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Article

Microparticle Production of Mefenamic Acid Using the Continuous Antisolvent Sonocrystallization Process

by
Salal Hasan Khudaida
,
Chia-Yi Lee
and
Chie-Shaan Su
*
Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 106, Taiwan
*
Author to whom correspondence should be addressed.
Processes 2025, 13(9), 2813; https://doi.org/10.3390/pr13092813
Submission received: 31 July 2025 / Revised: 27 August 2025 / Accepted: 29 August 2025 / Published: 2 September 2025
(This article belongs to the Special Issue 2nd Edition of Green Particle Technologies: Processes and Applications)
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Abstract

Continuous crystallizations have promising potential for effectively controlling and modifying the crystal properties of active pharmaceutical ingredients (APIs). In this study, a continuous antisolvent sonocrystallization process was developed to recrystallize a poorly water-soluble API, mefenamic acid, for microparticle production. This method offers advantages such as efficient sonication, enhanced heat removal, and potential for scalability. The effects of operating parameters, such as sonication intensity, crystallization temperature, antisolvent flow rate, and solution flow rate, were investigated and compared. Using continuous antisolvent sonocrystallization, the particle size of mefenamic acid was controlled within the range of 2.6–3.5 μm, achieving a narrower particle size distribution compared to the unprocessed sample. In addition, scanning electron microscopy (SEM) analysis confirmed that the sonocrystallized mefenamic acid exhibited an improved crystal shape. Analytical results from powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) showed that the crystal structure, spectroscopic characteristics, and thermal behavior of mefenamic acid remained unchanged after the sonocrystallization process.

1. Introduction

In the pharmaceutical industry, crystallization is a key unit operation because it directly influences the purity, shape, particle size characteristics, polymorphic form, and stability of active pharmaceutical ingredients (APIs), all of which significantly affect downstream processing, bioavailability, and efficacy [1,2,3]. Common crystallization methods, including melt crystallization, cooling crystallization, antisolvent crystallization, and evaporative crystallization, still have some disadvantages, including batch-to-batch variance, limited control over supersaturation, inefficient management of crystal properties, and challenges in scale-up [4,5]. To overcome these limitations, novel crystallization techniques, such as supercritical fluid crystallization [6,7], sonocrystallization [8,9], microfluidic crystallization [10], and laser-induced nucleation [11], have been developed. Among these, sonocrystallization has been extensively studied over the past few decades. Sonocrystallization involves the application of power ultrasound to a crystallization system, serving as an effective technique for process intensification. It adjusts the metastable zone width, reduces induction time, controls crystallization kinetics, and prevents crystal aggregation. This approach is particularly advantageous in managing mean particle size, crystal habit, nucleation rates, and polymorphic form, as well as narrowing the particle size distribution. These features make sonocrystallization especially valuable in the crystallization of APIs, where precise control over crystal properties is crucial for drug performance and manufacturability [12,13,14,15,16,17,18]. In this study, a sonocrystallization study for an API, mefenamic acid, was conducted. Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID) commonly used in clinical applications to relieve pain and inflammation. Control over its crystal properties was crucial for further downstream processing and formulation [19].
In addition to developing novel crystallization techniques, turning the crystallization process from batch operation to continuous operation also shows the potential in the API manufacturing [20]. In the literature, several studies have operated on sonocrystallization in a continuous crystallization concept. For example, Furuta et al. [21] controlled particle size in an API manufacturing process by employing continuous crystallization in a sonicated tubular system. Hadiwinoto et al. [22] produced crystals with optimal properties for pulmonary drug delivery in a single step using continuous sonocrystallization, plug-flow crystallization, and spray drying. Schmalenberg et al. [23] investigated the nucleation in continuous flow cooling sonocrystallization for coiled capillary crystallizers. However, despite the demonstrated effectiveness of continuous sonocrystallization in multiple pharmaceutical studies and its successful application in API recrystallization, laboratory-scale implementations typically rely on immersing the crystallizer in an ultrasonic bath. These approaches pose significant challenges for temperature control and scale-up, as ultrasonic energy generates heat, thereby complicating process design.
To address common challenges associated with sonocrystallization, such as poor temperature control, limited scalability, and uneven ultrasound distribution, this study aims to design an antisolvent sonocrystallization operated in a continuous mode. A flow cell equipped with an ultrasonic probe was installed in the sonocrystallization apparatus to introduce ultrasound efficiently. A poorly water-soluble API, mefenamic acid, was selected as the model compound to evaluate the effectiveness of this process. Mefenamic acid is classified as a Class II drug under the Biopharmaceutics Classification System (BCS) owing to its high permeability and low solubility [24]. According to this classification, its dissolution rate in the gastrointestinal tract is the primary factor limiting its absorption. Therefore, to enhance its bioavailability, two critical factors for successful formulation development, precise control of particle size and crystal habit, are essential [25]. For example, Dixit et al. designed mefenamic acid in different crystal forms (form I and form II) and particle sizes (4–12 μm) by recrystallization and spray drying to improve the dissolution behavior [26]. Iwasaki et al. used dry grinding to generate microparticles of mefenamic acid. In their study, with sufficient grinding time and rotor speed, the dissolution of mefenamic acid was enhanced considerably while the mean diameter of the sample was less than 5 μm [27]. In this study, the designed continuous antisolvent sonocrystallization was conducted to evaluate its feasibility in controlling the particle size and crystal habit of mefenamic acid. Furthermore, the influence of process parameters on the outcomes of continuous antisolvent sonocrystallization was investigated. To assess the impact of the process, the solid-state properties of mefenamic acid before and after sonocrystallization were analyzed and compared using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC).

