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Article

Physicochemical Properties and In Vitro Dissolution of Orally Disintegrating Films Based on Polysaccharides: The Case of Acetaminophen

by
Carolina Caicedo
1,*,
Natalia Ramírez Giraldo
2,
Leidy Portilla
3,
Laura Saldaña
3,
Giovanni González-Pérez
4 and
Abril Fonseca García
5,*
1
Grupo de Investigación Energías, Facultad de Ingeniería, Unidad Central del Valle del Cauca (UCEVA), Carrera 17a 48-144, Tuluá 763022, Colombia
2
Semillero de Investigación en Ciencia e Ingeniería de Materiales (CIMAT), Facultad de Ingeniería, Unidad Central del Valle del Cauca (UCEVA), Carrera 17a 48-144, Tuluá 763022, Colombia
3
Semillero de Investigación en Química Aplicada (SEQUIA), Facultad de Ciencias Básicas, Universidad Santiago de Cali, Pampalinda, Santiago de Cali 760035, Colombia
4
Departamento de Ingeniería Ambiental, Instituto Tecnológico de Nuevo León, Tecnológico Nacional de México, Av. Eloy Cavazos 2001. Col. Tolteca, Guadalupe 67170, Nuevo León, Mexico
5
Centro de Investigación en Química Aplicada (CIQA), Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI), Blvd. Enrique Reyna Hermosillo 140, Saltillo 25294, Coahuila, Mexico
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2025, 15(8), 4084; https://doi.org/10.3390/app15084084
Submission received: 16 February 2025 / Revised: 18 March 2025 / Accepted: 25 March 2025 / Published: 8 April 2025
(This article belongs to the Special Issue Advances in Biomaterials and Drug Technology)
Browse Figures
Versions Notes

Abstract

:
Due to advances in edible films based on polysaccharides that can carry an active pharmaceutical ingredient (API), these films now provide rapid and effective release upon consumption. These films provide an alternative to conventional drug delivery methods and are known as orally disintegrating films (ODFs). This study aimed to evaluate the capacity of an edible film composed of starch, chitosan, and maltodextrin to carry an API while maintaining its physicochemical and surface properties. Acetaminophen, a hydrophilic drug, was selected as the model API and incorporated into the edible film. The film achieved an API loading capacity of approximately 4.37 mg—comparable to the standard doses of certain hydrophilic drugs. Chemical analysis using vibrational spectroscopy revealed strong intermolecular interactions between the components. X-ray diffraction analysis confirmed these interactions through a decrease in crystallinity within the biopolymeric compounds, while the model API retained its structural ordering. However, water absorption values increased by approximately 90% in the edible film. Scanning electron microscopy images showed a homogeneous dispersion of the model API throughout the film, without aggregation, demonstrating that the film can effectively accommodate this drug concentration. Furthermore, the elasticity remained comparable in both formulations, with a Young’s modulus of 9.27 MPa for the control film and 9.38 MPa for the API-loaded film. Overall, the edible film developed in this study represents a promising system for API delivery.

