Ternary Solid Dispersions as an Alternative Approach to Enhance Pharmacological Activity

Introduction

The development of active pharmaceutical ingredients (APIs) plays a crucial role in modern treatment. APIs serve as the primary ingredient in pharmaceutical formulations, providing therapeutic benefits to patients.¹ They demonstrate pharmacological activity and frequently combined with other excipients to create stable dosage forms that are acceptable to patients.² Despite advancements in drug formulation and delivery systems, achieving optimal therapeutic outcomes is still a challenge for many APIs due to their limitations in solubility and bioavailability, which eventually hinder their clinical effectiveness.

Table 1 Impact of Ternary Solid Dispersion on Pharmacological Activity

Oral administration is the most frequently utilized route for drug delivery.^3–7 However, the development of oral formulations presents several challenges, one of which is the poor solubility of the drug candidates, which would significantly impact their oral bioavailability. The Biopharmaceutics Classification System (BCS) categorizes drugs based on their solubility and permeability, with Class II and IV compounds exhibiting limited bioavailability. This limitation hinders drug absorption and complicates the achievement of optimal therapeutic concentrations in the bloodstream.⁸ Consequently, numerous promising drug candidates fail to reach the market or require advanced formulation strategies that increase development complexity. According to current literature, approximately 40% of commercially available drugs exhibit low aqueous solubility, and 40–90% of new drug candidates are also reported to demonstrate poor water solubility.^9–12 Therefore, the development of novel strategies to enhance drug solubility is essential for improving the formulation of poorly water-soluble drugs.

Researchers have developed several formulation strategies to enhance the solubility and dissolution of poorly soluble drugs.^13,14 Amorphization is one such strategy, as it creates irregular molecules with higher free energy, facilitating dissolution and absorption in the body.¹⁵ However, amorphous drugs without excipients are highly susceptible to recrystallization during storage and dispersion.¹⁶ Amorphous solid dispersions (ASDs) and co-amorphous systems, commonly classified as binary systems, stabilize amorphous drugs, improving their dissolution rates and bioavailability.^17–20 Despite their effectiveness, some binary systems exhibit poor wettability and stability, which can hinder drug release and low solubility.^21,22 Recent studies have investigated ternary solid dispersions (TSDs), where the addition of a third component enhances the physicochemical properties.²³

A TSD system consists of an API dispersed within two different excipients in solid form. Adding a third component to a binary system enhances both solubility and stability by promoting intermolecular interactions between the API and solubilizer, which reduces the risk of recrystallization.¹⁹ TSDs have also shown significant potential in improving pharmacological activity, as the third component enhances drug release and bioavailability.^20,24 This formulation strengthens drug-biological system interactions, leading to better therapeutic outcomes. It is particularly beneficial for poorly soluble drugs²⁵ that require advanced strategies to improve pharmacological efficacy.¹⁹

Despite extensive research on TSD systems for enhancing API solubility in oral drug formulations, studies providing in-depth analyses of their impact on pharmacological activity remain limited. This review aims to elucidate the potential and mechanisms of TSDs in enhancing pharmacological activity through a comprehensive analysis of the current literature while highlighting key findings. Additionally, it proposes future research directions to advance therapeutic strategies for poorly soluble drugs.

Methods

This review is based on available literature from Scopus, PubMed, and Google Scholar, using the keywords “ternary solid dispersion” and “pharmacological activity”. The search focused on studies published since 2014 to ensure relevance to recent advancements. Reviews, opinion pieces, and unrelated studies were excluded. The selected literature specifically examines the role and mechanism of ternary solid dispersion systems in enhancing pharmacological activity. Figure 1 illustrates the study selection process.

Figure 1 The study design with the inclusion and exclusion criteria for this review.

Pharmacological Activity

Pharmacological activity refers to the biochemical or physiological effects of a drug or active compound upon interacting with a biological system.²⁶ These effects influence various pathways, including enzymatic activity, receptor binding,²⁷ or intracellular processes.^28,29 This parameter is a key for evaluating therapeutic efficacy, encompassing potency, efficacy, and dose-response relationship, all of which have driven pharmaceutical development.^30,31 Disease treatment widely uses various pharmacologically active compounds, including antibiotics, analgesics, anti-neurodegenerative, anticancer, antiviral, antimicrobial, and anti-diabetic agents.³² For instance, ibuprofen alleviates pain,³³ while amoxicillin targets bacterial infections,³⁴ highlighting the role of pharmacological activity in therapeutic interventions.

Beyond the development of pharmacologically potent compounds, conventional therapeutic approaches remain essential in disease management. Conventional drug delivery systems primarily include oral,³⁵ topical,³⁶ and parenteral routes.³⁷ Among these, oral administration is the most common due to its non-invasiveness and ease of use. This trend has led to the widespread adoption of tablets and capsules for API delivery.³⁸ Their simple formulation enhances patient adherence, supporting their extensive use.³⁹ Despite their widespread use, oral dosage forms face challenges, particularly with poorly soluble pharmaceuticals.⁴⁰ Limited solubility can significantly reduce pharmacological efficacy and therapeutic potential.⁴¹ The key factors contributing to this issue are as follows (Figure 2).

