategy to overcome these biopharmaceutical limitations, with ternary ASDs offering greater formulation flexibility and performance enhancement through the synergistic inclusion of functional third components.

Aims

This review aims to systematically explore and critically analyze the formulation strategies, comparative outcomes, and molecular mechanisms underlying ternary ASDs—specifically Drug:Polymer:Polymer, Drug:Polymer:Surfactant, Drug:Polymer:Excipient, and Drug:Drug:Polymer systems—in improving solubility, dissolution, stability, and pharmacokinetic performance. A comprehensive literature search was conducted across Scopus, PubMed, and Web of Science databases for peer-reviewed articles published between 2015 and 2025, focusing on experimental studies evaluating ternary ASDs. Studies were selected based on relevance to solubility enhancement, dissolution profile, in vitro–in vivo correlation, and mechanistic insights at the molecular level. Ternary ASDs demonstrated superior performance over binary systems, particularly those incorporating surfactants, which exhibited the highest solubility enhancement (up to 810.81-fold). Polymer–polymer and polymer–excipient systems also improved dissolution and pharmacokinetic parameters, although with lower magnitude. Mechanistically, ternary ASDs work through micellization, hydrogen bonding, molecular dispersion, and recrystallization inhibition, which collectively maintain supersaturation and improve absorption and bioactivity. Ternary ASD systems represent a scientifically rational and pharmaceutically significant advancement for formulating poorly soluble drugs. Their ability to modulate solubility, dissolution, and pharmacological outcomes through molecular-level interactions underscores their transformative potential in drug delivery. Future research should focus on tailoring ternary components based on physicochemical drug properties and predictive modeling.

Introduction

Poor aqueous solubility remains one of the most pervasive challenges in pharmaceutical development, particularly in the formulation of orally administered drugs (Attia and Ghazy, 2023; Bhalani et al., 2022; Salunke et al., 2022). An estimated 40–60 % of new chemical entities (NCEs) identified through high-throughput screening exhibit low water solubility, which directly compromises their dissolution rate, oral absorption, and ultimately, therapeutic efficacy (Budiman et al., 2019; Kawabata et al., 2011; Tran et al., 2019). This solubility-limited bioavailability significantly hinders the clinical translation of promising drug candidates and represents a critical barrier in the drug development pipeline (Di et al., 2012; Jermain et al., 2018; Kumari et al., 2023; Pandi et al., 2020; Shi et al., 2019; Zhuo et al., 2024). Overcoming this limitation requires not only technological innovation but also a deeper mechanistic understanding of formulation strategies that effectively address solubility enhancement at the molecular level (Kosaka et al., 2020; V A, S, et al., 2025).

Currently, several formulation strategies have been developed to address this issue, including salt formation (Gao et al., 2024; Meng et al., 2024; Yarlagadda et al., 2024; Zhang et al., 2024), particle size reduction (Abdollahi et al., 2024; Csicsák et al., 2023; Rashed et al., 2022), lipid-based systems (Alajami et al., 2022; Koehl et al., 2021; Nora et al., 2022; Zhu et al., 2024), and inclusion complexation (Munnangi et al., 2023; Oo et al., 2022; Schoeman et al., 2024; Tsunoda et al., 2023). Among these, the amorphous solid dispersion (ASD) method has become one of the most effective and extensively researched techniques to improve the solubility of poorly water-soluble drugs (Budiman and Aulifa, 2022; Koromili et al., 2023). ASDs can significantly improve dissolution rate and generate supersaturation in the gastrointestinal tract, by dispersing the drug in a polymeric matrix in its high-energy amorphous state (Polyzois et al., 2024; Yun et al., 2024). However, some of conventional binary ASDs, typically composed of a drug and a single polymer, have several limitations alongside their successes. These limitations include physical instability, low drug loading capacity, and inadequate recrystallization control, which may compromise long-term performance and limit their ability in industrial conversion (Budiman et al., 2024; Budiman et al., 2023b; Budiman et al., 2022; Newman et al., 2008).