1. Introduction

The oral administration of drugs through conventional dosage forms such as capsules, lozenges, and tablets, among others, presents limitations when used in geriatric, pediatric, dysphagic, psychiatric, and even animal patients [1]. One of the primary causes of these limitations is neuromuscular changes; however, they can also occur in patients with neurocognitive disorders [2]. Studies evaluating dysphagia have documented a prevalence of approximately 30% in individuals over 65 years of age who are hospitalized, leading to its classification as a new geriatric syndrome. Additionally, dysphagia is estimated to affect 50% of elderly residents in nursing homes and more than 40% of patients who have suffered strokes [2]. In the clinic, the need for this type of method of administration arises due to there being patients, such as babies or elderly people, with problems swallowing pills or capsules. Thus, there is a necessity to develop edible films that can release and deliver a hydrophilic drug quickly and a need for orodispersible dosage forms to demonstrate their ability to overcome these limitations. One promising alternative is orally disintegrating films (ODFs), which are polymer-based, thin (thickness ranging from >10 μm to <750 μm) [3], flexible, easy to administer, and stable during preparation, packaging, and transportation [1,2,3,4]. ODFs are generally composed of water-soluble polymers, plasticizers, and a pharmaceutical ingredient. Upon hydration, they adhere to the oral mucosa and release the drug for transmucosal or local therapy. This offers several advantages over conventional oral administration, primarily due to the high vascularization of the mucosa, which enables faster drug absorption. This improves bioavailability while preventing enzymatic degradation in the gastrointestinal tract and avoiding first-pass metabolism [5]. Additionally, the accessibility of the oral cavity and buccal mucosa facilitates the application and removal of drug delivery systems, making them convenient for both patients and caregivers. However, continuous saliva flow, as well as tongue and jaw movements, can limit their effectiveness. Furthermore, the permeability of the oral mucosa is lower than that of the small intestine, although this limitation can be mitigated by prolonged retention times [6]. There are two types of oral films: orodispersible ones that aim for rapid dissolution and bioadhesiveness that allows high solubility and absorption, leading to bioavailability of the drug [7], on the one hand, and mucoadhesive films that are intended for application on the oral mucosa, allowing controlled release of the active ingredient over an extended period.
Therefore, the polymer matrix responsible for transporting the active ingredient must integrate the characteristics of multiple compounds to enhance its application. The intrinsic properties of the polymers constitute a fundamental part of the synergy of the formulations. Biopolymers based on polysaccharides play a fundamental role due to the ability to form films in the presence of plasticizers and the organoleptic properties that they provide to the matrix–drug system. Among the biopolymers used in the process of formulating edible films from solutions, starch and chitosan have been extensively studied. Optimal ratios of 1.5:1 (starch–chitosan) have been identified, yielding excellent mechanical properties by balancing the flexibility of thermoplastic starch (TPS) with the rigidity of chitosan, due to the 1.5:1 relation showed an elongation of 61.1% [8], while T. Bourtoom et al. showed that the tensile strength is increased due to the addition of the chitosan to the blend. With rice starch, the best radios were 1:1 and 0.5:1 (starch–chitosan) with a 36 MPa and 38 MPa, respectively [9]. Also, Liu et al. determined that the E value of a blend of chitosan–starch increases due to the hydrogen bonds between NH3+ protonated from chitosan and the OH of the starch [10]. Studies have demonstrated that chitosan-based ODFs exhibit high mucoadhesiveness due to the positive charge of the amino group, which generates strong electrostatic interaction with the negatively charged salic acid residues present in the mucosa [11]. Disintegration times have also been demonstrated below 36 s, and when mixed with various plasticizers such as glycerol or sorbitol, chitosan films have exhibited high tensile strength and flexibility. The versatility of chitosan lies in its biocompatibility, non-toxicity to humans, and biodegradability. Additionally, it possesses antioxidant and antimicrobial properties and the ability to form homogeneous films [12]. On the other hand, starch is a non-ionic polysaccharide characterized by lower mucoadhesiveness; however, its interaction with the mucosa is facilitated through interpenetration of the polymer chains. In recent years, starch has been increasingly utilized for the development of thin films for drug delivery applications [13]. The botanical source from which starch is obtained determines its specific composition and microstructural rearrangements, influencing its crystallinity and, consequently, its physicochemical and biological properties. Cassava starch is considered a promising option for the development of ODF, as it has been shown to exhibit low disintegration times (approximately 10 s) and high tensile strength (~30 MPa) [14,15]. Multiple studies have demonstrated the synergy between starch and chitosan in films that present excellent antimicrobial properties, enabling various applications, including their use in the agricultural and food sectors as coatings for fruits to extend shelf life [16]. Additionally, the development of microparticles from unconventional manufacturing techniques, such as spray drying of starch–chitosan blends in the presence of surfactants, in which a bowl-shaped morphology is guaranteed, allows a potential for another range of applications related to microencapsulation [17]. Another carbohydrate with potential participation as an ingredient in the biofilm matrix is maltodextrin, an oligomer derived from starch, formed by ~10 glucose units. Maltodextrin serves as an effective ODF-forming agent [18], providing good viscoelastic and thixotropic properties (3500 mPa.s, total regeneration of the initial structure after 120 s, respectively) and short disintegration times due to its hydrophilic nature [19]. A maltodextrin film showed the capacity to load 13.4 mg of sodium diclofenac [20]; another maltodextrin film showed the capacity to load benzydamine hydrochloride [21]. Amylose has also been used for its encapsulation capacity, colorless appearance, and ability to provide thermal and oxidation protection [22,23]. This exhibits high flexibility, which makes maltodextrin a promising polymer for application in ODF as a formulating agent alone or mixed with other macromolecules. The most commonly used techniques for ODF manufacturing include solvent casting, hot-melt extrusion, and non-conventional methods such as additive manufacturing technologies (e.g., inkjet printing, semisolid extrusion 3D printing, and fused deposition modeling 3D printing). The solvent-casting technique involves dissolving the active compound, film-forming polymers, and additives in a suitable solvent to create a viscous solution or suspension. This mixture is then uniformly poured into a pre-designed mold and subjected to a drying process. The resulting films are characterized based on properties such as content uniformity, thickness, and morphology, among others [5].
In general, oral disintegration films allow the incorporation of active pharmaceutical ingredients (API) that can be released in a controlled manner. Interest in the manufacture of ODF by pharmaceutical companies has not been limited to mass production nor personalized medicine. Acetaminophen (A) is one of the most consumed drugs worldwide due to its therapeutic safety, effectiveness, and accessibility [24]. It is an N-acetyl-p-aminophenol derived of phenacetin with a low molecular weight (151 Da), and it demonstrates weak acidic behavior. Acetaminophen is commonly marketed in the form of capsules or tablets (including film-coated tablets and effervescent tablets), which are suitable for crushing but not intended for liquid formulations. Standard doses contain 500, 650, or up to 1000 mg of the drug [25]. Additionally, liquid formulations, such drops and syrup, are available. Acetaminophen has demonstrated rapid and effective analgesin and antipyretic action in infants, children, adolescents, and adults, with effects comparable to those of acetylsalicylic acid. Although it lacks the anti-inflammatory properties of salicylates, it is widely used as an alternative for patients with aspirin allergies or intolerance [26]. Therefore, this study aimed to evaluate the effect of incorporating model APIs into an ODF based on starch, chitosan and maltodextrin, focusing on its physicochemical and thermodynamic surface properties.

2. Materials and Methods

2.1. Materials

The following biopolymers were used: native cassava starch variety SM 707-17 (Manihot esculenta Crantz) from the “La Agustina” grating factory, located in Mondomo, Colombia; maltodextrin (Agenquímicos Ltd., Cali, Colombia). Chitosan (CH) and acetaminophen were standard reference materials (United States Pharmacopeia) and were supplied by Sigma Aldrich (St. Louis, MO, USA). They had a low molecular weight and a degree of deacetylation > 75%. Glycerol was purchased from Sigma Aldrich (density of 1.28 g/mL and purity of 99.5%). Buffer solution (di-sodium hydrogen phosphate/potassium dihydrogen phosphate) pH 7.0 (20 °C) Certipur® was obtained from Merck (Darmstadt, Germany). Glacial acetic acid (100% anhydrous) was obtained from Merck (Burlington, VT, USA).

