Enhancement of Solubility and Dissolution Rate of Poorly Water-Soluble Antifungal Drugs by Hot-Melt Extrusion Method

Poor water solubility is one of the most persistent formulation problems in oral drug development. For compounds whose intestinal permeability is adequate but dissolution is slow, the amount of drug presented to the absorptive membrane may remain below the level needed for consistent systemic exposure. This problem is especially relevant to lipophilic antifungal agents, for which long treatment courses, serious infections, comorbidities, acid-suppressive therapy, and variable nutritional status can magnify formulation-dependent differences in absorption [1].

Itraconazole (ITZ), posaconazole (POS), and griseofulvin are representative poorly soluble antifungal drugs. ITZ is a weakly basic, highly lipophilic molecule with very low aqueous solubility and strongly formulation-dependent oral absorption. POS is similarly lipophilic and has historically required enabling formulations to reduce food effects and improve exposure. Griseofulvin is a high-melting crystalline drug whose dissolution is strongly influenced by particle size and solid state. These molecules therefore provide demanding but informative models for evaluating advanced solubility-enhancement technologies.

Amorphous solid dispersions (ASDs) improve apparent solubility by placing a drug in a high-energy non-crystalline state and dispersing it within a polymeric matrix. Hot-melt extrusion (HME) is particularly attractive for ASD manufacture because it combines thermal energy and shear in a continuous process, avoids organic solvent removal, and can be linked to milling, pelletization, tableting, capsule filling, film formation, or fused-deposition three-dimensional printing. Nevertheless, HME is not simply a heating step. Successful performance depends on drug–polymer miscibility, melt rheology, thermal stability, screw design, mixing intensity, residence time, cooling rate, moisture exposure, and the mechanical history imposed during downstream processing.

The present review examines how HME can enhance the solubility and dissolution of poorly water-soluble antifungal drugs. It integrates mechanistic principles with formulation and process variables, critically evaluates representative ITZ, POS, and griseofulvin studies, and discusses how current QbD, PAT, biorelevant testing, and personalized manufacturing approaches can improve translation from laboratory extrudate to robust oral dosage form.

2. Review Approach

A targeted narrative literature search was conducted using PubMed, PubMed Central, Crossref-indexed publisher pages, and reference chaining. Search concepts combined “hot-melt extrusion”, “melt extrusion”, “amorphous solid dispersion”, “solubility”, “dissolution”, “bioavailability”, “itraconazole”, “posaconazole”, “griseofulvin”, “antifungal”, “HPMCAS”, “copovidone”, “Soluplus”, “quality by design”, “process analytical technology”, “tableting”, and “3D printing”.

Original experimental studies were prioritized, particularly those reporting formulation composition, extrusion conditions, solid-state characterization, dissolution, stability, downstream processing, or in vivo performance. Foundational papers were retained when required to explain ASD and HME mechanisms. The evidence was synthesized through July 2026. Because the search was designed to support a mechanistic and translational narrative rather than estimate a pooled treatment effect, no meta-analysis or formal risk-of-bias score was applied.

3. Why Poorly Soluble Antifungal Drugs Need Enabling Formulations

The oral performance of a poorly soluble drug is governed by the relationship between dose, equilibrium solubility, dissolution rate, gastrointestinal volume, precipitation tendency, permeability, and transit time. An increase in apparent solubility is useful only when the dissolved or colloidally dispersed drug remains available long enough to cross the intestinal membrane. Thus, a formulation that produces a brief concentration spike followed by rapid precipitation may perform less effectively than a formulation that generates a lower but sustained supersaturated concentration.

Antifungal molecules frequently combine aromatic heterocycles, halogenated groups, and rigid hydrophobic structures. These features support target binding but also strengthen crystal lattices and reduce hydration. ITZ further exhibits pH-sensitive ionization and complex dissolution behaviour during transfer from the stomach to the intestine. POS has low intrinsic solubility and a high dose burden. Griseofulvin is a classical dissolution-limited drug with a stable crystal lattice and a high melting point. For each drug, the formulation must reduce the energetic barrier to dissolution while limiting recrystallization in the solid state and precipitation in gastrointestinal fluid.

