Tablet Disintegration Research Articles

Chemical Distribution Uniformity Assessment of "Intra-Tablet" by Hyperspectral Raman Imaging Analysis.

This study aimed to develop a new index, Distribution Uniformity Index (DUI), to assess the "intra-tablet" homogeneity. High-resolution hyperspectral Raman imaging was adopted to scan a tablet to get the components' distribution. The heuristic algorithm was applied to generate a Raman heatmap with RGB colors quantitatively correlated with the concentrations of each component. DUI is defined as the ratio of the area under the uniformity curve of the sample image to that of the randomized image. The accuracy and applicability of DUI were verified by constructing model images with controlled uniformity and random regions. The effects of "intra-tablet" homogeneity on the disintegration and dissolution of spironolactone tablets were investigated. DUI value was directly obtained from heuristic visual analysis of macro-pixel from hyperspectral Raman images. A good linear relationship and good repeatability were confirmed between DUI and the uniformity of model images. The size of CaSO4·2H2O affected the "intra-tablet" homogeneity of spironolactone tablets, which was detected by the DUI value. The better "intra-tablet" homogeneity led to a higher disintegration and dissolution of spironolactone tablets. DUI represents a novel index to evaluate the "intra-tablet" homogeneity and is beneficial for formulation research and development.

Strap-on Buoyant Device to Enhance Gastrointestinal Tract Retention of Felodipine Osmotic Pump Tablets.

Osmotic pump systems require prolonged retention time in the stomach to provide enhanced bioavailability and regulated release, which is quite challenging. This study used a three-dimensional printing (3DP) technique combined with a gastro-retentive floating device (GRFD) to extend the retention of the osmotic pump in the stomach and enhance its bioavailability. The strap-on buoyant device was fabricated by stereolithography 3DP and incorporated a felodipine osmotic pump tablet used in clinical practice, which enabled it to float in the stomach or dissolution media without any floating lag time. The components of the device were affixed using a snap-fix mechanism. GRFD dissolution study revealed a notable in vitro floating capability, lasting over 24h, with a release profile similarity factor f2 = 65.28 compared to the naked tablet dissolution profile. The pharmacokinetics of felodipine osmotic pump in beagles showed a Cmax of 1.893 ng/mL, which increased to 4.511 ng/mL with GRFD. The delivery of an osmotic pump with GRFD enhanced the AUC0-∞ of felodipine from 10.20 ng/mL·h to 26.54 ng/mL·h. In conclusion, the strap-on buoyant device has been successfully designed to enhance gastrointestinal tract retention of felodipine osmotic pumps and bioavailability in beagles.

Various drugs used in oral disintegration tablet formulation

Oral drug administration is more widely accepted because it is used to provide between 50 and 60 percent of medications. The solid dosage forms are commonly utilized since they are simple to administer, precise in their dosage forms, beneficial for self-medication, and preventive of discomfort, and last but not least, the excellent level of patient adherence. The capsules and tablets are the most widely used solid dose form administered orally. Aside from ingesting it does not possess any noteworthy drawbacks. Water plays a crucial function in this swallowing process. Even following this, some people had difficulty swallowing. In order to prevent these issues, mouth dissolving tablets were developed. They have the benefit of not requiring water and don't require swallowing because they dissolve or disintegrate in saliva. In light of the design it began to behave in two ways: first, some tablets disintegrated quickly, taking just a few moments in saliva. Another kind of tablet is known as a "first disintegration tablet" since it contains some substances that slowed down the tablet's rate of breakdown. Review attention was drawn to the concise talk about mouth dissolving tablets and the most recent versions available.