2.2. Preparation of Oral Disintegrating Films

An aqueous suspension (TPS) of starch and glycerin was prepared with a proportion (weight/volume) of 5% (w/v) and 1.25% (w/v), respectively. This blend was homogenized by stirring, and, in turn, was subjected to heating until it reached a temperature of 70 °C for 10 min. Subsequently, the stirring was increased to 1200 rpm as the gelatinization of the polymer solution was observed. In parallel, a 2% (w/v) solution of chitosan in 1% glacial acetic acid was prepared. This solution was homogenized using vigorous stirring at room temperature for 30 min, during which time, complete dissolution of the chitosan was observed. Additionally, a third 5% (w/v) aqueous maltodextrin solution was prepared. This solution was homogenized by stirring at room temperature until the maltodextrin was completely dissolved.
The films were made according to the solvent-casting method. From the previously prepared solutions, the filmogenic solution is composed by a ratio of 60:20:20 of polymeric solutions of TPS–chitosan–maltodextrin (TPS-CH-M). The resulting film-forming solution was stirred for 10 min at 500 rpm and then subjected to ultrasonic treatment (Elmasonic Easy 120 H) at 27 kHz, 200 W, and 25 °C for 10 min. To remove air bubbles, the solution was placed under vacuum. The polymer solution was then poured into a cylindrical mold ensuring a height of 0.17 mm. This value was previously tested to formulate a film with a thickness of less than 0.05 mm; in all cases, these actions were carried out according to recommendations found in the literature [1]. The films were subsequently dried in a forced-ventilation oven (Binder, series 14291) at 65 °C for 3 h. After drying, they were demolded and conditioned at 25 °C and 50% relative humidity (RH) for 48 h before physical and chemical property evaluation. The thickness of the films was measured at five random points across five samples using a caliper (Fischer Darex, Le Chambon Feugerolles, France, 150 ± 0.1 mm). The average thickness formulated was 0.038 ± 0.004 mm.
The same process and polymer proportions used in the preparation of the previously described matrix were applied, with the incorporation of acetaminophen. The drug loading process was determined using a range between 0.025% and 10%, considering homogeneity and film-forming capacity. Various ratios of film-forming solution volume to drug mass were tested: 90:10, 95:5, 97:3, 91:1, 99.5:0.5, 99.75:0.25 (see Figure S1, Supplementary Information). Based on these trials, the selected maximum drug loading was 99.5:0.5. The preparation consisted of adding the model drug, acetaminophen, to the first solution (TPS solution) before heating. The amount added ensured a final film-forming solution containing 0.5% API. The solution was then poured into molds for drying and film formation, achieving a height of 0.17 mm in the cylinder. The films were conditioned for 48 h at 25 °C and 50% RH before evaluating their physical and chemical properties. Five random measurements were obtained from five API-containing films, yielding an average thickness of 0.044 mm ± 0.005 mm. Additionally, the surface pH was measured using a multiparameter pH meter with two channels (Hanna, HI5522). Readings were recorded after placing the ODFs in contact with distilled water at 37 °C for 30 s. Three repetitions were performed using 10 different films. The average pH value for films containing API was 6.651 ± 0.004, while the average pH value for films without acetaminophen was 6.758 ± 0.011. No significant differences were observed between the two.

2.3. Pharmaceutical Active Ingredient (API) Quantification

The determination was carried out in a UV-Vis spectrophotometer (Merck, Spectroquant Prove 600) at 243 nm. A calibration curve was prepared in a 0.1 M HCl solution using five defined proportions (20, 200, 400, 600, and 800 g.L−1) [27]. These concentrations were formulated from a stock solution prepared with acetaminophen (A). API-containing films were dissolved in a buffered aqueous solution at pH 6.8 and maintained at 37 °C under constant stirring at 50 rpm for 30 min [28]. After this period, the solution was filtered by gravity through 90 mm qualitative filter paper (Boeco, Germany) and subsequently passed through a nylon syringe filter with 0.45 μm pore size (Fisher Scientific, Hampton, NH, USA). Absorbance readings were recorded at 243 nm, using a film without API as a control.

2.4. Fourier-Transform Infrared Spectroscopy (FTIR)

The analysis was performed using FTIR spectroscopy with KBr pellets. This technique enabled the identification of different types of vibrations experienced by the bonds in the organic compound and the influence of its molecular environment. A Shimadzu spectrophotometer, model IR Affinity-1, was used for the measurements. The spectra were recorded in the range of 400 cm−1 and 4000 cm−1 at a resolution of 4 cm−1 at 45 scans.

2.5. X-Ray Diffraction Analysis (XRD)

The atomic arrangement of films was observed by XRD using Malvern-Panalytical equipment (Empyrean model, Worcestershire, UK). The measurements were carried out by Bragg–Brentano configuration of powder diffraction and platform (goniometer: Omega/2 theta, and platform configuration: reflection transmission spinner with 4 s rotation). The step was 0.02° and the time per step was 52 s. The measurement was made under the condition that Cu X-ray radiation was generated at 45 kV, 40 mA, and Cu Kα = 1.541 Å.

2.6. Simultaneous Thermal Analysis: Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC)

The thermal properties were studied using a TGA/DSC 2 STAR System thermogravimetric analyzer from Mettler Toledo (Schwerzenbach, Switzerland). The thermal degradation behavior and first- and second-order temperature transitions were analyzed. The heating rate was 20 °C/min, heated from its starting temperature of 25 °C to a final temperature of 600 °C. The system was fed by nitrogen that flowed at a rate of 50 mL/min over 10 ± 0.5 mg of material.

2.7. Mechanical Tests

The mechanical behavior was analyzed by calculating the tensile strength (TS) and the percentage of elongation at break (%E). The tests were conducted in accordance with ASTM standard (D882-12) [29], using a universal testing machine from the Hung TA Instrument Go brand. The test speed was 20 mm/min using rectangular specimens 2.5 cm wide and 12.0 cm long. Values were obtained guaranteeing the reading of five films fractured in the center; this was carried out for films with and without drug content.

2.8. Scanning Electron Microscopy (SEM)

The morphology analysis of the films was performed using a JCM 50000 instrument (JEOL, Tokyo, Japan) in the secondary electron mode at 10 kV. Film preparation was performed by fracturing the samples after freezing them in liquid N2. For this measurement, the samples were placed on carbon tape and gold-coated using a direct current sputter technique. Magnifications of the fracture surface were obtained.

