Synthetic routes to theranostic applications of carbon-based quantum dots doi: https://doi.org/10.5599/adme t.1950 387 ADMET & DMPK 11(3) (2023) 387-407; https://doi.org/10.5599/admet.1950 Open Access : ISSN : 1848-7718 http://www.pub.iapchem.org/ojs/index.php/admet/index Original scientific paper The interactions of model cationic drug with newly synthesized starch derivatives Justyna Kobryń1, Tomasz Zięba2, Magdalena Rzepczyńska1 and Witold Musiał1* 1Department of Physical Chemistry and Biophysics, Wrocław Medical University, Borowska 211A, 50 -556 Wrocław, Poland 2Department of Food Storage and Technology, Faculty of Biotechnology and Food Science, Wroclaw University of Environmental and Life Sciences, Chełmońskiego 37, 51-630 Wrocław, Poland *Corresponding Author: E-mail: witold.musial@umw.edu.pl; Tel.: + 48-717-840-228 Received: June 26, 2023; Revised: September 8, 2023; Published: September 20, 2023 Abstract Background and purpose: The aim of the work was to compare the interactions of three newly synthesized non-toxic starch derivatives, with varied anionic and non-ionic functional groups with methylene blue (MB) as a model cationic drug, and selection of starch derivative with highest affinity to the MB. Experimental approach: The native potato starch (SN), modified via acetylation (SM1), esterification and crosslinking (SM2) and crosslinking (SM3), was evaluated in MB adsorption studies and assessed by FTIR, PXRD, and DSC. Key results: The adsorption of MB on SM2 and SM3 matched the BET isotherm model, which confirmed physisorption on the low-porous surface. In the case of SM1, adsorption took place via electrostatic attraction between the heterogeneous adsorbent surface and the adsorbate, as demonstrated by the Freundlich plot. The FTIR confirmed vibrations assigned to N=C stretching bonds at 1600 cm-1 in the case of MB adsorbed on the SN and SM2. The most intense PXRD peaks belonged to SN and the least to SM2. In the DSC study, the thermal stability via ΔT was assessed, with SM2 of lowest ΔT value (179.8 °C). Conclusion: SM2 presented the best adsorption capacity, followed by SM3 and the weakest SM1. The interactions were confirmed in the adsorption studies and may reflect applications of the modified starches as drug carriers. In the FTIR study, a probable interaction between the OH- groups of SM2 and N+ of MB was revealed. The most amorphous struc- ture was shown for SM2, which was correlated with the lowest thermal stability provided by the DSC study. ©2023 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). Keywords potato starch, adsorption, interaction, methylene blue Introduction There are numerous newly developed carriers for therapeutic substances [1-3]. They are often completely new synthetic polymers [4,5]. Among polymers of plant origin, there are natural examples of potential carriers [6-10]. Wheat, maize and potato starch are available in large quantities from natural sources [11-13]. So far, starch has been modified by Utomo, Odeniyi, Singh et al. [14-16], among others. Previous publications have presented new methods for obtaining a number of starch derivatives [17-19] and proposed the potential use of some of them, including acetylated starch [20,21] and starch citrate [22]. The figure below shows the structural models of the modified potato starches created by the team from the University of Environmental and Life Science (Wrocław, Poland) (Figures 1a,b,c). https://doi.org/10.5599/admet.1950 https://doi.org/10.5599/admet.1950 http://www.pub.iapchem.org/ojs/index.php/admet/index mailto:witold.musial@umw.edu.pl http://creativecommons.org/licenses/by/4.0/ J. Kobryń et al. ADMET & DMPK 11(3) (2023) 387-407 388 a b c d Figure 1. Structural models of the adsorbates as: a - starch acetate (SM1), b - starch citrate (SM2), c - starch diphosphate (SM3) and the d - adsorbent methylene blue tautomers (MB). Some drugs have a 1,4-thiazine ring, which is included in the structure of methylene blue (MB). The study that used the similarity between MB and other molecules was performed on acridine and phenothiazine derivatives for anti-prion therapy [23]. Selected drugs include the 1,4-thiazine ring: phenothiazine, which has antiparasitic, antiseptic and antioxidant effects [24], promethazine, which has