Figure 2 Key factors influencing pharmacological activity.

Solubility of APIs

Molecular size significantly influences drug solubility and ultimately pharmacological efficacy.^42–44 Larger molecules often have lower aqueous solubility, limiting absorption and bioavailability. Research on cytochrome P450 inhibition shows that peak activity increases within a molecular size of the drug range of 300–500 Da but declines beyond this threshold due to poor solubility and reduced target interaction.⁴⁵

Bioavailability (Pharmacokinetics)

The efficacy of orally administered drugs depends on their dissolution in gastrointestinal fluids and permeability across biological membranes to reach systemic circulation.⁴⁶ Poor bioavailability, often due to low absorption or extensive first-pass metabolism, prevents drugs from reaching therapeutic plasma levels. Many drugs act by targeting specific receptors or enzymes, such as statins inhibiting HMG-CoA reductase to lower cholesterol⁴⁷ or proton pump inhibitors like omeprazole suppressing gastric acid production.⁴⁸ These mechanisms highlight the importance of bioavailability and solubility in optimizing API efficacy.

Interaction with Biological Targets (Pharmacodynamics)

Many APIs exert their therapeutic effects by selectively targeting receptors, enzymes, or biological pathways. Drug efficacy depends on binding affinity, as low affinity can lead to minimal pharmacological activity.⁴⁹ Poor target specificity may also trigger off-target interactions, increasing adverse effects and reducing therapeutic efficacy.^50,51

Formulation Considerations

Pharmaceutical stability is essential for maintaining drug efficacy during storage. Instability can cause API degradation, reducing therapeutic effectiveness. Formulation methods also impact stability. For example, amorphous drugs are inherently more unstable due to higher energy levels, leading to recrystallization over time.¹⁶ Therefore, additional techniques are often required to enhance long-term stability and optimize drug performance.

Microenvironment at the Site of Action

The pH of the microenvironment at the target site influences drug solubility, ionization, and efficacy. Suboptimal pH can hinder absorption and reduce therapeutic effects. Additionally, enzymatic activity may degrade the drug prematurely, further limiting its bioavailability and efficacy.⁵²

TSD systems offer an innovative solution to overcome these challenges. By utilizing synergistic interactions among multiple components, TSD enhances the solubility, stability, and bioavailability of poorly soluble APIs,⁵³ ultimately optimizing therapeutic efficacy.

Ternary Solid Dispersions (TSD)

Binary solid dispersions (BSDs) enhance API solubility and stability by combining polymeric carriers to form amorphous systems. However, they often suffer from limited physical stability, processing constraints, and precipitation during dissolution.⁵⁴ To overcome these limitations, TSD contains a third component, such as a secondary polymer, surfactant, small molecule, pH modulator, or adsorbent, to further optimize performance.⁵⁵ Studies have demonstrated that TSDs enhance solubility, prevent precipitation, improve stability and processability,²⁰ which makes them superior to BSDs.⁵⁶ The following sections provide detailed discussions of the types of TSD systems, as illustrated in Figure 3.

Figure 3 The type of ternary solid dispersion system. Adapted from Budiman A, Lailasari E, Nurani NV et al. Ternary solid dispersions: A review of the preparation, characterization, mechanism of drug release, and physical stability. Pharmaceutics. 2023;15(8):1–30. Creative Commons.25

API + Polymer + Polymer

This type of TSD employs two polymers, leveraging their distinct physicochemical properties to inhibit crystalline growth,¹⁵ enhance stability,⁵⁷ improve wettability, and enable controlled drug release.⁵⁸ Al-Obaidi et al found that adding poly[2-hydroxypropyl methacrylate] (PHPMA) to a griseofulvin-polyvinylpyrrolidone (PVP) system enhanced dissolution and wettability through hydrogen bonding.⁵⁸ Similarly, Prasad et al demonstrated that the ternary combination of indomethacin with an ionic copolymer of methacrylic acid and methyl methacrylate (Eudragit^® 100) and PVP K90 improved stability and dissolution significantly compared to the BSD systems, due to synergistic polymer effects that enhanced drug-polymer interactions and inhibited precipitation from supersaturated solutions.¹⁵

API + Polymer + Surfactant

Certain TSD formulations disperse a poorly water-soluble drug within a polymer matrix alongside an anionic, cationic, or non-ionic surfactant. These surfactants enhance drug-polymer interactions, improve dispersion, and promote absorption.⁵⁹ In some cases, the surfactant molecules synergize with the polymer, forming a coating on the drug particles and subsequently increasing dissolution efficiency.⁶⁰ Alhayali et al reported that the addition of Poloxamer 188 into an ezetimibe-PVP K30 system enhances the complex solubility and maintains supersaturation, which is important in improving oral drug absorption and bioavailability.⁶¹ Similarly, Chamsai et al found that D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) reduces interfacial tension and contributes to a more porous structure, improving the solubility of manidipine-copovidone.⁶²