To overcome the limitations of binary ASD systems, the pharmaceutical field has been looking for innovative ways to enhance the properties of these systems. One of the main strategies that have been explored is the use of ternary ASD systems. In ternary ASDs systems, the main components of the binary systems are incorporated with a third component, typically a surfactant, additional polymer, or small molecule stabilizer (Saberi et al., 2023; Tian et al., 2020). This approach has revealed significant potential to substantially increase kinetic and thermodynamic solubility of drugs, prevent drug recrystallization, and maintain supersaturation levels (Amaliah et al., 2025; Borde et al., 2021; Budiman et al., 2023a; Sohn et al., 2020). Mechanistic interactions between drug, polymer, and excipient components can result in synergistic effects that are not achievable in binary systems, such as micellar solubilization, hydrogen bonding stabilization, and nanocluster formation (Kosaka et al., 2020; Omagari et al., 2020; Pöstges et al., 2023; Zhao et al., 2019). As a result, ternary ASDs are rapidly emerging as a next-generation formulation approach with superior biopharmaceutical performance.

While several studies have investigated various ternary combinations and their effects on drug solubility, a systematic and quantitative synthesis of the available evidence remains absent. Existing literature is often fragmented—focusing on isolated case studies or limited formulation types—without offering a comparative framework that integrates formulation composition, mechanistic interaction, and solubility outcomes. To our knowledge, no comprehensive comparative evaluation has been conducted to determine which specific type of ternary ASD formulation—such as drug–polymer–polymer, drug–polymer–Surfactant, drug–polymer–small molecule or drug–drug–polymer—is most effective in improving drug solubility across diverse pharmaceutical compounds.

This review addresses this critical gap by presenting a scientifically rigorous and quantitatively grounded comparative assessment of ternary ASD systems, with a focus on solubility enhancement. Through comparative evaluation of peer-reviewed studies, we classify ternary systems based on their compositional design and mechanistic functionality, analyze their relative performance in solubility improvement, and identify key formulation principles driving their success. This review not only provides the first evidence-based ranking of ternary ASD strategies, but also offers mechanistic insights and practical guidance for rational formulation design.

Accordingly, the aim of this review is to critically evaluate and compare the solubility-enhancing efficacy of various ternary ASD systems, highlight the underlying molecular mechanisms responsible for their performance, and identify the most promising formulation strategies. By combining a systematic comparative approach with mechanistic interpretation, this review aspires to advance the current understanding of ternary ASDs and support the development of more effective drug delivery systems for poorly soluble compounds.

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Table 2. The impact of ternary system amorphous solid dispersion on release profile.

