This study evaluated melt sonocrystallization (MSC) as a solvent-free approach to improve the poor aqueous solubility and dissolution of puerarin, a BCS Class IV isoflavone. Puerarin was melted and rapidly quenched into ice-cold water, then probe-sonicated under controlled conditions. The MSC product (MSC-puerarin) was characterized by UV spectroscopy, dissolution testing, optical microscopy, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). MSC-treated puerarin showed increased apparent solubility and faster dissolution, reduced particle size with agglomeration tendency, and a crystal form conversion to puerarin monohydrate with decreased crystallinity and partial amorphization. Reduced particle size and amorphization are proposed as the main drivers of solubility enhancement.
Oral delivery is the predominant route for many therapeutics, but poor aqueous solubility limits the oral bioavailability of numerous drug candidates. Traditional formulation strategies (particle size reduction, cocrystals, solid dispersions, cyclodextrin complexes) can improve apparent solubility but often introduce process complexity, residual solvents, or stability concerns. MSC couples melting, ultrasonic dispersion, and rapid solidification to induce nucleation, refine crystals, and modify crystal habit under mild, solvent-free conditions. Prior MSC applications altered physicochemical properties of other drugs; however, MSC had not been applied to puerarin prior to this work.
Puerarin is an isoflavone derived from Pueraria lobata with reported cardiovascular and metabolic pharmacology but suffers from low water solubility and limited oral exposure. The authors selected puerarin to systematically investigate MSC effects on crystallography and solubility to inform formulation strategies for poorly soluble small molecules.
Puerarin (≥98%) was obtained commercially. Potassium bromide and ultrapure water were used for FTIR sample preparation and other assays. All other consumables and instruments were standard laboratory-grade equipment as reported in the study.
Exactly 400 mg of puerarin was heated to 206°C until fully molten. The molten puerarin was immediately poured into 8 mL of ice-cold deionized water under continuous stirring in a cylindrical glass vessel (approximately 20 mm diameter). The resulting suspension was cooled in an ice bath and sonicated with a probe-type ultrasonic disruptor using 5-second pulses alternating with 5-second rests for a total sonication time of 20 minutes. Ultrasound conditions were 20 kHz frequency and 300 W output, with a 6 mm probe tip immersed about 10 mm below the liquid surface while avoiding contact with the vessel bottom. After sonication and cooling, the dispersion was filtered and the collected solid dried under vacuum for 12 hours to yield MSC-puerarin.
Optical microscopy was used to compare untreated puerarin and MSC-puerarin. Raw puerarin was dispersed in liquid paraffin on a glass slide for observation. For MSC-puerarin, a wet aliquot of the suspension was placed on a slide and examined to assess particle size and agglomeration.
Preliminary equilibration experiments established that thermodynamic equilibrium was typically reached by 12 hours. Excess amounts of untreated or MSC-puerarin were added to 5 mL deionized water and shaken at 25°C (150 rpm). For isothermal solubility studies, samples were equilibrated for 12 hours at 25, 30, 35, 40, or 45°C. After filtration (0.22 µm), soluble drug concentration was measured by UV spectroscopy at 250 nm using a microplate reader. Experiments were performed in triplicate.
Dissolution of 20 mg equivalents of untreated puerarin or MSC-puerarin was performed in 100 mL deionized water at 25°C or 37°C with a paddle speed of 50 rpm. Aliquots were withdrawn over 24 hours at specified time points, filtered (0.22 µm) and assayed at 250 nm. Each dissolution experiment was performed in triplicate.
DSC scans were run on 3–5 mg samples in open aluminum crucibles, heated from 30°C to 220°C at 10°C min−1 to examine thermal transitions and crystallinity differences between untreated and MSC-treated puerarin.
PXRD patterns were collected between 2θ = 5° and 30° (Cu Kα radiation). Crystallographic fingerprinting compared untreated puerarin to MSC-puerarin to identify polymorphic or hydrate transformations and changes in peak intensities indicating altered crystallinity.
Samples mixed with KBr (mass ratio ~1:50) and pressed into pellets were scanned from 4000 to 400 cm−1 to evaluate molecular interactions, hydration state, and structural changes after MSC.
MSC-puerarin water content was assessed after vacuum drying to quantify hydration state; the Karl Fischer method was used as reported.
MSC processing converted puerarin into a product with markedly different physical and solid-state properties compared with untreated material. Optical microscopy revealed a reduction in particle size after MSC, with a propensity for the small particles to form agglomerates during rapid solidification. Solubility experiments, equilibrated at multiple temperatures and assayed at 250 nm, demonstrated higher apparent solubility for MSC-puerarin than for untreated puerarin under the tested conditions. Dissolution testing at 25°C and 37°C showed faster dissolution rates for MSC-puerarin across measured time points.
PXRD, DSC, FTIR, and TGA analyses jointly indicated a crystal form transformation: MSC-treated material displayed diffraction and thermal features consistent with conversion to puerarin monohydrate, accompanied by reduced overall crystallinity and partial amorphization. Thermogravimetric analysis and Karl Fischer moisture determination supported the presence of a hydrated form after MSC. The decrease in crystallinity and increased amorphous content, together with reduced particle size, are presented as the principal mechanisms driving the increased solubility and dissolution rate.
The MSC method used here is a solvent-free, single-step process combining melting, ultrasonic fragmentation, and rapid cooling. The specific ultrasound parameters (20 kHz, 300 W, pulsed operation) and rapid quench into ice-cold water facilitated nucleation and crystal habit modification without added solvents. The authors note MSC as a potentially scalable approach to improve oral formulations of poorly soluble drugs while avoiding some drawbacks of conventional solubilization strategies.
Melt sonocrystallization significantly improved the apparent solubility and dissolution rate of puerarin. MSC reduced particle size, promoted agglomeration of fine particles, and induced a solid-state conversion to puerarin monohydrate with decreased crystallinity and partial amorphization. These changes likely underlie the enhanced solubility and dissolution observed. MSC is presented as a solvent-free, efficient option for modifying the physicochemical properties of poorly soluble small molecules; the study provides experimental conditions and multiple analytical characterizations to support further formulation development. Details and raw data supporting these findings are provided in the article and associated data repository.