# Kinetics of benzophenone-3 release from clay minerals or organosilicates for sun protection formulation

Saddam Charaabi, Samar Issa, Anne-Marie Pensé-Lhéritier, Marc Le Borgne

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Saddam Charaabi, Samar Issa, Anne-Marie Pensé-Lhéritier, Marc Le Borgne. Kinetics of benzophenone-3 release from clay minerals or organosilicates for sun protection formulation. International Journal of Pharmaceutics, 2025, 682, pp.125920. 10.1016/j.ijpharm.2025.125920. hal-05159385

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# Kinetics of benzophenone-3 release from clay minerals or organosilicates for sun protection formulation

Saddam Charaabi<sup>a,b</sup>, Samar Issa<sup>a,*</sup> <sup>Δ</sup>, Anne-Marie Pensé-Lhéritier<sup>a,c</sup>, Marc Le Borgne<sup>b</sup>

## ARTICLE INFO

### Keywords:

Benzophenone-3

In vitro release

Lipophilic organosilicates

LAPONITE®

Montmorillonite

Sunscreen efficacy, rheology

## ABSTRACT

In this study, we evaluated the ability of three clay minerals and clay-like adsorbents, namely lipophilic organosilicates (OS<sub>L</sub>), LAPONITE® and montmorillonite (MMT), to extend the duration and released amount of UV filter. With only 4 % of benzophenone-3 (BZ-3), it was possible to obtain new sunscreen formulations stabilized by intercalating BZ-3 within the lamellar structures of the three adsorbents. The kinetics of BZ-3 release was studied through a membrane-free method in sink conditions using four mathematical kinetic models. The kinetics demonstrated that BZ-3 was released from the three adsorbents in a continuous and homogeneous way when powders of BZ-3 and OS<sub>L</sub> LAPONITE® or MMT were combined at a similar dosage. We then focused on the effects of adsorbed BZ-3 on OS<sub>L</sub> particles. The sun protection evaluation tests suggested that the formulation using BZ-3 and OS<sub>L</sub> was executed accurately and efficiently. The F2 (OS<sub>L</sub>-BZ-3) showed the most effective broadspectrum formulation with a higher λc (371) and UVA/UVB ratio (0.57) comparatively to F1 (with only 4% BZ3). Rheological analysis of F2 (OS<sub>L</sub>-BZ3) showed controlled viscosity, efficient spreadability, and enhanced structural integrity, which are key for uniform UV protection, stability, and consumer acceptability. The OS<sub>L</sub>-BZ-3 formulation provided an increased protection range and improved sunscreen photostability with respect to current regulations.

## 1. Introduction

Chemical filters are organic molecules with n-bonds forming a conjugated system. They can be solid or liquid, as well as lipophilic, hydrophilic, or completely insoluble in the formulation medium into which they are introduced (Ferreira et al., 2023) and play a role of ultraviolet (UV) light absorbers within each wavelength range (Lacerda et al., 2011). Among the organic filters providing effective protection over the entire UV range, benzophenone-3 (BZ-3), chemically known as 2-hydroxy-4-methoxybenzophenone (Fig. 1) (Lin et al., 2018), protects the skin from harmful UVA rays (320-400 nm) and enhances UVB (290-320 nm) protection of other sunscreen agents (Sanad et al., 2010). Furthermore, by absorbing UV rays, BZ-3 also helps to prevent the integrity of other cosmetic ingredients from sun deterioration and helps to stabilize complex formulations and color cosmetics (Mustieles et al., 2023). Consequently, BZ-3 is widely used in a variety of personal care products (Kim et al., 2023).

Despite its sun protective ability, BZ-3 was shown to penetrate the skin and cause photosensitivity (Jiang et al., 1998). Its use has also been associated with contact eczema (Singer et al., 2019) and may contribute to the rise in melanoma cases among sunscreen users (Calafat et al., 2008). Some studies have also shown that BZ-3 behaves like the hormone estrogen, speculating that it may cause breast cancer (Wang et al., 2011). These drawbacks are partially due to the free state of BZ-3 within formulations, BZ-3 burden on human health has been reported due to their wide use besides the metabolites generated after liver biotransformation (Mao et al., 2022). Therefore, there is an urgent need to further develop carriers to encapsulate this UV filter (Bordes et al., 2021). Several current carriers include liposomes (Severino et al., 2012), cyclodextrins (CDs) (Sarveiya et al., 2004), lipidic nanoparticles (NPs) (González, 2014), mesoporous silica gels (Li et al., 2014, Olejnik & Goscianska, 2024) and polymeric NPs (do Nascimento et al., 2012, Gilbert et al., 2016, Barbosa et al. 2019).

Due to their physicochemical stability, uniform porosity, great

<footnote><sup>a</sup> Ecole de Biologie Industrielle - EBI, UPR EBInnov®, 49 Avenue des Genottes, CS90009, 95895 Cergy-Pontoise, France</footnote>

<footnote><sup>b</sup> Small Molecules for Biological Targets Team, Centre de recherche en cancérologie de Lyon, Centre Léon Bérard, CNRS 5286, INSERM 1052, Université Claude Bernard Lyon 1, Univ Lyon, 8 avenue Rockefeller, 69373 Lyon, France</footnote>

<footnote><sup>c</sup> Current affiliation: FRMGaleSens, 37 rue de l'Amiral, 95000 Cergy, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: s.issa@hubebi.com (S. Issa).</footnote>
<figure><img src="image_4.png" /><figcaption>Fig. 1. Chemical structure of BZ-3.</figcaption></figure>

surface area, and biocompatibility, clay minerals have been widely employed as drug delivery carriers, biosensors, catalysts, and adsorbents (Aguzzi et al., 2007). Recent literature reviews showed clays and clay minerals uses in cosmetics and dermocosmetics (Moraes et al., 2017, Sarruf et al., 2024) and more specifically efficacy tests concerning photoprotection properties and comparative *in vitro* spectrophotometric methods. Among clay minerals, smectites are 2:1-layer planar phyllosilicates also known as TOT due to the combination of two tetrahedral sheets and one octahedral sheet. Smectites uses have been described in cosmetic formulation and can provide mechanical protection through the film formation when adhering to the skin after application (Carretero, M. I., & Pozo, M., 2010). Palygorskite and sepiolite are fibrous clays composed of both continuous two-dimensional (2D) TOT sheets with parallel structural tunnels/channels along the clay fibers. They have been described in dermopharmaceutical and cosmetic innovative formulations, as drug delivery systems (DDS) and in sunscreen formulations (Cao et al., 2022).