API + API + Polymer

In this approach, researchers integrate multiple APIs into a single system, which is particularly beneficial for combination therapies involving poorly soluble APIs.²⁰ For instance, the cyclodextrin (CD) complex with darunavir and ritonavir enhances the solubility and stability of ritonavir, which is important because it improves oral bioavailability and enhances pharmacokinetic performance.⁶³ Similarly, Riekes et al utilized polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus^®) as the carrier for ezetimibe (EZE)/lovastatin (LOV) to improve the dissolution profile of the combination drugs. Their study demonstrated high stability and rapid dissolution, with 92% of EZE and 83% of LOV dissolved within five minutes, which can be attributed to the hydrogen bonding interaction between the APIs and the polymer.⁶⁴

API + API + Small Molecule

In the context of TSD, the third component can sometimes refer to a small molecule that enhances the initial dissolution rate and stability of the system. Small molecules are non-peptide, biologically active compounds with molecular weights generally below 1000 Da, engineered for high selectivity, potency, and cellular permeability, establishing them as a fundamental component of modern pharmacotherapy due to their stability, ease of administration, and capacity to target diverse diseases.^65,66 It is important to distinguish that when the TSD consists of two APIs, the system may resemble co-amorphous dispersions, where both APIs and the small molecule interact to stabilize the amorphous form and improve drug performance. For example, Wairkar et al utilized magnesium aluminometasilicate (Neusilin^®) as a small molecule in the binary combination of nateglinide and metformin hydrochloride (NT-MT). The hydrogen bonding formed between NT, MT, and magnesium aluminometasilicate contributes to stabilizing the amorphous state in this TSD, leading to a notable improvement in NT dissolution, as well as enhancing flow properties and compressibility of the tablet formulation.⁶⁷ Similarly, Beyer et al integrated naproxen sodium, a small molecule salt form, into the naproxen-indomethacin binary system using quench-cooling. Their findings demonstrated that the TSD exhibited superior physical stability, with no signs of recrystallization over the 270-day observation period.⁶⁸

API + Carrier + Excipient

In this context, the carrier refers to a specific type of excipient that functions as the primary medium for dispersing the API, often replacing conventional hydrophilic polymers. Unlike general excipients, which may serve various supporting roles, carriers specifically facilitate homogeneous distribution of the API within the formulation, enhancing solubility and stability. Carriers in this TSD subtype may consist of lipids, pH modulators, and adsorbents (eg a mixture of polyethylene glycol glycerides (Gelucire^®50/13), magnesium aluminometasilicate).²⁰ The solubility of many drugs, typically weak acids or bases, is highly pH-dependent.⁶⁹ Hence, the variations in microenvironmental pH would influence drug activity, with weakly acidic drugs showing increased solubility at neutral or alkaline pH levels, while weakly basic drugs show higher solubility at acidic pH.⁷⁰ BSDs are often insufficient for solubilizing all pH-dependent drugs,⁶⁹ and studies have indicated that TSDs could enhance drug solubility through the addition of pH modulators such as acidifiers and alkalizers and suitable carriers.^71–74 Among the available alkalizers, the addition of 1% NaOH to a binary telmisartan system has been shown to substantially improve solubility by maintaining a stable pH across the dispersion matrix.⁷⁵ Citric acid inhibits the recrystallization of the binary GT0918-PVP K30 system and enhances its dissolution through the formation of hydrogen bonding between GT0918 and the citric acid.⁷⁶

BSD formulations often produce waxy products with poor flowability, low compressibility, and difficulty in pulverization.^77,78 Adsorption carriers help address these issues by enhancing surface area, preventing crystal growth, and stabilizing the APIs.^79,80 For instance, porous silica (Sylysia^® 350) improved the flowability and compressibility of Bosentan-Poloxamer 188 dispersion, converting them into a free-flowing powder and accelerating drug desorption.⁷⁹ Similarly, magnesium aluminometasilicate enhanced the surface area and flowability of carbamazepine-copovidone (Kollidone^® VA64) dispersions, leading to an improved dissolution profile.⁸¹

Pharmacological Activity of Ternary Solid Dispersions

Previous research has demonstrated the impact of TSD systems on the pharmacological activity of an API, including naturally derived compounds, as summarized in Table 1.

In vitro Studies of Ternary Solid Dispersion

Anticancer

Anticancer agents inhibit proliferation, induce apoptosis, or alter signaling in cancer cells.¹⁰¹ Their efficacy is often screened via in vitro assays like the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, which quantifies mitochondrial activity as an indicator for cell viability.^98,99 Nonetheless, poor solubility and bioavailability limit the effectiveness of many hydrophobic anticancer agents, necessitating advanced formulations to enhance treatment outcome.