antihistamine and anti-allergic effects [25], chlorpromazine and [26] thioridazine - as psychotropic drugs. The ionic interaction between the promethazine and Eudragit® was ascribed to the electrostatic interaction between the drug and ammonium groups in the polymer backbone [27]. The interactions of chlorpromazine with cyclodextrin were realized via ionic bonds between the ionized amine group of chlorpromazine and anionic group of cyclodextrin sulfate [28]. Another study, which exploited cyclic voltammetry, interpreted the interactions of chlorpromazine and thioridazine with bovine serum albumin nanoparticles as a result of hydrophobic interaction [29]. Therefore, research has been undertaken on MB as a model drug representing the structural features of some active pharmaceutical ingredients (API). These studies may determine whether similar drugs could adsorb on modified starch. To date, studies have analyzed the adsorption of MB and other dyes on activated carbon, minerals of natural origin such as perlite, clay and its derivatives, bentonite [30,31], and agricultural solid wastes [32]. In summary, the important group that led to the intermolecular activity may be the ammonia group, which specifically interacts with anionic functionals. Because of the wide potential application of modified potato starch [33-36], we decided to compare the adsorption capacity of selected starch derivatives, characterized by a distinct negative charge of carboxyl and phosphate groups, or a characteristic ester group, towards methylene blue as a cationic substance. The aim of the work was the evaluation of the prospective pharmaceutical applicability of three newly synthesized non-toxic starch derivatives, assessed via analysis of interactions of the starches, modified by varied acidic and non-ionic functional groups, with methylene blue, as a model cationic drug. The main question was the selection of the starch derivative with the highest affinity to the MB molecule. The possible interactions were evaluated in the terms of spectroscopic structural studies, as well as thermal assessments. The interactions, which may lead to drug release prolongation, were practically confirmed in the adsorption studies, which may reflect use of the above-mentioned modified starches as drug carriers for topical application, with retardant and prolonging effect against drug release process. ADMET & DMPK 11(3) (2023) 387-407 Model cationic drug and newly synthesized starch derivatives doi: https://doi.org/10.5599/adme t.1950 389 Materials The following materials were employed in the study: methylene blue (MB, Reko, Dzierżoniów, Poland) - a model active pharmaceutical ingredient (API), native potato starch (SN) (PPZ, Niechlów, Poland), modified potato starches (starch acetate - SM1, starch citrate - SM2 and starch diphosphate - SM3) prepared according to below-described methods. Methods Preparation of the modified starches The thermal and chemical modifications of native potato starch were conducted and resulted in acetylation (SM1), esterification and crosslinking (SM2), and crosslinking (SM3). Preparation of acetylated starch (SM1) The fractions of starch particles with an average volume moment diameter D [3,4] equal to 39.1 and 61.7 µm were separated from the native potato starch (SN) by measuring the volume diameter (Malvern laser particle size analyzer). Larger starch particles were acetylated with acetic anhydride in the amount of 13 cm3 /100 g of starch. After drying the acetylated starch, an initial gelatinization temperature of 49.17 °C was determined by differential scanning calorimeter Flash DSC (Mettler Toledo, Poland). The acetylated starch has been stirred for 24 h at 48 °C. It was then washed three times with five-liter portions of distilled water and separated from the slurry using the Contifuge Stratos (Heraeus, Germany) flow centrifuge. The obtained starch was dried for 24 h in an air dryer at 30 °C. Preparation of citrate starch (SM2) Native potato starch (SN) was esterified with citric acid. 10 g of citric acid per 100 g of starch dry matter was dissolved in 90 mL of water and thoroughly mixed. The resulting starch paste was left for 12 h at room temperature and then dried in an air dryer (Memmert, Germany) at 50 °C for 12 h. The starches were calcined for 3 h at 100 °C. The sample was rinsed three times with ethyl alcohol with a concentration of 95 mL of ethanol per 100 mL of solution, and each time, the solution was poured over the sediment. The washed precipitate was dried in an air dryer at 30 °C for 12 h. The obtained citrate starch was hardened at a temperature 2 degrees below the gelatinization temperature (determined by DSC), dried in an air dryer at 30 °C, ground in a laboratory mill and passed through a sieve with a mesh size of 400 μm [17]. Preparation of diphosphate starch (SM3) Native potato starch (SN) (94.6 wt.