Impact of Electromagnetic Field on the Physicochemical Properties, Permeability, and Accumulation of Salicylic Acid

Abstract

Transdermal drug delivery offers a non-invasive route for the systemic and localized administration of therapeutics; however, the skin’s barrier function limits its efficiency. This study investigates the application of various electromagnetic field (EMF) configurations to enhance the transdermal delivery of salicylic acid, a model compound with moderate lipophilicity and ionizability. Samples were exposed to pulsed, oscillating, static, and rotating magnetic fields, and their effects on physicochemical properties, thermal stability, skin permeation, and accumulation were evaluated. Structural analyses (FTIR, XRD) and thermal assessments (TGA, DSC) confirmed that EMF exposure did not alter the chemical structure or stability of salicylic acid. In vitro transdermal studies using porcine skin and Franz diffusion cells revealed that pulsed magnetic fields—especially with a 5 s on/5 s off cycle—and rotating magnetic fields at 30–50 Hz significantly enhanced drug permeation compared to controls. In contrast, static fields of negative polarity increased skin retention, suggesting their potential for controlled, localized delivery. These findings demonstrate that EMFs can be used as tunable, non-destructive tools to modulate drug transport across the skin and support their integration into transdermal delivery systems aimed at optimizing therapeutic profiles.

1. Introduction

Transdermal drug delivery systems (TDDSs) have become an important area of pharmaceutical research due to their ability to offer sustained release of active compounds while bypassing the gastrointestinal tract and hepatic first-pass metabolism. This route of administration improves patient compliance and reduces systemic side effects commonly observed with oral or injectable formulations. Despite these advantages, the efficiency of TDDSs is severely limited by the presence of the stratum corneum, a highly organized lipid–protein matrix that constitutes the main barrier to the diffusion of many therapeutic agents [1,2,3,4,5,6]. In order to enhance the skin permeability of active pharmaceutical ingredients (APIs), various physical and chemical enhancement techniques have been explored, including microneedles, iontophoresis, sonophoresis, and more recently, the application of electromagnetic fields (EMFs) [7,8,9,10,11,12,13].

EMFs are composed of electric and magnetic components and are known to interact with biological systems at both the cellular and molecular levels. They influence membrane structure, fluidity, and ion transport mechanisms, potentially affecting the rate of passive and facilitated diffusion through biological barriers. Depending on their characteristics, EMFs are classified as static (SMFs), oscillating (OMFs), pulsed (PMFs), or rotating magnetic fields (RMFs). Among these, RMFs have gained particular attention in pharmaceutical research due to their ability to induce hydrodynamic microflows and enhance mass transport without compromising tissue integrity [14,15,16,17]. Studies have demonstrated that RMFs can significantly increase the skin permeability of several NSAIDs, such as ibuprofen, naproxen, ketoprofen, caffeine, and paracetamol, by modifying physicochemical properties of the compounds and disrupting the lipid structure of the stratum corneum [13,18,19].

Salicylic acid (2-hydroxybenzoic acid) is a keratolytic agent of natural origin widely used in dermatology and cosmetology due to its anti-inflammatory, antimicrobial, and exfoliating properties. It is effective in the treatment of acne, psoriasis, calluses, and other hyperkeratotic conditions. Despite its relatively low molecular weight (138.12 Da) and moderate lipophilicity (log P ≈ 2.3), the ionization of its carboxylic group under physiological conditions leads to the formation of negatively charged species, which significantly hinders its passive transdermal absorption [20,21,22,23,24]. Formulations containing salicylic acid often require high concentrations or pH modification to enhance skin penetration, which can increase the risk of irritation or sensitization. Therefore, the development of alternative, non-invasive methods to improve its permeability is of great practical importance.

To date, no comprehensive study has evaluated the effect of various electromagnetic field types on the transdermal delivery of salicylic acid. Thus, the present research aims to investigate how different EMFs—namely oscillating, pulsed, static (positive and negative), and rotating magnetic fields—influence the transdermal permeability and skin accumulation of salicylic acid using porcine skin as a model. In addition to permeation studies, the potential changes in the physicochemical properties of the compound (including FTIR spectra, crystalline structure, solubility in water, partition coefficient, and thermal characteristics) induced by EMF exposure will also be evaluated. This work is intended to expand our understanding of EMF-assisted transdermal drug delivery and to provide new insights into optimizing non-invasive therapeutic systems based on widely used dermatological agents.