Hence, a technique combining mineral carriers and organic UV filters may improve UV-protection. Moreover, clay minerals could entrap the UV-filters to protect the bioactive molecules against decomposition and decrease skin absorption (Perioli et al., 2006). Da rocha et al. have demonstrated their photoprotective effect of thermosensitive antibiotics such as tetracycline and improved photostability when incorporated into the montmorillonite (MMT) structures (Da Rocha et al., 2019). Geoffrey et al. described the use of illite, interlayer-deficient mica, in sunscreen creams as a UV filter instead of inorganic and organic

compounds, providing unexpected photo-catalytic effects and causing allergic reactions (Geoffrey et al., 2019). However, natural clays extracted from quarries present severe contaminations by microorganisms, heavy metals and variations in their composition according to the geographic site of extraction (Aguzzi et al., 2007). Synthetic clay minerals have thus been synthesized to overcome these limitations, guaranteeing a reproducible composition, better adsorption, an improved specific surface, as well as reduced toxicity. Gamoudi et al. have described the adsorption-desorption profile of 2-amino-5-chlorobenzo-phenone (2A-5CB) on kaolinite, smectite, and organophilic smectite and showed their potential as DDS (Gamoudi et al., 2025).

Previous studies described the synthesis of lipophilic aluminum/calcium organosilicates (OSL) and presented an extensive characterization of their structure (Lorentz et al., 2014). Further investigations showed the optimal conditions of BZ-3 adsorption onto OSL particles, as well as a synthetic clay mineral, LAPONITE® and a natural clay mineral, MMT. OSL particles displayed a higher BZ-3 adsorption capacity (340 mg g⁻¹) compared to LAPONITE® (150 mg g⁻¹) and MMT (250 mg g⁻¹) (Charaabi et al., 2019). The previous studies focused on comparing OSL to clay minerals among the family of 2:1-layer phyllosilicates (two tetrahedral sheets and one octahedral sheet, also known as TOT) and the isotherm adsorption modeling has also been described (Charaabi et al., 2021).

The aim of the present work is to study the kinetics of BZ-3 release from OSL, LAPONITE® and MMT formulations using four mathematical models and considering the sunscreen evaluation profile of adsorbed BZ-3 onto three clay minerals and clay-like adsorbents, namely OSL, LAPONITE® and MMT, followed by a rheological study.

## 2. Materials and methods

### 2.1. Chemicals and reagents

Glycol propylene was purchased from Cooper (Paris, France), xanthan gum was kindly provided by Jungbunzlauer international AG (Basel, Switzerland), acrylates/C10-30 alkyl acrylate crosspolymer was kindly provided by Lubrizol, disodium salt of ethylenediaminetetraacetic acid (EDTA), cetyl alcohol, capric triglyceride, dicaprylyl carbonate were kindly provided by BASF (Ludwigshafen, Germany). Steareth-21, and steareth-2 were purchased from Croda (Montigny-le-Bretonneux, France), methylparaben was purchased from Seppic (Courbevoie, France). Cyclomethicone was kindly provided by Bluestar (Shrewsbury, United Kingdom) and triethanolamine was kindly provided by Angus (Buffalo Grove, IL, USA). BZ-3 (Eusolex® 4360) was purchased from Merck KGaA (Darmstadt, Germany) (Fig. S1. Supplementary Material) (Daina et al., 2017). Sodium hydroxide (NaOH) and hydrochloric acid (HCl) were purchased from Carlo Erba Reagents S.A.S. (Milano, Italy). Ethanol (> 99.9 %), methanol, water, acetic acid, and acetonitrile were HPLC Grade solvents and purchased from Fisher Chemicals (Hampton, NH, USA). The lipophilic organosilicate OSL was synthesized based on the synthesis described by (Lorentz et al., 2014). LAPONITE® XLG was purchased from Rockwood Additives Limited (Oxfordshire, United Kingdom) as mentioned by (Charaabi et al., 2019). Natural white-pinkish montmorillonite CosWHITE™ (Mt) was kindly provided by Argile du Velay®-ARVEL (Saint-Paulien, France) as previously reported (Charaabi et al., 2019). Milli-Q water (Millipore Corp.) (Burlington, MA, USA) had a specific resistivity of 18.20 MΩ.cm at 25 C.

### 2.2. Preparation of OS<sub>L</sub>-BZ-3, LAPONITE-BZ-3 and MMT-BZ-3 complexes

OSL-BZ-3, LAPONITE®-BZ-3 and MMT-BZ-3 complexes were prepared as previously described (Charaabi et al., 2019). Specifically, 0.5 g of each adsorbent was added to a solution of 0.6 g of BZ-3 in 25 mL of absolute ethanol. Each mixture was then kept under magnetic stirring and protected from light at 38 °C for 24 h. Each mixture was oven-dried
to obtain the three complexes. For comparison with the adsorbed samples, complexes were prepared by physical mixing and milling of each adsorbent with BZ-3 powder.

