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Learn more: PMC Disclaimer | PMC Copyright Notice Int J Pharm X . 2026 Apr 9;11:100541. doi: 10.1016/j.ijpx.2026.100541 Search in PMC Search in PubMed View in NLM Catalog Add to search Solvent-free aqueous spray drying of poorly soluble drugs enabled by hot-feed micellar solubilization and high-Tg polymer matrices Wenling Zheng Wenling Zheng a School of Resources and Chemical Engineering, Sanming University, Sanming, Fujian 365004, PR China b School of Chemical Engineering, Fuzhou University, Fuzhou 350116, Fujian, PR China Find articles by Wenling Zheng a, b , Hui Chen Hui Chen a School of Resources and Chemical Engineering, Sanming University, Sanming, Fujian 365004, PR China Find articles by Hui Chen a , Rongrong Xue Rongrong Xue a School of Resources and Chemical Engineering, Sanming University, Sanming, Fujian 365004, PR China Find articles by Rongrong Xue a , Ziqing Wu Ziqing Wu c School of Education and Music, Sanming University, Sanming, Fujian 365004, PR China Find articles by Ziqing Wu c , Yongming Liu Yongming Liu c School of Education and Music, Sanming University, Sanming, Fujian 365004, PR China Find articles by Yongming Liu c, ⁎ , Fenghua Chen Fenghua Chen a School of Resources and Chemical Engineering, Sanming University, Sanming, Fujian 365004, PR China Find articles by Fenghua Chen a, ⁎ Author information Article notes Copyright and License information a School of Resources and Chemical Engineering, Sanming University, Sanming, Fujian 365004, PR China b School of Chemical Engineering, Fuzhou University, Fuzhou 350116, Fujian, PR China c School of Education and Music, Sanming University, Sanming, Fujian 365004, PR China ⁎ Corresponding authors. [email protected] [email protected] Received 2025 Dec 18; Revised 2026 Mar 19; Accepted 2026 Apr 8; Collection date 2026 Jun. © 2026 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMC Copyright notice PMCID: PMC13092062 PMID: 42011261 Abstract Poor aqueous solubility limits the oral bioavailability of many BCS II drugs, while conventional spray drying of amorphous solid dispersions (ASDs) often relies on organic solvents. Here we develop an aqueous spray-drying (AQSD) strategy that couples temperature-boosted solubility with poloxamer-enabled micellar solubilization and a high-Tg polymer matrix. Using celecoxib (CEL) as a model drug, heating increased intrinsic solubility and poloxamer 407 (P407) further raised apparent solubility to a ≥ 1 mg·mL −1 feed window suitable for atomization. Binary CEL–P407 produced wax-like solids, whereas adding soluble starch (SS) or polyvinylpyrrolidone (PVP) improved solidification and yielded powdery, amorphous products. PXRD and vibrational spectroscopy supported amorphization and a P407-rich hydrophobic microenvironment in the hot feed. Compared with the binary, ternary systems improved powderability/yield (e.g., ∼50% for CEL–P407–SS vs ∼40% for CEL-P407), maintained target drug loading with minimal net loss during drying, and enhanced non-sink dissolution, with CEL remaining amorphous after storage. The framework was further validated using indomethacin, sulfamerazine, and aripiprazole, while highlighting limitations for thermally labile compounds. Overall, AQSD provides a practical green rule—hot-feed micellar solubilization coupled with a Tg-raising matrix—for early ASD formulation screening and solvent-free manufacturing. Keywords: Aqueous spray drying, Amorphous solid dispersion, Micellar solubilization, High-T g polymer, Poloxamer 407 Graphical abstract Open in a new tab List of chemical compounds used for this article Celecoxib indomethacin sulfamerazine aripiprazole poloxamer 407 polyvinylpyrrolidone soluble starch simvastatin carbamazepine sulindac 1. Introduction Poor aqueous solubility remains a major barrier to oral drug delivery. However, approximately 40% of marketed drugs and up to ∼90% of pipeline compounds are poorly water-soluble ( Xie et al., 2024 ; Nyamba et al., 2024 ), posing persistent formulation challenges ( Kumari et al., 2023 ; Lou et al., 2024 ). Improving solubility is particularly critical for Biopharmaceutics Classification System (BCS) Class II compounds (low solubility, high permeability), where dissolution limits bioavailability ( Hastedt et al., 2024 ). Among available enabling technologies, amorphous solid dispersions (ASDs) are a proven strategy to enhance apparent solubility and exposure ( Zhang et al., 2023a ; Liu et al., 2024 ; Chen et al., 2024 ), with hot-melt extrusion and spray drying as the two dominant manufacturing routes ( Konda and Dhoppalapudi, 2022 ; Dedroog et al., 2019 ). Spray drying offers mild processing, rapid drying, simple operation, and continuous production. However, poorly soluble drugs typically require organic solvents to achieve sufficient feed solubility ( Chen et al., 2024 ; Konda and Dhoppalapudi, 2022 ; Dedroog et al., 2019 ; Poozesh