---
title: "Melt sonocrystallization improves puerarin solubility and dissolution by forming monohydrate and p"
id: "plos-one-8-enhancing-the-solubility-of-puerarin-via-melt-sonocrystallization"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-8-enhancing-the-solubility-of-puerarin-via-melt-sonocrystallization"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646"
published_at: "2026-08-07T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Melt sonocrystallization improves puerarin solubility and dissolution by forming monohydrate and p
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-8-enhancing-the-solubility-of-puerarin-via-melt-sonocrystallization
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646)
- **Published At:** 2026-08-07T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study applied **melt sonocrystallization (MSC)** to puerarin, a BCS Class IV isoflavone with poor aqueous solubility and low oral bioavailability, to evaluate effects on solubility, dissolution, and crystal properties. - MSC processing: 400 mg puerarin melted at 206°C then poured into ice-cold water and probe-sonicated (20 kHz, 300 W) with 5 s on/5 s off pulses for 20 minutes while cooled. - Post-MSC material (MSC-puerarin) was collected by filtration and vacuum-dried; analytical methods included UV spectroscopy, dissolution testing, optical microscopy, **PXRD**, **DSC**, **TGA**, **FTIR**, and Karl Fischer moisture determination. - Solubility testing used excess drug equilibrated in deionized water at 25–45°C for 12 hours (equilibrium typically reached by 12 h), quantified at 250 nm by UV spectroscopy; dissolution used 20 mg equivalents in 100 mL water at 25°C or 37°C with 50 rpm paddles. - MSC-treated puerarin showed higher apparent solubility and faster dissolution than untreated puerarin under the conditions tested. - Morphology changed after MSC: reduced particle size and a tendency to agglomerate were observed by optical microscopy, consistent with ultrasound-induced fragmentation and rapid solidification. - Solid-state analyses (PXRD, DSC, FTIR, TGA) indicated a crystal form transformation to **puerarin monohydrate**, decreased crystallinity and partial **amorphization** after MSC treatment. - The authors propose that reduced particle size and partial amorphization are major contributors to the observed increases in solubility and dissolution rate; MSC is presented as a solvent-free, single-step approach to improving poorly soluble drugs. - Data supporting the findings, including raw datasets, are provided in the article and deposited in Zenodo; funding sources and competing interest statements are reported in the paper.
## Clinical Analysis & Structured Key Points
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[](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646) [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646) * 0 [Save](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#savedHeader) * 0 [Citation](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#citedHeader) * 18 [View](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#viewedHeader) * 0 [Share](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646#discussedHeader) Open Access Peer-reviewed Research Article # Enhancing the solubility of puerarin via melt sonocrystallization * Yaxiang Gong , Roles Conceptualization, Funding acquisition, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing * E-mail: Arnold_bear@126.com Affiliation Department of Pharmacy, Linyi People’s Hospital, Linyi, Shandong, China [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-4221-7131 ](https://orcid.org/0000-0002-4221-7131 "ORCID Registry") ⨯ * Jiafu Wen, Roles Data curation Affiliation Third Ward of Hand and Foot Surgery Department, Linyi People’s Hospital, Linyi, Shandong, China ⨯ * Wenqi Liu Roles Investigation, Methodology, Visualization Affiliation Department of Pharmacy, Linyi People’s Hospital, Linyi, Shandong, China ⨯ # Enhancing the solubility of puerarin via melt sonocrystallization * Yaxiang Gong, * Jiafu Wen, * Wenqi Liu ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: August 7, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0355646) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0355646) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0355646) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0355646) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#abstract0) * [Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#sec001) * [Materials and methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#sec002) * [Results and discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#sec014) * [Conclusion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#sec022) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#sec023) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0355646) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646) ![Accessible Data Icon](https://journals.plos.org/resource/img/accessible_data.svg)Accessible Data [ See the data ![Link Icon](https://journals.plos.org/resource/img/data_link_icon.svg) ](https://doi.org/10.5281/zenodo.21212670) This article includes the Accessible Data icon, an experimental feature to encourage data sharing and reuse. [Find out how research articles qualify for this feature.](https://theplosblog.plos.org/2023/07/accessible-data/) ## Abstract In this work, in order to improve the low solubility and poor oral bioavailability of puerarin, we first applied melt sonocrystallization (MSC) technology to systematically investigate the effects on its solubility and crystallographic properties. We applied MSC to treat puerarin, evaluated its solubilization effect using UV spectroscopy, and characterized it by dissolution rate, optical microscope, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR). Following MSC treatment, puerarin exhibited higher solubility and faster dissolution, the product displayed reduced particle size and a tendency to agglomerate. The results of PXRD, DSC, FTIR and TGA showed that the crystal form of