## 2.3. *In vitro* release studies and desorption kinetics

In vitro release of BZ-3 from the OS<sub>L</sub>, LAPONITE® or MMT was investigated using a membrane-free method (Hong et al., 2012) and under sink conditions (Siepmann and Siepmann, 2020). This latter condition means that for a dosage form placed in each medium, the concentration of BZ-3 in this medium is no greater than 20-30 % of its solubility. Compliance with this condition makes it possible to minimize the slowing-down effect linked to medium saturation, thus ensuring proper dissolution and the release of the active substance. Phosphate buffer saline (PBS) solution (0.1 M, pH 7.4) was used as dissolution medium (maintained at 32 °C ± 0.5, to mimic skin temperature). Samples OS<sub>L</sub>-BZ-3, LAPONITE®-BZ-3 and MMT-BZ-3 containing an equivalent amount of BZ-3 (5 mg) were first added to PBS pH 7.4 (100 mL) in a sealed flask. The suspension was stirred at the defined temperature, using a heating and magnetic steering plate at 150 rpm. One mL of the sample was withdrawn at fixed time intervals and the same volume of fresh medium was added accordingly to maintain sink conditions. The removed medium was centrifuged, filtered, and assayed for BZ-3 concentration by HPLC. The BZ-3 release rate from the adsorbent complex was compared with the physical mixture. All data are reported as an average of three measurements.

To better understand the release mechanism of BZ-3 from complexes *in vitro*, results were fitted with four mathematical models (Table 1): zero-order Eq. (1) (Xu et al., 2018), first-order Eq. (2) (Wang et al., 2018), Higuchi Eq. (3) (Wang et al., 2018) and Korsmeyer-Peppas Eq. (4) (Ritger and Peppas, 1987).

Where $q_t$ (mg g⁻¹) is the quantity of desorbed BZ-3 from the adsorbent-BZ-3 complexes at time t (min), $q_0$ (mg g⁻¹) is the initial quantity of BZ-3 in the adsorbent-BZ-3 complexes, $k_1$ (mg min⁻¹) is the pseudo-first-order release rate constant, and, $k_H$ (mg g⁻¹ min⁻⁰.⁵) is the Higuchi model rate constant, $k_{KP}$ (mg g⁻¹ min⁻¹) is the Korsmeyer-Peppas model rate constant.

## 2.4. High Performance Liquid Chromatography (HPLC) Analysis

The concentration of BZ-3 in all test samples was simultaneously analyzed using HPLC as detailed in our previous work (Charaabi et al., 2019).

## 2.5. Sunscreen formulation

Five cream formulations were prepared for the sun protection factor (SPF) evaluation tests (Table 2). Each formulation was made up of three phases containing 4 % BZ-3. The difference between each preparation lies in the nature of the inorganic UV filter with either OS<sub>L</sub> alone or the combination of BZ-3 with either OS<sub>L</sub> or one of the clay minerals. Thus, the five formulations (F) are as follows (Table 1): F1 (4 % BZ-3), F2 (mass of OS<sub>L</sub>-BZ-3 to obtain 4 % BZ-3), F3 (OS<sub>L</sub>), F4 (LAPONITE®-BZ-3, mass of LAPONITE®-BZ-3 to obtain 4 % BZ-3) and F5 (MMT-BZ-3, mass of MMT-BZ-3 to obtain 4 % BZ-3). To prepare each formulation, the same procedure was followed. Phases 1 and 2 were heated separately to reach 75 °C. Then phase 2 was slowly added to phase 1 with helical

<table><caption>**Table 1**
Kinetics model equations for BZ-3 release.</caption><tr><td>Zero-order</td><td>q<sub>t</sub> = q<sub>0</sub> + k<sub>0</sub>·t</td><td>(1)</td></tr><tr><td>First order</td><td>logq<sub>t</sub> = logq<sub>0</sub> - k<sub>1</sub>·t / 2.303</td><td>(2)</td></tr><tr><td>Higuchi</td><td>q<sub>t</sub> = k<sub>H</sub>·√t</td><td>(3)</td></tr><tr><td>Korsmeyer-Peppas</td><td>q<sub>t</sub> = k<sub>KP</sub>·t<sup>n</sup></td><td>(4)</td></tr></table>

stirring (900 rpm). After harmonization, the mixture was cooled to 40 °C with continued stirring. Phase 3 was added (900 rpm). Any losses due to evaporation were compensated by water (ISO, 2025).

## 2.6. *In vitro* determination of sun protection factor (SPF)

The *in vitro* determination of SPF was achieved using polymethyl methacrylate (PMMA) supports (Pelizzo et al., 2012), with a roughness of 6 mm, over which the sunscreen formulations were homogeneously applied with a sample ratio of 2.0 mg cm⁻² to form a uniform film, following the methodology described by Helioscience® (Heliotest N°1, Sun Protection Factor (SPF) and following the ISO 24443:2021 standardized methods. Assessment of UVA protection factor (UVA-PF) and Critical wavelength (CW) indications). The plates were then stored in the dark for at least 15 min before measurement. The UV transmittance through the PMMA plates was measured from 290 to 400 nm with a 1 nm interval using a transmittance analyzer (UV2000S, Labsphere, USA®). A PMMA plate coated with glycerin was used as the blank to calibrate the spectrophotometer's baseline transmittance. For each formulation tested, three PMMA plates were prepared. The transmittance was recorded for each sample, the software Labsphere Transmittance Analyzer SPF Report® calculated the SPF, the critical wavelength (λ<sub>c</sub>), and the UVA/UVB ratio (Miksa et al., 2015). The SPF of the formulations tested was determined according to Eq. (5) (Kelley et al., 1993).

$$ \text{SPFdeterminationSPF} = \frac{\int_{290}^{400} E_{\lambda} \cdot S_{\lambda} \cdot d_{\lambda}}{\int_{290}^{400} E_{\lambda} \cdot S_{\lambda} \cdot d_{\lambda} \cdot T} \quad (5) $$

Where $E_λ$: erythelial action spectrum of the wavelength λ (W·m⁻²·nm⁻¹), $S_λ$: spectral irradiance of the wavelength λ (W·m⁻²·nm⁻¹), $T_λ$: spectral transmittance of the wavelength λ (dimensionless), $d_λ$: the differential wavelength (nm).