2. Materials and Methods

2.1. Materials

The active compound used in this study was salicylic acid (SA), a representative of β-hydroxy acids, widely applied in dermatological formulations. SA of ≥99% purity was sourced from Sigma-Aldrich (Steinheim am Albuch, Germany). Analytical-grade solvents and reagents were employed throughout this study. Acetonitrile (≥99.9%, gradient grade for HPLC), methanol (≥99.9%, for HPLC), and phosphate-buffered saline (PBS, pH 7.4) tablets were obtained from Sigma-Aldrich (Steinheim am Albuch, Germany) as well. Orthophosphoric acid (≥99%) and potassium dihydrogen phosphate (analytical grade) were purchased from Merck (Darmstadt, Germany). Deionized water was used in all experimental procedures. Skin samples of porcine origin were acquired from a local meat processing facility and used as a model membrane in diffusion experiments due to their similarity to human skin in terms of permeability and structure.

2.2. Electromagnetic Field Exposure

Salicylic acid samples were subjected to exposure under different electromagnetic field conditions for a total duration of 8 h. The control group consisted of samples not exposed to any field. Five types of magnetic field configurations were applied in this study:

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Oscillating magnetic field (OMF): generated using alternating current (AC) with a frequency range of 45–65 Hz and magnetic induction values between 26 and 35 mT.

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Pulsed magnetic field (PMF): characterized by a 65 Hz current with magnetic induction up to 26 mT, operating in a cyclic on/off mode with pulse durations of 1–10 s.

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Static magnetic field—positive polarity (SMF+): produced using direct current (DC) with a supply voltage of 5–25 V and magnetic induction of 4–21 mT.

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Static magnetic field—negative polarity (SMF−): DC-generated with reverse polarity, voltage of 5–25 V, and induction of 3–15 mT.

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Rotating magnetic field (RMF): formed by the superposition of three AC fields (each 120° out of phase), delivering a rotating magnetic vector at 10–50 Hz and 33–45 mT magnetic induction.

The electromagnetic field parameters used in this study were selected to reflect commonly studied extremely low-frequency electromagnetic field (ELF-EMF) conditions, while also taking into account the technical constraints of the available instrumentation. Specifically, frequency ranges of 45–65 Hz for oscillating magnetic fields (OMFs) and 10–50 Hz for rotating magnetic fields (RMFs) were chosen to align with the ELF-EMF spectrum, typically defined as 3–300 Hz. This frequency range has been extensively investigated in biomedical research due to its potential biological relevance, including applications in bone regeneration, tissue repair, neurological modulation, and anti-inflammatory therapies [25,26,27].

Magnetic induction values between 3 and 45 mT were selected to ensure non-invasive exposure conditions that do not exceed internationally accepted safety thresholds and do not induce thermal or structural degradation of either the active compound or the biological membrane. The pulse durations applied in the pulsed magnetic field (PMF) configurations (1–10 s) were intended to mimic short, intermittent modulations of the skin barrier, allowing for reversible effects on permeability without causing sustained mechanical or thermal stress to the tissue. These experimental parameters were also supported by preliminary optimization trials conducted in-house, reflecting the operational capabilities of the electromagnetic field generator used in the present study.

All field exposures were performed in a custom-built reactor system equipped with integrated electromagnetic field generators. Each reactor chamber was maintained at a constant temperature (37.0 ± 0.1 °C) using a water-jacketed circulation system connected to a thermostatic controller. This setup permitted the simultaneous exposure of samples under different EMF types as well as a control sample.

Both pure salicylic acid (as the active pharmaceutical ingredient) and its 70% ethanol (EtOH) solutions were subjected to electromagnetic field exposure. In the case of the EtOH-based solutions, transdermal permeability studies were additionally carried out to evaluate the influence of EMF conditions on skin penetration efficiency.

2.3. In Vitro Transdermal Permeation

Permeation studies were conducted using Franz-type diffusion cells (Phoenix DB-6, ABL&E-JASCO, Vienna, Austria) with a diffusion area of 1.0 cm² and a receptor volume of 10 mL. Fresh porcine skin was mounted between the donor and receptor compartments, with the stratum corneum facing the donor side. The receptor chamber was filled with PBS (pH 7.4), maintained at 37.0 ± 0.1 °C, and continuously stirred.

The donor compartment was loaded with 1 mL of a 1% (w/v) salicylic acid solution prepared in 70% ethanol. Samples were collected from the receptor chamber at predetermined intervals (0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h), and the withdrawn volume was immediately replaced with fresh PBS. The amount of salicylic acid permeated was quantified using high-performance liquid chromatography (HPLC), as described below.

2.4. HPLC Analysis

The quantitative analysis of salicylic acid was performed using a Shimadzu Nexera-i LC-2040C 3D HPLC system (Kyoto, Japan) equipped with a diode array detector (DAD). Chromatographic separation was achieved using a Kinetex F5 column (150 × 4.6 mm, 2.6 µm; Phenomenex, Torrance, CA, USA). The mobile phase consisted of a mixture of acetonitrile, methanol, and potassium dihydrogen phosphate buffer (45:10:45 v/v/v), adjusted to pH 2.5 with orthophosphoric acid. The flow rate was set at 1.0 mL/min, the column temperature was maintained at 25 °C, and detection was carried out at 230 nm. Each sample was analyzed in triplicate, and concentrations were determined based on a calibration curve constructed from standard solutions.