2.9. Measurement of Sessile Drop

Contact angle measurements were performed using a goniometer (Ramé-Hart Instrument Co., Ltd., model 250, Succasunna, NJ, USA), with the addition of 20 μL of water at 25 °C on the polymer after 30 s. The image was recorded, and the contact angle was measured using the free software ImageJ, version 5.0.3. The results were obtained by averaging five measurements for each sample.

2.10. Absorption (Swelling) Test

The films were cut into 1 cm2 sections, and their initial weight (W0) was recorded. The film samples were then immersed in water at 23 °C, and their weight was measured at predetermined time intervals (5, 10, 15, 30, 45, and 60 min). Excess water on the surface was carefully removed from the swollen films with filter paper before recording the final weight (Wf) [30,31]. The percentage weight gain of the sample was calculated for three replicates using the following equation:
Absorption weight gain (%) = (Wf − W0)/W0 × 100

2.11. In Vitro Oral Disintegrating Time

The in vitro disintegration time of the films was analyzed using a chronometer to record the initial time (T0) and final time (Tf) of the test. Film samples were cut to dimensions of 2 cm × 3 cm (width × length). Each sample was placed flat in Petri dish, and 200 μL of distilled water at 37 °C was carefully added to the films surface. T0 was recorded at the exact moment the water was applied, and Tf was noted when the first perforation appeared. The disintegration time was calculated as the difference between Tf and T0 [32].

2.12. In Vitro Dissolution Time

The determination was carried out in a UV-Vis spectrophotometer (Merck, Spectroquant Prove 600) at 243 nm. The test consisted of dissolving 1.0 g of the film with acetaminophen in 25 mL of aqueous solution buffered at pH 6.8, maintaining a temperature of 37 °C with constant stirring at 50 rpm [33]. After 180 s, the solution was filtered by gravity through 90 mm qualitative filter paper (Boeco, Germany) and subsequently through a nylon syringe filter with a 0.45 μm pore (Fisher Scientific). Finally, the proportions of the film were measured for specific periods: 5, 8, 10, 15, and 30 min.

2.13. Sugars Determination (°Brix)

Total soluble solid (TSS) concentration in Brix (°) of the films with and without acetaminophen was measured under the official protocol (AOAC, 2012) [34], using a digital refractometer, ATAGO brand, reference: Pocket Refractometer PAL-3, with a range of 0–93%. The apparatus was calibrated with deionized water (refraction index = 1.3330 and °Brix at 37 °C), and the measurements of the sample were obtained (°Brix). A total of ~0.2 g of the sample was weighed and immersed in 5 mL of distilled water at 37 °C, ensuring temperature consistency throughout the test. An amount of 0.5 mL of the solution (distilled water in contact with the film) was obtained at 5, 8, 10, 15, and 30 min for measurement. The following conditions were available for the analysis without stirring and with magnetic stirring at 50 rpm, at 37 °C, for both cases.

2.14. Statistical Analysis

Means and standard deviations are presented, and analysis of variance (ANOVA) was used to compare mean differences in film characteristics. In addition, the comparison of means was performed using Tukey’s test at a significance level of 0.05. All statistical analyses were performed using IBM® SPSS® Statistics 25 software.

3. Results and Discussion

3.1. Quantification of the Active Pharmaceutical Ingredient (API)

The calibration curve was prepared using known contents of acetaminophen as the active ingredient, and from this curve, the content in the biopolymeric film was determined according to the Beer–Lambert law. The analysis was performed by ultraviolet-visible spectrophotometry at 243 nm, preparing five calibration standards (20, 200, 400, 600, and 800 g·L−1) from a 1% aqueous solution prepared with reference standard acetaminophen. Figure 1 shows the results of the absorbances at each of the known contents. The experimental value of the proportion in the film was determined from the equation of the straight line obtained by linear regression. The calibration curve obtained for quantification presented good linearity and a high correlation coefficient value (R2 = 0.9983), ensuring the accuracy of the calculated values.
API (%) = 0.47 ∗ 25 = 11.75%
The absorbance measurement of the film was 2.815, corresponding to a calculated experimental proportion of 0.47% (w/w), as shown in Figure S1. The formulated concentration was then multiplied by the dilution factor, which in this case was 25, resulting in a final proportion of 11.75% (w/w) API in the film. To determine the theoretical proportion of the ODF with API, the calculation was based on the initial proportion of the polymer mixture before oven drying, which was theoretically 0.5%. Given that 23 mL of the film-forming solution was used, the total amount of API was 0.11965 g. This proportion gave a recovery percentage of 98% when compared to the experimental result.
API (g) = (0.5 g API/100 g) × 23.93 g = 0.11965 g
API (%, w/w) = (0.11965 g de API/0.9994 g) × 100 = 11.97% (w/w)