Ternary System	API and The Main System	Improvement	Dissolution and Release Behavior	Ref
Drug: Polymer: Polymer	Atorvastatin: PS630: PEG 400	2.500	>90 % after 60 min (highest) F6 (PEG400): DE60 = 90.23, IDR = 6.79, MDR = 2.28; F2: DE60 = 88.28; Pure ACT: DE60 = 33.16, IDR = 1.15	(Sarabu et al., 2022)
Drug: Polymer: Polymer	Atorvastatin: PS630U: PEG400	2.500	>90 % after 60 min	(Sarabu et al., 2022)
Drug: Polymer: Polymer	Itraconazole: PovidoneK12: Povidon K12	5.830	7 μg/mL (supersaturation 6×)	(Meng et al., 2017)
Drug: Polymer: Polymer	Abirateron: kinetisol (HPBCD): HPMCAS126G	7.450	60 μg/mL after 90 min (The study demonstrates that the ternary ASD of abiraterone:HPBCD:HPMCAS 126G (10:80:10 w/w) achieved the highest dissolution and supersaturation compared to both the binary system (abiraterone:HPBCD) and other ternary variants, highlighting the critical role of HPMCAS 126G inclusion and optimal molar ratio in enhancing abiraterone release.	(Gala et al., 2020)
Drug: Polymer: Polymer	Indometacin: PVPVA: PEO	8.000	∼80 % after 75 min (Invitro: 7.5 % IND: >80 % after 75 min 15 % & 30 % IND: Doesn't dissolve, tablet form remains intact (pH 1.2), all formulation >80 % after 130 menit (pH 6.8)	(Pezzoli et al., 2019)
Drug: Polymer: Polymer	Indometacin: Eudragit EPO: PVPK30	10.000	<6 μg/mL	(Wang et al., 2020)
Drug: Polymer: Polymer	Itraconazole: HPMCAS: Poloxamer 188	20.750	10 % after 2 h	(Solanki et al., 2019)
Drug: Polymer: Polymer	Indometacin: HPMC: Mesoporous Silica	21.340	217.5 μg/mL (High-SME samples (2- and 3-kneading zones): Maintained supersaturation for up to 24 h → strong “parachute effect” → superior in vitro dissolution behavior)	(Hanada et al., 2018b)
Drug: Polymer: Polymer	Itraconazole: HPMCAS: Poloxamer 407	41.490	40 % after 2 h	(Solanki et al., 2019)
Drug: Polymer: Polymer	Celecoxib (10 %): MA-EA: HPC	53.330	10 % after 80 min	(Pöstges et al., 2022)
Drug: Polymer: Polymer	Regorfanib: HPMCAS: Povidone	61.670	(<10 μg/mL at 90 min) (In vitro Gastric simulation (FaSSGF): RGF_PVP: after 120 min in acidic medium, release dropped to ∼4 μg/mL.RGF_HPMCAS: unaffected, showing resistance to gastric fluid. Co-administered HPMCAS: not sufficient to protect against gastric fluid effects. In vivo AUC: 166.8 → 241.5 mg·h/L (not statistically significant, p = 0.34) tmax: 2.25 vs 2.5 h. High inter-individual variability in both groups)	(Müller et al., 2021)
Drug: Polymer: Polymer	Regorfanib: Povidone: HPMCAS	61.670	(<10 μg/mL at 90 min) (In vitro Gastric simulation (FaSSGF): RGF_PVP: after 120 min in acidic medium, release dropped to ∼4 μg/mL.RGF_HPMCAS: unaffected, showing resistance to gastric fluid. Co-administered HPMCAS: not sufficient to protect against gastric fluid effects. In vivo AUC: 166.8 → 241.5 mg·h/L (not statistically significant, p = 0.34) tmax: 2.25 vs 2.5 h. High inter-individual variability in both groups)	(Müller et al., 2021)
Drug: Polymer: Polymer	Curcumin: HPMC E5: Solupus (F1-F3)	77.500	F3 formulation, containing 20 % Soluplus®, achieved the highest dissolution rate: 91 % ± 3.89 %, compared to pure curcumin which exhibited only 10 % ± 2.58 % dissolution.	(Ishtiaq et al., 2024)
Drug: Polymer: Polymer	Nimodipin (10–30 %): HPMCE5: Eudragit	666.670	>85 % after 30 min (In vitro: >85 % API dissolved in 30 min (immediate release target)	(Hörmann et al., 2018)
Drug: Polymer: Surfactant	L-tetrahydropalmatine:Hydroxypropyl Methylcellulose Phthalate:Poloxamer 188	1.470	<50 %	(Tung et al., 2021)
