Platform Technology and Alternative Strategies for Mitigating Cross-Linking in Soft Gelatin Capsules: Development, Evaluation, and Mechanistic Insights

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Cross-linking impairs shell solubility, delays disintegration, and compromises drug release and bioavailability. Objectives: To develop and evaluate modified soft gelatin shell formulations incorporating water-soluble polymers and cellulosic excipients for their ability to mitigate cross-linking and maintain pharmacopeial disintegration compliance under real-time and accelerated stability conditions. Methods: Six modified shell formulations (FT1–FT6) incorporating HPMC, Microcrystalline Cellulose (MCC PH105), Povidone K30, or Hydroxypropyl Cellulose (Klucel LF) were prepared and filled with reactive model fills including aged omega-3 fatty acid esters, flaxseed oil, omega-3 triglycerides, L-Arginine, and glucosamine–chondroitin systems. Six conventional gelatin shells (FC1–FC6) served as controls. Disintegration testing was performed per USP across ICH Q1A(R2) accelerated (40°C/75% RH), intermediate (30°C/65% RH), and long-term (25°C/60% RH) conditions over six months. Accelerated cross-linking stress was applied via formaldehyde treatment and gamma irradiation. Results: All modified formulations maintained USP compliance (≤30 min) throughout six months under all stability conditions, with a peak mean disintegration of 14 min 49 sec at the 6-month accelerated station. Conventional controls failed as early as the 2-month accelerated time point. FT4 (Povidone K30) showed the most robust protection for L-Arginine fills (≤12 min post-formaldehyde challenge), while HPMC-based formulations (FT1, FT2) performed reliably with oxidised lipid fills. Conclusion: Incorporation of water-soluble polymers into the gelatin shell matrix provides an effective, scalable, and commercially practicable strategy for cross-linking mitigation. The approach is compatible with conventional rotary die manufacturing and applicable across diverse fill chemistries, supporting the development of robust softgel dosage forms for challenging pharmaceutical candidates. soft gelatin capsules cross-linking gelatin shell modification disintegration stability Povidone K30 HPMC oral drug delivery BCS Class IV Figures Figure 1 Figure 2 Figure 3 Figure 4 Highlights Modified gelatin shells with water-soluble polymers resist cross-linking during stability All six modified formulations passed USP disintegration over 6-month ICH studies Povidone K30 offered strongest protection in amino acid (L-Arginine) fill systems Conventional gelatin controls failed as early as 2 months under accelerated conditions Platform is compatible with standard rotary die manufacturing at industrial scale 1. Introduction Soft gelatin capsules (softgels) represent one of the most commercially established and technically sophisticated oral dosage forms for the delivery of lipophilic, poorly water-soluble, and BCS Class II/IV drug substances [ 1 , 2 ]. Their capacity to encapsulate liquid, semi-liquid, and suspension-based matrices within a hermetically sealed shell confers important biopharmaceutical advantages: improved dissolution rate, enhanced gastric dispersibility, and superior dose-uniformity relative to solid oral forms. These attributes have made softgels the preferred choice for a growing range of nutraceutical, over-the-counter, and prescription products [ 1 , 3 ]. Despite these advantages, the gelatin shell — a film of hydrolysed collagen protein plasticised with glycerin — is inherently susceptible to