Conventional approaches such as micronization, salt formation, cyclodextrin complexation, lipid systems, nanosuspensions, and solvent-prepared solid dispersions can be effective, but each has limitations. Micronization increases surface area without eliminating lattice energy; salts are not feasible for every molecule; lipid systems may be sensitive to digestion and food; nanosuspensions require physical stabilization; and solvent-based ASD methods require solvent selection, containment, and residual-solvent control. HME offers a complementary strategy that can produce molecularly dispersed drug continuously and with comparatively compact manufacturing equipment.

4. Pharmaceutical Basis of Hot-Melt Extrusion

In HME, a premixed or separately fed API–excipient blend is conveyed through a heated barrel by one or two rotating screws. Conveying elements transport material, while kneading and mixing elements generate distributive and dispersive mixing. The material softens or melts, the drug dissolves in the polymer-rich phase or becomes finely dispersed, and the homogeneous melt exits through a die. Rapid cooling then kinetically traps the drug in an amorphous or molecularly dispersed state.

Twin-screw extruders are generally preferred for pharmaceutical ASDs because screw elements can be configured to balance conveying, mixing, devolatilization, and residence time. However, single-screw equipment can be useful for small-scale screening and filament production. The relevant thermal history is not represented by barrel set temperature alone. Actual melt temperature, torque, pressure, shear, SME, feed rate, screw speed, fill level, and residence-time distribution determine whether sufficient mixing is achieved before thermal degradation occurs.

The process window is commonly positioned above the softening or glass-transition region of the formulation but below the degradation thresholds of the API and excipients. Plasticizers, surfactants, water, or low-molecular-weight polymers can reduce melt viscosity and processing temperature. Conversely, excessive plasticization can lower the Tg of the final ASD, increase molecular mobility, and reduce storage stability. HME development therefore requires simultaneous optimization of manufacturability and product performance rather than isolated maximization of drug release.

5. Mechanisms of Solubility and Dissolution Enhancement

5.1 Conversion of crystalline drug to a high-energy amorphous state

Crystalline dissolution requires disruption of an ordered lattice. In an amorphous phase, long-range order is absent and the free energy is higher, so the chemical potential driving dissolution is increased. HME can amorphize a drug by melting it, dissolving it in a polymer below its melting point, or combining thermal and mechanical energy. PXRD halo patterns and disappearance of the crystalline melting endotherm in DSC are commonly used to support amorphization, although neither method alone proves molecular homogeneity.

Amorphization is beneficial but metastable. If drug loading exceeds the thermodynamic or kinetic capacity of the polymer, drug-rich domains may form during processing or storage. Molecular mobility rises when temperature or absorbed moisture lowers the effective Tg. A physically stable ASD therefore requires an adequate polymer fraction, favourable interactions, and packaging conditions that keep the product well below its mobility threshold.

5.2 Improved wetting, dispersion, and matrix-controlled release

Hydrophilic and amphiphilic polymers improve contact between the drug and aqueous medium. As the matrix hydrates, drug is released as molecular species, nanoparticles, nanodroplets, or mixed colloids. The polymer may also reduce interfacial tension and prevent aggregation of hydrophobic drug. The dissolution profile is consequently governed by both drug thermodynamics and polymer hydration, erosion, swelling, or ionization.

Polymer choice must match the intended site of release. Copovidone and Soluplus® can support rapid hydration across a broad pH range, whereas HPMCAS provides pH-dependent dissolution and strong precipitation inhibition in the intestine. HPMC and HPC can act as hydrophilic matrices or functional ternary additives. Enteric–hydrophilic polymer combinations may protect the formulation in gastric fluid and then accelerate release after pH transition.

5.3 Generation and maintenance of supersaturation

ASDs can transiently produce concentrations above crystalline equilibrium solubility. This “spring” effect is valuable only when precipitation is delayed by a “parachute” mechanism. Polymers can inhibit nucleation, crystal growth, or both by adsorbing to drug-rich surfaces, increasing solution viscosity, interacting with drug molecules, or stabilizing colloidal species.