%), sodium trimetaphosphate (1.2 wt.%), sodium carbonate (2.1 wt.%) and sodium chloride (2.1 wt.%) were introduced into the reaction vessel, 500 mL of distilled water at 45 °C was added. The mixture was adjusted to pH 10.5 with a 3 % NaOH solution. It was kept at 45 °C for 30 minutes with constant stirring, then neutralized with 8 % HCl to pH 6.5-6.8. The cross-linked starch was washed several times with distilled water on a funnel under vacuum and dried for 48 h at 25 °C. After obtaining starch diphosphate, it was hardened for 24 h at 2 degrees below the gelatinization temperature, dried in an air dryer at 30 °C, milled and sieved through a sieve with a mesh size of 200 μm. Determination of the potential number of functional groups of modified starches Based on the recipe for preparing individual modified starches, the mass values of substrates attached to native starch (SN), such as acetic anhydride, trimethaphosphate and citric acid, were converted to moles. The converted values per gram of SN are given in Table 1. https://doi.org/10.5599/admet.1950 J. Kobryń et al. ADMET & DMPK 11(3) (2023) 387-407 390 Table 1. Number of moles of individual functional groups of modified starches per 1 g of SN. Modified starch Concentration, mmol g-1 Carbonyl groups Carboxyl groups Phosphate groups SM1 2.74 - - SM2 - 1.56 - SM3 - - 0.12 Spectroscopic evaluation Fourier transform infrared spectroscopy (FTIR) Fourier-transform infrared spectroscopy (FTIR) and attenuated total reflectance (ATR) appetizer (Nicolet 380 FTIR, Thermo Scientific, Waltham, MA, USA) with OMNIC ™ software were used to determine possible interactions between MB particles and starch. The formulations of MB adsorbed on every 50 mg of starch (SN, SM1, SM2 and SM3) were dried at 40 °C and compared with a physical mixture of MB and starch in a weight ratio of 1:10 and with the standards of the pure substances. The spectra of powders were recorded at wavelengths of 400 to 4000 cm-1 at 32 scans per sample and a resolution of 4 cm−1. Powder X-ray diffraction (PXRD) analysis The analysis of starch was supplemented by X-ray diffraction measurements (PXRD). The powder PXRD data were recorded on a Bruker D2 PHASER diffractometer (Bruker AXS, Karlsruhe, Germany) with a Lynxeye detector using Cu Kα radiation (0.15418 nm). All samples were measured at 295 K with 3.0 mm slit and 1.0 mm shutter. Diffractograms were obtained between 7.5° and 40° (2) (step size of 0.02° (2) and 0.25 s per step). The X-ray generator operated at 30 kV and 10 mA. The PXRD patterns were processed using the software Diffrac.Eva V 3.2. (Bruker AXS). The percentage of crystallinity and amorphousness of the tested starch samples in relation to SN was determined. Thermal analysis Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC 214 Polyma, Netzsch, Selb, Germany) was performed to investigate the samples of dried adsorbed MB on 50 mg starches (SN, SM1, SM2, SM3), their physical mixtures of 1:10 w/w and pure ingredients. The grated samples of 3 to 5 mg were explored in aluminium pans with lids under a nitrogen atmosphere, with a flow rate of 50 mL min-1. The thermograms were recorded at a constant heating rate of 5 °C min-1 in the temperature range from 0 to 350 °C. Evaluation of the adsorption kinetics of MB on the modified starches The absorbance study was performed using four 50 mL conical flasks (A, B, C, D) as a series. 