## 2.7. *In vitro* determination of UVA protection factor (PF-UVA) and UVA/UVB ratio

SPF measures protection against UV-induced erythema caused by short wavelength UVA (320–340 nm) and UVB radiation. This spectrum covers wavelengths causing DNA damage and induction of skin tumors. Longer wavelengths of solar UV can also contribute to skin damage (Lavker and Kaidbey, 1997). Thus, it is necessary to introduce the *in vitro* determination of UVA Protection Factor (PF-UVA) using the same procedure as described for the SPF. Calculations were made using Eq. (6):

$$ \text{PF - UVAdeterminationPF - UVA} = \frac{\int_{290}^{400} E_{\lambda} \cdot S_{\lambda} \cdot d_{\lambda}}{\int_{290}^{400} E_{\lambda} \cdot S_{\lambda} \cdot d_{\lambda} \cdot T} \quad (6) $$

To reinforce the sun protection evaluation of a formulation, both the level of UVA/UVB ratio (Diffey, 1994, Dayan, 2016) and the critical wavelength (λ<sub>c</sub>) were used with the mentioned classification into five categories (Diffey, 1994). A good UVA protection corresponds to a UVA/UVB ratio between 0.41 and 0.60, superior protection at a ratio between 0.61 and 0.8 and maximum protection with a ratio > 0.8.

## 2.8. Determination of the critical wavelength (λc)

The λ<sub>c</sub> is another measurement of the UVA protective capacity of a product, and it is defined by the smaller wavelength in which the product's absorption equals 90 % of the total absorption according to Eq. (7) (Diffey, 2000):
<table><caption>**Table. 2**

Formulations' composition prepared for the sun protection factor (SPF) evaluation tests.</caption><thead><tr><th></th><th>Ingredients</th><th>Role</th><th>F1</th><th>F2</th><th>F3</th><th>F4</th><th>F5</th></tr></thead><tbody><tr><td rowspan="10">Phase 1</td><td>Water</td><td>Aqueous phase</td><td>71.44</td><td>63.68</td><td>67.69</td><td>44.68</td><td>57.26</td></tr><tr><td>Propylene glycol</td><td>Moisturizing solvent</td><td>1.00</td><td>1.00</td><td>1.00</td><td>1.00</td><td>1.00</td></tr><tr><td>Xanthan gum</td><td>Thickening agent</td><td>0.60</td><td>0.60</td><td>0.60</td><td>0.60</td><td>0.60</td></tr><tr><td>acrylates/C10-30 alkyl acrylate crosspolymer</td><td>Rheology modifier</td><td>0.15</td><td>0.15</td><td>0.15</td><td>0.15</td><td>0.15</td></tr><tr><td>Disodium EDTA</td><td>Stabilizer Chelating agent</td><td>0.08</td><td>0.08</td><td>0.08</td><td>0.08</td><td>0.08</td></tr><tr><td>BZ-3</td><td>UV filter</td><td>4.00</td><td>**</td><td>**</td><td>**</td><td>**</td></tr><tr><td>OS<sub>L</sub>-BZ-3</td><td>UV filter-adsorbent complex</td><td>**</td><td>11.76</td><td>**</td><td>**</td><td>**</td></tr><tr><td>OS<sub>L</sub></td><td>UV filter-adsorbent complex</td><td>**</td><td>**</td><td>7.67</td><td>**</td><td>**</td></tr><tr><td>LAPONITE®-BZ-3</td><td>UV filter-adsorbent complex</td><td>**</td><td>**</td><td>**</td><td>30.76</td><td>**</td></tr><tr><td>MMT-BZ-3</td><td>UV filter-adsorbent complex</td><td>**</td><td>**</td><td>**</td><td>**</td><td>18.18</td></tr><tr><td rowspan="7">Phase 2</td><td>Cetyl alcohol</td><td>Consistency agent</td><td>1.00</td><td>1.00</td><td>1.00</td><td>1.00</td><td>1.00</td></tr><tr><td>Steareth-21</td><td>Emulsifier</td><td>2.50</td><td>2.50</td><td>2.50</td><td>2.50</td><td>2.50</td></tr><tr><td>Steareth-2</td><td>Emulsifier</td><td>3.00</td><td>3.00</td><td>3.00</td><td>3.00</td><td>3.00</td></tr><tr><td>Capric triglyceride</td><td>Oily phase</td><td>6.50</td><td>6.50</td><td>6.50</td><td>6.50</td><td>6.50</td></tr><tr><td>Dicaprylyl carbonate</td><td>Emollient oily phase</td><td>6.50</td><td>6.50</td><td>6.50</td><td>6.50</td><td>6.50</td></tr><tr><td>Methylparaben</td><td>Preservative</td><td>1.00</td><td>1.00</td><td>1.00</td><td>1.00</td><td>1.00</td></tr><tr><td>Cyclomethicone</td><td>Volatile oily phase</td><td>2.00</td><td>2.00</td><td>2.00</td><td>2.00</td><td>2.00</td></tr><tr><td>Triethanolamine</td><td>Stabilizer Buffer</td><td>0.22</td><td>0.22</td><td>0.22</td><td>0.22</td><td>0.22</td></tr><tr><td colspan="8">Total (100 g)</td></tr></tbody></table>

$$ \text{Thecriticalwavelength}(\lambda c)\text{determination} = 0.9 \int_{290}^{400} A(\lambda) d\lambda \quad (7) $$

Where A is the absorption (dimensionless) and λ the wavelength (nm). With respect to the critical wavelength, the maximum UVA protection is achieved with λc ≥ 370 nm (Bielfeldt et al., 2018). Furthermore, a good sunscreen substance needs to be a broad-spectrum UVB and UVA photoprotection product.