2.5. Physicochemical and Spectroscopic Characterization

To assess the influence of electromagnetic field exposure on the structural integrity and physicochemical properties of salicylic acid.

FTIR spectroscopy: spectra were recorded on a Nicolet 380 FTIR spectrometer (Thermo Scientific, Waltham, MA, USA) using the ATR technique in the range of 4000–400 cm⁻¹ with a resolution of 4 cm⁻¹.

X-Ray diffraction (XRD): crystalline forms were identified using an Aeris X-ray diffractometer (Malvern Panalytical, Malvern, UK) with Cu-Kα radiation (λ = 1.54056 Å) in a 2θ range of 7°–90°.

Thermogravimetric analysis (TGA): Thermal stability was examined using a Netzsch TG 209 F1 Libra analyzer (Selb, Germany), heating samples from 25 °C to 1000 °C at 10 °C/min in nitrogen and air atmospheres.

Differential scanning calorimetry (DSC): melting behavior and phase transitions were assessed using a DSC 250 (TA Instruments, New Castle, DE, USA) in a three-cycle program (heating–cooling–heating) over a temperature range specific for salicylic acid (−90 °C to 190 °C).

Solubility determination: saturated aqueous solutions of salicylic acid were prepared by stirring the excess compound in deionized water for 24 h at 25 °C, followed by filtration and HPLC quantification.

Lipophilicity (log P): the n-octanol/water partition coefficient was determined using the shake-flask method with a subsequent HPLC analysis of the aqueous phase.

2.6. Skin Accumulation Study

At the end of the permeation experiment, skin samples were excised, washed, and analyzed to quantify the amount of salicylic acid retained in the tissue. Extraction was performed using ethanol, followed by centrifugation and HPLC analysis of the supernatant. Results were expressed as micrograms of compound per gram of skin tissue (µg/g).

2.7. Statistical Analysis

All experiments were performed in triplicate. Data are expressed as mean ± standard deviation (SD). Statistical comparisons were carried out using a one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test (α < 0.05) for pairwise comparisons. Additional comparisons between the control and field-exposed samples were performed using the Mann–Whitney U test. Statistical analyses were conducted using Statistica 13 (StatSoft, Poland).

3. Results and Discussion

3.1. Influence of Electromagnetic Fields on the Physicochemical Properties of Salicylic Acid

FTIR Spectroscopy

FTIR spectra of control and field-exposed salicylic acid samples are presented in Figure 1, while individual spectra for each condition are provided in the Supplementary Material (Figure S1a–p). The characteristic absorption bands observed in the FTIR spectra confirm the presence of salicylic acid across all samples, irrespective of electromagnetic field exposure.

Notably, the absorption bands at 1652 cm⁻¹ and 1441 cm⁻¹ correspond to the asymmetric and symmetric stretching vibrations of the carboxylic C=O group, respectively. Additional prominent peaks were observed at 1291 cm⁻¹, 1208 cm⁻¹, 1152 cm⁻¹, 887 cm⁻¹, 756 cm⁻¹, 690 cm⁻¹, 657 cm⁻¹, and 530 cm⁻¹, all of which are characteristic of salicylic acid functional groups.

The comparative analysis between the control and treated samples indicated no significant spectral shifts or band loss, suggesting that electromagnetic field exposure—whether oscillating, pulsed, static (positive or negative polarity), or rotating—did not induce any structural changes to the salicylic acid molecule. Minor differences in absorption intensities were noted, but are attributed to slight concentration differences during ATR-FTIR crystal deposition rather than EMF-induced effects.

3.2. X-Ray Diffraction (XRD)

A comparison of X-ray diffraction (XRD) patterns of salicylic acid samples before and after electromagnetic field exposure is presented in Figure 2, while individual diffractograms for each condition are provided in the Supplementary Material (Figure S2a–p).

The obtained diffractograms confirm the crystalline nature of salicylic acid across all examined samples, regardless of the type of magnetic field applied. Distinct diffraction peaks were consistently observed at 2θ values of approximately 11°, 17°, and 25°, with only slight positional variations. Minor differences in peak intensities were noted in EMF-exposed samples compared to the control, which was not subjected to any field treatment. These changes may indicate slight modifications in the crystalline form of salicylic acid induced by exposure to an electromagnetic field.