40 mL 6 mg L-1 MB was added for each flask. The SN, SM1, SM2 and SM3 starch probes of 2, 5, 10, 25, 50, 125, 250, 500, 750 and 1000 mg were placed in the flasks during the series, respectively. The flasks were put on the orbital shaker (at 100 rpm) at 22±0.5 °C. Four measurements of absorbance were proceeded based on the pharmacopoeial method by sampling the MB solution volumes of 3 mL in every 5, 10, 15, and 20 minutes , and than in equal periods up to 4 h. The solution was returned to the flasks. Analysis of taken samples was done by the spectrophotometer UV/VIS Jasco V-530 (Tokyo, Japan) at 663 nm, according to the available bibliography [37-39], and compared to the absorption spectrum of MB. A standard curve based on three series of measurements with five concentration points from 0.5 to 5.0 mg L-1 was prepared. The results were examined according to pseudo-zero-order kinetics and first-order kinetics. ANOVA statistical test was performed for independent groups at the significance level α = 0.05. Freundlich, Langmuir and BET isotherm models were taken for analysis of adsorption processes (Table 2). BET isotherm equation was adapted to ADMET & DMPK 11(3) (2023) 387-407 Model cationic drug and newly synthesized starch derivatives doi: https://doi.org/10.5599/adme t.1950 391 form BET isotherm for liquid phase adsorption [40], where kBET(s) applies to the equilibrium constant of adsorption of the first layer and kBET(L) refers to the equilibrium constant of adsorption of upper layers. Table 2. Isotherm and kinetics models applied for evaluation of obtained data, Cs - concentration of substance in the solution in the equilibrium state (e.s.), qt - adsorbed quantity of adsorbate in time, q -adsorbed quantity of adsorbate in the e.s., qm - maximum monolayer capacity, kF, kL and kBET - adsorption equilibrium constants, k1, k2 - equilibrium rate constants, 1/n - constant, t - time, a - slope, b - intercept, r2 - regression coefficient. Applied model General equation Parameters Freundlich 1/ F s = n t q k C 1 a n = F lnb k= - r2 Langmuir ( ) m L s L s = 1 q k C q k C+ m 1  a q = m L 1 b q k = - r2 BET ( ) ( )( ) ( ) ( )( ) m s BET s s s sBET L BET L BET s = 1- 1- +   q C k q C k C k C k    ( ) ( ) ( ) ( ) BET L BET L BET s m BET s 2 - = k k k a q k ( ) ( ) ( ) BET s BET L mBET s -2 =   k k b k q ( ) mBET s 1 =c k q r2 Pseudo - 1st order ln(q-qt) = lnq - k1t q k1 - r2 Pseudo - 2nd order 2 2 1 = + t t t q k q q q k2 - r2 The values of q and qt were calculated by the equations (1) and (2): ( )0 sC -C = V q m (1) ( )0C -C = t t V q m (2) where C0 is initial concentration of the solution (mg L-1), Ct is concentration of the solution in time t (mg L-1), V is volume of solution (L) and m is adsorbent mass (g). Equation (3) was used for the adsoprption (%) calculation: 0 0 Adsorption 100tm m m  − =     (3) where m0 - the initial mass of the adsorbate, mt - is the adsorbate mass after time t. Determination of the effect of MB adsorption on the pH of starch The effect of MB adsorption on starch pH was investigated. The suspensions of pure starch in distilled water and suspensions of starch with adsorbed MB were prepared according to adsorption conditions (50 mg starch per 40 mL of water). pH measurements were taken after 1 and 72 h at 22±2 °C. Each measurement was taken three times. An ANOVA test with α = 0.05 was performed for these measurements. Results The results of the starch synthesis procedures yielded products with structures that conf ormed to the patterns (Figure 1 in the Introduction), and the appearance was as shown in Figures 2A and 2B. The molar ratio of functional groups added to the modified starches was converted per 1 g of native starch. Spectroscopic evaluations FTIR spectroscopy The FTIR spectrum of pure MB showed a broad peak from 3219 to 3364 cm -1, indicating an O-H bending bond. The sharp peaks at 3050 cm-1 and in the range of 817 to 884 cm-1 were responsible for the presence of C-H or =C-H bonds in the aromatic ring. Similarly, a sharp peak around 2700 cm -1 may have occurred due to the C-H stretching bonds [41]. https://doi.org/10.5599/admet.1950 J. Kobryń et al. ADMET & DMPK 11(3) (2023) 387-407 392 Figure 2. Images of actual appearance (above) and images magnified 10 times with a stereoscopic microscope (SMZ-171-TLED, Motic, Hongkong, China) (below) of A - SM1, B - SM2, C - SM3; petri dish diameter = 10 cm. Characteristic peaks interacting at 1596 cm-1 might have been assigned to N=C stretching bonds. The peaks in the range 1420-1490 cm-1 most likely belonged to the stretching C=C-C bonds in the aromatic