Development and Characterization of Fast-Dissolving Tablets to Enhance Bioavailability of BCS Class II Drugs by Solid Dispersion Method

Background: Rapid tablet or capsule dissolution requires the tablet to disintegrate and dissolve at a higher rate, enhancing drug dissolution and bioavailability. Suitable disintegrants have shown an appreciable rate of disintegration or dissolution. Using factorial design for formulation to improve bioavailability is a key focus in pharmaceutical research to enhance dissolution Methods: Azelnidipine (Azp) tablets were formulated with Hydroxypropyl β-cyclodextrin (HβCD), β-cyclodextrin (βCD), and Kolliphor HS15 (HS15) to enhance solubility. A 23 factorial design optimized the formulation, focusing on disintegration time (DT) and time for 90% dissolution (T90). Eight formulations (F1-F8) were prepared using the kneading method. Tablets were evaluated for physical properties, drug content, friability, dissolution, and drugexcipient interactions (FTIR and DSC). The optimal formulation (F9) was determined via desirability analysis. Results: Tablets showed acceptable Carr's index (CI), Hausner ratio (HR), and Angle of Repose (AR). Increasing βCD concentration decreased DT, enhancing water absorption and faster dissolution. βCD tablets had the lowest DT among the formulations, with F4 showing the best disintegration. Higher HS15 concentration also reduced DT, with F8 achieving the highest drug release (T90%) within 60 minutes. R² values ranged from 0.922 to 0.994, indicating high predictability. The optimal formulation had a desirability of 1.0, consisting of 3.523 mg HS15, 28.4 mg βCD, and 1.49 mg βCD, with a DT of 102 ± 1.13 seconds and 98% dissolution. FTIR and DSC confirmed no drug–excipient interactions. Conclusion: Optimized super disintegrant concentrations and wet granulation techniques resulted in tablets with strong mechanical properties, rapid disintegration, and consistent drug content. Future research and in vivo studies should explore additional excipient combinations.

Effect of Disintegrating Agents on Red Ginger (Zingiber officinale Roxb) Dry Extract Fast Disintegrating Tablets Using Direct Compression Method

Red ginger (Zingiber officinale Roxb) is one of the medicinal plants that is effective as a medicine for nausea and vomiting. One of the techniques for developing traditional medicinal products is to make fast disintegrating tablets (FDT). This research aims to compare the effect of these various disintegrating materials on the physical properties of FDT. FDT red ginger extract is made using the direct compression method. The tablets obtained were physically evaluated including weight uniformity, hardness, friability, and disintegration time. The statistical results using the one-way ANOVA test show that between tablet formulas there are significant differences in tablet disintegration time with differences in the type of disintegrating agent. The data obtained shows that all formulas meet the physical properties test requirements for tablets. The tablet formula using crospovidone produces tablets with high hardness, low friability, and fast disintegration time

Effects of Glass Bead Size on Dissolution Profiles in Flow-through Dissolution Systems (USP 4).

The effects of glass bead size in the conical space of flow-through cells on the dissolution profiles were investigated in a USP apparatus 4. Dissolution tests of disintegrating and non-disintegrating tablets in flow-through dissolution systems were performed using semi-high precision glass beads with diameters ranging from 0.5mm to 1.5mm. Computational fluid dynamics (CFD) was used to evaluate the effect of shear stress from the dissolution media flow. The use of smaller glass beads in a larger cell resulted in a faster dissolution of the model formulations under certain test conditions. The effect on the dissolution was highly dependent on the size of the beads in the top layer, including those in contact with the tablets. The absence of a bead-size effect on the dissolution of an orodispersible tablet in a small cell can be explained by the floating fragments during the test. CFD analysis showed that smaller bead diameters led to greater shear stress on the tablet, which was correlated with the dissolution rate. Hence, fluid flow through the narrow gaps between the small beads generated strong local flows, causing shear stress. The size of the glass beads used in flow-through cells affects the dissolution rate of tablets by altering the shear stress on the tablets in certain cases (e.g., direct deposition of the formulation on glass beads, large cells, and very low flow rates). Thus, glass bead size must be considered for a robust dissolution test in a flow-through cell system.