3.2. Fourier-Transform Infrared (FTIR) Spectroscopy

Figure 2 shows the spectra obtained from the natural polymers—starch, chitosan, and maltodextrin—where a broad band associated with bond stretching is observed in the large region from 3600 cm−1 to 3100 cm−1. This band corresponds to the O–H stretching of the multiple hydroxyl groups present in both the participating molecules (glycerol, A) and macromolecules (biopolymers). In this same region, the vibration of the amino group (N-H) corresponding to chitosan (CH) and acetaminophen appears to be located. Next, defined bands corresponding to asymmetric and symmetric stretching of C–H bonds were observed between 2925 cm−1 and 2850 cm−1, respectively. These vibrations are related to the hydrocarbon chain, methyl, and methylene groups present in the different organic compounds. At a wavelength of ~1680 cm−1, the vibrational stretching mode of the carbonyl (C=O) present in the amides of chitosan is shown, which is partially deacetylated (up to 75%) and acetaminophen [35]. A nearby band appears at 1695 cm−1 of the water molecule, which achieved strong interactions with the other components until crystallization was achieved in the system. Another region of great importance in the spectrum corresponds to C–O interactions (ether zone) that begin at ~1300 cm−1 up to 949 cm−1 [36]. In this area, significant changes are evident corresponding to hydrogen bond interactions between the different components as has been discussed and published in previous works. Finally, it was found that in the area known as fingerprints, bands appear at 838 cm−1 and 514 cm−1 which are related to characteristic vibrations of the disubstituted aromatic ring in the para (p-) position and the deformation of the phenyl ring outside the plane, respectively. For the TPS-CH-M-A samples, some intensity changes can be seen in characteristic bands for APIs over the control (TPS–CH–M) as a result of the addition of =C–OH groups of the phenol (as part of the molecule of acetaminophen). Also, a change is observed in the ratio of bands 1016 cm−1 and 990 cm−1 that becomes similar to the API in the TPS–CH–M–A with respect to TPS-CH-M. This broadening is attributed to limited intermolecular interactions due to the incorporation of the aromatic molecule, which induces steric hindrance and reduces polarity in the mixture. Overall, no new bands indicative of intramolecular reactions among the components were detected. This is crucial for application purposes, as maintaining the active component’s structural integrity is essential.
Previously, the presence of functional groups in the polysaccharides used—starch, maltodextrin, and chitosan—was discussed. The prominent –OH and –NH2 groups confer hydrophilic properties. Furthermore, chitosan exhibits biosorbent qualities, including cationic and macromolecular structures with excellent sorption capacity [37]. According to studies conducted by Nawaz et al. (2023) [38], various interaction mechanisms involving biopolymers have been identified, such as electrostatic attraction, electron donor–acceptor interactions (π–π), and hydrogen bonding [39]. In this case, acidic conditions are employed to solubilize chitosan and achieve optimal miscibility within the film-forming mixture, which subsequently transitions to the solid state. In solution, the capacity for interaction among components is enhanced through mechanical and ultrasonic means during mixing. The slightly acidic pH, which remains close to neutrality, maintains the positive charge of the –NH2 group, thereby maximizing adsorption. This phenomenon has been discussed by other authors through the calculation of thermodynamic properties, demonstrating that the process is spontaneous, endothermic, and based on a physisorption mechanism [40]. The interaction model proposed based on infrared analysis aligns with the representation in Figure 2a, where the individual components of each mixture, including the TPS–CH–M plasticizers, are depicted. In the case of the mixture containing acetaminophen (TPS–CH–M–A, Figure 2b), an interaction model is presented that illustrates the system’s integration, wherein van der Waals interactions play a role (see Figure 3). Due to its small molecular size, acetaminophen can readily diffuse into the matrix and distribute uniformly throughout the mixture. This facilitates maximum interaction with the biopolymers while preventing structural transformations or modifications, such as cross-linking reactions or esterifications.

3.3. X-Ray Diffraction (XRD) Analysis

Figure 4 shows the diffraction patterns of the biopolymer films and the active ingredient, both as a mixture and independently. A broad band (<10° and ~30°) is observed in the TPS–CH–M blend, reaching its maximum at 13.8° (2θ). This result is attributed to the mixture of chitosan, maltodextrin, and starch, which exhibits an amorphous structure according to the analysis. Regarding acetaminophen, the XRD pattern confirms its crystalline nature, as expected, given that acetaminophen is a drug with known polymorphic forms. The identified diffraction planes at 15.6°, 23.9°, 26.4°, and 32.5° (2θ) correspond to the (101), (211), (−20), and (−311) planes, respectively [41]. Based on the indexing of the X-ray pattern, the acetaminophen used in this study exhibits a monoclinic structure, also known as Form I [42]. The TPS–CH–M–A film displayed small peaks at 23.5° and 32.3° 2θ, which, according to the X-ray pattern of API, correspond to the API present in the edible film. The incorporation of the API into the TPS–CH–M matrix induces slight modifications in its crystalline structure, as evidenced by peak shifts toward lower angles. This shift suggests an expansion of the unit cell in Form I, which may be attributed to strong interactions between the API and the TPS–CH–M matrix, leading to subtle structural alterations in the API.

3.4. Simultaneous Thermal Analysis (TGA-DSC)

The thermal behavior of the films based on starch, chitosan, maltodextrin, and the active pharmaceutical ingredient was analyzed using TGA and DSC, as evidenced in Figure 5 and Figure 6, respectively. For the TGA curves and the respective derivatives (DTG) obtained for each polymer mentioned above, two very similar stages of mass loss are identified. The first stage occurs around 100 °C and is attributed to the loss of water and volatile components. The second stage, observed around 300 °C, corresponds to the degradation and decomposition of the compounds. Among the analyzed samples, TPS exhibits the lowest thermal stability, as evidenced by continuous weight loss with a maximum slope between 25 °C and 270 °C. Thus, the TGA thermogram of the TPS film demonstrated a weight loss in three stages. In the first stage, the loss of moisture was observed at a temperature below 100 °C. The second stage indicated the degradation of the plasticizer between 250 °C and 275 °C. The third stage is related to the decomposition of the polymeric material between 300 °C and 350 °C. The above is corroborated by the DSC curve through the endothermic peaks. As for the active ingredient, a moisture loss of ~15% is observed in the TGA curve, followed by excellent stability in which the mass content is not altered. The initial degradation temperature (T0) is observed at 272 °C, and it ends at 354 °C (final degradation temperature, Tf). The thermal behavior of the ternary TPS–CH–M mixture suggests the presence of weak intermolecular interactions. In polymeric systems, high viscosity in physical mixtures, along with steric hindrance caused by coiled polymer chains, limits the extent of interaction between components [43]. The TPS–CH–M blend presented a maximum degradation temperature equal to 290 °C, while the TPS–CH–M–A blend decreased its value significantly by 20 °C. The incorporation of the API in a solid state is distributed and inserted between the polymer chains, limiting the interactions and blocking the dissipation of thermal energy [44]. DSC provides insight into the thermal transitions characteristic of different materials. Neat starch exhibits a second-order transition (see broad band between 50 °C and 65 °C). On the other hand, starch in the presence of plasticizers and under thermomechanical process conditions presents an increase in heat absorption due to the change in the polymeric network. This process, known as gelatinization, is highly dependent on plasticizer content. For TPS, a transition in heat flow is observed beginning at approximately 50 °C and reaching an endothermic minimum at 87.9 °C. This process concludes around 150 °C. Similarly, maltodextrin presents a less pronounced endothermic event near 100 °C. The glass transition of chitosan occurs at 67.4 °C within an endothermic band extending up to approximately 100 °C, which is associated with the evaporation of solvents, such as water and acetic acid. The TPS–CH and TPS–CH–M mixtures undergo complete gelatinization due to extensive intermolecular interactions between the polymeric components. These blends demonstrate enhanced thermal stability, as corroborated by TGA, which reveals an increase in degradation temperatures. Additionally, the thermal transitions are delayed, with a glass transition temperature (Tg) of 124.7 °C and a melting temperature (Tm) of 156.8 °C. These results are not comparable to those obtained in the molten state or through reactive extrusion, emphasizing the significance of processing variables during mixing [45]. The melting temperature of acetaminophen is 86.2 °C, with around 40 °C above and below due to the polymorphism that this compound experiences [46,47]. The glass transition of TPS–CH–M–A is around 70 °C, located within an endothermic peak that continues up to 110 °C related to the volatilization of solvents and plasticizers. In the case of TPS–CH–M, the melting temperature and the glass transition peak are not detected. The above highlights the susceptibility to change experienced in the polymeric matrix due to interactions of the active ingredient [48].