3.3. Thermogravimetric Analysis (TGA)

A thermogravimetric analysis was performed to evaluate the thermal stability of salicylic acid samples subjected to various electromagnetic field exposures. The results are summarized in

Table 1. Thermal stability parameters of salicylic acid samples exposed to electromagnetic fields compared to the control. Measurement error for temperature values: ±0.5–1.0 °C; decomposition rate: ±1.2%/min.

Sample	Tm [°C]	Tonset [°C]	Td5% [°C]	Td50% [°C]	Tmax (°C) %/min
Control	160.1	166.3	141.7	178.2	190.8 (−36.83)
OMF 45 Hz	159.9	164.8	141.6	177.7	189.8 (−34.98)
OMF 55 Hz	160.0	166.0	141.4	178.0	189.7 (−37.34)
OMF 65 Hz	159.5	166.2	142.5	178.7	190.6 (−34.72)
PMF 1/1	160.1	165.7	141.4	177.8	189.6 (−35.10)
PMF 5/5	159.9	166.1	142.7	178.5	189.1 (−36.71)
PMF 10/10	160.0	166.4	142.6	178.7	190.3 (−36.89)
SPM +5 V_SA	159.6	164.6	142.5	178.2	187.6 (−34.97)
SPM +15 V_SA	159.7	165.7	142.4	178.5	190.8 (−34.71)
SPM +25 V_SA	159.7	165.7	140.9	177.5	189.4 (−37.47)
SPM −5 V_SA	159.9	165.8	142.9	178.4	189.9 (−34.42)
SPM −15 V_SA	159.8	164.8	141.7	178.0	190.1 (−34.30)
SPM −25 V_SA	159.6	165.9	142.3	178.6	190.3 (−34.29)
WPM 10 Hz_SA	160.4	165.3	142.1	178.3	190.3 (−35.04)
WPM 30 Hz_SA	160.1	165.0	141.7	177.9	189.6 (−34.59)
WPM 50 Hz_SA	159.8	162.5	142.9	178.1	191.4 (−33.19)

T_m—melting temperature, T_onset—onset of decomposition, T_d5%—temperature at 5% weight loss, T_d50%—temperature at 50% weight loss, T_max—the maximum decomposition temperature.

, presenting key thermal parameters, including the melting temperature (T_m), the onset of decomposition (T_onset), temperatures at 5% and 50% weight loss (T_d^5%, T_d^50%), and the maximum decomposition temperature (T_max), along with the corresponding decomposition rate. Individual TG curves for each sample are available in the Supplementary Material (Figure S3a–p).

Small differences in thermal stability were observed among the salicylic acid samples. The lowest melting point (159.5 °C) was found in the sample exposed to an oscillating magnetic field at 65 Hz (OMF 65 Hz), while the highest value (160.4 °C) occurred in the sample subjected to a rotating magnetic field at 10 Hz (RMF 10 Hz).

The onset of decomposition ranged between 162.5 °C (RMF 50 Hz) and 166.4 °C (PMF 10/10). Temperatures corresponding to a 5% weight loss varied from 140.9 °C (SMF +25 V) to 142.9 °C (SMF −5 V and RMF 50 Hz), and a 50% weight loss was recorded between 177.5 °C and 178.7 °C. The maximum decomposition temperature varied from 187.6 °C to 191.4 °C, with associated decomposition rates ranging from −34.97%/min to −33.19%/min.

Despite minor differences observed in onset and degradation temperatures across various EMF configurations, the overall thermal stability of salicylic acid remained comparable to the control. Specifically, most values of T_onset, T_d^5%, T_max varied within a narrow range of approximately 1–2 °C. Given the known measurement uncertainty for thermogravimetric analysis (estimated at ±0.5–1.0 °C for temperature and ±1.2%/min for decomposition rate), these variations are considered to fall within the range of experimental error. As such, we interpret them as non-significant and not indicative of any measurable destabilization or degradation effect caused by electromagnetic field exposure.

3.4. Differential Scanning Calorimetry (DSC)

Table 2. Phase transition temperatures of salicylic acid before and after exposure to an electromagnetic field.

Sample	TDSConset [°C]	TDSCmax [°C]	∆Hm [J/g]
Control	158.95	162.69	222.90
OMF 45 Hz	159.13	162.62	171.23
OMF 55 Hz	158.97	162.56	195.13
OMF 65 Hz	159.08	162.90	179.19
PMF 1/1	159.16	162.25	139.75
PMF 5/5	158.84	162.31	198.56
PMF 10/10	159.27	162.37	138.98
SMF +5 V	158.93	162.28	180.19
SMF +15 V	158.87	161.93	184.21
SMF +25 V	158.89	161.86	179.45
SMF −5 V	159.09	162.34	140.41
SMF −15 V	158.80	162.25	233.70
SMF −25 V	158.90	162.10	189.29
RMF 10 Hz	158.82	162.12	204.53
RMF 30 Hz	158.86	161.86	186.17
RMF 50 Hz	158.88	162.16	-

T_DSConset—melting onset temperature; T_DSCmax—peak melting temperature; ∆Hm—melting enthalpy.

presents the phase transition temperatures of salicylic acid samples following exposure to various electromagnetic fields, compared to the untreated control. Individual DSC thermograms for each sample are provided in the Supplementary Material (Figure S4a–p).