MSC treated puerarin transformed into puerarin monohydrate, with a decrease in crystallinity and partial amorphization. The reduction in particle size and amorphization may be the driving forces of the increase in solubility and dissolution. In summary, MSC can significantly improve the solubility and dissolution of puerarin, providing new ideas for enhancing its bioavailability and improving its oral formulations. ## Figures ![Fig 7](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g007) ![Fig 8](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g008) ![Fig 9](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g009) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g003) ![Fig 4](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g004) ![Fig 5](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g005) ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g006) ![Fig 7](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g007) ![Fig 8](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g008) ![Fig 9](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g009) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0355646.g003) **Citation:** Gong Y, Wen J, Liu W (2026) Enhancing the solubility of puerarin via melt sonocrystallization. PLoS One 21(8): e0355646. https://doi.org/10.1371/journal.pone.0355646 **Editor:** Zheng Yuan, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, CHINA **Received:** April 16, 2026; **Accepted:** July 22, 2026; **Published:** August 7, 2026 **Copyright:** © 2026 Gong et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** All raw data supporting the findings of this study are provided in the paper, figures, and Supporting Files. All raw data have been deposited in Zenodo and are freely accessible at: [ ]. A consolidated Excel file (raw data.xlsx) is also provided as [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#sec023). **Funding:** This research was supported by Research Development Fund of the Affiliated Hospital of Shandong Second Medical University (2024FYQ049) and Linyi Key Research and Development Program (Medical Science) (2025YX0061), all were received by Yaxiang Gong, the corresponding author of this article. The sponsors or funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study. **Competing interests:** The authors have declared that no competing interests exist. ## Introduction Oral administration remains the most common and convenient route in clinical practice; however, a large amount of new molecular entities are abandoned because of poor aqueous solubility, which leads to incomplete dissolution in the gastrointestinal fluids and, consequently, inadequate systemic exposure [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref001)–[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref005)]. Therefore, how to improve the apparent solubility and dissolution rate of drugs through pharmaceutical methods while maintaining the stability of their chemical properties has become a key scientific problem that urgently needs to be solved in the field of pharmacy. Traditional solubilization strategies such as reducing particle size, preparing cocrystal, preparing solid dispersions or cyclodextrin inclusion complexes can improve the solubility and dissolution of drugs to a certain extent, but they generally have drawbacks such as complex processes, residual organic solvents, or poor stability [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref006)–[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref011)]. In recent years, MSC has provided new ideas for the research of insoluble drugs due to its ability to induce nucleation, refine crystals, and regulate crystal habits through cavitation effect under mild conditions [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref012),[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref013)]. MSC developed on this basis couples drug melting, ultrasonic dispersion, and rapid solidification, synergistically improving the solubility and dissolution rate. For example, Vaibhavkumar et al. improved the physicochemical properties of rosiglitazone through MSC, and increased its solubility and dissolution [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref014)]; M Manish et al. improved the physicochemical properties of ibuprofen through melt sonocrystallization technology, resulting in improved compressibility [[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref015)]. MSC could effectively regulate the crystal form and particle size of active pharmaceutical ingredients by precisely controlling the ultrasound frequency, intensity, and duration. This process can transform drugs that were originally difficult to dissolve in water into uniform, stable, and controllable crystals, thereby increasing the solubility, significantly improving its dissolution rate and bioavailability, reducing the use of additional excipients, and lowering potential adverse reactions. Puerarin is a small molecule drug extracted from the plant pueraria lobata, which belongs to isoflavone compounds [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref016)–[20](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref020)]. It has pharmacological effects such as coronary artery dilation, antioxidant, anti-inflammatory, etc [[21](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref021)–[25](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref025)]. Therefore, it could be used in clinical treatment of cardiovascular and cerebrovascular diseases and diabetes [[26](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref026)–[29](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref029)]. However, as a biopharmaceutics classification system (BCS) Class IV drug, puerarin displays poor equilibrium solubility in water, leading to insufficient oral bioavailability and constituting a key problem that restricts its formulation development and clinical efficacy [[30](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref030)–[33](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355646#pone.0355646.ref033)]. Therefore, selecting