and Bilgili, 2019 ; Singh and Van den Mooter, 2016 ; Davis and Walker, 2018 ), which introduces cost, safety, and environmental burdens. Developing aqueous spray-drying (AQSD) routes with biocompatible surfactants and polymers therefore represents a green alternative for solvent-free ASD production ( Sipos et al., 2022 ). Aqueous feed design for spray drying generally requires the integration of an effective solubilization mechanism—surfactant-, polymer-, or temperature-driven—with a solid-state matrix capable of promoting amorphization during droplet-to-particle conversion ( Kelsall et al., 2024 ; Al-Akayleh et al., 2022 ; Li et al., 2020 ). Among available pharmaceutically acceptable surfactants, toxicity and biodegradability concerns limit the use of some anionic species ( Wang et al., 2015 ), while cloud-point behavior complicates processing with certain amphiphilic polymers ( Hughey et al., 2013 ). In this context, poloxamer 407 (P407) is attractive because it forms non-ionic micelles above its critical micelle concentration and temperature and exhibits broad compatibility with common polymeric matrices ( Dumortier et al., 2006 ; Ban et al., 2017 ). In parallel, polymeric excipients such as polyvinylpyrrolidone (PVP), hypromellose acetate succinate (HPMCAS), Eudragit®, and soluble starch (SS) are widely used in ASD formulations to inhibit crystallization and to increase the effective glass transition temperature ( T g ), thereby improving processability and solid-state stability ( Kapourani et al., 2025 ). The physicochemical basis of drug–polymer miscibility, intermolecular interactions, and amorphous stability has been extensively established through foundational work by Taylor et al. ( Konno and Taylor, 2006 ; Newman et al., 2015 ; Hancock and Zografi, 1997 ), providing a robust framework for rational excipient selection in ASD design. In addition, a range of thermodynamic and mechanistic tools have been developed to rationalize amorphous miscibility and stability. T g -based mixing models, such as the Gordon–Taylor Eq. ( Gordon and Taylor, 1952 ), are widely used as practical, first-pass estimators to gauge the relative T g -raising potential of excipients and to inform processing windows. More elaborate equation-of-state approaches have also been explored to describe drug–polymer interactions from a molecular thermodynamic perspective ( Prudic et al., 2014 ; Dohrn et al., 2021 ). Rather than replacing experiments, these tools are most valuable when combined with rapid experimental feedback to guide formulation screening and de-risk processing decisions at an early stage. Dissolution performance represents another critical dimension of ASD evaluation. Conventional single-phase dissolution tests are routinely employed to assess supersaturation generation and maintenance, whereas more sophisticated approaches—such as biphasic dissolution systems or gastric-to-intestinal transfer models—have been introduced to improve physiological relevance and mechanistic resolution ( Brouwers et al., 2009 ; Hens et al., 2014 ). These advanced methodologies are increasingly applied in mechanistic studies and late-stage formulation optimization. However, for early formulation development and comparative screening, simpler time-course dissolution measurements under controlled conditions remain widely used and informative. Despite these advances, a generalizable feed-design rule that simultaneously addresses solubilization, processability, and solid-state robustness in AQSD remains underdeveloped. In this work, we combine temperature-boosted intrinsic solubility with P407 micellar solubilization to maintain drug solubilization up to atomization and target ≥1 mg·mL −1 apparent solubility for spray drying ( Bao et al., 2024 ). Heating increases intrinsic solubility, while micelles further enhance it. High- T g polymer matrices (PVP or SS) are then employed to elevate the effective glass transition, thereby avoiding supercooled liquid and ensuring powdery dispersions. Using this strategy, we explore solvent-free spray drying of poorly soluble drugs into robust amorphous solid dispersions with enhanced dissolution. This green processing route offers a practical framework for early formulation screening of BCS II compounds, which is directly relevant to sustaining supersaturation and improving oral absorption. The resulting formulation concept and process logic are summarized in Scheme 1 . Scheme 1. Open in a new tab Design and strategy of aqueous solution spray drying formulation to prepare ASDs of poorly soluble drugs. 2. Experimental section 2.1. Materials and reagents Celecoxib (CEL, C₁₇H₁₄F₃N₃O₂S, 99%), indomethacin (IMC, C 19 H 16 ClNO 4 , 99%), sulfamerazine (SMR, C 11 H 12 N 4 O 2 S, 99%), aripiprazole (ARP, C 23 H 27 C l2 N 3 O 2 , 99%), PVP K30 (PVP), soluble starch (SS, (C₆H₁₀O₅) n , AR) were bought from Aladdin Scientific Corp., China. Packaged poloxamer 407 (P407, 95%) was bought from BASF Corp., USA. Ethanol (AR) was bought from Sinopharm Chemical Reagent Co., Ltd., China. 