Only slight differences in phase transition temperatures were observed between field-exposed samples and the control. The onset temperature ranged from 158.80 °C (SPM −15 V) to 159.27 °C (PPM 10/10), while the peak melting temperature was lowest (161.86 °C) for samples exposed to a static magnetic field with positive polarity at 25 V (SMF +25 V) and a rotating magnetic field at 30 Hz (RMF 30 Hz).

More pronounced differences were observed in the melting enthalpies (∆H_m), which ranged from 138.98 J/g (PMF 10/10) to 233.70 J/g (SMF −15 V). These discrepancies are partly due to the known phenomenon that salicylic acid undergoes partial decomposition during melting, complicating the precise determination of the enthalpy values.

It is hypothesized that the small shifts in melting temperature may reflect minor modifications in the crystalline form of salicylic acid caused by exposure to various electromagnetic fields. However, all values remain within a narrow range, suggesting that the thermal behavior of the compound remains largely consistent.

3.5. In Vitro Transdermal Permeation of Salicylic Acid

The effect of various electromagnetic field (EMF) configurations on the transdermal permeability of salicylic acid was evaluated using porcine skin and Franz-type diffusion cells over 8 h. These time-dependent effects of electromagnetic field exposure on the cumulative transdermal delivery of salicylic acid are summarized in Figure 3, which illustrates the penetration profiles for each EMF configuration over the 8 h experimental period.

Table 3. Permeation parameters of salicylic acid exposed to different magnetic fields during the 8 h permeation and a control sample without exposure to the electromagnetic field. Mean ± SD, n = 3; α = 0.05 (mean ± SD, n = 3). *—statistically significantly higher penetration compared to the control. The statistically significant difference was estimated by ANOVA using Tuckey’s test.

Sample	Q8h [µg]	JSS [µg/cm2∙h]	KP∙103 [cm/h]	LT [h]	D∙104 [cm2/h]	Km	Q%8h
Control	335.418 ± 38.597	74.29	7.43	3.78	1.10	3.37	3.35
OMF 45 Hz	148.440 ± 45.398	44.87	4.49	4.47	0.93	2.41	1.48
OMF 55 Hz	172.926 ± 53.549	47.00	4.70	4.40	0.95	2.48	1.73
OMF 65 Hz	224.520 ± 49.953	80.24	8.02	5.51	0.76	5.30	2.25
PMF 1/1	408.603 ± 111.225 *	100.37	10.04	4.52	0.92	5.44	4.09
PMF 5/5	638.752 ± 102.536 *	132.64	13.26	2.89	1.44	4.61	6.39
PMF 10/10	394.851 ± 31.171	83.22	8.32	2.84	1.47	2.84	3.95
SMF +5 V	222.4669 ± 23.2904	35.49	3.55	1.88	2.21	0.80	2.22
SMF +15 V	451.0258 ± 122.687 *	68.78	6.88	0.84	4.97	0.69	4.51
SMF +25 V	268.0432 ± 39.0018	82.68	8.27	4.99	0.84	4.95	2.68
SMF −5 V	107.927 ± 37.683	34.79	3.48	5.11	0.82	2.13	1.08
SMF −15 V	128.512 ± 8.614	41.55	4.15	5.05	0.82	2.52	1.29
SMF −25 V	238.275 ± 40.975	36.05	3.60	1.43	2.91	0.62	2.38
RMF 10 Hz	327.782 ± 67.522	106.70	10.67	5.21	0.80	6.68	3.28
RMF 30 Hz	385.265 ± 95.819	130.18	13.02	5.09	0.82	7.96	3.85
RMF 50 Hz	330.749 ± 92.657	115.20	11.52	5.23	0.80	7.24	3.31

Q_8h—cumulative amount permeated, J_SS—steady-state flux; K_P—permeability coefficient; L_T—lag time; D—diffusion coefficient in the skin; K_m—skin partition coefficient; and Q_%8h—percent drug permeated after 8 h; * L_T < 0.

summarizes the calculated permeation parameters, including the cumulative amount permeated after 24 h (Q_24h), steady-state flux (J_SS), permeability coefficient (K_P), lag time (L_T), diffusion coefficient (D), skin partition coefficient (K_m), and percentage permeated after 24 h (Q%_24h).