Modeling and evaluation of ivermectin release kinetics from 3D-printed tablets.

Aim: This study focused on evaluating the influence of geometric dimensions on the drug release kinetics of 3D-printed tablets.Materials & methods: An ink based on Gelucire 50/13 was prepared to print ivermectin-loaded tablets. The ink was characterized physicochemically and tablet dissolution tests were carried out.Results: The results confirmed the suitability of the ink for 3D printing at a temperature >46°C. Changes in the crystallinity of ivermectin were observed without chemical interactions with the polymer. 3D printed tablets with varied proportional sizes showed dual behavior in their release profiles, while tablets with only thickness reduction exhibited zero-order kinetics.Conclusion: These findings highlight the versatility of 3D printing to create systems with specific and customized release profiles.

Investigating the effects of formulation variables on the disintegration of spray dried amorphous solid dispersion tablets

Amorphous solid dispersion (ASD) tablets based on hydrophilic polymer carriers may encounter disintegration challenges. In this work, the effect of different formulation composition variables on the ASD tablet disintegration performance was systematically studied. GDC-0334: copovidone (PVPVA) 60: 40 ASD prepared by spray drying was selected as the model ASD system. The effects of ASD loading, filler type and ratio, disintegrant type and level were then investigated using tablets made by direct compression process. Tablet disintegration time increased with the increase of ASD loading, especially when ASD loading exceeded 50 %. At the same tablet solid fraction, when lactose was used as the soluble filler, faster tablet disintegration time was observed compared to the tablets with mannitol as the soluble filler. Among the three tested disintegrants, croscarmellose sodium performed the best in facilitating the ASD tablet disintegration, followed by sodium starch glycolate, and crospovidone was the poorest. When croscarmellose sodium was used as the disintegrant, 5 % level was sufficient to enable ASD tablet disintegration at 60 % ASD loading and further increase of croscarmellose sodium level to 8 % did not provide additional benefit. Water uptake experiments were performed on selected tablets and the results demonstrated a positive correlation with tablet disintegration time, indicating water penetration is a major contributing step for the disintegration of our ASD tablets. Overall, this work provides a rationale for excipient selection and insights into building a platform formulation approach for developing immediate-release ASD tablets.

Enhanced Anti-Inflammatory Activity of Kaempferia galanga Extract by Solid Self-Nanoemulsifying Drug Delivery System and Its Development in Fast Disintegrating Tablet

The increasing global incidence of osteoarthritis (OA) emphasizes the need for effective treatments, particularly for the elderly. Conventional OA treatments pose administration challenges, leading to patient discomfort due to difficulties in administration. Herbal formulations offer an alternative to mitigate these issues. Kaempferia galanga (KG) contains ethyl p-methoxycinnamate, a compound displaying anti-inflammatory properties that hold promise for OA treatment. This study explores the formulation of a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of Kaempferia galanga extract (KGE) and evaluates its anti inflammatory efficacy, subsequently developing it into a fast disintegrating tablet (FDT) dosage form. Initially, a liquid SNEDDS (L-SNEDDS) was prepared with varying surfactant and co surfactant concentrations. The optimal formula of L-SNEDDS (FL2) using tween 80: cremophor RH 40: PEG 400 in a ratio of 1:1:2 demonstrated favorable characteristics, including transmittance of 86.93 ± 1.16%, emulsification time of 28 ± 2.65 s, particle size of 27.79 ± 2.00 nm, PDI of 0.21 ± 0.014, and zeta potential of -12.57 mV. FL2 was solidified using aerosil 200 to produce S-SNEDDS and tested for anti-inflammatory efficacy in vivo using a carrageenan induced rat model. Results showed enhanced anti-inflammatory efficacy of KGE via S-SNEDDS, marked by reduced edema volume. Afterward, FDT S-SNEDDS were prepared using the direct compression method by comparing different types of superdisintegrants. The formulation using the combination of crospovidone and croscarmellose sodium (FT2) demonstrated excellent flow properties, tablet disintegration time of 63 s, wetting time of 34.01 ± 7.87 s, friability of 0.19%, and hardness of 3.53 ± 6.16 kg/cm2. The dissolution test indicated a better dissolution profile for FT2 compared to other formulations. In conclusion, this research presents the potential of FDT S-SNEDDS as a promising drug delivery system for enhancing the therapeutic effects of Kaempferia galanga extract in treating inflammatory conditions such as osteoarthritis.