cross-linking reactions during storage. Cross-linking involves the formation of covalent bonds between adjacent polypeptide chains of gelatin, most commonly via nucleophilic addition of ε-amino groups (lysine residues) and N-terminal amines to carbonyl-bearing species [ 4 , 5 ]. The resulting network densification reduces shell hydrophilicity, restricts water uptake, and ultimately impairs or prevents disintegration and drug release — a phenomenon with direct clinical implications for formulations in which the drug's absorption is rate-limited by dissolution [ 5 , 6 ]. Two mechanistically distinct classes of cross-linking are recognised in softgel systems. Chemically induced cross-linking is driven by reactive species migrating from the fill material or packaging environment into the gelatin shell; these include saturated and unsaturated aldehydes generated from lipid peroxidation (furfural, acrolein, malondialdehyde), free amino acids (L-Arginine, glucosamine, chondroitin), and reducing sugars [ 5 , 7 ]. Self-induced (autogenous) cross-linking arises from the intrinsic reactivity of gelatin chains under elevated temperature and humidity conditions. In practice, both pathways may operate simultaneously and are difficult to deconvolute without specific physicochemical analysis. Several mitigation strategies have been explored previously, including reduction of fill peroxide value, addition of antioxidants to fill formulations, selection of low-permeability packaging films, and complete substitution of gelatin with alternative polymers such as hydroxypropyl methylcellulose (HPMC), pullulan, or modified starch [ 6 , 8 , 9 ]. While effective, alternative shell materials typically require specialised encapsulation conditions and carry higher raw material cost, and their regulatory acceptance pathways differ from those for conventional gelatin. A formulation-based strategy that preserves gelatin as the primary shell material while incorporating selected excipients to counteract cross-linking would therefore offer a practical and commercially attractive alternative [ 9 , 10 ]. The present study was designed around this hypothesis. We incorporated water-soluble polymers — HPMC (two viscosity grades), Povidone K30, Hydroxypropyl Cellulose (Klucel LF), and Microcrystalline Cellulose — into the gelatin shell at defined concentrations, prepared capsules filled with deliberately reactive model fills representing worst-case cross-linking scenarios, and evaluated the resulting formulations under a full ICH stability programme. Accelerated chemical stress models (formaldehyde treatment and gamma irradiation) were additionally employed to probe the mechanistic basis of observed protection. The findings reported herein establish a robust, scalable, and mechanistically coherent platform for cross-linking management in soft gelatin capsule development. 2. Materials and Methods 2.1 Materials All materials were of pharmaceutical or analytical grade. Gelatin (GELITA® Bovine Bone Gelatine, 110 bloom and 160 bloom) was sourced from Gelita AG, Eberbach, Germany. Glycerin was obtained from Vance Bio Energy Sdn. Bhd., Malaysia. HPMC grades 6 cps and 3 cps (Methocel E6 and E3 Premium LV) were supplied by Dow Chemical Company Ltd., USA. Microcrystalline Cellulose PH105 (Avicel® PH-105) was from FMC International Health and Nutrition. Povidone K30 (Plasdone K-29/32) and HPC LF (Klucel LF) were from Ashland, Texas City, USA. Fill materials included aged Omega-3 Acid Ethyl Esters (EPA 36%/DHA 24%; Huatai, China), Flaxseed Oil 50% ALA (Sanmark Ltd.), Omega-3 Triglycerides DHA 50 TG (Kinomega, China), L-Arginine (Shanghai Kyowa Amino Acid Co. Ltd., China), Glucosamine Hydrochloride (Coastal Laboratories), Chondroitin Sulfate Sodium (BioGen Extracts), White Beeswax (Poth Hille & Co. Ltd., UK), Soybean Lecithin (Bperfect India Ltd.), Hydrogenated Vegetable Oil BBS-C NF Type-II (Abitec Corporation, USA), and Soybean Oil (AOS Products Pvt. Ltd., India). Full material details including batch numbers are provided in Table 1 . Table 1 Material resource details. S.No. Material Name Trade Name Batch No. Manufacturer / Supplier 1 Gelatin 110 bloom GELITA® Bovine Bone Gelatine 646918 Gelita AG, Eberbach, Germany 2 Gelatin 160 bloom GELITA® Bovine Bone Gelatine 641317 Gelita AG, Eberbach, Germany 3 Glycerin Refined Glycerine D210726-13-1 Vance Bio Energy Sdn. Bhd., Malaysia 4 HPMC 6 cps Methocel E6 Premium LV D011G7PL02 Dow Chemical Company Ltd., USA 5 HPMC 3 cps Methocel E3 Premium LV D011K52L02 Dow Chemical Company Ltd., USA 6 MCC PH105 Avicel® PH-105 51529C FMC International Health and Nutrition 7 Povidone K30 Plasdone K-29/32 0002663456 Ashland, Texas City, USA 8 HPC LF Klucel LF 229477 Ashland, Texas City, USA 9 Purified Water — — In-house 10 Omega-3 AEE (EPA-36%/DHA-24%) Omega-3 Fatty Acid Esters EE3624-200902 Huatai Biopharmaceuticals, China 11 Flaxseed Oil 50% ALA — FL020112-5 Sanmark Ltd. 12 Omega-3 TG (DHA 50 TG) KinOmega 1050TG 231031-1050TG-0 Kinomega, China 13 L-Arginine — 20053209 Shanghai Kyowa Amino Acid Co. Ltd., China 14 Glucosamine HCl — CL02032223161 Coastal Laboratories 15 Chondroitin Sulfate Sodium — CS1015045 BioGen Extracts 16 White Beeswax — 14133 Poth Hille & Company Ltd., UK 17 Soybean Lecithin — CSL Lot 2301-02 Bperfect India Ltd. 18 Hydrogenated Vegetable Oil BBS-C NF Type-II 223A2C Abitec Corporation, USA 19 Soybean Oil Soya Oil SOY/14112022 AOS Products Pvt. Ltd., India 2.2 Equipment Encapsulation was performed on a GIC Engineering SUPRA BT/044 − 06 rotary die machine (USA). Gelatin preparation was carried out in a 50-litre jacketed stainless-steel gelatin melting tank (Pharma Tech Pvt. Ltd., India) equipped with a vacuum degassing system. Disintegration testing was conducted using an Electrolab EDI-2SA basket-rack assembly per USP . 2.3 Methods 2.3.1 Gel Mass Preparation All gel formulations were prepared using a standardised protocol. Purified water (plus 5% extra volume to compensate for evaporation) and glycerin were blended manually in a stainless-steel container and transferred to the preheated gelatin melting tank. The measured gelatin (single or blended bloom type) was added and heated to 70 ± 5°C over 30–45 minutes under continuous stirring until fully dissolved. Vacuum (− 20 to − 30 in Hg) was applied to remove entrapped air, with periodic visual inspection against a white LED background. For polymer-containing formulations, HPMC, Povidone K30, or Klucel LF was hydrated separately in a portion of purified water under slow mechanical stirring (≈ 250 RPM) for 3–5 hours to produce a lump-free solution. MCC PH105 was dispersed in water prior to incorporation. Hydrated polymer solutions were added to the hot gelatin mass and mixed under vacuum for 30 minutes to ensure homogeneity. The final gel mass was transferred to a preheated holding tank at 52°C and matured for ≥ 4 hours before encapsulation. Formulation-specific excipient selections and concentrations are described in Table 2 . The preparation workflow is illustrated in Fig. 2 . Table 2 Gel mass formulation compositions (% w/w; batch size 15 kg). S.No. Ingredient FT1 FT2 FT3 FT4 FT5 FT6 1 Gelatin 110 bloom (%) 38.50 38.50 23.72 32.25 32.25 25.00 2 Gelatin 