The control sample, which was not exposed to any electromagnetic field, exhibited a cumulative permeation of 335.42 ± 38.60 µg and a steady-state flux of 74.29 µg/cm²·h. Among the tested field types, the statistically significant increased enhancement of salicylic acid permeation was observed in samples treated with pulsed magnetic fields (PMFs), particularly the 5/5 s cycle configuration (5 s on/5 s off), which resulted in the highest permeation (638.75 ± 102.54 µg), J_SS (132.64 µg/cm²·h), and K_P (13.26 × 10⁻³ cm/h). This enhancement was accompanied by a relatively short lag time (2.89 h) and moderate values of D and K_m, suggesting a favorable balance between skin penetration rate and partitioning.

Rotating magnetic fields (RMFs) also significantly improved transdermal delivery, especially at higher frequencies (30 Hz and 50 Hz), yielding high flux values (130.18 and 115.20 µg/cm²·h, respectively) and high permeation efficiencies (Q_24h > 330 µg; Q%_24h > 3.3%). These effects may be attributed to RMF-induced microfluidic movement within the diffusion medium and structural reorganization within the stratum corneum, facilitating increased drug transport.

In contrast, oscillating magnetic fields (OMFs) showed limited efficacy in enhancing salicylic acid permeation, particularly at lower frequencies (45 and 55 Hz), which resulted in Q_24h values significantly below the control (148.44 ± 45.40 µg and 172.93 ± 53.55 µg, respectively). Interestingly, the OMF at 65 Hz yielded better results, with improved flux (80.24 µg/cm²·h) and permeability (K_P = 8.02 × 10⁻³ cm/h), suggesting a frequency-dependent response in the OMF group.

Static magnetic fields (SMFs) had divergent effects, depending on polarity and voltage. Samples exposed to positive polarity SMFs at higher voltages (15–25 V) demonstrated enhanced permeation compared to other SMF configurations, with Q_24h values of 451.03 ± 122.69 µg (SMF +15 V) and 268.04 ± 39.00 µg (SMF +25 V), significantly higher than those under negative polarity SMFs. The SMF −5 V and −15 V variants resulted in the lowest overall permeation (Q_24h ≈ 108–129 µg), highlighting the importance of field orientation and intensity in modulating barrier properties.

The statistical analysis (ANOVA with Tukey’s post hoc test, α = 0.05) revealed significant differences between the control and multiple EMF-treated groups, particularly PMFs and RMFs at optimized settings, which outperformed the control in nearly all permeation parameters.

Pulsed and rotating magnetic fields significantly enhanced the transdermal delivery of salicylic acid, likely due to their ability to transiently alter the barrier properties of the stratum corneum and improve mass transport. These findings support the potential utility of EMF-based enhancement strategies in topical formulations of ionizable and moderately lipophilic compounds such as salicylic acid.

3.6. Skin Accumulation of Salicylic Acid

The amount of salicylic acid retained in the skin after 8 h of exposure was measured for each sample and is summarized in Figure 4. The control sample showed a moderate level of skin accumulation (4205.29 µg/g), which served as the baseline for evaluating the effect of electromagnetic fields (EMFs) on transdermal deposition. Among the tested field types, static magnetic fields with a negative polarity (SMF −15 V and −5 V) produced the highest skin accumulation values, reaching 4661.08 µg/g and 4595.02 µg/g, respectively. These values notably exceeded the control, indicating that SMFs of this polarity may hinder transdermal diffusion and instead promote drug retention within the skin tissue, likely due to the reduced mobility or altered diffusion kinetics of charged salicylate ions. In contrast, the RMF at 50 Hz led to the lowest observed accumulation (2474.31 µg/g), suggesting that this configuration strongly favors transdermal transport over retention. Similarly, the OMF at 65 Hz (2797.66 µg/g) and SMF +25 V (2921.33 µg/g) showed a substantially reduced accumulation, which may reflect an enhanced flux through the skin and decreased local deposition. The PMF-exposed samples presented mixed outcomes. The PMF one/one and five/five resulted in moderate accumulation (3624.48 µg/g and 3740.42 µg/g), while the PMF ten/ten showed a further reduction (3317.42 µg/g). These differences may relate to how pulse frequency and duration affect transdermal gradients and drug–membrane interactions. Interestingly, the OMF at 45 Hz and 55 Hz, as well as SMF +5 V, showed increased accumulation compared to the control (4647.21, 4485.15, and 4430.44 µg/g, respectively), despite not significantly improving permeation. This further supports the idea that these EMFs may alter drug distribution by favoring local retention. The results demonstrate that EMFs can distinctly modulate the balance between skin permeation and accumulation. Fields such as the RMF 50 Hz promote transdermal flux, thereby reducing residual skin load. In contrast, certain SMFs and low-frequency OMFs may favor skin accumulation, which could be potentially useful for topical therapeutic strategies requiring local drug reservoirs.