Surfactants may improve wetting and lower HME processing temperature, but their effects are system-dependent. A surfactant can increase initial release yet partition into drug-rich phases, alter drug activity, or weaken polymer-mediated precipitation inhibition. In ITZ–HPMCAS systems, carefully selected surfactant levels improved acidic release and processability, whereas excessive mobility or incompatible phase behaviour can compromise stability [8,9].

5.4 Drug-rich colloids and apparent solubility

During ASD dissolution, analytical filtration may classify submicron drug-rich colloids as “dissolved” drug. These colloids can act as a reservoir that replenishes molecularly dissolved drug and may improve membrane flux, but their contribution depends on size, stability, composition, and the rate of molecular exchange. ITZ–HPMCAS studies have shown that very high apparent supersaturation can coexist with colloidal particles, emphasizing the need to distinguish total dispersed drug from freely dissolved drug [8].

Mechanistic dissolution testing should therefore combine conventional concentration measurement with particle-size analysis, ultracentrifugation or appropriate filtration, membrane-flux testing, and, where feasible, biphasic or dissolution–permeation methods. This is especially important for antifungal ASDs because pH transition and bile components can substantially change speciation.

Table 1. Functional roles of common HME formulation components for poorly soluble antifungal drugs

6. Formulation Design Strategy

6.1 API assessment

Preformulation should define melting point, degradation onset, Tg of the amorphous drug, glass-forming ability, pKa, logP/logD, crystalline polymorphism, dose, and pH–solubility profile. Thermal analysis should be interpreted with chemical-assay data because disappearance of a melting peak can reflect dissolution in polymer, amorphization, or degradation. For weak bases such as ITZ and POS, dissolution must be tested across gastric-to-intestinal pH transition rather than in a single medium.

Drug–polymer miscibility can be estimated using solubility parameters, Flory–Huggins modelling, melting-point depression, film casting, small-scale melt screening, or spectroscopic mapping. These tools reduce the experimental space but do not replace extrusion trials, because shear, water content, and residence time can create states that are not reproduced by equilibrium calculations.

6.2 Polymer selection

An ideal polymer should dissolve or intimately mix with the drug during processing, inhibit crystallization during storage, promote release at the desired gastrointestinal site, tolerate the extrusion temperature, and support downstream manufacture. Strong hydrogen bonding or other specific interactions may improve miscibility and reduce drug mobility, but excessively strong interactions can slow release.

HPMCAS is especially useful for ITZ and POS because its hydrophobic substituents support drug interaction while succinoyl groups provide pH-dependent ionization. Copovidone offers a lower-viscosity and broadly soluble matrix with established HME use. Soluplus® combines polymeric and surfactant character. HPMC and HPC can improve biorelevant partitioning when used in ternary systems. No polymer is universally superior; the choice must be made against the target product profile.

6.3 Drug loading and phase behaviour

High drug loading reduces dosage-form mass but narrows the physical-stability margin. Below the drug solubility in the polymer, a single-phase ASD may be obtained. Above that level, the product can remain apparently amorphous because crystallization is slow, yet it may contain drug-rich domains that accelerate phase separation during storage. Drug loading also changes melt viscosity, torque, compaction, disintegration, and release.

For ITZ–PVPVA systems, drug loading has been shown to affect mechanical and tableting behaviour, demonstrating that solid-state optimization cannot be separated from downstream manufacturability [13]. A practical approach is to establish a loading range rather than a single target and evaluate it under stressed humidity, milling, compression, and dissolution conditions.

6.4 Plasticizers, surfactants, and ternary systems

Plasticizers lower the processing temperature by increasing chain mobility. Surfactants can serve the dual roles of plasticization and dissolution enhancement. In ITZ–HPMCAS extrudates, poloxamers and TPGS improved extrusion feasibility and acidic release at selected levels [8]. However, plasticizer level must be controlled because it may reduce Tg, increase tackiness, alter filament dimensions, or change the release mechanism.