2. Materials and Methods

2.1. Materials

Mefenamic acid, with a minimum purity of 98%, was supplied by Tokyo Chemical Industry (Tokyo, Japan). Its properties, including molecular weight, melting temperature, water solubility, chemical formula, and molecular structure, are summarized in Table 1. According to the solubility behavior of mefenamic acid [28,29], for recrystallizing the mefenamic acid by antisolvent addition, acetone and water were selected as the solvent and antisolvent, respectively. The solvent acetone was purchased from Sigma-Aldrich (St. Louis, MO, USA) with a purity of 99.5%. Deionized water was produced in the laboratory using a UNISS Pure Product II 15UV system. No further purification of the chemicals was performed before use.

2.2. Experimental Apparatus

The experimental setup for the continuous antisolvent sonocrystallization is shown in Figure 1. The system consists of an ultrasonic device (Branson Ultrasonics, S450D, St. Louis, MO, USA), a 100 mL flow cell, a 250 mL jacketed vessel, a heating/cooling circulator (Lauda, ECO RE 415 Silver, Baden-Württemberg, Germany), a plunger pump (FMI, Q3CSC, NY, USA), a syringe pump (KDS 100, MA, USA), and a vacuum filtration device. The ultrasonic device, comprising a probe, generator, and controller, delivers ultrasonic waves to the crystallization mixture within the flow cell. The flow cell, a small jacketed chamber mounted on the ultrasonic probe, allows the crystallization mixture to pass through under controlled conditions. The jacketed vessel was used as the antisolvent storage tank. The syringe pump introduces the mefenamic acid solution at a controlled flow rate, while the plunger pump regulates the flow of the antisolvent. The heating/cooling circulator regulates the temperature of both the antisolvent storage tank and the flow cell. An oil-free vacuum pump is used for vacuum filtration.
The continuous antisolvent sonocrystallization began by loading the antisolvent into the flow cell, with its flow rate controlled by the plunger pump. The heating/cooling circulator and the sonication were then switched on and set to the designed temperature and intensity. Afterward, the mefenamic acid solution, prepared at a specified concentration and fully dissolved, was loaded into a syringe and then injected by the syringe pump into the flow cell, where it mixed with the antisolvent supplied by the plunger pump. The antisolvent and mefenamic acid solution continuously flowed and mixed in the flow cell. The solution exiting from the flow cell was transferred to the vacuum filtration device to filter the produced solid. Upon complete injection of the API solution, the plunger pump was stopped. At the end of the experiment, all equipment, including the ultrasonic device, syringe pump, and heating/cooling circulator, was turned off. The resulting mefenamic acid crystals were collected from the filter paper and dried in an oven at 50 °C. Finally, the dried crystals were weighed to determine the recovery and prepared for further analysis. The recovery is defined as the mass percentage of the final powdered mefenamic acid relative to the initially dissolved mefenamic acid, and can be calculated using the following equation.
R e c o v e r y   %   =   M a s s   o f   m e f e n a m i c   a c i d   r e c o v e r e d I n i t i a l   m a s s   o f   m e f e n a m i c   a c i d   d i s s o l v e d   ×   100