ring. Vibration from 1340 to 1360 cm-1 revealed the presence of C-N stretching bonds in aromatic tertiary amine [41] and peaks from 1059 to 1064 cm-1 and 661 cm-1 are related to C-S-C stretching bonds in heterocycle [42]. The pure starches FTIR spectra indicated a broad peak of O-H stretching bond at about 3300 cm-1, C-O stretching vibration at the range 1185-1347 cm-1, especially the strong peak at 1240 cm-1 for SM1 (Figure 3 b), C-O stretching bond at 930 cm-1 [43] and O-H bending bond at 988 cm-1 [44] (Figure 3). a b c d Figure 3. The FTIR spectra of methylene blue (MB), the pure starches (a) SN, (b) SM1, (c) SM2 and (d) SM3, the physical mixture and the experimental formulation of the starches with adsorbed MB, respectively. ADMET & DMPK 11(3) (2023) 387-407 Model cationic drug and newly synthesized starch derivatives doi: https://doi.org/10.5599/adme t.1950 393 The plot of the spectrum of adsorbed MB on the starch (red line) mostly followed the plot of the spectrum of the respective starch in its pure state (green line). However, there were locations where individual peaks were in excess. The peaks assigned to N=C stretching bonds at about 1600 cm -1 appeared in the case of MB adsorbed on the SN and SM2, however, to a very slight extent (Figure 3 a,c). The peak indicating the presence of the C=O bond of the acetyl group at 1730 cm-1 [45] was spotted on the SM1 spectra (Figure 3b). PXRD Diffractograms of modified starches were compared to those of SN (Figure 4). The peaks with the highest intensity were in the 2 range from 17.2 to 17.4°. The most intense belonged to SN and the least to SM2. The proportion of crystallinity and amorphousness for the tested samples was determined using the amorphous subtraction method [46,47] and presented in Table 3. Table 3. Composition of crystallinity and amorphousness for SM1, SM2 and SM3 samples compared to SN (n = 3). Starch types SN SM1 SM2 SM3 Crystallinity, % 14.3 ± 0.80 9.8 ± 0.14 3.2 ± 0.26 5.7 ± 0.75 Amorphousness, % 85.7 ± 0.80 90.2 ± 0.14 96.8 ± 0.26 94.3 ± 0.75 2 / ° Figure 4. The diffractograms of acetylated starch (SM1), starch citrate (SM2) and starch diphosphate (SM3) compared to native starch (SN). Thermal properties DSC analysis results shown in Figure 5 compared pure MB and evaluated starches with adsorbed MB and physical mixtures of these components. The thermograms showed the results of heat flow measurements from 0 to 350 °C taken in two cycles, with a cooling interval in between. The exothermic direction has been marked with an appropriate arrow (exo). The results of DSC testing of native and modified starches under two heating cycles are shown in Figure 6. The glass transition midpoint temperatures Tg, the difference in the heat capacity between the transition from glass to the liquid state ΔCp and ΔT - difference between onset crystallization temperature and Tg were analyzed using Proteus 7.0 software (Netzsch, Selb, Germany). The results are shown in the Supplementary material, Table S1. https://doi.org/10.5599/admet.1950 J. Kobryń et al. ADMET & DMPK 11(3) (2023) 387-407 394 a b c d e f g h Figure 5. The DSC thermograms of methylene blue (MB), the pure starches (SN, SM1, SM2 and SM3), physical mixtures, and the experimental formulations of the starches with adsorbed MB. The subfigures (a,b,c,d) represent thermograms of the first heating cycle and (e,f,g,h) the rmograms of the second heating cycle. ADMET & DMPK 11(3) (2023) 387-407 Model cationic drug and newly synthesized starch derivatives doi: https://doi.org/10.5599/adme t.1950 395 a b Figure 6. The DSC thermograms of the starches (SN, SM1, SM2 and SM3). The subfigure (a) represents thermograms of the first heating cycle and (b) the second heating cycle. Adsorption tests The graphs showing the course of MB adsorption on starch showed the lowest saturation for SN and the highest for SM2 for 2 mg starch samples. It was 7.60 mg g-1 for SN and 22.86 mg g-1 for SM2 (Figure 7). a b c d Figure 7. The plot of MB adsorption on the starch samples with time: (a) SN, (b) SM1, (c) SM2, (d) SM3; ● - 2 mg, ○ -5 mg, ■ - 10 mg, □ - 25 mg, ▲ - 50 mg, Δ - 125 mg, ♦ - 250 mg, ◊ - 500 mg, - - 750 mg, + - 1000 mg, n = 4, at 22±0.5 °C and 6.0 mg L-1 MB solution with pH 4.26. The amount of adsorbed MB increased with the