Real-time prediction of dissolution profiles of coated oral dosage forms

Optical coherence tomography (OCT) has emerged as an in-line monitoring technique for pharmaceutical coating processes based on a representative number of samples. In this study, an approach was developed to correlate the coating thickness measured in-line via OCT with the resultant tablet dissolution profile. This strategy enables prediction of the dissolution profile of coated oral dosage forms for each individual state of the coating process in real-time. Correlation models were developed for a tablet pan coating process and for a pellet fluid-bed coating process. The feasibility of the correlation models was tested using different process parameters and types of coating formulations. This work demonstrated that using the OCT data to predict dissolution could possibly form a unique way of assuring drug product quality and establishing a control strategy within the real-time release testing (RTRT) concept.

REVIEW : OF SUPERDISINTEGRANT INGREDIENTS IN FAST DISINTEGRANT TABLET TABLET PREPARATIONS

This study aimed to evaluate the potential of synthetic and natural disintegrating agents in fast-disintegrating tablet (FDT) formulations. The methodology used includes a comprehensive literature review on the definition, characteristics, working mechanisms, and applications of super disintegrants in the manufacture of FDTs. The results of the study showed that super disintegrants play an important role in facilitating rapid disintegration of tablets. Synthetic super disintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate have the advantage of lower concentrations and better intragranular effectiveness. On the other hand, natural superdisintegrants such as mucilages, gums, and polysaccharides from plants have easy availability, affordable prices, non-toxic properties, and biologically acceptable characteristics. In conclusion, the selection of an appropriate super disintegrant, whether synthetic or natural, is a key factor in effective FDT formulation and providing rapid disintegration. The combination of using super disintegrants at the granulation stage (intragranular) and before compression (extragranular) can produce better performance compared to a single method. Keywords: FDT, Super disintegrant, Synthetic, Natural

Formulation, Development and Optimization of Silymarin Loaded Nanoparticle Orodispersible Tablets for its Anti-inflammatory Activity

The objective of this work was to enhance the anti-inflammatory properties of silymarin by developing and refining an orodispersible tablet formulation loaded with nanoparticles. Formulation development and optimization of silymarin-loaded nanoparticle orodispersible tablet for its anti-inflammatory activity is the focus of this research paper. Nanoparticle drug delivery systems can help to overcome these limitations by enhancing solubility and absorption. Disintegration and dissolution of Orodispersible tablets take place in the mouth rapidly without water, providing a faster onset of action. These nanoparticles were then incorporated into orodispersible tablets containing superdisintegrants and sweeteners using direct compression. A Box-Behnken design was utilized to systematically optimize the tablet formulation based on responses including disintegration time, wetting time, hardness and friability. After 15 minutes, SL-NP Formulation -3, which contains 5% crospovidone as a superdisintegrant, demonstrated maximal drug release, or 98.5%. Rats with paw edema caused by carrageenan were used to test the anti-inflammatory potential. Following three hours, the 400 mg/kg dose showed a strong 48% inhibition; the impact grew to 52% after three hours. Overall, the development of silymarin nanoparticle orodispersible tablets shows promise for improving the anti-inflammatory effects of silymarin through a synergistic combination of nanoencapsulation and rapid disintegrating tablet technologies.