4. Discussion

The present study aimed to evaluate how various electromagnetic field (EMF) configurations influence the transdermal delivery and skin retention of salicylic acid, with a particular focus on improving permeability and enabling controlled release. The findings demonstrate that EMFs, especially pulsed and rotating magnetic fields, can serve as promising tools in modulating the skin barrier and transport dynamics of this moderately lipophilic compound.

Among the tested EMF types, pulsed magnetic fields (PMFs) showed the most pronounced enhancement of salicylic acid permeability. The PMF configuration with a 5 s on/off cycle (PMF 5/5 s) led to a nearly two-fold increase in cumulative drug permeation and steady-state flux compared to the control. This effect likely results from transient disruptions in the stratum corneum’s barrier function, which enhances passive diffusion and facilitates faster skin penetration. Rotating magnetic fields (RMFs), particularly at 30 Hz and 50 Hz, also significantly improved transdermal delivery. RMFs likely enhance permeation by inducing microfluidic movement and reorganizing the skin’s lipid layers, thereby reducing barrier resistance. Interestingly, oscillating magnetic fields (OMFs) exhibited a frequency-dependent effect. While lower frequencies (45–55 Hz) reduced permeation, the OMF at 65 Hz showed a moderate enhancement, suggesting that the optimization of field parameters is critical in achieving a desirable delivery profile. Static magnetic fields (SMFs) displayed highly variable effects, depending on voltage and polarity. Positive polarity SMFs at higher voltages enhanced transdermal flux, whereas negative polarity fields significantly suppressed it. These findings suggest that field orientation and strength significantly influence skin permeability, potentially through interactions with charged species or the alignment of lipid domains.

Rotating magnetic fields, on the other hand, appear to enhance drug transport predominantly through convective phenomena. The continuous change in magnetic vector orientation can generate Lorentz forces in the conductive donor and receptor media, resulting in micro-scale vortices and shear flows. These fluid movements may reduce the effective thickness of the unstirred aqueous boundary layer, which is a known rate-limiting step in transdermal diffusion. This mechanism is supported by recent experimental data showing enhanced ibuprofen permeation in RMF-exposed systems due to boundary layer thinning [13,19,28].

Static magnetic fields (SMFs), particularly those with a negative polarity, may exert a different type of effect—one that does not directly enhance permeation but rather modifies retention. It has been suggested that SMFs could interact with diamagnetic lipid molecules in the stratum corneum, subtly altering their orientation or dynamics, and potentially limiting lateral molecular diffusion. As a result, higher accumulation within skin layers may occur even in the absence of an increased flux across the membrane [16,19].

To enable a more quantitative comparison of these effects, enhancement ratios (ER = J_SS,EMF/J_SS,control) were calculated for each EMF configuration (Table S1, Supplementary Materials). Notably, the PMF 5 s on/5 s off mode produced approximately 1.8-fold higher ER values than the highest OMF setting (65 Hz), supporting the role of time-varying amplitude in enhancing transdermal delivery. Likewise, RMFs at 30 Hz and 50 Hz consistently outperformed amplitude-matched SMF and OMF setups, underscoring the additional contribution of vector rotation to transdermal transport efficiency.

The enhanced transdermal permeability of salicylic acid observed under pulsed and rotating electromagnetic field conditions, in contrast to the more modest effects of static and oscillating fields, may be associated with several biophysical processes that act synergistically to modulate skin barrier properties. Although the precise mechanisms remain incompletely understood and are still under investigation, several plausible hypotheses can be formulated based on prior studies.

Pulsed magnetic fields are characterized by high-gradient, time-varying electromagnetic signals that may influence the organization of the stratum corneum lipid matrix. It is postulated that such exposures can lead to transient alterations in membrane fluidity and lipid packing, potentially creating short-lived aqueous channels that enhance passive drug diffusion. While this mechanism has not been definitively demonstrated for salicylic acid, similar increases in permeability have been observed for nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen when exposed to pulsed or modulated EMFs [16,18,19,28].

Rotating magnetic fields (RMFs), on the other hand, appear to enhance drug transport, predominantly through convective phenomena. The continuous change in magnetic vector orientation can generate Lorentz forces in the conductive donor and receptor media, resulting in micro-scale vortices and shear flows. These fluid movements may reduce the effective thickness of the unstirred aqueous boundary layer (UAL), which is a known rate-limiting step in transdermal diffusion. This mechanism is supported by recent experimental data showing enhanced ibuprofen permeation in RMF-exposed systems due to the thinning of the boundary layer [13,19].