2.3. Characterization

Several analytical techniques were employed to compare and analyze the solid-state properties of mefenamic acid before and after the sonocrystallization process. A scanning electron microscope (SEM, Hitachi, S-3000H, Tokyo, Japan) was utilized to examine the crystal habit of mefenamic acid. Before analysis, the sample was mounted on double-sided tape and gold-coated using a vacuum sputter coater. The particle size was measured using a laser diffraction particle size analyzer (PSD, Shimadzu, SALD-2300, Kyoto, Japan). In principle, when a particle is irradiated with a laser beam, it scatters light in all directions. The particle size characteristics are then determined from the intensity distribution pattern of the collected scattered light. Approximately 20 mg of the sample was suspended in 15 mL of deionized water containing a few drops of Tween 80 surfactant. The suspension was vortexed, sonicated, and then analyzed to determine the mean particle size and particle size distribution. The reported mean particle size was averaged from at least two replicates. Powder X-ray diffraction (PXRD, PANalytical, X’Pert3 Powder, Almelo, The Netherlands) was employed to determine the crystal structure and polymorphic form of mefenamic acid. The sample was evenly distributed onto the PXRD sample holder at room temperature. The scanning rate was set to 13°/min from 10° to 50°. Fourier-transform infrared spectroscopy (FTIR, Perkin Elmer, Spectrum Two, CT, USA) and differential scanning calorimetry (DSC, Perkin Elmer, DSC 4000, CT, USA) were used to evaluate the spectroscopic characteristics and thermal properties of mefenamic acid. For FTIR analysis, approximately 1–3 mg of the sample was placed on an attenuated total reflectance (ATR) sample holder and scanned over a wavenumber range of 4000 to 650 cm−1 with a resolution of 1 cm−1. In the DSC analysis, approximately 2 mg of the sample was sealed in an aluminum pan, and the thermogram was recorded from 50 °C to 250 °C at a heating rate of 10 °C/min, using nitrogen as the purge gas.