## 2.9. Rheological analysis

The rheological analysis of the prepared formulations was performed rheological tests were assessed using an MCR 301 rheometer (Anton Paar; Graz, Austria) at 25 °C, controlled by the RheoCompass software (version 1.31) at a constant temperature of 25 °C, using a serrated plate-plate P35/Ti/SE measuring geometry. The gap thickness between the plates was 0.5 mm. Temperature equilibration was carried out for 3 min prior to the beginning of the measurements. The sample was placed on the support and the measuring cone was positioned. To carry out the measurement, a speed range of 1 to 100 revolutions per minute was

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Comparative cumulative release of BZ-3 from adsorption vs. physical mixture. (A) OS<sub>L</sub>, (B) LAPONITE®, (C) MMT adsorbed BZ-3 and (D) Comparative release of the three complexes.</figcaption></figure>
chosen over a period of 300 s (Gaspar & Maia Campos, 2003).

## 2.10. Statistical analysis

Data was analyzed using single-factor analysis of variance (ANOVA) and presented as mean values ± standard error of the mean (SEM) from at least six independent measurements. The comparison among groups was made using the independent sample Student's t-test. The difference between variants was considered significant if the p-value < 0.05.

# 3. Results and discussions

## 3.1. *In vitro* release studies

The *in vitro* dissolution assay is important to evaluate the bioavailability and the stability of the adsorbent to predict its *in vivo* performance (Carlan et al., 2017). The potential release of BZ-3 from OS_L, LAPONITE® and MMT was tested using PBS at pH 7.4 at 37 °C as a dissolution medium. Fig. 2 presents the release profiles for different formulations, comparing the release behavior of adsorbed systems with their corresponding physical mixtures. A physical mixture prepared by mixing and milling BZ-3 with the different adsorbents was used as control. The release data show that the cumulative BZ-3 concentration in the dissolution medium rises in a biphasic manner, in which faster release is observed followed by sustained release. The physical mixture showed a rapid release in the first hour of about 100% BZ-3 for the three adsorbents. Moreover, the OS_L-BZ-3, LAPONITE®-BZ-3, and MMT-BZ-3 complexes provided a controlled release without delivering the total amount of BZ-3. This could be explained by the adsorption mechanism and intraparticular diffusion, as previously described (Charaabi et al., 2021). Indeed, BZ-3 is likely entrapped within the lamellar structure of clay minerals or organosilicates.

For OS_L, in the case of OS_L-BZ-3 complexes, the gradual fast release was obtained within 250 min of release time and the (%) cumulative release decreased to reach only 70 % BZ-3 after 5 h.

BZ-3 was released from LAPONITE® after 400 min following rapid kinetics, though no burst release was observed at the beginning of the release, the desorption profile is almost linear. This phenomenon can be attributed to the release of loosely bound BZ-3 molecules from the edges of interlayer spaces and free surfaces followed by subsequent release of BZ-3 from the interlayer space of LAPONITE® due to de-intercalation. Similar results have been reported for the desorption of dexamethasone from LAPONITE® (Fraile et al., 2016). The later stage of slower release (after 400 min) of BZ-3 was governed by a combination of BZ-3 diffusion and LAPONITE® dissolution. The release profile showed that ~50 % of the incorporated BZ-3 was released in 400 min, and it increased nonlinearly to ~85 % in 1400 min. This clearly showed the ability of LAPONITE® to control BZ-3 release (Fraile et al., 2016).

For MMT, the burst release of BZ-3 was followed by a controlled release process. 80 % of the adsorbed BZ-3 was desorbed by the end of the experiment. This stage of controlled release process observed in the case of the three adsorbents can be due to the ion-exchange process between the intercalated drug and the alkali metal ions of the buffer (Zhang et al., 2006a). Similar results have been reported in the case of the release of ibuprofen from MMT (Zheng et al., 2007). Moreover, based on the release profiles of BZ-3 from the three adsorbents, the percentage of BZ-3 released did not reach 100 %. This is probably due to the characteristic of the ion-exchange reaction, i.e., this is an equilibrium process, and the interlayer entrapped BZ-3 cannot be exchanged completely (Joshi et al., 2009).

## 3.2. Kinetics of the *in vitro* release

The study of the kinetics of the *in vitro* release with the determination coefficient ($R^2$) showed that the Higuchi model (Wang et al., 2018) (Table.3) is more relevant to describe the release mechanism of BZ-3