enhancement of the mass of starch samples. The parameter values, adjusted to the tested kinetics models, based on the correlation factor, are given in the Supplementary material, Table S2. Table 4 exhibits the parameters adapted to the chosen isotherm models. The samples of the starches were divided into two categories dependent on the mass; “A” was between 2 and 125 mg and “B” was between 250 and 1000 mg. Freundlich isotherm described in a satisfactory way adsorption equilibriums of https://doi.org/10.5599/admet.1950 J. Kobryń et al. ADMET & DMPK 11(3) (2023) 387-407 396 MB adsorbed on the SN A, SM1, SM2 and SM3 B. The Freundlich exponent 1/n between 0.5723 and 0.9221 for SN “A” and SM1 “B” indicated favorable adsorption for which 1 ≤ 1/n. The adsorption on SM2 “B” had the largest value of kF. The adsorption on SM1 “A” had the lowest kF-value. In the case of the Langmuir isotherm, only SM2 “B” and SM3 “B” gave a satisfactory value of r2. However, in this case, the values of qm and kL were negative. The largest r2 values for the BET isotherm belonged to SM2 “B” and SM3. Table 4. Parameters of selected isotherm models for adsorption of 6 mg L-1 MB solution on SN, SM1, SM2 and SM3 starches. A - applies to 2 to 125 mg, B - applies to 250 to 1000 mg of the adsorbents (n = 4). Isotherm model Parameters SN SM1 SM2 SM3 A B A B A B A B Freundlich 1/n 0.5723 1.0254 4.8442 0.9221 2.4503 3.5491 2.4769 1.5960 kF / L g-1 2.1632 0.9702 0.0010 0.3727 0.3964 7.7983 0.1407 0.5681 r2 0.9071 0.8096 0.8467 0.8834 0.8954 0.9162 0.9083 0.9981 Langmuir kL / L g-1 0.3020 -0.0712 -0.1593 0.0488 -0.1671 -1.2145 -0.1317 -0.2738 qm / mg g-1 8.9767 -12.594 -0.3920 7.9177 -4.7619 -0.4387 -3.4807 -1.5094 r2 0.6793 0.0771 0.5560 0.0836 0.7378 0.9220 0.8701 0.9684 BET kBET(s) / L mg-1 1.4106 4.7971 0.5151 0.7223 0.0216 5.1912 1.8188 0.7352 kBET(L) / L mg-1 0.0821 0.6768 0.0741 0.1666 0.1399 1.2943 0.1539 0.2591 qm / mg g-1 3.3822 0.0318 0.0290 0.3175 27.676 0.2730 1.4069 0.4535 r2 0.7331 0.3582 0.6907 0.2395 0.7706 0.9334 0.9434 0.9813 Determination of the effect of MB adsorption on the pH of starch The pH of starch suspensions with adsorbed MB compared to that of pure starch suspensions was higher for SM2 and lower for SN and SM1. In addition, there was a proportional increase in pH v alues after 72 h (Figure 8). a b Figure 8. Comparison of pH values of starch suspensions with adsorbed MB to pure starch suspensions after (a) 1 h and (b) 72 h at 22±2 °C (n = 3). No significant differences were observed between the pH values of SN-MB and SM1-MB after 1 h (Figure 8a). Discussion Spectroscopic evaluations FTIR spectroscopy Due to the appearance of peaks at 1599 cm-1 assigned to the C=N bond on the FTIR spectrum of samples of adsorbed MB on SN and SM2, we postulate the existence of an interaction between the N+ ion derived from MB and the OH- group belonging to starch, which probably leads to enhanced adsorption of the dye on the polymer. This observation coincides with the mechanism of MB adsorption on black olive stone carried out by Al-Ghouti et al. [48]. ADMET & DMPK 11(3) (2023) 387-407 Model cationic drug and newly synthesized starch derivatives doi: https://doi.org/10.5599/adme t.1950 397 PXRD According to Table 3, the SN was the most crystalline, and SM2 the least. The crystallinity of SM increased according to the following pattern, SM2 SM2 > SM3 > SM1 (Figure 7). The hydroxyl, carboxyl and phosphate groups of starch favored MB binding to the polymer to the greatest extent, while the acetyl groups had the greatest effect on the reduction of adsorption capacity. The rationale for the decreased sorption capacity could be the blocking of starch functional groups in the structure of starch polymer or the specific activity of functional groups towards MB. Dipa et al. [37] observed the effect of NaOH-derived hydroxyl groups on the increase of MB adsorption on kaolinite. However, these were groups added to kaolinite. In our case, only the carboxyl, phosphate and acyl groups originated from acids and were added during the starch modification process. Physisorption may be taken into account in the case of SN and SM3. It differs for SM2 and SM1, where acid groups can affect MB adsorption. Similar conclusions were issued by Huang et al. [80] after studying the