Static magnetic fields (SMFs), particularly those with a negative polarity, may exert a different type of effect—one that does not directly enhance permeation but rather modifies retention. It has been suggested that SMFs could interact with diamagnetic lipid molecules in the stratum corneum, subtly altering their orientation or dynamics, and potentially limiting lateral molecular diffusion. As a result, higher accumulation within skin layers may occur even in the absence of an increased flux across the membrane [16,19,28].

These observations suggest that EMF-induced changes in skin permeability are multifactorial, depending not only on field strength but also on waveform characteristics such as pulse duration or vector rotation. PMFs may promote transient barrier modulation, while RMFs introduce convective enhancement mechanisms. SMFs, in contrast, may affect the mobility and retention profile of the drug within the skin.

To enable a direct cross-comparison, enhancement ratios (ER = J_SS,EMF/J_SS,control) were calculated for each electromagnetic field configuration (Table S1, Supplementary Materials). These ER values revealed two major trends. First, among field types with similar magnetic induction values, pulsed magnetic fields (PMF), especially the 5 s on/5 s off configuration, generated approximately 1.8 times higher enhancement ratios compared to continuous oscillating fields (OMFs at 65 Hz), suggesting that instantaneous amplitude spikes play a critical role in promoting drug permeation. Second, rotating magnetic fields (RMFs) at 30 Hz and 50 Hz consistently outperformed both OMF and SMF setups with comparable field strengths, indicating that dynamic vector rotation adds a direction-dependent enhancement mechanism. These findings collectively suggest that both field intensity peaks and rotational dynamics contribute to modulating transdermal permeability, and that their relative significance depends on waveform characteristics.

Skin accumulation data revealed that certain EMF configurations could selectively favor drug retention over permeation, indicating potential for reservoir-type release systems. Notably, SMFs with a negative polarity (−5 V and −15 V) yielded the highest levels of skin-retained salicylic acid, despite poor permeation metrics. This suggests a reduced molecular mobility or altered partitioning behavior, which promotes local retention—a desirable feature for topical therapies that require sustained skin-level presence. Conversely, the lowest levels of accumulation were observed under the RMF 50 Hz and OMF 65 Hz, aligning with their high permeability profiles. These configurations appear to favor rapid drug clearance through the skin with minimal local deposition, making them suitable for systemic delivery via the transdermal route. PMFs produced intermediate results depending on the pulse cycle. PMF five/five, which demonstrated peak permeation performance, also led to moderate retention, suggesting a favorable balance for applications requiring both rapid onset and prolonged therapeutic presence.

The ability of electromagnetic fields to fine-tune transdermal drug delivery is evident in their dual effect: enhancing penetration while selectively modulating accumulation. Such control is particularly beneficial in designing systems tailored for specific therapeutic outcomes—either to achieve fast systemic absorption or to create topical reservoirs for localized action. Importantly, none of the applied EMFs caused the structural degradation of salicylic acid, as confirmed by FTIR and XRD analyses, ensuring the chemical integrity of the active compound post-treatment. This stability supports the safe application of EMF-assisted delivery strategies in pharmaceutical and cosmeceutical formulations.

5. Conclusions

The results of this study confirm the potential of electromagnetic field (EMF) application as a physical method for enhancing the transdermal delivery of salicylic acid. Among the tested configurations, pulsed magnetic fields, particularly the five/five on/off cycle, and rotating magnetic fields at frequencies of 30 Hz and 50 Hz, exhibited the most pronounced enhancement in drug permeation. These field types significantly increased the cumulative amount permeated, steady-state flux, and permeability coefficient, while also reducing the lag time, indicating their capacity to disrupt the skin barrier and facilitate drug transport transiently. This study also highlights the role of EMF configuration in modulating not only the rate of transdermal permeation but also the extent of skin accumulation. Static magnetic fields of negative polarity were associated with an increased retention of salicylic acid in the skin, suggesting a mechanism that favors local drug deposition. This dual effect—the ability to either promote systemic delivery or encourage localized retention—demonstrates the versatility of EMFs in tailoring release profiles according to therapeutic needs. Physicochemical analyses, including FTIR, XRD, TGA, and DSC, confirmed that exposure to electromagnetic fields did not alter the molecular structure or significantly affect the thermal stability of salicylic acid. The absence of chemical degradation ensures the safety and integrity of the active compound, which is critical for pharmaceutical and cosmetic applications.

Collectively, these findings support the use of electromagnetic stimulation as a non-invasive, tunable method for optimizing transdermal drug delivery. By selecting appropriate EMF parameters, it is possible to enhance drug permeation through the skin or increase drug retention within the skin tissue, thereby enabling both fast-acting and sustained-release topical therapies. This approach offers a promising platform for the development of next-generation transdermal systems, particularly for moderately lipophilic and ionizable active pharmaceutical ingredients.