3. Results and Discussion

3.1. The Effect of Operating Parameters

Since mefenamic acid is a poorly water-soluble API, with an aqueous solubility of only 20 mg/L at 30 °C, water was chosen as the antisolvent. According to the solubility data from the literature [28,29] and the miscibility property with water, acetone was selected as the solvent. Table 2 presents the experimental conditions and results, including recovery, mean size, and span values for the continuous antisolvent sonocrystallization experiments. Four operating parameters were investigated, including sonication intensity, crystallization temperature, antisolvent flow rate, and solution injection flow rate. To screen the key operating parameters in the continuous antisolvent sonocrystallization, the one-factor-at-a-time approach was used in this study. The designed interval of the operating parameters was referred to our previous sonocrystallization investigation [4,17,18]. To meet the goal of high throughput, the solution concentration was fixed at about 90% of the saturated value at 25 °C. The span values were used to describe the particle size distribution using the following definition.
S p a n   =   D 90   −   D 10 D 50
where D10, D50, and D90 are the particle sizes at which 10, 50, and 90% of the distribution is smaller.
To study the effect of sonication intensity, intensities of 10%, 30%, 50%, and 70% were used while maintaining the other operating parameters constant. A comparative experiment (experiment 2) for antisolvent crystallization without applying sonication was also designed to validate the beneficial effect of sonication. Table 2 shows that, by applying sonication, the mean size of mefenamic acid could be successfully reduced from 6.4 μm (experiment 2) to about 3.1 μm (experiment 3). Applying sonication in the crystallization system generally reduces induction time, thereby enhancing the nucleation rate and resulting in the production of small particles [30,31]. However, further increasing the sonication intensity shows a negligible effect on the mean particle size of mefenamic acid, with average sizes only ranging from 2.8 μm to 3.1 μm within the sonication intensity range from 10% to 70%. On the other hand, applying intense sonication is favorable for further reducing the particle size distribution. The span of applying 70% sonication intensity was decreased to 1.5, compared with 1.8 when applying 10% sonication intensity. The intense sonication may bring the local heat region to redissolve the fine crystals, which benefits the production of mefenamic acid crystals with a narrow size distribution.
To investigate the effect of temperature, three crystallization temperatures were employed during sonocrystallization: 25 °C, 35 °C, and 45 °C (Experiments 1, 6, and 7). Table 2 shows that the mean size of sonocrystallized mefenamic acid increased from 2.6 μm to 3.2 μm as the crystallization temperature increased. As the temperature rises, the saturated solubility of mefenamic acid in the solvent/antisolvent mixture increases, thereby reducing supersaturation. In crystallization, lower supersaturation often favors the formation of larger particles [32,33]. The temperature shows a noticeable effect on the mean size of mefenamic acid. Additionally, the experimental results show that the recovery tends to decrease with increasing temperature owing to the increase in saturated solubility.
The effect of antisolvent flow rate was investigated at three different settings: 10 mL/min, 25 mL/min, and 50 mL/min at a fixed solution flow rate of 2.5 mL/min. These settings represent the solution-to-antisolvent ratio increasing from 1:4 to 1:20. In general, a higher solution-to-antisolvent ratio implies a stronger antisolvent effect, which facilitates nucleation. In this study, as shown in experiments 1, 8, and 9 in Table 2, an increase in the antisolvent flow rate shows a negligible effect on the mean particle size. The mean size of sonocrystallized mefenamic acid was around 3.0 μm for the three antisolvent flow rates. Sonication may dominate the nucleation behavior and efficiently control the mean particle size while the effect of the antisolvent strength becomes minor.
Finally, the solution injection flow rate was investigated at three different settings: 1.0 mL/min, 2.5 mL/min, and 7.5 mL/min (Experiments 1, 10, and 11) at a fixed antisolvent flow rate of 10 mL/min. The results listed in Table 2 indicate that increasing the solution injection flow rate from 2.5 mL/min to 7.5 mL/min decreased the solution-to-antisolvent ratio. The weakened antisolvent strength is unfavorable for the recrystallization of mefenamic acid, resulting in a decrease in recovery, an increase in mean particle size, and an enlargement in particle size distribution. However, when the solution injection rate decreases from 2.5 mL/min to 1.0 mL/min, mefenamic acid particles with a large mean size but a narrow size distribution were generated. This behavior can be explained as follows: when the drug solution is introduced slowly into the antisolvent, the nucleation rate is lower, resulting in fewer nuclei and a larger average particle size [34,35]. Based on the overall results, an injection rate of 2.5 mL/min appears to be the most suitable condition for the continuous antisolvent sonocrystallization of mefenamic acid.