Drug: Polymer: Surfactant	griseofulvin:Soluplus: Sodium dodecyl sulfate (SDS)	2.060	Ternary HyNASD formulations composed of GF:Sol:SDS at 1:5:0.05 ratios achieved exceptionally high GF supersaturation—up to 300 % within 20 min, surpassing both physical mixtures and traditional nanocomposites. In contrast, binary systems or formulations without SDS failed to exceed ∼50 % supersaturation, underscoring the critical role of SDS for wettability and Sol polymer for recrystallization inhibition	(Rahman et al., 2020)
Drug: Polymer: Surfactant	griseofulvin:HPC: Sodium dodecyl sulfate (SDS)	2.120	Ternary HyNASD formulations composed of GF:Sol:SDS at 1:5:0.05 ratios achieved exceptionally high GF supersaturation—up to 300 % within 20 min, surpassing both physical mixtures and traditional nanocomposites. In contrast, binary systems or formulations without SDS failed to exceed ∼50 % supersaturation, underscoring the critical role of SDS for wettability and Sol polymer for recrystallization inhibition	(Rahman et al., 2020)
Drug: Polymer: Surfactant	Atorvastatin: PS530U: Tween 80	2.500	>90 % after 60 min	(Sarabu et al., 2022)
Drug: Polymer: Surfactant	Atorvastatin: PS630: Tween 80	2.500	>90 % after 60 min	(Sarabu et al., 2022)
Drug: Polymer: Surfactant	Bicalutamide: Copovidone: Vit E TPGS	6.510	Ternary ASDs with 1.5–3 % TPGS showed slightly faster BCL release and higher supersaturation than binary systems, but cryomilling reduced performance (∼18 μg/mL).	(Moseson et al., 2023)
Drug: Polymer: Surfactant	Bicalutamide: Copovidone: SDS	6.630	Formula with 3 % SDS maintained fast, congruent release even after cryomilling, indicating greater formulation resilience.	(Moseson et al., 2023)
Drug: Polymer: Surfactant	Felodipine: PVPVA: DATPEGS	8.120	0.001 mg/min/cm2	(Saboo et al., 2021)
Drug: Polymer: Surfactant	Ritonavir: Polyvinylpyrrolidone vinyl acetate: Poloxamer 407	15.910	77 % release in 75 min (pH 2.0), ∼9 % release in 15 min (pH 6.8), 65 % dissolution in 60 min (FeSSIF-V2)	(Siriwannakij et al., 2021)
Drug: Polymer: Surfactant	Ritonavir: Polyvinylpyrrolidone vinyl acetate: Span 20	15.910	47 % release at 75 min (pH 2.0) ∼9 % release in 15 min (pH 6.8), 71 % dissolution in 120 min (FeSSIF-V2)	(Siriwannakij et al., 2021)
Drug: Polymer: Surfactant	Itraconazole: PVP-VA: SLS	17.640	4 μg/mL up to 60 min	(Deshpande et al., 2018)
Drug: Polymer: Surfactant	Ritonavir: PVPVA: Span 20	22.220	>90 % after 1 h	(Wu et al., 2023)
Drug: Polymer: Surfactant	Itraconazole: Eudragit: TPGS	79.620	4 μg/mL up to 60 min	(Deshpande et al., 2018)
Drug: Polymer: Surfactant	Felodipine: PVPVA:TPGS	123.080	>55 % Release at 60 min	(Saboo et al., 2021)
Drug: Polymer: Surfactant	Amphotericin B: HPMCAS 912: Sodium Deodecyl Sulfate (125)	168.860	ternary ASDs (AmB + Surfactant + polymer) increased the dissolution concentration of Amphotericin B (AmB) by up to 90-fold, whereas binary ASDs (AmB + Surfactant only) achieved about a 40-fold increase, despite using 7.5× more Surfactant than the ternary system	(Smith-Craven et al., 2024)
Drug: Polymer: Surfactant	Itraconazole: Soluplus: SLS	199.600	4 μg/mL up to 60 min	(Deshpande et al., 2018)
Drug: Polymer: Surfactant	itraconazole: HPMCAS-HF: TPGS	213.760	4 μg/mL up to 60 min	(Deshpande et al., 2018)
Drug: Polymer: Surfactant	Ritonavir (30 %): PVPVA: Tween	283.780	6 mg/min/cm2	(Yang et al., 2023)
Drug: Polymer: Surfactant	Itraconazole: HPMCAS: DATPEGS	352.700	20 % after 2 h	(Solanki et al., 2019)
Drug: Polymer: Surfactant	Ritonavir (30 %): PVPVA: SDS	567.570	7 mg/min/cm2	(Yang et al., 2023)
Drug: Polymer: Surfactant	Ritonavir (30 %): PVPVA: Span	810.810	4 mg/min/cm2	(Yang et al., 2023)
Drug: Poymer: Excipient	Ritonavir: Copovidon: Colloidal silicon dioxide (Ph 1)	1.680	>60 % release in 60 min (pH 1.0)	(Njoku et al., 2020)