Ternary ASDs can separate functions: one polymer provides drug miscibility and storage stability, while another improves hydration, partitioning, or tableting. Bachmaier and co-workers found that low-viscosity HPC, particularly HPC-UL, improved ITZ partitioning in biphasic dissolution and enhanced in vivo exposure when added to an HPMC-based ASD [10]. Such results support function-led excipient design rather than reliance on a single carrier.

7. Process Engineering, QbD, and PAT

A rational HME process begins with a quality target product profile defining dosage form, strength, release site, dissolution, stability, and patient-use requirements. CMAs include API particle properties, polymer grade, moisture, drug loading, surfactant level, and feed-blend uniformity. CPPs include barrel-zone temperatures, screw configuration, screw speed, feed rate, torque, melt pressure, residence time, and cooling conditions. CQAs include assay, content uniformity, residual crystallinity, degradation products, Tg, extrudate morphology, particle size after milling, dissolution, supersaturation maintenance, and stability.

DoE is valuable because HME variables interact. Increasing screw speed may shorten residence time but increase shear rate; increasing feed rate can increase fill and pressure while reducing the energy delivered per unit mass; stronger kneading may improve amorphization but also elevate melt temperature. Thiry et al. used preformulation and multivariable optimization to define a design space for continuous ITZ ASD manufacture [6]. More recently, in-line UV–visible monitoring has been applied to ITZ–Kollidon® VA64 extrusion to track conformational and process-related changes in real time [14].

PAT tools may include near-infrared, Raman, UV–visible, torque, pressure, melt temperature, and spectroscopic imaging. Their value is greatest when the measured signal is linked to a CQA through a validated model. For example, an in-line spectral change can indicate drug dissolution or molecular environment, but it should be correlated with off-line PXRD, DSC, assay, and dissolution. The ultimate goal is a control strategy that detects drift before product failure rather than merely documenting the final extrudate.

Table 2. Representative critical attributes and process parameters in antifungal ASD development

8. Characterization of HME-Based Antifungal ASDs

No single analytical method is sufficient to characterize an ASD. PXRD detects crystalline diffraction but may miss low levels of crystallinity. DSC identifies thermal transitions but can be affected by overlapping polymer events and sample history. Modulated DSC can improve Tg interpretation. FTIR and Raman spectroscopy provide evidence of drug–polymer interactions and spatial homogeneity. Solid-state nuclear magnetic resonance and dielectric spectroscopy can provide deeper information on molecular environment and mobility when available.

SEM reveals extrudate fracture surfaces and milled-particle morphology but does not establish amorphization. Rheology and torque measurements support process-window selection. Dynamic vapour sorption is important because water plasticizes many polymers. HPLC or stability-indicating chromatography is essential for detecting thermal degradation.

Dissolution testing should reflect the intended biopharmaceutic mechanism. A single-compartment test may rank formulations incorrectly when the drug undergoes gastric ionization, intestinal supersaturation, precipitation, or colloid formation. Two-stage pH-shift methods, biorelevant media, biphasic dissolution, and membrane-flux tests are therefore preferred for mechanistic development. Thiry et al. demonstrated that the apparent ranking of ITZ formulations can depend strongly on the dissolution medium [7].

Table 3. Analytical toolkit for HME-based antifungal ASDs

9. Evidence for Individual Antifungal Drugs

9.1 Itraconazole: the principal HME model

ITZ is the most extensively investigated antifungal model for HME-based ASD development. Early melt-extrusion formulation studies established that polymer ratio and processing conditions influence extrudate clarity, torque, Tg, and dissolution [3]. Janssens et al. later showed that preparation method can affect apparent drug–polymer miscibility and solid-state supersaturation in ITZ–Eudragit® E systems [4]. These findings are important because a formulation that appears homogeneous immediately after manufacture may occupy a metastable region with limited long-term tolerance.

Lang et al. evaluated ITZ–HPMCAS compositions prepared by thin-film freezing and subsequently processed by HME. Addition of hydrophilic carriers and increased mixing improved acidic release and reduced precipitation after transfer to neutral medium. Extrusion temperature and screw configuration were influential, demonstrating that identical composition can produce different performance when the mixing history changes [5].