2.2. UV–Vis calibration curves Each drug was dissolved in 50%( v /v) ethanol-water solution and serially diluted to 0–100 μg·mL −1 (10 μg·mL −1 increments). UV–Vis absorbance (Shimadzu UV-2550, Japan) was measured at 250 nm (CEL), 320 nm (IMC), 285 nm (ARP), and 270 nm (SMR) to construct linear calibration curves. 2.3. Apparent solubility in aqueous media 2.3.1. Equilibrium solubility vs temperature An excess of drug (20 mg) was added to 20 mL deionized water and equilibrated at 26, 60, or 90 °C overnight, or at 100 °C for 10 min, in a foil-covered beaker to minimize evaporation. Additional drug was added stepwise until visible undissolved solids remained. Suspensions were equilibrated at the target temperature under magnetic stirring (300 rpm), then filtered (PES 0.22 μm), and the filtrate was diluted with 50% ( v /v) ethanol–water as needed and quantified by UV–Vis. 2.3.2. Excipient-enabled apparent solubility and mixed-excipient screening Additive effects were assessed by replacing water with surfactant/polymer solutions at specified concentrations. For mixed-excipient screens, the total excipient concentration was kept constant (10 mg·mL −1 ) while varying the P407: polymer mass ratio (e.g., P407 5 + SS 5 mg·mL −1 ; P407 8 + PVP 2 mg·mL −1 ) to identify a sprayable feed window and guide the final ternary composition for AQSD. Triplicates were performed. Apparent solubility was calculated from calibration curves ( R 2 ≥ 0.999). 2.4. Aqueous feed preparation and polymer/micelle–governed AQSD 1 g of raw drug and 9 g of polymers (e.g., 9 g of P407, 4.5 g of P407 and 4.5 g of SS, 7.2 g of P407 and 1.8 g of PVP) were dissolved in 1 L of boiling deionized water, and then the solution was spray dried (Shanghai Pilo-tech YC-015, inlet temperature: 180 °C, outlet temperature: ∼110 °C, feed rate: 10 mL·min −1 , atomization air pressure: 24 bar, drying air flow rate: 30 m 3 ·h −1 ). For very poorly soluble drugs (e.g., ARP), the drug load was reduced to 5 wt% (0.5 g drug +9.5 g excipients per liter) to maintain a sprayable feed. The feed was maintained at ∼95–100 °C up to atomization, and all filters/lines were preheated to minimize cooling-induced precipitation prior to atomization. 2.5. Reference amorphous standards CEL (100 mg) was melted on a 220 °C hot plate for ∼1 min and rapidly cooled to form a transparent glass, which was ground to obtain amorphous powder. 2.6. Drug assay ASD (20 mg) was dissolved in 20 mL of 50% ( v /v) ethanol–water and quantified by UV–Vis using the standard curves ( n = 3). 2.7. Apparent dissolution testing Raw drug (10 mg) or ASD containing 10 mg drug was added to 100 mL medium (37 °C): deionized water, HCl solution (pH 1.2) and PBS buffer solution (pH 7.4). At defined times (1, 2, 4, 6, 8, 10, 12, 24 h), samples were filtered (PES 0.22 μm, Membrane Solutions Inc., USA), mixed 1:1 with ethanol to suppress recrystallization, and analyzed by UV–Vis ( n = 3). 2.8. Solid-state and spectroscopic characterization Powder X-ray diffraction (PXRD: Cu Kα, 5–30°, 2° min −1 ; Philips X'Pert Pro, Netherlands), FT-IR (400–4000 cm −1 , 2 cm −1 ; Shimadzu IRAffinity-1S, Japan), and confocal Raman spectroscopy (532 nm, 5 mW, 0.02 s, 1000 scans, 50–3400 cm −1 ; Thermo DXR3xi, USA) were performed. Vibrational spectral shifts (selected bands) were used qualitatively to indicate drug microenvironment changes consistent with micellar incorporation. 2.9. Calculations and estimates Dry-state mixture glass transitions ( T g,mix ) were projected using a generalized multicomponent Gordon–Taylor expression based on dry-basis mass fractions ( Fauche et al., n.d. ); for simplicity we used r ᵢ = 1 (i.e., neglecting density/Δ C ₚ differences) and treated the estimates as qualitative only. Full equations, inputs, and assumptions are provided in the Supporting Information (Section S1, Eq. S1 and Table S1). These estimates were used qualitatively to set safe drying windows relative to T g,wet . They do not include water plasticization and are not a substitute for DSC. 3. Results 3.1. Temperature- and P407-assisted increase in apparent solubility CEL ( Fig. 1 a, top) is a COX-2 inhibitor (BCS II) ( Hyun et al., 2019 ; Saxena et al., 2020 ) with pH-independent low aqueous solubility ( Seedher and Bhatia, 2003 ) but good solubility in many organic solvents, and its ASDs can be easily prepared via spray drying its organic solutions such as methanol and acetone ( Verma et al., 2022 ; Puri et al., 2010 ; Chen et al., 2015 ). Raising temperature markedly increases the intrinsic aqueous solubility of CEL ( Fig. 1 b): from ∼1.5 μg·mL −1 at 25 °C to ∼7 μg·mL −1 at 60 °C, ∼72 μg·mL −1 at 90 °C, and ∼ 0.18 mg·mL −1 at 100 °C. The pharmaceutical surfactant P407 further enhances the apparent solubility when added at concentrations above commonly