Drug: Poymer: Excipient	Fenofibrate (20 %): PVPVA: HPL	21.190	in FeSSIF medium: Dissolution profiles of FEN in all formulations showed higher initial drug concentrations (supersaturation) ∼100 μg/mL followed by gradually decreasing drug concentrations at 60 min reflecting recrystaliztion	(Czajkowski et al., 2023)
Drug: Poymer: Excipient	Ritonavir: Copovidon: Colloidal silicon dioxide (Ph 6,8)	30.000	>30 % dissolution in 60 min (pH 6.8)	(Njoku et al., 2020)
Drug: Poymer: Excipient	Ritonavir: Copovidon: Colloidal silicon dioxide (Ph 2)	31.000	>50 % release in 60 min (pH 2.0)	(Njoku et al., 2020)
Drug: Poymer: Excipient	Fenofibrate (20 %): PVPVA: HPL	75.190	in FaSSIF medium: Dissolution profiles of FEN in all formulations showed higher initial drug concentrations (supersaturation) ∼100 μg/mL followed by gradually decreasing drug concentrations at 60 min reflecting recrystaliztion	(Czajkowski et al., 2023)
Drug: Polymer: Surfactant	Ritonavir: Polyvinylpyrrolidone/vinyl acetate:Sodium dodecyl sulfate (30 %DL)	–	>70 % Release at 30 min	(Yang et al., 2023)
Drug: Polymer: Surfactant	Ritonavir: Polyvinylpyrrolidone/vinyl acetate:Span 20 (30 %DL)	–	100 % Release at 45 min	(Yang et al., 2023)
Drug: Polymer: Surfactant	Ritonavir: Polyvinylpyrrolidone/vinyl acetate:Span 85 (30 %DL)	–	100 % Release at 45 min	(Yang et al., 2023)
Drug: Polymer: Surfactant	Ritonavir: Polyvinylpyrrolidone/vinyl acetate:Tween 80 (30 %DL)	–	>50 % Release at 90 min	(Yang et al., 2023)
Drug: Polymer: Surfactant	Ritonavir: PVPVA: SLS	–	80 % at 90 min	(Indulkar et al., 2022)
Drug: Polymer: Surfactant	Ritonavir: PVPVA: span 20	–	40 % at 90 min	(Indulkar et al., 2022)
Drug: Polymer: Surfactant	Ritonavir: PVPVA: span 85	–	90 % at 90 min	(Indulkar et al., 2022)
Drug: Polymer: Surfactant	Ritonavir: PVPVA: TPGS	–	90 % at 90 min	(Indulkar et al., 2022)
Drug: Polymer: Surfactant	Ritonavir: PVPVA: tween 80	–	30 % at 90 min	(Indulkar et al., 2022)
Drug: Drug: Polymer	Sulfamethoxazole (SMZ): trimethoprim (TMP): Eudragit EPO	6.400-fold for SMZ and 1.9-fold for TMP	80 % at 10 min	(Li et al., 2022)
Drug: Drug: Polymer	sulfamethoxazole: trimethoprim: Polyacrylic acid (PAA)	2.600-fold for SMZ and 4.600-fold for TMP	80 % at 10 min	(Li et al., 2022)
Drug: Drug: Polymer	ezetimibe (EZE): lovastatin (LOV): Soluplus®	18.000-fold for EZE and 6.000-fold for LOV	92 % of EZE and 83 % of LOV dissolved within 5 min.	(Riekes et al., 2016)
Drug: Drug: Polymer	ritonavir (RTV): lopinavir (LPV): PVP	3.000	60 % at 20 min.	(Trasi and Taylor, 2015)
Drug: Drug: Polymer	ritonavir (RTV): lopinavir (LPV): HPMCAS	3.000	60 % at 20 min.	(Trasi and Taylor, 2015)
Drug: Drug: Polymer	flutamide (FL): bicalutamide (BIC): PVP	2.000-fold for FL and 3.000-fold for BIC	25 % of FL and 5 % of BIC dissolved after 60 min.	(Pacult et al., 2019)
Drug: Drug: Polymer	cefdinir (CEF): curcumin (CUR): PVP	2.250	90 % of CEF in 30 min.	(Naama et al., 2025)

Arif Budiman, Lisa Efriani Puluhulawa, Faradila Ratu Cindana Mo’o, Nurain Thomas, Melvern Theodorik S. Biu, Febrina Amelia Saputri, Siti Farah Rahmawati, Diah Lia Aulifa, Salma Amaliah, Agus Rusdin, Comparative evaluation of ternary amorphous solid dispersions: Identifying optimal excipient systems for enhancing drug solubility, International Journal of Pharmaceutics: X, Volume 10, 2025, 100461, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2025.100461.

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Comparative evaluation of ternary amorphous solid dispersions: Identifying optimal excipient systems for enhancing drug solubility

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