Thiry et al. selected polymers using DSC, thermogravimetric analysis, and solubility-parameter concepts, then developed a continuous HME process and design space for ITZ ASDs [6]. A subsequent study reported improved bioavailability of HME-produced ITZ solid dispersions using an experimental framework intended to reduce animal use [7]. Together, these studies provide a useful model of progression from preformulation to process optimization, discriminating dissolution, and in vivo confirmation.

Solanki et al. examined HPMCAS systems in which surfactants acted as plasticizers. HPMCAS showed useful miscibility with ITZ, and selected ternary compositions could be extruded at manageable temperature. Fifteen percent surfactant increased acidic drug release relative to HPMCAS alone, while pH-shift testing generated very high apparent supersaturation that included colloidal drug species [8]. Their downstream study showed that tablet formulation and disintegration determine whether extrudate-level advantages are retained [9].

Bachmaier et al. used low-viscosity HPC grades as functional additives in HPMC-based ITZ ASDs. Biphasic dissolution and in vivo results supported improved partitioning and oral exposure, particularly with HPC-UL [10]. Triboandas et al. applied QbD principles to formulate and compact ITZ–Kollidon® VA64 ASD tablets, demonstrating the importance of compaction variables and excipient selection [11]. Mishra et al. similarly showed that milling and tableting of ITZ–HPMCAS extrudates require systematic optimization because particle size and tablet composition influence flow, compactability, disintegration, and dissolution [12].

Recent work has extended ITZ HME into real-time process monitoring, personalized dosage forms, and high-drug-loading products. In-line UV–visible spectroscopy has been used with sequential DoE to understand extrusion and conformational changes [14]. Extruded ITZ systems have also been coupled with additive manufacturing, although dense printed structures may substantially slow release. Milliken et al. reported approximately 63% release in 30 min from directly compressed HPMCAS ASD tablets, compared with only 3–6% from two 3D-printed formulations, illustrating that dosage-form architecture can outweigh the favourable solid state of the ASD [18].

9.2 Posaconazole

POS provides strong evidence that HME can improve both dissolution and systemic exposure. Fule and Amin prepared Soluplus®-based HME ASDs with selected surfactants and reported amorphization, improved dissolution, and several-fold enhancement of in vivo bioavailability compared with crystalline POS and a marketed suspension [19]. The work also highlighted the usefulness of complementary miscibility and molecular-interaction tools.

Li et al. compared HME and spray-dried POS–HPMCAS ASDs at 25% drug loading. Although the two processes produced different in vitro release patterns, their in vivo performance in cynomolgus monkeys was similar, showing that conventional dissolution differences do not always translate directly into exposure differences [20]. This result supports use of mechanistic and biorelevant tests rather than reliance on a single compendial method.

Kramarczyk et al. compared different polymers for HME POS ASDs and showed that polymer type strongly affects amorphization, molecular mobility, dissolution, and physical stability [21]. The collective POS literature indicates that HPMCAS, Soluplus®, and copovidone-based systems can be effective, but release site, polymer ionization, and precipitation control must be aligned with the clinical dosage form.

9.3 Griseofulvin

Griseofulvin differs from ITZ and POS because its high melting point and strong crystallinity can make full molecular dispersion difficult without high thermal stress. HME can nevertheless enhance performance through amorphization, solid-crystal suspension formation, or intensive particle-size reduction within a polymer matrix.

Bennett et al. studied binary, ternary, and quaternary dispersions containing griseofulvin with enteric and hydrophilic polymers. The combination of polymers improved in vitro dissolution and showed that an enteric polymer can be complemented by a rapidly hydrating vinyl-pyrrolidone polymer [22]. Reitz et al. demonstrated an HME-generated solid crystal suspension in which particle-size reduction produced a 3.5-fold increase in dog bioavailability relative to a physical mixture and performance comparable with or slightly above a marketed product [23]. These findings show that HME does not always need to achieve complete amorphization; a stable, finely dispersed crystalline phase may be preferable when the API has a high melting point or limited amorphous stability.

Table 4. Representative HME studies involving poorly soluble antifungal drugs