<table><caption>**Table 3**
Parameters for BZ-3 release from the three complexes.</caption><thead><tr><th>Kinetic Models</th><th>OS<sub>L</sub></th><th>LAPONITE®</th><th>MMT</th></tr></thead><tbody><tr><td>Pseudo-zero-order</td><td></td><td></td><td></td></tr><tr><td>R<sup>2</sup></td><td>0.806</td><td>0.934</td><td>0.830</td></tr><tr><td>k<sub>0</sub></td><td>0.005</td><td>0.004</td><td>0.002</td></tr><tr><td>Pseudo-first order</td><td></td><td></td><td></td></tr><tr><td>R<sup>2</sup></td><td>0.501</td><td>0.669</td><td>0.530</td></tr><tr><td>k<sub>1</sub></td><td>0.0040</td><td>0.0012</td><td>0.0018</td></tr><tr><td>Higuchi</td><td></td><td></td><td></td></tr><tr><td>R<sup>2</sup></td><td>0.992</td><td>0.998</td><td>0.957</td></tr><tr><td>k<sub>H</sub></td><td>1.700</td><td>2.800</td><td>2.450</td></tr><tr><td>Korsmeyer-Peppas</td><td></td><td></td><td></td></tr><tr><td>R<sup>2</sup></td><td>0.935</td><td>0.995</td><td>0.952</td></tr><tr><td>k<sub>KP</sub></td><td>0.04</td><td>0.010</td><td>0.030</td></tr><tr><td>n</td><td>0.536</td><td>0.573</td><td>0.498</td></tr></tbody></table>

from OS_L-BZ-3 with an $R^2$ of 0.992 (Table 3). According to the Higuchi model, the buffer penetrates the OS_L matrix and dissolves the embedded BZ-3, meaning that its release is predominately controlled by diffusion. The diffusion exponent value n (0.536) ranged between 0.5 and 1.0 in the Korsmeyer-Peppas model, emphasizing that BZ-3 release mechanism is a non-Fickian transport type diffusion release (Ritger and Peppas, 1987), which exhibits both diffusion- and swelling-controlled release processes with an $R^2$ of 0.935.

The fitting results of BZ-3 release profiles from LAPONITE® and MMT based on the different kinetics release models used in this study are summarized in Table 3. The release of BZ-3 from LAPONITE® and MMT followed the Higuchi kinetics with a satisfactory coefficient ($R^2$ of 0.998 for LAPONITE® and $R^2$ of 0.957 for MMT). This was also true for the Korsmeyer-Peppas model of release kinetics (Table 2) with a high level of fitting ($R^2$ of 0.995 for LAPONITE® and, $R^2$ of 0.952 for MMT). The value of n was 0.573 and 0.498 for LAPONITE® and MMT, respectively. A value of n ranging between 0.45 and 0.89 indicates that the BZ-3 release mechanism from the two clay minerals was also controlled by a non-Fickian transport mechanism, which is a combination of diffusion and adsorbent dissolution in a physiological solution (Zhang et al., 2006b).

## 3.3. *In vitro* determination of SPF

To better evaluate the UV protection, sunscreen formulations were prepared in this study according to the protocol in Fig. 3, the *in vitro* SPF values and UVA values of the sunscreen creams, BZ-3, OS_L-BZ-3, OS_L-LAPONITE® and MMT-BZ-3 were then measured.

As shown in Fig. 4, the SPF of F3 (only OS_L) was about 4, F1 (free BZ-3) had a higher SPF value of 8.1 and the highest SPF of 13 for the F2 (OS_L-BZ-3) which was 40 % higher than formulation with free BZ-3. OS_L-without BZ-3 presented a low protection against UV rays and in parallel BZ-3 offered greater UV protection than OS_L.

Similarly, the PF-UVA value of F2 (OS_L-BZ-3) was 6.7 which represents a 63 % higher protection than that provided by F1 of 4.2. These results suggest that OS_L-BZ-3 was well dispersed in the emulsion cream. The highest SPF and UVA values of OS_L-BZ-3 are described with the highest synergistic UV protection effect. Similar results were reported using BZ-3 with sol-gel mesoporous silica as an adsorbent (Li et al, 2014, Olejnik & Goscińska, 2024).

## 3.4. Critical wavelength $\lambda c$ and UVA/UVB ratio

According to the critical wavelength method (Diffey, 1994), F2 (OS_L-BZ-3) provided the maximum protection against UVA rays, showing $\lambda c$ higher than 370 nm. Based on these results, all these compounds are characterized by 4 stars in the broad-spectrum rate classification (Diffey, 1994). F5 (LAPONITE®-BZ-3) showed non-negligible UVA protection ($\lambda c$ = 368 nm). For F1, F3 and F5, the obtained values of $\lambda c$, indicated that these formulations could not give maximum protection against UVA
<figure><img src="image_6.png" /><figcaption>Fig. 3. Formulation preparation for the SPF evaluation.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>Fig. 4. Values of SPF and PF-UVA of the five formulations, dimensionless. F1 (4% BZ-3), F2 (OS<sub>L</sub>-BZ-3), (F3 4% OS<sub>L</sub>), F4 (MMT-BZ-3), and F5 (LAPONITE®-BZ-3). The data are presented as mean ± SEM (standard error of the mean) value (n = 6) (**), p < 0.05, (***), p < 0.01.</figcaption></figure>

<table><caption>**Table 4**

In vitro value obtained for λc (nm) and UVA/UVB ratio.</caption><thead><tr><th>Formulations</th><th>λc (nm)</th><th>UVA/UVB ratio</th></tr></thead><tbody><tr><td>F1 BZ-3</td><td>361</td><td>0.53</td></tr><tr><td>F2 OS<sub>L</sub>-BZ-3</td><td>371</td><td>0.57</td></tr><tr><td>F3 OS<sub>L</sub></td><td>361</td><td>0.60</td></tr><tr><td>F4 MMT-BZ-3</td><td>362</td><td>0.08</td></tr><tr><td>F5 LAPONITE®-BZ-3</td><td>368</td><td>0.55</td></tr></tbody></table>

(Table 4 and Fig. 5).

On the other hand, when applying the UVA Star Rating System to the UVA/UVB ratio (Bielfeldt et al., 1994), OS<sub>L</sub>-BZ-3 and MMT-BZ-3 fall into the moderate to superior level (ranging between 0.46 and 0.76; 2-3 stars), whereas LAPONITE®-BZ-3 showed the highest UVA protection (UVA/UVB ratio of 0.8).