reported micellization thresholds under the present hot-feed conditions (100 °C). As a working hypothesis, we attribute this solubility enhancement to incorporation of CEL into P407 micelles or micelle-like hydrophobic aggregates. In triplicate measurements (mean values shown), CEL increases from 0.18 mg·mL −1 (water) to 0.96, 3.6, and 5.6 mg·mL −1 at 1, 5, and 10 mg·mL −1 P407, respectively; a non-monotonic decrease is observed at 100 mg·mL −1 (4.26 mg·mL −1 ), probably due to viscosity-limited mass transfer and crowding-induced micellar reorganization outside the practical feed window ( Dumortier et al., 2006 ). Based on these data, the feed design window of 5–10 mg·mL −1 P407 at 100 °C reliably achieves ≥1 mg·mL −1 apparent solubility for CEL ( Fig. 1 c, red circles), satisfying the solubilization requirement for AQSD. Fig. 1. Open in a new tab Temperature- and P407-assisted solubilization of CEL at 100 °C, with spectroscopic evidence of a P407-rich hydrophobic microenvironment in solution. (a) Molecular structures of CEL and P407, (b) apparent aqueous solubility of CEL at different temperatures, (c) apparent aqueous solubility of CEL vs P407 concentration at 100 °C, (d) IR, (e) Mid-frequency Raman, (f) Low-frequency Raman spectra of CEL samples including raw CEL, amorphous CEL, P407, and CEL-P407, (g) PXRD pattern of CEL samples including raw CEL, amorphous CEL, P407, and CEL-P407, and (h) optical images of raw P407 and CEL-P407. Vibrational spectroscopy provides molecular-level evidence that CEL experiences a hydrophobic microenvironment in the hot aqueous feed ( Fig. 1 d, Table 1 ). IR and Raman spectra in high-frequency are strongly interfered by the bands of P407 (Fig. S1) and do not provide useful information, so the mid- and low- frequency spectra were analyzed here. In addition, because the feed ratio of CEL for AQSD is only 10%, the CEL intensities are low and some weak CEL bands are absent in ASDs in IR spectra. Thus, 5 mid-frequency IR bands of amorphous CEL ( Fig. 1 d, Table 1 ) are selected as references based on the principle that the bands are not absent in CEL-P407. 4 IR bands of amorphous CEL (1157, 760, 743, 627 cm −1 ) are similar to those of raw CEL (1160, 760, 743, 629 cm −1 ) with a difference less than 4 cm −1 . Only IR band at 619 cm −1 of v (NH 2 ) of raw CEL and that at 615 cm −1 of amorphous CEL are different and can be used to distinguish Form III and amorphous phase. CEL-P407 shows IR band at 615 cm −1 , indicating that CEL in CEL-P407 is more similar to amorphous CEL than to crystalline CEL. In addition, CEL–P407 exhibits a band at 1165 cm −1 ( νs (S=O)), consistent with altered local polarity around the sulfonamide group. Table 1. Characteristic IR and Raman bands in the mid-frequency range. 5 IR and 13 Raman bands of amorphous CEL are selected as references based on the principle that bands are not absent in CEL-P407. Raw Amorphous CEL-P407 Assignment ( Verma et al., 2022 ; Santiago et al., 2020 ; Xiang et al., 2023 ) IR 1160 1157 1165 v s (S=O) 760 760 760 pyrazole 743 743 743 benzene 629 627 627 pyrazole 619 615 615 v (NH2) Raman 397 408 408 627 627 627 benzene 644 642 641 742 743 741 benzene 970 975 975 γ (CH) 1159 1156 1166 v as (S=O) 1193 1186 1187 β (CH) 1201 1201 1200 1374 1374 1374 δ as (CH) 1521 1519 1518 1549 1556 1555 γ (NH2) 1574 1599 1597 benzene 1612 1616 1616 benzene Open in a new tab In mid-frequency Raman ( Fig. 1 e), 13 mid-frequency Raman bands of amorphous CEL are selected as references based on same principle. 7 Raman bands of amorphous CEL can be distinguished from raw CEL with a difference > 2 cm −1 , and 6 bands of CEL-P407 exhibits similarity with those of amorphous CEL, and one band at 1166 cm −1 is different from that of raw CEL and amorphous CEL. The peak at 1166 cm −1 in CEL-P407 is characteristic v as (S=O), which has a right shift compared to raw CEL and amorphous CEL, again consistent with CEL engaging a hydrophobic P407-rich microenvironment. These spectroscopic signatures do not assign a precise aggregate structure but are consistent with CEL partitioning into PPO-rich hydrophobic domains—micelles or micelle-like aggregates—that are expected to form under the high-temperature, above-CMC conditions used here. According to literature ( Alexandridis et al., 1994 ; Bohorquez et al., 1999 ), micellization of P407 is governed by both CMC and CMT (critical micelle temperature), and the CMC decreases as temperature increases while higher polymer concentration lowers the CMT; therefore, the P407 levels used here—already above the room-temperature CMC—are expected to remain in the micellized/aggregated regime under the hot-feed temperatures. Low-frequency Raman spectroscopy ( Fig. 1 f) exhibits weak bands at 203 and 241 cm −1 for amorphous CEL, whereas Raman bands at 60, 79, 99, 202 and 249 cm −1 for raw CEL. CEL-P407 presents bands at 77 and 278 cm −1 related to semicrystalline P407 ( Fig. 