Evaluating the application of an arabinoxylan-rich fraction from brewers’ spent grain as a release modifier of drugs

Abstract This study evaluated the possible use of a fraction of brewers’ spent grain rich in arabinoxylans (BSG-AX) as an excipient that modifies the release of class III drugs (Biopharmaceutics Classification System), by determining the release profile of metformin hydrochloride (MH), in a water medium. The cumulative percentage of MH release showed the best linear fit when modeled with the cumulative distribution function (CDF) of the Weibull distribution (R2 = 0.993 ± 0.001). According to the Korsmeyer-Peppas model, the first stage of MH release is regulated by a super case-II transport mechanism controlled by the expansion and relaxation of BSG-AX. Finally, with the Hixson-Crowell model, a release rate (kHC) of 0.350 ± 0.026 h−13 was obtained (R2 = 0.996 ± 0.007). BSG-AX constitutes a suitable material for producing prolonged drug release vehicles; however, additional research is required to provide a better encapsulation of the active ingredients to ensure their optimal applicability and performance. Graphical Abstract


Introduction
Brewers' spent grain (BSG) is a valuable by-product in terms of quantity produced and chemical composition and a potential source of hydroxycinnamic acids (HCa), such as p-coumaric acid (p-Ca) and ferulic acid (Fa), and of polysaccharides, as it is a rich material in cellulose and hemicelluloses (mussatto 2014).also, BSG is a potential source for extracting arabinoxylans (aX) (mussatto 2014;pérez-Flores et al. 2019).
the physicochemical and structural characteristics of aX (molar mass, arabinose/ xylose ratio, and HCa profile), functional properties, and applicability will depend on the source and extraction method (Saulnier et al. 2007;pérez-Flores et al. 2019).the extraction method must not degrade the hemicelluloses since a molecular mass higher than 5 kda is required in high-valuable products such as barrier films or hydrogels (persson et al. 2009).
aX can be used as a food additive, in cosmetics, green chemistry, and pharmaceutical industries (Li & Yang 2016).a previous work evaluated the functionality of a film based on a bagasse fraction rich in arabinoxylans (BSG-aX) as a caffeine release matrix (pérez-Flores et al. 2019).the aX resist the digestive action of gastrointestinal enzymes and retain their integrity in the upper gastrointestinal tract, but once they reach the colon, they are degraded by bacterial polysaccharidases and release the drug (Beneke et al. 2009;mendez-Encinas et al. 2018).therefore, they could be potential materials for designing and developing oral drug delivery systems (ddS), such as modified-release dosage formulations (mRdF).
metformin hydrochloride (mH) is an n,n-dimethyl biguanide glucose-lowering agent, which was used in this work as a model molecule.it is a class iii drug in the Biopharmaceutics Classification System (BCS), meaning is a highly soluble hydrophilic drug with low permeability through biological membranes (Bouriche et al. 2021).
therefore, the objective of this study was to evaluate the possible use of a BSG-aX as an excipient that modifies the release of drugs by determining the release profile of mH in an aqueous medium to encourage this line of research and technology, thus contributing to the BSG integration in a circular economy.

FT-IR spectra
the absorption bands in the Ft-iR spectrum of the BSG-aX were assigned by comparing with literature values for other aX-rich lignocellulosic tissue extracts (Figure S2a). the absorption bands between 3000 and 3600 cm −1 (oH stretching as broadband) can be assigned to alcohols, water, ethers, phenols and related compounds.the band at 2927 cm −1 (aliphatic saturated CH stretching) has been previously correlated with lipidic content in the material.the band at 1645 cm −1 , corresponding to amide i, is related to protein content.also, the region between 1200 and 900 cm −1 is characteristic of polysaccharides related to aX. the strong band around 1044 cm ) is related to a lateral chain arabinoside and a high substitution of (α-L-araf) in C-3 of the (β-d-Xylp) residues.also, bands at 1076 cm −1 and 900 cm −1 (β-glycosidic bond, antisym.out-of-plane δ) were observed (iqbal et al. 2011;Hromádková et al. 2013;pavlovich-abril et al. 2016;pérez-Flores et al. 2019).
on the other hand, the absorption bands in the Ft-iR spectrum were assigned by comparing them with the literature values of mH (Figure S2b).Bands corresponding to asymmetric and symmetric stretching vibrational modes of primary metformin amines (nH 2 ) were observed at 3368 cm −1, and 3290 cm −1 , respectively, and a band at 3150 cm −1 due to the n-H secondary stretching, and characteristic bands at 1626 cm −1 and 1550 cm −1 assigned to C-n stretching were observed (Corti et al. 2007;nayak et al. 2013;Chowdary et al. 2014;nayak et al. 2016).
Finally, the absorption bands in the Ft-iR spectrum of the mixture of BSG-aX and mH were assigned as shown in Figure S2c. in this Ft-iR, a decrease in signal intensity as a function of absorbance can be observed.the reduction in the intensity of the characteristic mH bands at 3368 cm −1 , 3290 cm −1 , and 1626 cm −1 , was attributed to the formation of hydrogen bonding between the drug and polymer (Jagdale et al. 2011).
due to polymeric networks formation, drugs can be entrapped or attached to a polymer with different kinds of bonds or interactions, such as hydrogen bonding (Li & mooney 2016).as a carbohydrate polymer, aX has polar oH groups as part of its structure (Figure S1). on the other hand, mH molecules are stabilized by n-H•••Cl and n-H•••n hydrogen bonds (Childs et al. 2004).
Consistent with previous studies, aX interact with BCS class iii drugs such as atenolol (at), lamivudine (Lam), and famotidine (Fam) through hydrogen bonding.as stated in the actual work, mH belongs to class iii drugs.
in relation to this, akbar et al. ( 2012) published a quantitative-structure-property relationship (QSpR) study on pharmacological release where they evaluated compounds such as at, Lam and Fam in matrices with aX, finding that one of the important property descriptors is global softness, which is related to the prediction of reactivity, where the greater the softness, the greater the chemical reactivity (Fuentealba et al. 2000).this can be linked to the ease in the formation of hydrogen bonds between these compounds and the aX matrix, since they present amino, hydroxyl and carbonyl groups in their structures, which are highly reactive, referring to a delayed release effect as a consequence of this type of interaction.
these results confirmed that BSG-aX is an ideal material to encapsulate mH successfully.