Given that formulation with free BZ-3 showed a low λc (360 nm) and a UVA/UVB ratio of 0.53, this implies that its adsorption onto OS<sub>L</sub>, LAPONITE® and MMT enhanced its UVA protection. Therefore, the formulations F2, F4 and F5 can also be considered protective against

UVA radiation (Table 4). The In vitro evaluation of a

The SPF *in vivo* evaluation of the sunscreen formulations has not been conducted. Mao et al. described *in vivo* evaluation of BZ-3 in commercially available formulations (4%). BZ-3 was detected in human urine, blood, breast milk, placenta, and amniotic fluid with potential transplacental transfer (Mao et al., 2022). The authors described limitations but clearly health burden effects of BZ-3 included generated oxidative stress, body mass index (BMI) changes, endometriosis, and pubertal development.

The interactions between BZ-3 and OS<sub>L</sub> could be explained by the synergy of a combination of different interactions:

* Van der waals forces

* Hydrophobic interactions between the aromatic or alkyl moieties of BZ-3 and the grafted organic groups on the OS<sub>L</sub> surface

* Hydrogen bonding, involving the hydroxyl and carbonyl function- alities of BZ-3 with polar groups such as silanols on the material.

* In the presence of aromatic functionalities on the OS<sub>L</sub> (e.g., phenyl groups), π-π stacking interactions can also contribute to adsorption.
<figure><img src="image_8.png" /><figcaption>Fig. 5. Critical wavelength λc (nm) and UVA/UVB ratio.</figcaption></figure>

<figure><img src="image_9.png" /></figure>

Experimental evidence, including reduced surface area, and shifts in FTIR spectra, confirmed the presence and nature of these interactions. Altogether, these results indicated a multimodal adsorption mechanism, combining both physical and chemical interactions, which ensures efficient and stable immobilization of BZ-3 within the organosilicate layers.

A deeper understanding of the mechanisms involved in organosilicates could be explored by means of Molecular dynamics as described by Zhou et al. for clay minerals (Zhou et al., 2025).

### 3.5. Rheological analysis of the three formulations

To assess the rheological behavior of the clay mineral/organosilicate-based sunscreen formulations, the relationships between shear stress (A) and viscosity(B) as function of shear rate were analyzed for the three different formulations (Fig. 6). All formulations exhibit a viscoelastic behavior with shear-thinning (pseudoplastic), where viscosity decreases as the shear rate increases. This feature is helpful in sunscreen formulations and is common for industrial applications. A high viscosity is observed at rest which enhances storage stability and prevents phase separation while allowing easy spreadability upon application (Lu et al., 2021). The curves appear to show different slopes indicating differences in the apparent viscosity behavior of all formulations. Viscosity decreases significantly with increasing shear rate and stabilizes at shear rates above 60 s⁻¹, indicating a transition toward a more fluid-like state under application conditions.

The shear stress vs. shear rate profiles reveals differences in

structural integrity and flow resistance among the formulations (Fig. 6A). F1 (BZ-3 only) shows the lowest shear stress values, ranging from 15 Pa at 5 s⁻¹ to approximately 40 Pa at 100 s⁻¹, indicating weak internal structuring. While this enhances spreadability, it may result in poor retention on the skin and potential instability over time. F2 (OSL-BZ-3 complex) exhibits intermediate behavior, with shear stress increasing from 20 Pa (5 s⁻¹) to 55 Pa (100 s⁻¹), suggesting that the OSL-BZ-3 network enhances interactions between formulation components, leading to a more structured system. F3 (OSL only) demonstrates the highest resistance to shear, with shear stress values exceeding 30 Pa (5 s⁻¹) and reaching 90 Pa (100 s⁻¹), confirming that it is the most structured and rigid formulation. However, excessive structuring may hinder ease of application, potentially leading to uneven coverage and poor consumer experience (García-Villén et al., 2025).

Viscosity vs. shear rate curves further confirms these trends (Fig. 6B). F1 (BZ-3) starts with the lowest viscosity (12 Pa.s at 5 s⁻¹) and drops rapidly to 2 Pa.s at 100 s⁻¹, ensuring effortless spreading but posing a risk of excessive flow, uneven distribution, and potential dripping. F2 (OSL-BZ-3 complex) exhibits moderate viscosity (18 Pa.s at 5 s⁻¹, decreasing to 4 Pa.s at 100 s⁻¹), providing a well-balanced structure that enhances both spreadability and stability, making it ideal for sunscreen applications. The gel-like network formed by OSL-BZ-3 helps retain UV filters on the skin while preventing phase separation. F3 (OSL only) has the highest viscosity (35 Pa.s at 5 s⁻¹, decreasing to 8 Pa.s at 100 s⁻¹), ensuring high stability but reducing spreadability, which may lead to thicker application layers and streaking on the skin.

The increase in viscosity and yield stress in F2 (OSL-BZ-3) can be

<figure><img src="image_10.png" /><figcaption>Fig. 6. Shear stress (A) and viscosity(B) as function of shear rate for the 3 formulations.</figcaption></figure>
attributed to particle aggregation within the formulation. The presence of OS<sub>L</sub> in F3 leads to larger, more rigid aggregates, as confirmed by its higher viscosity. However, when BZ-3 is incorporated into the OS<sub>L</sub> network (F2), interactions between OS<sub>L</sub> and BZ-3 modify the structuring effect, leading to a better balance between viscosity and flowability. Similar behavior has been reported in studies on organoclay-based emulsions, such as those by Torres et al. and Calixto et al. demonstrating that organoclay-UV filter interactions significantly influence the rheological properties of emulsions (Martinović et al., 2024, Calixto et al., 2018).