1 g) and band at 240 cm −1 related to amorphous CEL. These results indicate that CEL in CEL-P407 is amorphous. The results from the PXRD also confirmed this point, i.e., the pattern of CEL-P407 does not have signals of crystalline CEL ( Fig. 1 g), indicating that the existing form of CEL is amorphous. Taken together, temperature-boosted solubility combined with P407-enabled hydrophobic-domain solubilization provides a favorable molecular environment for CEL prior to atomization. These observations pertain to the solution state and do not imply that discrete micellar structures persist in the dried solids. Indeed, the resulting binary CEL–P407 ASD forms a translucent, wax-like material similar to neat P407 ( Fig. 1 h), highlighting the need for a high- T g matrix to reinforce solid-state properties. 3.2. Coupling P407-enabled solubilization with high- T g polymers for ASDs In spray-dried amorphous systems, the glass transition temperature ( T g, wet ) at the wet state is lowered due to residual moisture, thereby defining the softening critical point: as the product temperature approaches it, particles soften and coalesce, causing wall sticking, poor morphology, and even increased molecular mobility that drives phase separation and crystallization. Raising the dry-state T g with a high- T g matrix shifts T g,wet upward at comparable moisture contents, enlarging the safe processing window and promoting early shell solidification. In practice, this translates to better powderability/yield and more persistent supersaturation during dissolution ( Adhikari et al., 2005 ; Lechanteur and Evrard, 2020 ). In our case, the dry T g value of amorphous CEL is ∼52 °C ( Wang and Sun, 2019 ), whereas P407—being semicrystalline—exhibits only a weak, low-temperature glass transition associated with its amorphous PPO-rich fraction (reported around −69 to −66 °C ( Zhang et al., 2023b )). Because P407 exhibits only a weak low-temperature glass transition, T g elevation must be provided by the polymeric matrix while maintaining compatibility with P407-enabled solubilization. Soluble starch (SS) ( T g ≈ 84 °C) ( de Moura Ferraz et al., 2024 ) and Polyvinylpyrrolidone (PVP) ( T g ≈ 180 °C) ( Fitzpatrick et al., 2002 ) satisfy these criteria. SS modestly increases CEL solubility at 100 °C (0.70 mg·mL −1 at 10 mg·mL −1 SS) and, importantly, does not diminish P407-based solubilization (2.8 mg·mL −1 for P407 5 + SS 5 mg·mL −1 ) ( Fig. 2 a). PVP alone provides limited solubilization (0.17 mg·mL −1 at 10 mg·mL −1 ) and increasing PVP fraction can attenuate P407-enabled solubilization. Therefore, we screened mixed feeds at a fixed total excipient level (10 mg·mL −1 ) and found that P407:PVP ≥ 4:1 retains a practical solubilization window (2.3 mg·mL −1 for 8 mg·mL −1 P407 + 2 mg·mL −1 PVP) ( Fig. 2 a). Fig. 2. Open in a new tab High- T g polymers raise the effective glass transition and reinforce solid-state performance. (a) Polymer screening at 100 °C: apparent solubility of CEL for SS (10 mg·mL −1 ), PVP (10 mg·mL −1 ), and mixed feeds P407 5 + SS 5 and P407 8 + PVP 2 (total excipient concentration fixed at 10 mg·mL −1 ). (b) Gordon–Taylor estimates of dry-state mixture T g for CEL–P407 (1:9), CEL–P407–SS (10%–45%-45%), and CEL–P407–PVP (10%–72%-18%). (c) optical images of ternary CEL-P407-SS and CEL-P407-PVP. (d) PXRD pattern for raw SS, PVP, spray drying SS, and ternary AQSD formulations. (e) IR, (f) Mid-frequency Raman, (g) Low-frequency Raman spectra of CEL-P407-SS and CEL-P407-PVP. (h) Schematic formation processes of CEL ASDs including CEL-P407 and CEL-P407-SS. Using the literature-supported T g of P407's amorphous fraction (≈ −67 °C) together with reported T g values for CEL, SS, and PVP in a simplified Gordon–Taylor treatment (Eq. S1), the estimated dry-state mixture T g values are approximately −55 °C for CEL–P407 (1:9), +13 °C for CEL–P407–SS, and − 11 °C for CEL–P407–PVP ( Fig. 2 b). Although these values are approximate and neglect water plasticization and density/Δ C p (the heat-capacity step) differences, they capture the qualitative trend that addition of high- T g polymers, especially SS, raises the effective T g relative to the binary CEL–P407 system, consistent with the observed transition from wax-like solids to powders in the ternaries ( Fig. 2 c ). This is further supported by the powder appearance: the CEL–P407–PVP product shows pronounced flake-like agglomerates and cohesion, whereas CEL–P407–SS forms a finer, looser, more granular and near free-flowing powder ( Fig. 2 c), in line with the higher effective T g of the SS-containing formulation. Notably, although the absolute T g values are low, the relative ordering (SS > PVP > > no polymer) correlates with the experimental powderability. Moreover, the effective T g,wet during drying is dominated by residual-water plasticization and cannot be inferred from dry T g estimates alone. In practice, rapid solvent