160 bloom (%) — — 10.65 10.75 10.75 9.00 3 Glycerin (%) 25.10 25.10 28.90 22.00 22.00 21.00 4 HPMC 6 cps (%) 1.75 — — — — — 5 HPMC 3 cps (%) — 1.75 — — — — 6 MCC PH105 (%) — — 3.33 — — 5.00 7 Povidone K30 (%) — — — 2.00 — 5.00 8 HPC – Klucel LF (%) — — — — 2.00 — 9 Purified Water (%) 34.65 34.65 33.40 33.00 33.00 35.00 2.3.2 Fill Medicament Preparation Reactive fills were deliberately selected or conditioned to generate worst-case cross-linking challenges across different chemical classes: FT1 – Aged Omega-3 Ethyl Esters Rancid, aged omega-3 fatty acid ethyl esters (EPA 36%/DHA 24%) with elevated peroxide value, simulating oxidatively degraded lipid fills [ 19 , 20 ]. FT2 – Expired Flaxseed Oil Expired flaxseed oil with peroxide value 15.0 meq/kg, representing a high primary oxidation product scenario [ 19 ]. FT3 – Aged Omega-3 Triglycerides Old rancid omega-3 TG (DHA 50 TG) containing both primary and secondary lipid oxidation byproducts [ 20 ]. FT4 and FT5 – L-Arginine Suspension L-Arginine (150 mg/capsule) dispersed in soybean oil–lecithin–beeswax–hydrogenated vegetable oil matrix. The wax components were melted at 65 ± 5°C, cooled to < 40°C, combined with the oil–lecithin phase, and L-Arginine incorporated under stirring prior to deaeration [ 21 , 22 ]. FT6 – Glucosamine–Chondroitin System Glucosamine HCl (125 mg) and Chondroitin Sulfate Sodium (107.8 mg) dispersed in soybean oil–lecithin–beeswax matrix by the same melt-disperse-deaerate protocol [ 23 , 24 ]. Table 3 Fill medicament compositions (mg per capsule; batch size 3000 capsules). S.No. Ingredient FT1 FT2 FT3 FT4 FT5 FT6 1 Omega-3 AEE (EPA-36%/DHA-24%) 350.0 — — — — — 2 Flaxseed Oil 50% ALA — 550.0 — — — — 3 Omega-3 TG (DHA 50 TG) — — 350.0 — — — 4 L-Arginine — — — 150.0 150.0 — 5 Glucosamine Hydrochloride — — — — — 125.0 6 Chondroitin Sulfate Sodium — — — — — 107.8 7 White Beeswax — — — 9.00 9.00 5.00 8 Soybean Lecithin — — — 8.00 8.00 12.00 9 Hydrogenated Vegetable Oil — — — 10.00 10.00 — 10 Soybean Oil — — — 323.0 323.0 170.2 Fill weight (mg/capsule) 350.0 550.0 350.0 500.0 500.0 420.0 2.3.3 Encapsulation Capsules were manufactured on a GIC SUPRA BT/044 − 06 rotary die machine. Matured gel mass was transferred to the preheated spreader box under air pressure, spread over chilled casting drums to form gelatin ribbons of 32–34 thou thickness, and simultaneously filled and sealed at the die roll assembly via a rotary pump. Key process parameters are provided in Table 4 . Table 4 Encapsulation process parameters. S.No. Parameter Limit FT1 FT2 FT3 FT4 FT5 FT6 1 Die Size (minim) 6–12 6 25 6 12 12 7.5 2 Die Shape Oval/Round Oval Round Oval Oval Oval Oval 3 Spreader Box Temp (°C) 55–65 56.2 55.9 58.2 59.6 58.3 59.1 4 Segment Temp (°C) 36–46 36.4 36.2 39.2 38.5 37.9 37.9 5 Machine Speed (RPM) 2.0–4.0 2.5 2.0 2.0 2.0 2.0 2.0 6 Ribbon Thickness (thou) 32–34 32 32 32 32 32 32 7 Casting Drum Temp (°C) 12–17 13.5 14.0 14.2 14.2 14.4 14.4 8 Gelatin Solution Temp (°C) 50–55 52.5 52.8 53.7 54.2 54.5 54.5 2.3.4 Drying, Polishing, and Packaging Wet capsules were tumble-dried for one hour, transferred to stainless-steel trays, and dried in a controlled room at 25°C and 20–25% RH until target hardness was reached (typically 48–72 hours). Dried capsules were weight-sorted, polished with a 70% IPA-moistened lint-free cloth, and packaged in 100 mL HDPE bottles with screw caps and induction seals. No desiccant was included, to prevent masking of moisture-driven cross-linking. 