Recent studies on TSD highlight their potential to improve anticancer efficacy by enhancing drug solubility and bioavailability. Lee et al⁹⁸ assessed the cytotoxic effects of chrysin and TSD chrysin using lauryl ether and aminoclay in HT29 colorectal cancer cells. The TSD chrysin exhibited significantly greater cytotoxicity than pure chrysin, with a CC₅₀ of 26.3 μM, whereas pure chrysin exhibited no cytotoxicity even at 160 μM. The TSD formulation’s enhanced solubility of chrysin was responsible for this improvement. Mane et al⁹⁹ similarly examined the anticancer properties of pure DOCE, binary, and ternary systems of DOCE on MCF-7 breast cancer cells. Figure 4 shows the ternary systems exhibited the highest cell growth inhibition (IC₅₀= 22.08 μg/mL), followed by the binary system (27,52 μg/mL), and pure DOCE (36.93 μg/mL). The increased inhibition resulted from heightened solubility and bioavailability via complexation with β-CD and HPMC, underscoring the critical role of solubility enhancement in augmenting anticancer efficacy.

Figure 4 The IC50 values of pure DOCE, binary, and ternary DOCE formulations against MCF-7 breast cancer cells. Each bar represents the concentration (μg/mL) of formulation required to inhibit 50% of cell growth. DOCE: pure docetaxel. Binary-DOCE: docetaxel with β-cyclodextrin (β-CD). Ternary-DOCE: docetaxel with β-CD and hydroxypropyl methylcellulose (HPMC). Adapted from Mane PT, Wakure BS, Wakte PS. Ternary inclusion complex of docetaxel using β-cyclodextrin and hydrophilic polymer: Physicochemical characterization and in-vitro anticancer activity. J Appl Pharm Sci. 2022;12(12):150–161. Creative Commons.99

Anticholinesterase

Anticholinesterases inhibit cholinesterase enzymes, primarily acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which degrade acetylcholine.¹⁰² By preventing this degradation, anticholinesterases augment acetylcholine levels, rendering them crucial for treating neurological disorders such as Alzheimer’s disease.¹⁰³ However, the low solubility of many drug candidates limits their bioavailability, reducing therapeutic efficacy. Recent research has investigated novel formulations to address solubility constraints and improve anticholinesterase effectiveness, as evidenced by Rosiak et al.⁸⁵

Rosiak et al⁸⁵ assessed the anticholinesterase activity of FIS, binary FIS-methacrylic acid-ethyl acrylate copolymer (FIS-BSD), and ternary FIS-methacrylic acid-ethyl acrylate copolymer-HP-β-cyclodextrin (FIS-TSD) employing a spectrophotometric technique, wherein enzyme inhibition was quantified by the color intensity of thiocholine generated on a 96-well plate. The inhibitory effects of FIS, FIS-BSD, and FIS-TSD on AChE and BChE were evaluated by comparing their absorbance with control samples (water). The results showed that pure FIS demonstrated minimal inhibitory efficacy (0.40% ± 0.03% for AChE and 3.64% ± 0.23% for BChE). However, improvements in solubility with BSD and TSD approaches significantly enhanced enzyme inhibition. The inhibition by FIS-BSD (AChE inhibition: ~20% and BChE inhibition: ~30%) was further enhanced by FIS-TSD (39.91% ± 3.47% for AChE and 42.62% ± 1.01% for BChE), exceeding previous FIS formulations and illustrating the vital role of solubility improvement in augmenting neuroprotective efficacy.

Anti-Inflammatory

Anti-inflammatory drugs reduce inflammation by obstructing the synthesis of pro-inflammatory mediators such as nitric oxide (NO), cytokines, and prostaglandins.¹⁰⁴ However, many APIs, especially in crystalline form, struggle to achieve anti-inflammatory efficacy due to inadequate solubility and bioavailability. Restricted solubility impedes absorption, diminishing their capacity to attain appropriate therapeutic concentrations at the target location.

Recent studies of TSD, including those by Sohn et al¹⁹ and Ishtiaq et al,⁸⁴ have explored the potential to overcome solubility difficulties and enhance anti-inflammatory activity. Sohn et al¹⁹ assessed the anti-inflammatory efficacy of piroxicam (PRX) and PRX-TSD using Poloxamer 407 (P407) and colloidal silica dioxide in LPS-induced RAW 264.7 cells. The research revealed that PRX samples diminished NO generation at a concentration of 25 μg/mL, with PRX-TSD exhibiting the most significant suppression (0.42 ± 0.01 μg/mL), followed by commercial piroxicam formulation (0.44 ± 0.01 μg/mL) and pure PRX (0.56 ± 0.01 μg/mL). PRX-TSD also exhibited the highest NO inhibition (26.6 ± 1.1%), signifying greater anti-inflammatory efficacy attributed to its enhanced solubility. Ishtiaq et al⁸⁴ similarly showed that TSD curcumin using HPMC E5 and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (CUR-TSD) markedly prevented protein denaturation (80% ± 3.16) in contrast to pure CUR (49% ± 2.91). The increased inhibition was ascribed to the superior solubility and bioavailability of CUR in the TSD, rendering it more efficacious against inflammatory processes.