an appropriate strategy to overcome the physicochemical limitations of puerarin and break through its solubility barrier is of great significance for further improving its oral bioavailability and promoting the development of oral formulations. Several strategies have been employed to improve the solubility of puerarin specifically, including nanoparticle formulation, solid dispersions, and cocrystals. However, these methods often suffer from complex preparation processes, residual organic solvents, or poor long-term stability. In contrast, melt sonocrystallization (MSC) offers a solvent-free, single-step approach that reduces particle size. To date, MSC has not been applied to puerarin. In view of this, we selected puerarin as the model drug to systematically investigate the influence of MSC on its crystallographic properties and solubility, aiming to provide an efficient and green reference for the solubilization of poorly soluble drugs. We prepared solubilized puerarin with higher solubility and dissolution rate via melt sonocrystallization and conducted systematic characterization-morphological analysis, powder X-ray diffraction, thermogravimetric analysis and infrared spectroscopy-laying a solid foundation for further exploration of puerarin formulation potential and optimization of its clinical application, while also offering insights for enhancing the solubility of other poorly soluble drugs. ## Materials and methods ### Materials Puerarin (≥98%) was purchased from Solarbio Science & Technology Co., Ltd. (Beijing, China). Potassium bromide (≥99%) was obtained from Bide Pharma Co., Ltd. (Shanghai, China). Ultrapure water (18.2 MΩ·cm) was produced with a Milli-Q system (Millipore, USA). ### Melt sonocrystallization of puerarin Exactly 400mg of puerarin was weighed using an analytical balance (Shanghai Liangping Instrument Co., Ltd., China) and heated to 206°C until molten. The molten material was immediately poured into 8 mL of ice-cold deionised water under continuous stirring, contained in a cylindrical glass vessel with about 20 mm diamater. The suspension was immediately transferred to an ice bath and sonicated with a probe-type ultrasonic disruptor (Ningbo Xinzhi Biotechnology Co., Ltd., China) using 5-s pulses followed by 5-s rest intervals for a total processing time of 20 min, the operation parameters were as follow: ultrasonic frequency of 20 kHz, output power of 300 W, probe diameter of 6 mm, and probe immersion depth of about 10 mm below the liquid surface, ensuring complete immersion without contact with the vessel bottom. During the ultrasound process, the suspension was consistently cooled in an ice bath. The resultant dispersion was filtered, and the collected solid was dried under vacuum for 12 h to yield the melt-sonocrystallized product (MSC-puerarin). ### Morphological analysis A small quantity of raw puerarin was dusted onto a glass slide, dispersed in a drop of liquid paraffin, and examined under a optical microscope (Olympus, Japan). After MSC treatment, an aliquot of the still-wet puerarin suspension was similarly transferred onto a slide and inspected. ### Solubility determination Preliminary experiments were conducted to establish the time required to reach thermodynamic equilibrium. Excess MSC-puerarin (approximately 50 mg) was added to 5 mL of deionized water in sealed vials and shaken at 25°C (150 rpm). Aliquots were withdrawn at 6, 12, 24, and 48 hours, filtered (0.22 µm), and analyzed by UV spectroscopy at 250 nm. Equilibrium was confirmed when consecutive measurements differed by less than 5% (typically achieved by 12 hours). Based on the equilibration study, excess amounts of untreated puerarin or MSC-puerarin were introduced into 5 mL of deionized water. For each experimental run, one aliquot of raw puerarin and one aliquot of MSC-puerarin were measured under identical conditions. The suspensions were equilibrated at 25, 30, 35, 40, or 45°C under shaking for 12h. After filtration (0.22 µm), the filtrate was analysed at 250 nm using UV spectroscopy mode, this process was operated using a SpectraMax M5 microplate reader (Molecular Devices, USA) and each experiment was performed in triplicate (n = 5). ### Dissolution rate Powder dissolution was assessed using an RC-806 dissolution tester (Tianda Tianfa Technology Co., Ltd., China). Samples equivalent to 20 mg of puerarin or MSC-puerarin were dispersed in 100 mL deionized water maintained at 25°C or 37.0°C with paddle speed of 50 rpm. Aliquots (2 mL) were withdrawn at 0.17(10 min), 0.5, 1, 2, 4, 7, 10, 12, and 24 h, filtered (0.22 µm), diluted appropriately, and assayed using UV spectroscopy mode of a SpectraMax M5 microplate reader (Molecular Devices, USA) and each experiment was performed in triplicate (n = 5). ### Differential scanning calorimetry (DSC) Samples of untreated puerarin or MSC-puerarin were analysed by Differential scanning calorimetry. Approximately 3–5 mg of puerarin and MSC-puerarin in an open aluminum crucible. The heating rate was 10°C min-1 and the measurement range was 30–220°C. The data was analyzed using NETZSCH Proteus thermal analysis software (Version 4.2). ### Powder X-ray diffraction Samples of untreated puerarin or MSC-puerarin were analysed on a Bruker D8 Advance diffractometer (Cu Kα, λ = 1.5406 Å, 40 kV, 40 mA). Data were collected between 2θ = 5−30°, the step was 0.05° and the scan speed was 4° min-1. ### Fourier transform infrared spectrophotometry (FTIR) Take potassium bromide crystals and dry them at 60°C for 10 hours. Take an excess of puerarin raw material and MSC-treated puerarin, mix them with potassium bromide in a mass ratio of 1:50, press them into tablets, scan them in the range of 4000-400cm-1, and perform infrared spectroscopy analysis using a Nicolet iS5 FT-IR spectrometer (Thermo Fisher Scientific, USA). ### Karl Fischer moisture determination After vacuum dried at 25°C for 24 h, the water contents of MSC-puerarin were measured by a V20 Karl-fische
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