removal, compositional heterogeneity, and early shell vitrification during droplet drying can yield mechanically stable particles even when the bulk-average dry T g is low. PXRD verifies amorphization for the CEL formulations ( Fig. 2 d). Both ternaries—CEL–P407–SS and CEL–P407–PVP— only show diffraction peaks of P407 at 2 θ of 19.3° and 23.4°, lack raw drug reflections. IR spectra ( Fig. 2 e), mid-frequency ( Fig. 2 f ) and low-frequency ( Fig. 2 g) Raman spectra of CEL–P407–SS and CEL–P407–PVP exhibit similar bands with that of CEL-P407, indicating preservation of amorphous CEL and a modified local environment arising from interactions with P407 and polymer. These signatures describe solid-state interactions and do not imply preserved micellar structures after drying. To provide a qualitative thermodynamic perspective, a minimal PC-SAFT trend analysis was performed and is reported in the Supporting Information. Using pseudo-component representations, the analysis suggests comparatively more favorable CEL–P407 interactions than CEL–SS or CEL–PVP (Fig. S2). These trends are consistent with the experimentally observed role of P407 in solution-state solubilization. A working mechanistic interpretation ( Fig. 2 h) is that, in the hot aqueous feed, P407 forms micelles or micelle-like hydrophobic aggregates that sequester CEL into PPO-rich domains; hydrophobic CEL partitions into the PPO-rich core, consistent with S=O band shifts indicating weaker hydrogen bonding to water. The assembly of CEL molecule within the hydrophobic core of P407 will result in an increase in the size/aggregation number of these hydrophobic domains. A simple concentration calculation indicates that one P407 micelle or micelle-like hydrophobic aggregate can encapsulate ∼7.5 CEL molecules in the condition of 10 mg·mL −1 of P407 at 100 °C (Fig. S3). Upon drying, such aggregates necessarily collapse and reorganize, giving rise to amorphous P407-rich regions rather than discrete micelles. SS, being nonionic and high- T g , co-solidifies around these domains without disrupting solubilization in solution, while PVP—despite offering stronger T g elevation—can partially suppress P407-enabled solubilization at high levels. Thus, P407 primarily governs solution-state solubilization, whereas SS and PVP govern solid-state stabilization, together yielding robust amorphous powders under AQSD conditions. 3.3. Contents, dissolution profiles, and stability As described above, under fixed AQSD conditions, formulation selection strongly influences droplet-to-particle conversion and processing. The binary CEL–P407 produced waxy, sheet-like solids with a ∼ 40% yield ( Fig. 3 a), whereas the ternaries formed white powders; CEL–P407–SS reached ∼50%, and CEL–P407–PVP held ∼40%. All values comfortably exceed the ∼25% AQSD yield reported previously (ref. ( Craye et al., 2015 )). Fig. 3. Open in a new tab Product yield, contents, dissolution profiles, and short-term stability for CEL under fixed AQSD settings. (a) Product yield (%) under identical conditions. (b) Assay at release (wt%): measured vs target for fresh powders. (c) Dissolution profiles at 37 °C in water (left), pH 1.2 (middle), and pH 7.4 (right). (d) Short-term stability (3 months): PXRD patterns (left), CEL contents (middle) and dissolution profiles (right) of samples. The content measurement results indicate that the drug content in the product matches the feed ratio 10 wt% ( Fig. 3 b): 10.4 ± 0.7 wt% (CEL-P407), 9.8 ± 0.3 wt% (CEL–P407–SS), and 10.0 ± 0.7 wt% (CEL–P407–PVP). The agreement with the target indicates no measurable net drug loss during processing and no evidence of significant degradation detectable by assay under the present AQSD conditions. Here, “volatilization/gasification-like losses” denotes net drug loss during hot-feed atomization and drying (e.g., loss to the exhaust stream), rather than implying a high equilibrium vapor pressure of crystalline CEL. By contrast, prior AQSD work without P407 reported markedly reduced recovered drug loading (∼50% of the intended load) ( Zheng et al., 2025 ), which was attributed to volatilization/gasification-like losses under hot-feed/drying conditions; our results are consistent with P407 micelles mitigating this loss pathway. At 37 °C, dissolution is robustly enhanced across water, pH 1.2 and pH 7.4 ( Fig. 3 c). In water, crystalline CEL reached only ∼2.7 μg·mL −1 at 24 h, whereas amorphous dispersions rose by an order of magnitude: CEL–P407 peaked near ∼90 μg·mL −1 (12 h ) before declining, CEL–P407–PVP sustained ∼60 μg·mL −1 at 24 h with a slower late-time drop, and CEL–P407–SS stabilized near ∼20 μg·mL −1 . Trends in pH 1.2 and pH 7.4 were consistent. Stability is consolidated in Fig. 3 d. After 3 months, PXRD pattern persisted for all CEL dispersions; assay remained near target—9.6 ± 0.6 wt% (CEL-P407), 9.4 ± 0.4 wt% (CEL–P407–SS), 9.8 ± 1.2 wt% (CEL–P407–PVP)—and dissolution relative to fresh was largely retained (e.g., CEL–P407 and CEL–P407–PVP preserved the characteristic early-time rise and high mid-time levels). Taken together, Fig. 3 a–d show that ternary designs not only convert feeds into powders more reliably than the wax-prone binary but also hit the intended loading without volatilization losses and maintain functional release under the fixed operating window. 