Antioxidant

Antioxidants counteract free radicals, preventing oxidative harm. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay is commonly used to evaluate this activity in vitro by measuring absorbance at 517 nm, where a decrease in the absorbance indicates stronger antioxidant activity.¹⁰⁵ Numerous crystalline active substances exhibit diminished antioxidant capacity owing to inadequate solubility, limiting their efficacy in free radical scavenging.

Several studies on TSD, including those by Anwer et al⁹² and Ishtiaq et al⁸⁴ have demonstrated that enhancing solubility via TSD markedly improves antioxidant activity. Anwer et al⁹² found that the TSD of DIOS using β-CD and PEG 6000 exhibited superior DPPH radical scavenging activity (75% at 100 μg/mL), outperforming DIOS-PEG 6000 (58–65%) and pure DIOS (25–55%). This improvement was attributed to the enhanced solubility within the TSD system, resulting in greater dissolution and radical scavenging efficacy. Similarly, Ishtiaq et al⁸⁴ reported that CUR-TSD demonstrated significantly higher antioxidant activity with a DPPH inhibition of 93% ± 5.30, compared to 69% ± 4.79 for pure CUR. The greater efficacy of CUR-TSD was attributed to its improved solubility, overcoming CUR’s inherent poor solubility and augmenting its capacity to effectively scavenge free radicals.

Antimicrobial

Antimicrobial activity refers to a compound’s capacity to suppress or eradicate microorganisms, encompassing bacteria, fungi, viruses, and protists. Sun et al⁹⁶ investigated the inhibitory effects of TSD toltrazuril using Ca(OH)₂ and PEG 6000 (TOL-TSD) against Toxoplasma gondii and observed a marked increase in inhibition rates with elevated drug concentrations, particularly at lower doses. Nonetheless, the rate of growth inhibition diminished with increasing drug doses, reaching approximately 75% at 50 μg/mL and between 85% and 100% at 100 μg/mL. In comparison, TOL-BSD achieved inhibition rates of 60% and 70%, while pure TOL exhibited the lowest efficacy at 50% and 65%, respectively.

In addition to antiparasitic activity, enhancing solubility is vital for augmenting antibacterial efficacy. This was demonstrated by Ishtiaq et al⁸⁴ who evaluated the antibacterial activity of CUR and CUR-TSD against Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Escherichia coli. The findings indicated that CUR-TSD demonstrated markedly superior antibacterial efficacy than pure CUR, as evidenced by larger zones of inhibition and reduced minimum inhibitory concentration (MIC) values. The reduced antibacterial activity of CUR was ascribed to its hydrophobic characteristics. In contrast, the superior efficacy of CUR-TSD was likely due to its enhanced solubility and improved bacterial cell membrane penetration, rendering it more potent against both Gram-positive and Gram-negative bacteria. These results illustrate the importance of TSD in enhancing the bioavailability and antibacterial effectiveness of poorly soluble compounds.

In vivo Studies of Ternary Solid Dispersion

Anticancer

Bajracharya et al⁸⁶ assessed the co-administration of LW6, a BCRP inhibitor, with topotecan, a topoisomerase inhibitor, for metastatic ovarian carcinoma and small-cell lung cancer. Since BCRP limits topotecan’s oral bioavailability, the study examined LW6’s effect on enhancing its pharmacokinetics. The results showed a tenfold increase in topotecan’s oral bioavailability with TSD-LW6 compared to pure LW6, highlighting the role of BCRP inhibition. The improved solubility and dissolution of TSD likely resulted in elevated LW6 concentrations in the intestinal lumen, thereby augmenting its inhibitory impact on BCRP. These findings highlight TSD’s potential in optimizing oral bioavailability and therapeutic efficacy.

Anti-Alzheimer

Andrographolide, a diterpene lactone, exhibits various pharmacological properties and has been explored as a potential treatment for Alzheimer’s disease.¹⁰⁶ Serrano et al¹⁰⁷ demonstrated that andrographolide reduces β-amyloid (Aβ) levels and modulates amyloid plaque formation in the hippocampus and cortex of young mice, which improves cognitive deficits in both young and mature Aβ PPswe/PS-1 Alzheimer’s disease mice models. Nonetheless, its poor water solubility and low oral bioavailability have hindered further clinical development.

Fang et al⁹⁰ examined the anti-Alzheimer’s efficacy of ternary co-amorphous andrographolide (AP-TSD) using OMT and pHCA in Caenorhabditis elegans as an in vivo model. The AP-TSD formulations were safe (Figure 5), exhibiting no significant decline in survival rates, even at high concentrations. Compared to crystalline AP, AP-TSD significantly delayed nematode paralysis caused by Aβ aggregation, with the AP-TSD system exhibiting the strongest anti-Alzheimer’s effects. The findings indicate that TSD-based formulation could enhance stability, solubility, and pharmacological activity, presenting a promising strategy for the treatment of Alzheimer’s disease.