3.5. Mechanical Properties

The mechanical performance of TPS–CH–M and TPS–CH–M–A are shown in Table 1. These values were calculated from the stress–strain curves obtained from uniaxial tensile tests performed until failure. Figure 7 displays the stress–strain curves of TPS–CH–M and TPS–CH–M–A films. Based on the analysis of these curves, both films exhibit two distinct regions: the elastic region and the plastic region. This behavior is characteristic of thermoplastic biopolymers [49]. In the plastic region, the TPS–CH–M film presents a smaller elastic area compared to TPS–CH–M–A. This difference results in a higher elastic modulus for the film containing the API, increasing from 9.27 MPa in TPS–CH–M to 9.38 MPa in TPS–CH–M–A. This increase can be attributed to the incorporation of the API, which introduces an elastomeric behavior at the onset of the elastic region [50]. Additionally, the narrowing of the yield zone in the API-containing film leads to a lower yield point of 17.67 MPa for TPS–CH–M–A compared to 17.17 MPa for TPS–CH–M. The incorporation of the API also affects the failure behavior of the film, causing it to break with minimal non-uniform plastic deformation. In TPS–CH–M, the tensile strength at yield and the breaking point are both 24.21 MPa, whereas in TPS–CH–M–A, these values differ, with a tensile strength at yield of 24.54 MPa and a breaking point of 23.39 MPa. Overall, the incorporation of the API enhances the film’s toughness, increasing it by 8%. Consequently, the addition of the API to the edible film improves its mechanical properties.

3.6. Morphological Analysis

The morphology profile of TPS-CH-M and TPS-CH-M-A films was analyzed using SEM, and it is presented in Figure 8. The TPS-CH-M and TPS-CH-M film exhibits a uniform surface without cracks, and the films’ structure appears homogeneous. No observable porosity is detected in either film. The incorporation of the API into the edible film is evident in the morphological analysis. A homogeneous distribution of small accumulations, likely associated with the presence of the API, is observed throughout the TPS-CH-M-A film. In contrast, the TPS-CH-M film appears dense and uniform without such accumulations. The dense, low-porosity morphology of these films is shown to be similar to other formulations under 3D printing techniques [51].

3.7. Contact Angle

The contact angle results are presented in Table 2. The reported values indicate that the hydrophilic nature of chitosan predominates is consistent with findings from previous studies. It is important to note that these values (69.18°) fall within the range of hydrophilic compounds responding to short analysis times (30 s) [52]. However, the water absorption (AW) results differ significantly between the two films, increasing the absorption of TPS–CH–M–A by 90% compared to the TPS–CH–M control. This effect may be attributed to the uniform distribution of acetaminophen particles within the polymer matrix, which likely reduces intermolecular interactions between polymer chains. Consequently, a greater number of water molecules can penetrate and interact with the material during submersion. The TPS–CH–M exhibited a contact angle of 62.18° ± 0.12°, confirming its hydrophilic nature, as materials with contact angles below 90° are considered hydrophilic [53]. The incorporation of the API into the edible film led to a slight increase in the contact angle to 62.91° ± 0.03°. However, despite this increase, both films remain within the hydrophilic category. The results suggest that the incorporation of API does not have a significant effect on the wettability of TPS–CH–M. However, regarding AW, it is evident that the presence of API in the film enhances water uptake. The TPS–CH–M film exhibited an AW of 321.28%, whereas TPS–CH–M–A showed an increased AW of 410%, representing a 28% rise. This result is favorable, as higher water absorption can facilitate faster film disintegration, a phenomenon promoted by water interaction.

3.8. In Vitro Disintegration Test

3.8.1. Disintegrating Time

According to the results obtained in Table 3, the images show the formation of a gel associated with starch and chitosan polymers [54]. Extensive research has discussed the applications of starch-based films as edible coatings, which can form gels upon contact with water. The polymer structure loses compaction (increases in free volume) due to the exchange of kinetic energy of the water molecules at the time of interaction. This is because this system exceeds the energy of the hydrogen bonds present in the macromolecule. At this point, the starch gradually absorbs water until the granules complete their destructuring, burst, and form a new mixture of viscous consistency and flow [55]. Similarly, in the case of chitosan, water hydroxyls penetrate the structure, reducing the availability of hydroxyl groups, weakening intramolecular hydrogen bonds, and affecting solubility. Water acts as a strong hydrogen bond donor and acceptor, making it an excellent agent for gelling chitosan. Consequently, water molecules integrate into the chitosan network, disrupting its three-dimensional structure [56]. The breakdown of hydrogen bonds increases molecular mobility, which, in turn, enhances the flexibility of the films [57]. The disintegration time test was conducted by placing the film in a Petri dish containing water at 37 °C, as studied by other researchers [21,32,58,59]. To minimize subjectivity in determining the endpoint of the film, API release was measured gradually in solution. Additionally, the test considered visible film rupture and swelling tendencies in the sample holder. In this case, fracture was observed, along with a significant increase in diameter from the initial time point (0 min) to 5 min. Furthermore, the film became translucent, indicating increased fluidity of the polymeric matrix.