3.2. The Solid-State Property Comparison

To demonstrate the beneficial effect of sonication on the particle size and crystal habit, Figure 2 compares the SEM images of unprocessed mefenamic acid, crystals obtained from experiment 2 (crystallization without sonication), and crystals obtained from experiment 1 (crystallization with sonication). As can be seen, both the unprocessed and non-sonicated recrystallized samples exhibited larger particle sizes and irregular crystal habits. In contrast, the application of sonication led to significantly smaller particle sizes and more uniform, well-defined crystal shapes. These observations suggest that sonication is effective in controlling both particle size and crystal shape, resulting in more regular and consistent morphologies. Figure 3 also compares the particle size distributions of the three samples. The results demonstrate that sonocrystallization yields crystals with smaller particle sizes and a narrower size distribution compared to both the unprocessed and non-sonicated samples.
To further investigate the effect of sonication on the physical properties of mefenamic acid, Figure 4, Figure 5 and Figure 6 present the results of PXRD, DSC, and FTIR analyses for unprocessed mefenamic acid, particles obtained from experiment 2, and particles obtained from experiment 1. As shown in Figure 4, the PXRD patterns of the recrystallized samples, both with and without sonication, are consistent with those of the unprocessed mefenamic acid, confirming that no polymorphic transformation occurred. These patterns are in agreement with PXRD data for mefenamic acid previously reported by Panchagnula et al. [36]. The PXRD findings are further supported by DSC analysis, as shown in Figure 5. The DSC thermograms of all three samples exhibit endothermic peaks consistent with the form I polymorph of mefenamic acid, again indicating the absence of polymorphic changes during sonocrystallization. In addition, the first endothermic peak in the DSC thermogram indicates the solid–solid transition of form I mefenamic acid to form II mefenamic acid. The differences in the first endothermic peak between the three samples may be attributed to the modifications in particle size, crystal habits, and disorders in crystals during the recrystallization process. Similar observations were also reported in the literature for different commercial mefenamic acid samples [36] and mefenamic acid samples before and after the supercritical antisolvent processing [37]. The FTIR spectra shown in Figure 6 confirm that the molecular structures of all samples remain identical. The characteristic absorption band at 3313 cm−1, attributed to the N–H stretching vibration, is observed in all samples, consistent with the form I polymorph. These results are in agreement with the findings of Cunha et al. [38], further confirming the structural stability of mefenamic acid during sonocrystallization processes.

4. Conclusions

A continuous antisolvent sonocrystallization process was developed in this study to efficiently deliver sonication and demonstrate its effectiveness in modifying the particle size and crystal habit of mefenamic acid. The effects of operating parameters such as sonication intensity, crystallization temperature, antisolvent flow rate, and solution injection flow rate were investigated. The resulting mefenamic acid particles exhibited regular shapes, narrow size distributions, and mean sizes ranging from 2.6 to 3.5 μm. The results showed that operating at a low crystallization temperature and an intermediate solution injection flow rate were favorable for producing smaller mefenamic acid particles, while the effects of the sonication intensity and antisolvent flow rate were minor. Finally, PXRD, DSC, and FTIR analyses confirmed that the crystal structure of mefenamic acid remained consistent as form I before and after sonocrystallization. These findings demonstrate that continuous antisolvent sonocrystallization is an effective and intensified crystallization technique for API microparticle production.

Author Contributions

Conceptualization, C.-S.S.; Methodology, C.-Y.L.; Supervision, C.-S.S.; Validation, S.H.K. and C.-Y.L.; Writing—original draft, S.H.K.; Writing—review and editing, S.H.K. and C.-S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the [National Science and Technology Council] grant number [NSTC 113-2221-E-027-009-MY3]. The APC was funded by the [National Science and Technology Council].