Figure 5 Visualization of Caenorhabditis elegans survival rate and mean paralysis time under different treatments. Pictogram rows (top): Each worm icon represents 5% of the total C. elegans population. Teal worms = alive/active (not paralyzed), gray worms = dead/paralyzed. Bar chart (bottom): Shows the mean time to paralysis (hours) for each treatment group. Control refers to C. elegans without active compound, while andrographolide represents the pure active compound. The ternary system of andrographolide consists of andrographolide formulated with oxymatrine (OMT) and p-hydroxycinnamic acid (pHCA). Adapted from Eur J Pharm Biopharm. Volume 181. Fang X, Hu Y, Yang G, Shi W, Lu S, Cao Y. Improving physicochemical properties and pharmacological activities of ternary co-amorphous systems. 22–35, Copyright 2022, with permission from Elsevier.90

Anti-Hyperlipidemic

Faraji et al⁹³ and Torrado-Salmerón et al⁹⁴ reported enhanced antihyperlipidemic efficacy of TSD atorvastatin (AT-TSD) in high-fat diet (HFD)-induced hyperlipidemia rats compared to pure AT. Faraji et al⁹³ found that pure AT reduces triglyceride (TG) and total cholesterol (TC) levels after 14 days (p < 0.01), while TSD and PM formulations showed greater lipid-lowering effects (p < 0.001) due to improved solubility and absorption. Torrado-Salmerón et al⁹⁴ demonstrated that AT-TSD using CCS and K significantly reduced TC, TG, and low-density lipoprotein (LDL) levels while preserving high-density lipoprotein (HDL) concentrations. This effect was attributed to increased AT permeability and P-glycoprotein inhibition by surfactants, facilitating hepatic lipid clearance and lipogenesis suppression. These findings highlight AT-TSD’s ability to improve antihyperlipidemic therapy by addressing solubility limitations.

The TSD system has also shown the antihyperlipidemic efficacy of simvastatin (SIM). Mahboobian et al⁸² demonstrated the antihyperlipidemic efficacy of SIM-TSD using polyoxyl 40 stearate and PEG 12000. On day 14, SIM-TSD significantly reduced TC levels (p < 0.001) and limited the TG increase to 4.70%, as compared to 65.52% in the HFD group. Unlike PM and pure SIM, which showed no significant effects, SIM-TSD exhibited an improved solubility and dissolution, resulting in greater in vivo efficacy. The study confirmed the significance of hydrophilic carriers and surfactants in enhancing drug wettability and absorption, in line with the findings on AT and rosuvastatin described earlier.

Anti-Inflammatory

The TSD system enhances the anti-inflammatory efficacy of poorly soluble drugs. Amin and Hussain⁹⁷ revealed that TSD lornoxicam using polyethylene glycol glycerides and polysorbate 80 (LOR-TSD) reduced paw edema by 50% relative to the binary system (60%) and the pure drug (70%). Alshehri et al¹⁰⁰ showed that FLF-TSD using β-CD and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer achieved 67.63% inhibition, compared to 43.06% for pure FLF after six hours. Haq et al⁸⁹ confirmed that AD-TSD using KSR and Poloxamer 407 improved inflammation control compared to pure AD in mitigating carrageenan-induced paw edema and ameliorating arthritic conditions in Wistar rats. These findings underscore the potential of TSD in improving drug solubility, absorption, and therapeutic efficacy for anti-inflammatory agents.

Anti-Hypoglycemic

Pisay et al⁸³ established that TSD glibenclamide using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and Poloxamer 407 (GLB-TSD) markedly improved anti-hypoglycemic efficacy in comparison to pure GLB and the commercially available product. In type II diabetic Sprague-Dawley rats, GLB-TSD rapidly lowered blood glucose (128 ± 17 mg/dL at 0.5 hours) and sustained lower glucose levels for 4 hours. This was ascribed to an almost three-fold augmentation in oral bioavailability, which was proven to be statistically significant in comparison to the non-TSD form of the drug (p < 0.005).

Anti-Diabetic

The antidiabetic efficacy can be improved by the TSD system, as evidenced by the research conducted by Zhaojie et al⁹¹ Their research showed that TSD of berberine using sodium caprate and PEG 6000 (BR-TSD) showed a significantly improved efficacy. At 25 mg/kg, BR-TSD reduces fasting blood glucose, TC, and TG levels in diabetic rats, comparable to berberine (100 mg/kg) and commercial tablets. At 100 mg/kg, BR-TSD surpassed berberine and metformin in hypoglycemic and triglyceride-lowering effects, highlighting its potential for type II diabetes treatment.