adsorption of Pb2+ ions on activated carbon with additional functional groups. Pb2+ ions were adsorbed according to three mechanisms: (1) in mesopores, (2) via bonds between -OH and C=O and Pb2+, (3) H+ from the acidic carboxyl and phosphate groups is replaced by the Pb2+ ion. An additional element worth highlighting is the effect of the method of preparation of modified starches on their structure. Two of our SM2 and SM3 starches were prepared using the crosslinking method, which provides increased starch stabilization by forming bridges between hydroxyl groups and anhydroglucoses [81]. Kapelko et al. [17] found crosslinking reactions caused a decrease in solubility in water and a decrease in phase transition. Shen et al. [82] used corn starch and citric acid, malic acid, succinic acid and 1,2,3,4-butanetetra- carboxylic acid (BTCA) as cross-linkers. They observed that the acid with more carboxyl groups (citric acid and BTCA) showed higher crosslinking degrees and enhanced mechanical properties than acids with two carboxylic groups. Moreover, as they are used in food modification, poly-carboxylic acids are in the category ADMET & DMPK 11(3) (2023) 387-407 Model cationic drug and newly synthesized starch derivatives doi: https://doi.org/10.5599/adme t.1950 401 of safe chemicals [83]. In the case of SM1 and SM3, the chemically modified starches with a low degree of substitution (DS) are permitted for use in the food industry and are denoted with the symbol “E” followed by an appropriate number. Among others, acetylated starch (E1420) and di-starch phosphate (E1412) belong to this group [84]. Conclusions Citrate starch (SM2) presented the best adsorption capacity, followed by phosphate starch (SM3), and acetylated starch (SM1) showed the weakest adsorption capacity, according to the adsorption results. MB adsorption on SM2 and SM3 followed the BET isotherm model, which shows the physical adsorption of the cationic dye on the low-porous surface. In the case of SM1, MB adsorption probably took place via electrostatic attraction between the heterogeneous adsorbent surface and the adsorbate molecules, as indicated by the Freundlich adsorption model. Spectral methods confirmed the adsorption capacity of SM2. In the FTIR study, a probable interaction between the OH- groups of SM2 starch and N+ of MB was revealed on the basis of characteristic vibration of the C=N bond in the adsorbent derived from MB at 1600 cm-1. The DSC results showed the lowest thermal stability of SM2 correlated with its amorphous structure. Moreover, according to DSC, the possibility of interaction between SM2 or SM3 and MB was demonstrated via the existence of an exothermic peak belonging to MB in samples of these two adsorbents. The appearance of endothermic peaks in the case of SM2 and SM3 samples with adsorbed MB in the second heating cycle confirmed the interaction between the adsorbents and the adsorbates. The effect of the manufacturing method of the modified starches on their durability was noted. SM2 and SM3 starches were prepared using the crosslinking method, which provided increased starch stabilization. The above presented properties and, in addition, the "safe chemistry" and slightly acidic pH of the tested starches make them useful, especially citrate starch, as carriers for biologically active substances containing cationic groups, in topical skin applications. The present research confirms our previous studies on lidocaine hydrochloride. The modified starches may be the potential carriers in the form of hydrogels, similar to the hydrocolloid dressings. Author contributions: Conceptualization, J.Kobryń and W.Musiał; methodology, J.Kobryń, W.Musiał and T.Zięba; formal analysis, J.Kobryń, M.Rzepczyńska and W.Musiał; investigation, J.Kobryń, W.Musiał, M.Rzepczyńska and T.Zięba; resources, W.Musiał; data curation, J.Kobryń and W.Musiał; writing—original draft preparation, J.Kobryń and W.Musiał; writing—review and editing, J.Kobryń, W.Musiał and T.Zięba; visualization, J.Kobryń, W.Musiał and T.Zięba; supervision, W.Musiał; project administration, W.Musiał; funding acquisition, W.Musiał. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Wroclaw Medical University, grant No SUBZ.D060.23.025. 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