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Experimental apparatus of the continuous sonocrystallization process.
Figure 1. Experimental apparatus of the continuous sonocrystallization process.
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Figure 2. SEM images of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Figure 2. SEM images of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
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Figure 3. Comparison of particle size distribution of unprocessed mefenamic acid, mefenamic acid particles obtained from Exp. 2 (without sonication), and mefenamic acid particles obtained from Exp. 1 (with sonication).
Figure 3. Comparison of particle size distribution of unprocessed mefenamic acid, mefenamic acid particles obtained from Exp. 2 (without sonication), and mefenamic acid particles obtained from Exp. 1 (with sonication).
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Figure 4. Comparison of the PXRD patterns of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Figure 4. Comparison of the PXRD patterns of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Processes 13 02813 g004
Processes 13 02813 g005
Figure 5. Comparison of the DSC thermograms of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Figure 5. Comparison of the DSC thermograms of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Processes 13 02813 g005
Processes 13 02813 g006
Figure 6. Comparison of the FTIR spectra of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Figure 6. Comparison of the FTIR spectra of (a) unprocessed mefenamic acid, (b) mefenamic acid particles obtained from Exp. 2 (without sonication), and (c) mefenamic acid particles obtained from Exp. 1 (with sonication).
Processes 13 02813 g006
Table 1. Physical properties of mefenamic acid.
Table 1. Physical properties of mefenamic acid.
CompoundMefenamic Acid
IUPAC name2-(2,3-Dimethylphenyl) aminobenzoic acid
StructureProcesses 13 02813 i001
FormulaC15H15NO2
CAS No.61-68-7
Mw241.28
Tm (°C)230–231 (a)
Aqueous solubility20 mg/L (at 30 °C) (a)
SupplierTokyo Chemical Industry
Product numberM1782
Purity (%)>98.0
(a) Value acquired from PubChem: https://pubchem.ncbi.nlm.nih.gov (accessed on 13 July 2025).
Table 2. Experimental conditions and results for continuous sonocrystallization of mefenamic acid.
Table 2. Experimental conditions and results for continuous sonocrystallization of mefenamic acid.
Exp. No.Operating ParametersResults
Intensity (%)Temp.
(°C)		Fantisolvent
(mL/min)		Fsolution
(mL/min)		Conc. (a)
(mg/mL)		Recovery (%)Mean Size (μm)Span
(-)
Unprocessed------------------33.4 ± 2.774.6
13035102.51679.53.0 ± 0.171.9
2 (b)035102.51675.76.4 ± 0.252.1
31035102.51686.83.1 ± 0.141.8
45035102.51682.42.8 ± 0.151.7
57035102.51680.83.0 ± 0.131.5
63025102.51684.82.6 ± 0.071.6
73045102.51674.83.1 ± 0.131.8
83035252.51682.93.0 ± 0.082.0
93035502.51682.92.9 ± 0.132.7
103035101.01682.23.3 ± 0.152.2
113035107.51678.83.5 ± 0.081.4
(a) Concentrations were designed at about 90% of the saturated value at 25 °C. (b) Recrystallization experiment without applying sonication.
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Khudaida, S.H.; Lee, C.-Y.; Su, C.-S. Microparticle Production of Mefenamic Acid Using the Continuous Antisolvent Sonocrystallization Process. Processes 2025, 13, 2813. https://doi.org/10.3390/pr13092813

AMA Style

Khudaida SH, Lee C-Y, Su C-S. Microparticle Production of Mefenamic Acid Using the Continuous Antisolvent Sonocrystallization Process. Processes. 2025; 13(9):2813. https://doi.org/10.3390/pr13092813

Chicago/Turabian Style

Khudaida, Salal Hasan, Chia-Yi Lee, and Chie-Shaan Su. 2025. "Microparticle Production of Mefenamic Acid Using the Continuous Antisolvent Sonocrystallization Process" Processes 13, no. 9: 2813. https://doi.org/10.3390/pr13092813

APA Style

Khudaida, S. H., Lee, C.-Y., & Su, C.-S. (2025). Microparticle Production of Mefenamic Acid Using the Continuous Antisolvent Sonocrystallization Process. Processes, 13(9), 2813. https://doi.org/10.3390/pr13092813

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