Hepatoprotective

Hwang et al⁸⁷ examined the hepatoprotective properties of SL-TSD via in vivo research utilizing CCl₄-induced hepatotoxicity in rats. The findings indicated that SL-TSD significantly reduces aspartate transaminase (AST) levels and liver deterioration, unlike SL powder and commercial formulations. Similarly, Torrado-Salmerón et al⁹⁴ reported that AT-TSD using CCS and K alleviated high-fat diet-induced liver injury, reducing steatosis, inflammation, and hepatocyte ballooning compared to the pure AT group. This API also resulted in a substantial drop in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS), indicating a reduction in liver damage and an enhancement in liver function.

Discussion and Author’s Perspective

TSDs offer an advanced formulation strategy to enhance the solubility and bioavailability of poorly soluble APIs. Unlike BSDs, which involve dispersing an API within a polymer matrix, TSDs integrate a third component to improve the physicochemical characteristics of the formulation. The primary objective of TSD development is to enhance drug dissolution and stability, addressing the issues associated with the restricted solubility of numerous novel therapeutic candidates. By overcoming these challenges, TSDs offer a promising strategy for enhancing drug absorption and optimizing therapeutic effects, ultimately leading to enhanced pharmacological activity and stronger interactions with biological systems.

To comprehensively evaluate the therapeutic potential of TSDs, in vitro and in vivo studies are crucial to assess their impact on the pharmacological activity of the formulated APIs. In vitro studies provide a controlled laboratory environment to examine the formulation’s interactions with biological systems at the cellular level, offering preliminary insights into efficacy and potential therapeutic advantages. Conversely, in vivo studies seek to assess TSD formulations in living creatures to ascertain the therapeutic efficacy of the drug in systemic circulation and its dynamic consequences.

The pharmacological advantages of TSDs can be predicted using theoretical models, such as the Conductor-like Screening Model for Real Solvents (COSMO-RS) and machine learning models.^108,109 While these models indirectly assess pharmacological activity, they estimate key formulation parameters─such as solubility, miscibility, and physical stability─that are strongly associated with therapeutic outcomes. These theoretical models are further supported by in vitro and in vivo studies. In vitro studies have indicated that TSDs can increase cellular uptake and improve pharmacological responses across various disease models. Research has indicated that TSDs could significantly enhance antioxidant, anti-inflammatory, anticancer, antibacterial, and anticholinesterase activities, highlighting their potential for optimizing drug performance.

Through in vivo studies, TSD formulations have demonstrated significant improvement in the bioavailability of poorly soluble drugs by increasing plasma concentrations, accelerating absorption, and enhancing the therapeutic efficacy of various pharmacological agents, including antihyperlipidemic, anticancer, anti-inflammatory, anti-hypoglycemic, anti-Alzheimer’s, antidiabetic, antioxidant, antibacterial, and hepatoprotective drugs. These findings demonstrate the ability of TSDs to optimize drug delivery by improving the pharmacokinetic and pharmacodynamic properties of APIs.

The enhancement of pharmacological efficacy by a TSD system is attributed to an increased solubility, stability, and bioavailability of the active compounds, as illustrated in Figure 6. Many crystalline APIs exhibit strong intermolecular interactions and high lattice energy, leading to thermodynamic stability but poor aqueous solubility. Overcoming this lattice energy is crucial for dissolution, often resulting in slow dissolution rates and restricted bioavailability. BSD systems address this limitation by adding hydrophilic carriers to diminish lattice energy and improve solubility. By interacting with the polymer, the crystalline structure is partially disrupted, transforming the drug into an amorphous state with lower lattice energy and greater molecular mobility. Nonetheless, some BSDs still suffer from limited wettability and dissolution rates, which restrict API absorption. TSDs introduce a third component to further optimize these properties, improving solubility, dissolution, and bioavailability.

Figure 6 The proposed mechanism underlying the enhancement of the pharmacological activity of active pharmaceutical ingredients in ternary solid dispersion systems. Abbreviation: API, active pharmaceutical ingredients.

TSD systems offer an advanced approach to improving drug solubility, stability, and absorption through the addition of an extra component, such as a polymer, surfactant, or other excipients. By significantly reducing lattice energy, TSDs promote the transformation of drugs into a high-energy amorphous state with enhanced molecule mobility and diminished intermolecular interactions, leading to improved solubility and bioavailability. These systems enhance drug wettability, reduce particle size, and inhibit recrystallization, ensuring prolonged supersaturation. Additionally, TSDs facilitate molecular-level API dispersion, accelerate dissolution, improve membrane permeability, and inhibit efflux transporters that limit drug absorption. The synergistic effects of drug carriers in TSD formulations optimize interactions with biological membranes, enabling more effective drug delivery and subsequently demonstrating superior efficacy across various pharmaceutical applications.