3.4. Cross-drug validation of the approach To assess generality beyond CEL, we applied the same AQSD design to indomethacin (IMC), sulfamerazine (SMR), and aripiprazole (ARP). Polymer–composition screens at 100 °C guided the feed windows (Fig. S4a), the resulting products were powders ( Fig. 4 a) and amorphous by PXRD (Fig. S4b) for the successful formulations, and the cross-drug summaries are compiled in Fig. 4 a–c. Fig. 4. Open in a new tab Cross-drug validation of the AQSD design. (a) Optical images of ternary IMC-P407-SS, SMR-P407-PVP and ARP-P407-SS. (b) Fold increase in dissolution at the common reference condition (water, 24 h, 37 °C) for the best-performing formulation of each drug (relative to the crystalline raw drug). (c) Drug content in powder of the best-performing formulation of each drug. Annotations indicate formulation, and amorphous status by PXRD (✓/✗). Dash line means target (feed ratio). IMC. PXRD confirmed amorphous dispersions for IMC–P407 and IMC–P407–SS. In water (37 °C), the apparent solubility of IMC–P407–SS reached ∼53 μg·mL −1 at 24 h versus ∼7.9 μg·mL −1 at 24 h for crystalline IMC (Fig. S4d), evidencing a pronounced uplift (6.7 times that of raw IMC, Fig. 4 b). IMC contents of IMC-P407 and IMC-P407-SS are 9.8 ± 0.3 wt% and 10.2 ± 0.6 wt%, respectively, which matched the 10 wt% target ( Fig. 4 c). SMR. Full amorphization required a high- T g polymer: SMR–P407–PVP removed SMR reflections by PXRD and delivered a ∼ 1.7-fold endpoint increase ( Fig. 4 b, i.e., 0.48 vs 0.28 mg·mL −1 at 24 h, Fig. S4d), whereas SMR–P407 and SMR–P407–SS retained SMR peaks (Fig. S4c). Assay content met the 10 wt% target ( Fig. 4 c). We note that this uplift at the common reference point (water, 24 h) is modest relative to CEL, IMC, and ARP. This may reflect drug-specific dissolution and supersaturation-maintenance behavior (e.g., faster re-equilibration/recrystallization and/or a less pronounced contribution from P407-enabled hydrophobic-domain solubilization under our conditions), and the use of a single 24 h endpoint may mask early-time benefits that are not sustained. ARP. Due to the extremely low aqueous solubility of ARP, the drug loading was reduced to 5 wt% to maintain a clear, sprayable true-solution feed under the hot-feed condition. At 5 wt% drug, ARP–P407–SS was amorphous by PXRD and achieved a ∼ 25-fold enhancement at 24 h ( Fig. 4 b, ∼72 vs ∼2.6 μg·mL −1 , Fig. S4d); assay content matched the 5 wt% target ( Fig. 4 c). Together, these cross-drug outcomes demonstrate broader applicability across several model drugs for the temperature-boosted, micelle-assisted solubilization + high- T g matrix design logic, while highlighting that the magnitude of the benefit and the practical feed window remain drug-dependent and that matrix choice can be outcome-defining. 4. Discussion 4.1. Robustness of AQSD Conventional spray drying comprises atomization, droplet heating, solvent removal, and powder collection. AQSD adds a bulk hot-feed step. AQSD has the potential to be scaled, for example by heat-integration and minimizing hot-hold time; however, industrial translation will require case-by-case evaluation of (i) achievable aqueous feed windows, (ii) excipient burden/dose strength, and (iii) drug thermal stability, as well as appropriate post-drying moisture control. The persistent bottleneck is aqueous solubility. The present rule—temperature-boosted solubility + P407 micellar solubilization + a high- T g matrix—reliably raised apparent solubility into the ≥1 mg·mL −1 window across several drugs, enabling 10 wt% loads (or 5 wt% for very insoluble ARP). Under a fixed operating window, the ternary designs also improved powderability/yield relative to a wax-prone binary. We note, however, that some actives (e.g., simvastatin, carbamazepine, sulindac; Fig. S5) showed thermal degradation in hot water, resulting in measured assay < feed—a clear limitation of AQSD that sets formulation boundaries. 