Content Uniformity and Invitro Dissolution of Amlodipine Half Tablets

Tablet splitting technique is a practice that is carried out in hospitals and community pharmacies. The aim is to achieve dose flexibility, reduce tablet size, ease swallowing, and save cost. This technique is prone to variation in the weight of split tablets, mass loss, and content uniformity. Its effectiveness is subject to the tablet characteristics, method of splitting, and patient’s knowledge and skill. This practice increases the risk of inaccurate dosing, uneven distribution of drug substances, and potential loss of efficacy or adverse effects. This study aimed to determine the effect of splitting amlodipine tablets on weight variation, content uniformity, and in-vitro dissolution. Four brands of amlodipine 10mg tablets from the Kenya pharmaceutical market were evaluated. For each brand, weight variation and content uniformity tests were conducted as per the European Pharmacopoeia. Dissolution test was performed on 6 split tablets according to the British Pharmacopoeia. All the brands of amlodipine half tablets tested for weight variation were within acceptable limits. Only one individual mass was outside the 85-115% limit of the average weight, being 83.87%. Three of the four brands complied with the content uniformity test. One brand had 2 split tablets having amlodipine content out of the limit of 85-115%. Three brands complied with the dissolution test requirement for amlodipine tablets at the S1 stage. One brand had at least 75% of the amount of amlodipine (5mg) dissolved for the half tablets that were tested. The study shows variation in content uniformity and dissolution test for one brand each. All the brands met the pharmacopeia requirements for the tablet weight variation test.

Optimization of a Twin screw melt granulation process for fixed dose combination immediate release Tablets: Differential amorphization of one drug and crystalline continuance in the other

Interest in Twin Screw Melt Granulation (TSMG) processes is rapidly increasing, along with the search for suitable excipients. This study aims to optimize the TSMG process for immediate-release tablets containing two different drugs. The hypothesis is that one poorly water-soluble drug requires amorphous conversion for improved dissolution, while the other water-soluble drug, with a higher melting point (Tm), remains more stable in its crystalline form. Ibuprofen (IBU) and Acetaminophen (APAP) were chosen as the model drug combination to test this hypothesis. Various diluents, binders, and disintegrating agents were assessed for their impact on processability, crystallinity, disintegration, and dissolution during development. The temperatures used during processing were below the Tm of all components, except for IBU. Melted IBU acted as a granulating aid in addition to the binders in the formulation, facilitating granule formation. Physicochemical analyses by Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) confirmed the complete conversion of IBU into an amorphous state and the preserved crystalline nature of APAP. Saturation solubility studies showed an improvement in IBU’s solubility by ∼ 32-fold in 0.1 N HCl. Poor tablet disintegration performance led to the addition of disintegrating agents, where osmotic agents (sorbitol and NaCl) were found to significantly enhance disintegration compared to super disintegrants. The optimized formulation showed an enhanced IBU release (∼20 %) compared to the physical mixture (∼12.5) in 0.1 N HCl dissolution studies.

A data-driven approach to predict the in vitro dissolution time of sustained-release tablets using raw material databases and machine learning algorithms

Tablets are the most typical dosage forms of pharmaceutical inventions. Sustained-release (SR) tablet formulations are designed to release the drug gradually in the bloodstream and often require less frequent dosing. Current strategies to optimize sustained-release tablet dissolution time still rely on the traditional approach, which is time-consuming and expensive. In the present context, we have demonstrated alternate machine learning and deep learning models through the TPOT AutoML platform. Six machine learning (ML) models were compared to improve the methodology for dissolution time prediction, particularly the decision tree regressor (DTR), gradient boost regressor (GBR), random forest regressor (RFR), extra tree regressor (ETR), XGBoost regressor (XGBR), and deep learning (DL). The obtained results indicated that machine learning methods are convincing in speculating the dissolution time, especially the random forest regressor, but upon hypertuning of the deep neural network, the deep learning model with a 10-fold cross-validation scheme demonstrated superior predictive performance with an NRMSE of 8% and an R2 of 0.92. The major essentials affecting the dissolution time of SR tablets were explained using the SHAP method.