Furthermore, the hysteresis loop area, which represents the thixotropic behavior of the formulations (Fig. 7), is noticeably larger for F1 (BZ-3 only), indicating limited structural recovery after shear removal. In contrast, F2 (OS<sub>L</sub>-BZ-3) shows a smaller hysteresis loop, meaning that its structure rebuilds more efficiently after shear stress is removed, ensuring better long-term stability while maintaining good spreadability. This is a crucial property for sunscreen applications, as formulations must recover their structure quickly post-application to prevent UV filter migration while remaining easy to apply (Zhou et al., 2020). Similar results have been observed in sunscreen formulations with hydrophilic clays Bentonite® (Cao & Butcher, 2006).

## 4. Conclusion

This study described the kinetics release profile of adsorbed BZ-3 onto three clay minerals and clay-like adsorbents, namely OS<sub>L</sub>, LAPONITE® and MMT, the SPF evaluation and rheological study.

We showed that our experimental data fitted the Higuchi model best, indicating a non-Fickian transport mechanism. OS<sub>L</sub> particles ensured a constant long-term release of BZ-3. The kinetics demonstrated that BZ-3 was released from the three adsorbents in a continuous and homogeneous way. Sun protection test results suggested that the sunscreen formulation using BZ-3 and OS<sub>L</sub> was accurate and efficient. OS<sub>L</sub> complexed with only 4 % of BZ-3 was found to present the highest sun protection for F2 (OS<sub>L</sub>-BZ3, SPF 13) 40% higher than F1 (free BZ-3, SPF 8.1). For UVA protection, F2 showed a PF-UVA of 6.7 corresponding to 63% increase over F1 (PF-UVA = 4.2).

This suggests that the adsorption of BZ-3 onto OS<sub>L</sub> particles enhanced the efficacy of sunscreen formulation. The entrapment of sunscreen agents with interlamellar structure of OS<sub>L</sub> particles could provide the advantage of decreasing the amount of BZ-3 released, thus maintaining the composition of the formulation within the regulatory range (Commission regulation, 2022) of less than 6 % BZ-3, as described by the Scientific Committee on Consumer Safety (SCCS). BZ-3 is insoluble in water and is difficult to incorporate in a cream base. After entrapment of BZ-3 in OS<sub>L</sub> particles, it was easily incorporated into a cream base without any crystallization problem commonly observed with BZ-3. The

topical application of cream formulations containing OS<sub>L</sub>-BZ-3 could also be more effective at protecting against UV-induced erythema through the formation of a film over the skin which itself acts as a physical barrier to UV radiation.

Overall, F2 (OS<sub>L</sub>-BZ-3) presents the most balanced rheological profile, making it the optimal formulation for sunscreen applications. It ensures controlled viscosity, efficient spreadability, and enhanced structural integrity, which are key for uniform UV protection, stability, and consumer acceptability. And the, the

In conclusion, the results of this study emphasize the relevance of OS<sub>L</sub> particles as a new topical delivery system for enhancing the sunscreen efficacy of BZ-3. Further studies should investigate the toxicity of organosilicates following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline Q8 (R2) on pharmaceutical development and using Fourier Transform Infrared Spectroscopy (FTIR) imaging spectroscopy to observe the diffusion within the skin layers (Cozzi et al., 2018).

This study allowed the use of BZ-3 as a model molecule, nonetheless the *in vivo* SPF analysis should be conducted to give further indications. The adsorption-desorption behavior of the molecules, using clay minerals or organosilicates, as well as their rheological properties could enable their use as innovative excipients in controlled release, particularly for photosensitive active ingredients, such as antibiotics in the treatment of acne.

### CRediT authorship contribution statement

**Conceptualization** S.C., S.I., A.-M.P.L., M.L.B., **Data curation** S.C., S.I., **Formal analysis** S.C., S.I., **Funding acquisition** S.I., A.-M.P.L., M. L.B., **Investigation** S.C., **Methodology** S.C., S.I., A.-M.P.L., M.L.B., **Project administration** S.C., S.I., A.-M.P.L., M.L.B., **Resources** S.I., A.-M.P.L., M.L.B., **Software** S.C., **Supervision** S.I., A.-M.P.L., M.L.B., **Validation** S.C., S.I., A.-M.P.L., M.L.B., **Visualization** S.I., M.L.B., **Writing – original draft** S.C., S.I., A.-M.P.L., M.L.B., **Writing – review & Editing** S.C., S.I., A.-M.P.L., M.L.B.,

### Funding

The authors gratefully acknowledge the financial support of the Fonds Social de l'Ecole de Biologie Industrielle (EBI) for the full funding of this study. Marc Le Borgne would like to thank "Institut Convergence PLAsCAN" (ANR-17-CONV-0002).

### CRediT authorship contribution statement

**Saddam Charaabi:** Writing – review & editing, Writing – original draft, Software, Project administration, Investigation, Data curation, Conceptualization. **Samar Issa:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. **Anne-Marie Pensé-**

<figure><img src="image_11.png" /><figcaption>**Fig. 7.** Flow curve for (A) F1 and (B) F2. Differences in OS<sub>L</sub>-BZ-3 complexes internal network structure depending on shear-thinning profiles when subjected to shear rates.</figcaption></figure>
**Lhéritier:** Writing – review & editing, Writing – original draft, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.
**Marc Le Borgne:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgements

The authors would also like to thank Marjorie Lassalle for her assistance in sunscreen formulation and Jean-Claude Hubaud Helioscience® for the sun protection assays. The authors would also like to thank Brigitte Manship for editing the manuscript.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijpharm.2025.125920.

## Data availability

Data will be made available on request.

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