3.8.2. Dissolution Time

Gradual measurements of the release profile of the API incorporated in the polymeric matrix were made from dissolution. The release was evaluated by determining the concentration of the compound over time. To simulate the salivary mucosa, the analysis was conducted in an aqueous medium at pH 6.8. The results indicated that the polymeric film released approximately 73% of the API within 10 min and achieved complete release within 15 min, maintaining a constant proportion after 30 min (See, Figure 9). Given these results, the proposed ODF can be classified as a very fast dissolving dosage form, since, according to the WHO, a drug is considered very fast dissolving when no less than 85% of the labeled amount of the drug has dissolved in 15 min, at pH 6.0 and 7.4 under the established conditions [58]. The fast release time obtained is directly attributed to the polymers used in the preparation of the ODF, since the release rate can be influenced by hydrophilic or hydrophobic characteristics of all the components of the matrix; in addition, the interaction between them can significantly influence the dissolution rate of the active ingredient. Generally, the presence of hydrophilic polymers such as chitosan or starch facilitates rapid dissolution upon contact with saliva, thereby efficiently releasing the active compound [59]. Under these conditions, the film demonstrated a low disintegration time (<60 s), meeting the European Pharmacopoeia (Ph. Eur.) standard [60]. The acceptance criterion for ODF disintegration time is classified as “fast”, ranging between 30 and 180 s [21]. According to the physicochemical characterization of the TPS–CH–M and TPS–CH–M–A films, the incorporation of API at 0.5% w/w into the TPS-CH-M filmogenic solution resulted in a film with suitable properties for ODF applications. This film exhibited a density of 1.554 g/mL, and API quantification confirmed that the model drug accounted for approximately 11.75% of the total polymer film mass. Given that a typical ODF measures 3 cm × 2 cm, the total mass of the TPS–CH–M film is approximately 37.2 mg, with a total drug load of around 4.37 mg. Therefore, this film could serve as a potential platform for delivering drugs with a similar dosage requirement, such as naloxone, which is used for rapid opioid overdose reversal at a dose of approximately 0.4 mg. Additionally, this system could be adapted for drugs soluble in water, ethanol, or ethanol/water mixtures, such as loperamide, which is used for the treatment of acute diarrhea.

3.8.3. Total Soluble Solids (TSSs)

The sugar content of the samples was determined under the same conditions as the in vitro dissolution tests. Figure 10 shows dissolved sugars (°Brix) results for the TPS-CH-M and TPS-CH-M-A samples. In general, an increase in values is observed as the dissolution time progresses [61]. This effect is more pronounced in the first 5 min for the TPS-CH-M-A sample compared to TPS–CH–M. The increase in values is indicative of the release of the oligosaccharide maltodextrin into the solution and partial disintegration of the starch [62]. This phenomenon is attributed to the free volume generated by acetaminophen particles within the polymer chains. The presence of these particles creates spaces that facilitate water molecule penetration during dissolution. This behavior is similar to that observed in microencapsulation systems composed of polysaccharide mixtures, as reported by Zahid-Hasan et al. (2023) [63]. Additionally, these findings corroborate the results discussed in Section 3.7, which explain how dissolved sugars in the formulations contribute to moisture absorption, thereby limiting the availability of free water in the medium. After 10 min, the sugar content values of both samples became comparable, and at this stage, their impact on ODF applications is considered negligible.

4. Conclusions

The development of an edible film based on starch, chitosan, and maltodextrin capable of supporting a model drug such as acetaminophen was successfully achieved, opening the possibility of using this film for the delivery of other low-dose drugs. This formulation can be employed as an ODF. The physicochemical properties of the ODF demonstrated that the preparation method was optimal, ensuring miscibility between the polymeric components and achieving a homogeneous distribution of acetaminophen particles throughout the film, as corroborated by morphological analysis. The dispersion of the drug could be further improved through physical methods to prevent the accumulation of acetaminophen particles. The infrared spectroscopy technique demonstrated the intermolecular interactions between the polymeric chains and the active ingredient. Additionally, X-ray diffraction analysis revealed an expansion in the monoclinic unit cell, indicating drug ordering. However, long-range atomic ordering within the polymer blend was absent, confirming an amorphous structure, and no chemical reactions were induced by the drug. Thermal analysis using DSC confirmed phase transitions in the mixtures, including first-order transitions such as melting—where the drug’s fusion enthalpy decreased—and second-order transitions such as the gelatinization (disappearance) of polymeric components. In contrast, the degradation temperatures of TPS–CH–M and TPS–CH–M–A exhibited similar behavior. The mechanical properties, including maximum strength, toughness, and elastic modulus, were slightly enhanced, suggesting that the mechanical behavior of TPS–CH–M–A resembles that of a composite material. Regarding the film’s hydrophilic properties, as determined by contact angle measurements and subsequent water absorption analysis, a 28% increase in water absorption was observed in the film containing API compared to the TPS–CH–M control. Water facilitates the degradation of polysaccharides, thereby increasing the release of soluble solids and promoting drug release.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/app15084084/s1, Figure S1: Picture of biopolymeric films with different API concentrations (90:10, 95:5, 97:3, 91:1, 99.5:0.5, 99.75:0.25, polymer-drug ratio).