A two-stage mechanistic reduced-order model of pharmaceutical tablet dissolution: Population balance modeling and tablet wetting functions

We propose a two-stage reduced-order model (ROM) of pharmaceutical tablet dissolution that is comprised of (i) a mechanistic dissolution function of the active pharmaceutical ingredient (API) and (ii) a tablet wetting function. The former is derived from a population balance model, using a high-resolution finite volume algorithm for a given API crystal size distribution and dissolution rate coefficient. The latter is obtained from the mechanistic understanding of water penetration inside a porous tablet, and it estimates the rate at which the API is exposed to the buffer solution for a given formulation and the dimensions of the tablet, contact angle, and surface tension between the solid and liquid phases, liquid viscosity, and mean effective capillary radius of the pore solid structure. In turn, the two-stage model is mechanistic in nature and one-way coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. The two-stage model correlates dissolution profiles with critical process parameters (CPPs), critical material attributes (CMAs), and other crucial critical quality attributes (CQAs). We demonstrate the model’s versatility and effectiveness in predicting the dissolution profiles of diverse pharmaceutical formulations. Specifically, we formulate and fabricate acetaminophen and lomustine solid tablets using different API content and size distributions, characterize their dissolution behavior, and estimate capillary radius as a function of tablet porosity. The estimations generated by the proposed models consistently match the experimental data across all cases investigated in this study.

Mathematical Modeling of the Gastrointestinal System for Preliminary Drug Absorption Assessment.

The objective of this study is to demonstrate the potential of a multicompartmental mathematical model to simulate the activity of the gastrointestinal system after the intake of drugs, with a limited number of parameters. The gastrointestinal system is divided into five compartments, modeled as both continuous systems with discrete events (stomach and duodenum) and systems with delay (jejunum, ileum, and colon). The dissolution of the drug tablet occurs in the stomach and is described through the Noyes-Whitney equation, with pH dependence expressed through the Henderson-Hasselbach relationship. The boluses resulting from duodenal activity enter the jejunum, ileum, and colon compartments, where drug absorption takes place as blood flows countercurrent. The model includes only three parameters with assigned physiological meanings. It was tested and validated using data from in vivo experiments. Specifically, the model was tested with the concentration profiles of nine different drugs and validated using data from two drugs with varying initial concentrations. Overall, the outputs of the model are in good agreement with experimental data, particularly with regard to the time of peak concentration. The primary sources of discrepancy were identified in the concentration decay. The model's main strength is its relatively low computational cost, making it a potentially excellent tool for in silico assessment and prediction of drug adsorption in the intestine.

Functionality of wet-granulated disintegrant in comparison to directly incorporated disintegrant in a poorly water-soluble tablet matrix

Tablet disintegration is crucial for drug release and subsequent systemic absorption. Although factors affecting the disintegrant’s functionality have been extensively studied, the impact of wet granulation on the performance of disintegrants in a poorly water-soluble matrix has received much less attention. In this study, the disintegrants, crospovidone (XPVP), croscarmellose sodium (CCS) and sodium starch glycolate (SSG), were wet-granulated with dibasic calcium phosphate dihydrate as the poorly water-soluble matrix and polyvinylpyrrolidone as the binder. The effect of wet granulation was studied by evaluating tablet tensile strength and disintegratability. Comparison between tablets with granulated or ungranulated disintegrants as well those without disintegrants were also made. Different formulations showed different degrees of sensitivity to changes in tablet tensile strength and disintegratability post-wet granulation. Tablet tensile strength decreased for tablets with granulated disintegrant XPVP or CCS, but to a smaller extent for SSG. While tablets with granulated XPVP or CCS had increased disintegration time, the increment was lesser than for SSG, suggesting that wet granulation impacted a swelling disintegrant more. The findings showed that tablets with wet-granulated disintegrant had altered the disintegrant’s functionality. These findings could provide better insights into changes in the disintegrant’s functionality after wet granulation.