Despite the promising advantages of TSD systems, several formulation and scale-up challenges remain. From a formulation perspective, the selection of appropriate ratios and combinations of the API, polymer, and third component is critical, as their physicochemical interactions substantially influence solubility enhancement, physical stability, and pharmacokinetic efficacy. Maintaining the amorphous state of the API, essential for enhanced solubility, requires stringent control over processing parameters such as temperature, solvent evaporation rate, and mixing homogeneity. Suboptimal formulation or processing may lead to recrystallization, phase separation, or chemical degradation, ultimately reducing therapeutic performance. Moreover, the addition of a third component introduces additional complexity, necessitating comprehensive compatibility assessments with both the API and polymer to ensure stability and prevent adverse interactions.

Furthermore, the rational design of TSD formulations requires critical evaluation of third components, such as polymers, surfactants, acids/bases, pH modulators, adsorbents, and small molecule additives, due to their pivotal role in modulating intermolecular interactions, stabilizing the amorphous phase, and enhancing dissolution. Their compatibility with both the API and primary polymer matrix is essential to prevent recrystallization, phase separation, or chemical degradation. However, these components may pose risks related to toxicity, metabolic effects, or regulatory compliance. For example, certain surfactants can exhibit dose-dependent cytotoxicity or unintended membrane interactions, while emerging additives often lack comprehensive safety data. Although polymers such as PVP and HPMC are generally recognized as safe and effective crystallization inhibitors, their performance can vary depending on the API’s properties. Similarly, adsorbents and pH modifiers can improve stability and microenvironmental solubility but require careful characterization to avoid unintended interactions. Novel lipids and polymeric carriers offer promising functionality but demand thorough preclinical evaluation due to limited toxicological data. Thus, selection of third components must be determined by their functional efficacy in vitro, as well as their biocompatibility, toxicological profile, regulatory status, and suitability for long-term therapeutic use.

From a manufacturing perspective, scaling up TSD formulations using techniques such as hot-melt extrusion, spray drying, or solvent evaporation introduces significant technical challenges. Achieving consistent product quality and batch-to-batch reproducibility requires precise control over critical process parameters, including feeding rate, mixing duration, drying efficiency, residual solvent content, and particle size distribution. Equipment limitations and operational complexity often lead to increased production costs and extended processing times. Additionally, maintaining the long-term physical and chemical stability of the amorphous form during storage and distribution remains a major concern. These scale-up and stability issues necessitate systematic process development using design-of-experiment (DoE) studies, real-time process monitoring, and rigorous long-term stability testing under various environmental conditions.

Cost-effectiveness is a crucial consideration for the industrial viability of TSD formulations. The reliance on specialized carriers, high-performance excipients, and advanced manufacturing technologies can substantially elevate production costs. Therefore, developing economically feasible TSDs requires strategic excipient selection, simplification of production processes, and, where possible, the addition of cost-efficient third components that deliver comparable functional benefits without compromising product performance.

Regulatory approval of TSD products necessitates comprehensive physicochemical characterization, toxicological assessment, long-term stability studies, and validated manufacturing protocols. These requirements highlight the importance of systematic preclinical and pharmacokinetic investigations, supported by rigorous quality assurance protocols, to ensure successful clinical translation and eventual commercialization of TSD-based drug products.

Future research should focus on optimizing TSD formulations to enhance reproducibility and therapeutic efficacy for clinical applications. Key areas of exploration include refining amorphization techniques, selecting the optimal third component, and improving processing methodologies to enhance drug release and bioavailability. The exploration and addition of novel surfactants, polymers, and excipients hold significant promise for expanding the applicability of TSDs across a broader range of APIs, particularly those with challenging physicochemical properties.

Emerging research directions involve the integration of high-throughput formulation screening and machine learning-based predictive modeling to efficiently identify optimal TSD combinations. Comprehensive pharmacokinetic, toxicological, and preclinical studies remain critical to elucidate the in vivo behavior, safety profile, and systemic effects of TSDs, especially when adding novel or less-characterized excipients. The development of robust in vitro–in vivo correlation (IVIVC) models, alongside long-term physical stability assessment and detailed toxicity studies, both acute and subchronic, will be essential to support regulatory submissions and clinical translation. Collectively, these focused research strategies will significantly enhance the translational potential of TSD systems and accelerate their adoption into advanced pharmaceutical development pipelines.

Conclusion

In conclusion, TSDs significantly enhance the solubility, stability, and pharmacological efficacy of poorly soluble drugs. The addition of a third component in TSD formulations improves drug solubility, prolongs supersaturation, and prevents recrystallization, resulting in superior bioavailability and therapeutic outcomes. In vitro and in vivo studies consistently demonstrate that TSD-based formulations outperform BSDs in dissolution, absorption, and pharmacological optimization across various therapeutic applications. These advancements reinforce the potential of TSDs in drug development, particularly for oral drug administration. However, challenges in large-scale production, cost-effectiveness, and regulatory compliance must be addressed for successful clinical and commercial transition. Overcoming these barriers will maximize TSDs’ therapeutic benefits and broaden their role in modern pharmacology.