Evaluation of BSG-AX as release modifier excipient
the values of the coefficients of determination (R 2 ) and the slopes when adjusting the experimental data of mH release to an aqueous medium with different mathematical models are shown in table S1.While in Figure S3 the plots of some of these models are shown.
the cumulative percentage of mH release (Figure S3a) showed the best linear fit when modeled with the cumulative distribution function (CdF) of the Weibull distribution (R 2 = 0.993 ± 0.001) (Figure S3b).
the CdF of the Weibull distribution has a geometric parameter which is the slope of the equation (β) values of β > 1 have been associated with a case-ii type transport which is the combination of phenomena such as diffusion, erosion and macromolecular ratio of polymer chains; in this case, the release mechanism is quite complex: the rate of release initially increases non-linearly up to the inflection point and after that decreases asymptotically, in this case, the shape of the curve is sigmoidal (papadopoulou et al. 2006;Sitta et al. 2014;Kobryń et al. 2017;Corsaro et al. 2021).this behavior can be observed in Figure S3a, where the cumulative percentage mH release adopted a sigmoidal shape since, at 4.50 h, 68.64 ± 4.14% of mH was released into the aqueous medium, and from the 5 h, an asymptotic behavior was observed, reaching the maximum amount of drug released (W ∞ ) at 6 h, with a value of 70.981 ± 2.18% of mH.
therefore, the CdF of the Weibull function fits the whole release process, providing a statistical description, unlike the other mathematical models that only allow adjusting a part of the experimental data and not the entire process, according to the values of the table S1.For this investigation, a value of β of 1.515 ± 0.059 (Figure S3b), therefore the release of mH was through a case-ii transport mechanism.
the results coincide with those obtained after adjusting the experimental data corresponding to the first 60% of the release of mH with the model of Korsmeyer-peppas also called 'power law' (W W t / ∞ < 0.60) (Figure S3c), since several authors have shown that the Korsmeyer-peppas model applies only to the first 60% of the release profile and is not an appropriate equation to describe the complete release profile (Wu et al. 2019;Heredia et al. 2022).the adjustment with this model allowed to obtain a value of n of 1.580 ± 0.150 (R 2 = 0.997 ± 0.009), which indicates that the first stage of the release of mH is regulated by a super case-ii transport mechanism controlled by swelling and relaxation of the polymer (BSG-aX) (Figure S3c), characteristic condition for values of n≥ 1 (das et al. 2013).Finally, the Hixson-Crowell model was used to determine the release rate constant of the mH k HC ( ), adjusting the data corresponding to the first 60% of the release (Figure S3d), getting a k HC of 0.350 ± 0.026 (R 2 = 0.996 ± 0.007); this is because the mechanism is based on the disintegration of the BSG-aX and therefore, the surface changes continuously during the process (mircioiu et al. 2019).thus, mathematical kinetic models allow the characterization of some dissolution parameters and the best description of the drug release process.and in this case, it allowed us to evaluate the functionality of BSG-aX as a release-modifying excipient.
drug release properties can change by using different concentrations of a biopolymer.For example, when using carboxymethyl arabinoxylan as a drug carrier of rabeprazole sodium, the swelling of hydrogels increased by increasing the concentration of the biopolymer.Hence, the swelling was directly proportional to drug release.other factors changing the swelling ratio are the accessibility of ionizable functional groups, the accessible free spaces of the expanded polymer matrix, and polymer chain relaxation (tulain et al. 2018).

Scanning electron microscopy
the micrographs obtained by SEm at different magnifications revealed the morphology of BSG-aX powder (Figure S4). the sample presented aggregated particles with irregular shapes and rough and porous surfaces.in addition, the size of the particles found was heterogeneous and greater than 100 µm in length.these morphological characteristics can be attributed to the method of extract drying (de anda-Flores et al. 2020).
the pore size and specific surface area are relevant factors to consider when discussing possible biopharmaceutical applications of porous materials.Generally, the larger the pores, the smaller the specific surface area, which is essential as it determines the loading capacity of the material.therefore, materials with smaller pores will have a higher loading capacity in a lower volume of material (mendez-Encinas et al. 2019).So, the results show that BSG-aX is a potential material for the development of mRdF.

Conclusions
the BSG-aX constitute a potential material for the development of mRdF since it has shown functionality as a modifying agent for the release of a drug of biopharmaceutical classification iii, such as mH.these results promote the integration of the by-products of the brewing industry within a high-impact circular economy as it is a biopharmaceutical application.However, additional research is required to compare the extraction methods that allow obtaining the BSG-aX with the best chemical properties, the drying methods of the material, the chemical or physical modification of the BSG-aX to improve its performance, encapsulation methods, the inclusion of other drugs and release profiles in different media.