Investigation of Groundnut Shell Powder as Potential Super Disintegrant in Chronotherapeutic Delivery of Sacubitril–valsartan

ABSTRACT Context: Chronotherapeutic delivery of antihypertensives plays a potential role in the treatment by providing a therapeutic amount of drug at the target site in the body. Sacubitril–valsartan (SV), an angiotensin receptor neprilysin inhibitor, has been indicated for the treatment of hypertension. The study explores the formulation and evaluation of compression-coated tablets (CCTs) of SV using a natural super disintegrant in the core tablet for chronotherapeutic drug delivery. Aim and Objective: The main objective of the current investigation is to study the applicability of groundnut shell powder (GSP) as super disintegrant and its role in chronotherapeutic drug delivery. Materials and Methods: Core tablets of SV were prepared using different concentrations of natural excipient (GSP) and compression coated. The CCT was evaluated for the postcompression tableting properties, in vitro drug release, Fourier transform infra red spectroscopy (FTIR), and stability studies and compared the disintegrating property with a synthetic excipient (crospovidone). Results: The results of the in vitro dissolution performance of core tablets indicated that the incorporation of GSP as a super disintegrant significantly reduced the disintegration time. Optimized core tablets were subjected to compression coating using a graded concentration of cellulose acetate phthalate as coating polymer and evaluated tableting properties and dissolution performance. Among all the formulations, CCT5 with 8% GSP in the core, coated with 300 mg coating polymer shown 6 h lag time followed by the rapid release of the drug within 1 h. Accelerated stability studies on optimized formulation revealed that there were no significant changes in the tableting parameters after storage indicating the stability of the formulation. Conclusion: The use of natural disintegrant in the core tablet offers a promising approach for rapid release of drug from CCT after a lag time of 6 h to achieve chronotherapy of SV.

Mechanochemical Synthesis of Cross-Linked Chitosan and Its Application as Adsorbent for Removal of Per- and Polyfluoroalkyl Substances from Simulated Electroplating Wastewater.

Chitosan is a promising adsorbent for removing a wide range of pollutants from wastewater. However, its practical application is hindered by instability in acidic environments, which significantly impairs its adsorption capacity and limits its utilization in water purification. While cross-linking can enhance the acid stability of chitosan, current solvent-based methods are often costly and environmentally unfriendly. In this study, a solvent-free mechanochemical process was developed using high-energy ball milling to cross-link chitosan with various polyanionic linkers, including dextran sulfate (DS), poly[4-styrenesulfonic acid-co-maleic acid] (PSSM), and tripolyphosphate (TPP). The mechanochemically cross-linked (MCCL) chitosan products exhibited superior adsorption capacity and stability in acidic solutions compared to pristine chitosan. Chitosan cross-linked with DS (Cht-DS) showed the highest Reactive Red 2 (RR2) adsorption capacity, reaching 1559 mg·g-1 at pH 3, followed by Cht-PSSM (1352 mg·g-1) and Cht-TPP (1074 mg·g-1). The stability of MCCL chitosan was visually confirmed by the negligible mass loss of Cht-DS and Cht-PSSM tablets in pH 3 solution, unlike the complete dissolution of the pristine chitosan tablet. The MCCL significantly increased the microhardness of chitosan, with the order Cht-DS > Cht-PSSM > Cht-TPP, consistent with the RR2 adsorption capacity. When tested on simulated rinsing wastewater from chromium electroplating, Cht-DS effectively removed Cr(VI) (98.75% removal) and three per- and polyfluoroalkyl substances (87.40-95.87% removal), following pseudo-second-order adsorption kinetics. This study demonstrates the potential of the cost-effective and scalable MCCL approach to produce chitosan-based adsorbents with enhanced stability, mechanical strength, and adsorption performance for treating highly acidic industrial wastewater containing a mixture of toxic pollutants.