4.2. Roles of Surfactant and Polymer Surfactant-enabled solubilization is well established, yet within the constrained palette of pharmaceutically acceptable surfactants, P407 occupies a distinctive niche. Above its critical micelle temperature, P407 assembles into PPO-core/PEO-shell micelles that provide hydrophobic domains capable of incorporating CEL. The IR/Raman shifts observed here are consistent with CEL partitioning into PPO-rich cores, which rationalizes the substantial solubility enhancement in the hot aqueous feed and, consistent with prior observations, mitigation of volatilization/gasification-like losses during atomization and drying. The polymers, by contrast, exert their influence primarily during droplet-to-particle conversion. SS is nonionic and did not show visible clouding under the explored feed conditions, and raises the mixture T g without penalizing P407-driven solubilization, improving shell solidification and powderability/yield. Although neat PVP has a higher T g than SS, our composition-specific Gordon–Taylor estimates indicate that the SS-containing ternary achieves a higher effective T g than the PVP-containing ternary ( Fig. 2 b), consistent with the improved powderability observed for CEL–P407–SS ( Fig. 2 c). Consistent with this division of roles, SS primarily improves processing robustness and powderability, whereas PVP provides stronger precipitation inhibition during dissolution, leading to a more sustained parachute phase ( Fig. 3 c). Gordon–Taylor projections rationalize the observed processing margin. Open questions remain regarding the fate of micelle-derived domains after drying and their coupling to residual-water distributions and late-time dissolution behavior; these are natural targets for future structure–property studies. Taken together, the combined roles of micelles and polymers can be distilled into a formulation decision framework, where upstream solubilization is coupled to downstream amorphization. This framework is summarized in Fig. 5 . Fig. 5. Open in a new tab Decision framework for AQSD formulations. 4.3. Limitations and outlook High-temperature exposure can degrade heat-labile actives; shortening the hot-feed residence time (e.g., inline/continuous heating, minimized hold-up) should mitigate risk. The current laboratory setup used ∼1 h of solution heating and ∼ 2 h of drying; pipeline/loop designs could reduce both temperature and time. AQSD is generally unsuitable for metastable molecules such as certain antibiotics, proteins, or highly labile extracts. Achieving very high feed concentrations (>10 mg·mL −1 ) remains challenging; aqueous suspension spray drying may complement AQSD when solubility ceilings are reached. More advanced dissolution methodologies, such as biphasic or transfer models, have been developed to decouple molecular supersaturation from colloidal solubilization and to improve physiological relevance. While such approaches are valuable for late-stage formulation optimization, the present work employs conventional non-sink dissolution as an early-stage screening tool to compare formulation robustness under fixed processing conditions. 5. Conclusions By combining elevated temperature, P407 micelle–assisted solubilization, and high-Tg polymer matrices, the AQSD route enabled solvent-free production of ASDs of CEL, IMC, SMR, and ARP. Rather than a simple excipient blend, the system functions through a dual mechanism: micelle encapsulation of the drug, which raises apparent solubility in the hot feed and is consistent with reduced volatilization/gasification-like losses during drying, and polymer-assisted amorphization, whereby a high- T g matrix improves processability without disrupting micellar solubilization in the hot feed. Spectroscopic signatures and processing outcomes were consistent with drug partitioning into P407 micelles in the hot feed, while incorporation of SS or PVP elevated the theoretical T g and facilitated the formation of robust amorphous dispersions. Across the systems examined, AQSD yielded powders with accurate assay, higher recovery than wax-prone binary controls, markedly enhanced dissolution, and confirmed stability for CEL. Overall, these results define a generalizable, green design rule—temperature-boosted, micelle-assisted solubilization coupled with a high-Tg matrix—for solvent-free ASD manufacturing, with direct relevance to sustaining supersaturation and improving oral absorption of poorly soluble BCS II drugs. CRediT authorship contribution statement Wenling Zheng: Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation. Hui Chen: Visualization, Formal analysis, Data curation. Rongrong Xue: Validation, Supervision, Resources, Methodology. Ziqing Wu: Writing – review & editing, Visualization, Methodology. Yongming Liu: Writing – review & editing, Supervision, Funding acquisition. Fenghua Chen: Writing – review & editing, Writing – original draft, Validation, Supervision, Resources, Methodology, Funding acquisition, Conceptualization. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments This work was funded by National Natural Science Foundation of China (Grant No. 22005175), Natural Science Foundation of Fujian Province (Grant No. 2025J011059), Education and Research Project for Young and Middle-aged Teachers in Fujian Province (Grant No. JAT231112, JAT241136), and Research Support Project of Sanming University (Grant No. 23YG14S, 23YG15S). 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