Author Contributions

Conceptualization, C.C. and A.F.G.; methodology, C.C.; software, C.C.; validation, C.C. and A.F.G.; formal analysis, C.C., A.F.G., N.R.G., L.P., L.S. and G.G.-P.; investigation, C.C., A.F.G., N.R.G., L.P. and L.S.; resources, C.C. and A.F.G.; data curation, C.C. and A.F.G.; writing—original draft preparation, C.C., A.F.G., N.R.G., L.P. and L.S.; writing—review and editing, C.C., A.F.G. and G.G.-P.; visualization, C.C.; supervision, C.C. and A.F.G.; project administration, C.C.; funding acquisition, C.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Vice-Rector for Research of Unidad Central del Valle del Cauca under project No. PI-1300-50.2-2025-11.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

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

Acknowledgments

The authors extend thanks to Beatriz E. Reyes Vielma for technical support.

Conflicts of Interest

The authors declare no conflicts of interest.

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Applsci 15 04084 g001
Figure 1. Calibration curve for determination of acetaminophen content.
Figure 1. Calibration curve for determination of acetaminophen content.
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Figure 2. FTIR spectra of the individual and mixed components involved in the biopolymeric films studied; (a) global spectrum 4000 cm−1 and 500 cm−1, and (b) amplification between 1800 cm−1 and 900 cm−1.
Figure 2. FTIR spectra of the individual and mixed components involved in the biopolymeric films studied; (a) global spectrum 4000 cm−1 and 500 cm−1, and (b) amplification between 1800 cm−1 and 900 cm−1.
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Figure 3. Molecular interaction models of (a) TPS-CH-M and (b) TPS-CH-M-A.
Figure 3. Molecular interaction models of (a) TPS-CH-M and (b) TPS-CH-M-A.
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Figure 4. XRD patterns of TPS-CH-M and TPS-CH-M-A.
Figure 4. XRD patterns of TPS-CH-M and TPS-CH-M-A.
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Figure 5. (a) TGA and (b) DTG curves of the different components used in the production of films with and without API.
Figure 5. (a) TGA and (b) DTG curves of the different components used in the production of films with and without API.
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Figure 6. DSC curves of the different components used in the production of films with and without API.
Figure 6. DSC curves of the different components used in the production of films with and without API.
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Figure 7. Tensile strength and elongation at break of the films with and without acetaminophen.
Figure 7. Tensile strength and elongation at break of the films with and without acetaminophen.
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Figure 8. SEM micrographs of (a) TPS-CH-M and (b) TPS-CH-M-A films.
Figure 8. SEM micrographs of (a) TPS-CH-M and (b) TPS-CH-M-A films.
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Figure 9. Percent of drug released at certain dissolution times.
Figure 9. Percent of drug released at certain dissolution times.
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Figure 10. Quantification of sugar at different dissolution times of the polymeric film loaded with the drug.
Figure 10. Quantification of sugar at different dissolution times of the polymeric film loaded with the drug.
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Table 1. The mechanical performance of TPS-CH-M and TPS-CH-M-A.
Table 1. The mechanical performance of TPS-CH-M and TPS-CH-M-A.
Mechanical PropertiesODF PristineODF with API
E (MPa)9.279.38
Yield point (MPa)17.7617.67
Tensile strength yield (MPa)24.2124.54
Breaking point (MPa)24.2123.39
Resilience (MPa)17.8415.04
Tenacity (MPa)61.2866.01
Table 2. Contact angle and water absorption (AW) at the surface of TPS-CH-M and TPS-CH-M-A films.
Table 2. Contact angle and water absorption (AW) at the surface of TPS-CH-M and TPS-CH-M-A films.
SampleContact Angle (°) and PictureAW (%)
TPS–CH–M62.18 ± 0.12Applsci 15 04084 i001321.28 ± 2.85
TPS–CH–M–A62.91 ± 0.03Applsci 15 04084 i002410.52 ± 3.03
Table 3. Picture of films in contact with water at 37 °C.
Table 3. Picture of films in contact with water at 37 °C.
SampleTime (min)
058101530
TPS–CH–MApplsci 15 04084 i003Applsci 15 04084 i004Applsci 15 04084 i005Applsci 15 04084 i006Applsci 15 04084 i007Applsci 15 04084 i008
TPS–CH–M–AApplsci 15 04084 i009Applsci 15 04084 i010Applsci 15 04084 i011Applsci 15 04084 i012Applsci 15 04084 i013Applsci 15 04084 i014
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MDPI and ACS Style

Caicedo, C.; Ramírez Giraldo, N.; Portilla, L.; Saldaña, L.; González-Pérez, G.; Fonseca García, A. Physicochemical Properties and In Vitro Dissolution of Orally Disintegrating Films Based on Polysaccharides: The Case of Acetaminophen. Appl. Sci. 2025, 15, 4084. https://doi.org/10.3390/app15084084

AMA Style

Caicedo C, Ramírez Giraldo N, Portilla L, Saldaña L, González-Pérez G, Fonseca García A. Physicochemical Properties and In Vitro Dissolution of Orally Disintegrating Films Based on Polysaccharides: The Case of Acetaminophen. Applied Sciences. 2025; 15(8):4084. https://doi.org/10.3390/app15084084

Chicago/Turabian Style

Caicedo, Carolina, Natalia Ramírez Giraldo, Leidy Portilla, Laura Saldaña, Giovanni González-Pérez, and Abril Fonseca García. 2025. "Physicochemical Properties and In Vitro Dissolution of Orally Disintegrating Films Based on Polysaccharides: The Case of Acetaminophen" Applied Sciences 15, no. 8: 4084. https://doi.org/10.3390/app15084084

APA Style

Caicedo, C., Ramírez Giraldo, N., Portilla, L., Saldaña, L., González-Pérez, G., & Fonseca García, A. (2025). Physicochemical Properties and In Vitro Dissolution of Orally Disintegrating Films Based on Polysaccharides: The Case of Acetaminophen. Applied Sciences, 15(8), 4084. https://doi.org/10.3390/app15084084

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