2.3.5 Stability Study Design Stability testing followed ICH Q1A(R2) guidelines over six months under accelerated (40 ± 2°C/75 ± 5% RH), intermediate (30 ± 2°C/65 ± 5% RH), and long-term (25 ± 2°C/60 ± 5% RH) conditions. Evaluation parameters included description/appearance, average fill content, and disintegration time (USP ). The stability protocol is summarised in Table 5 . Table 5 Stability protocol (ICH Q1A(R2)). Stability Condition 40°±2°C / 75 ± 5% RH (Accelerated) 30°±2°C / 65 ± 5% RH (Intermediate) 25°±2°C / 60 ± 5% RH (Long-term) Test Parameter 1M 2M 3M 6M 3M 6M 3M 6M Description / Appearance ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Average Fill Content (mg) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Disintegration Time – USP (≤ 30 min) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 2.3.6 Disintegration Testing Disintegration was determined per USP in purified water at 37 ± 2°C using an Electrolab EDI-2SA basket-rack assembly (n = 6). Results are reported as mean ± SD. Capsules not disintegrating within 30 minutes were classified as FAILS. 2.3.7 Accelerated Chemical Stress Testing Formaldehyde treatment Dried capsules were immersed in methanol-based formaldehyde solution at 37°C for 30 minutes, washed in 90% ethanol for 30 minutes, and redried before disintegration testing [ 25 , 26 ]. Gamma irradiation Capsules were exposed to controlled ⁶⁰Co γ-ray doses as an orthogonal stress model. Irradiation generates free radicals that induce oxidative cross-linking through gelatin side-chain reactions, complementing the aldehyde-driven pathway [ 25 , 27 ]. 3. Results 3.1 Capsule Appearance All modified shell formulations (FT1–FT6) and conventional controls were successfully prepared at 15 kg batch scale and produced acceptable capsules (smooth surface, intact seam, uniform colour). FT3 and FT6 (MCC-containing) showed slight opacity relative to the other formulations, consistent with the particulate nature of dispersed MCC within the gelatin film. Capsule photographs for each trial formulation are shown in Fig. 3 . 3.2 Disintegration Stability – Modified Shell Formulations (FT1–FT6) All six modified formulations maintained USP compliance (≤ 30 min) throughout the full six-month stability study at all three ICH conditions (Table 6 ). Initial disintegration times ranged from 1 min 40 sec (FT1, FT4) to 3 min 4 sec (FT6). Under accelerated conditions (40°C/75% RH), disintegration times increased progressively, reaching a group mean of 14 min 49 sec at the 6-month station — remaining comfortably within the pharmacopeial limit. The highest individual value recorded at any time point was 17 min (FT1 at 6M accelerated), still compliant. Under intermediate and long-term conditions, the mean maximum values were 8 min 6 sec (30°C/6M) and 4 min 49 sec (25°C/6M), respectively, confirming that reduced temperature and humidity substantially attenuated the cross-linking drive. Table 6 Disintegration stability data — Modified Shell Formulations (FT1–FT6). n = 6; values expressed as mean (mm:ss ± SD); USP compliance limit ≤ 30 min. Modified Shell Formulations (FT1–FT6) – Disintegration Time (mm:ss) Trial/Formulation Initial 1M (40°C) 2M (40°C) 3M (40°C) 6M (40°C) 3M (30°C) 6M (30°C) 3M (25°C) 6M (25°C) FT1 (HPMC 6 cps) 1:40 3:54 5:42 8:09 17:00 4:10 7:37 3:25 3:40 FT2 (HPMC 3 cps) 2:14 4:10 6:13 11:16 15:00 5:24 6:20 3:45 4:37 FT3 (MCC PH105) 1:51 3:49 5:22 9:46 13:55 4:39 8:40 3:24 3:33 FT4 (Povidone K30) 1:40 4:30 6:45 7:00 11:16 5:18 7:43 4:09 5:10 FT5 (Klucel LF) 2:10 5:50 7:30 13:48 16:20 6:07 9:08 3:55 5:46 FT6 (PVP + MCC) 3:04 5:15 8:00 12:05 15:24 6:50 9:21 4:13 6:05 Mean ± SD 2:06 ± 0:31 4:35 ± 0:48 6:40 ± 0:55 10:21 ± 2:32 14:49 ± 2:02 5:25 ± 0:58 8:06 ± 1:07 4:06 ± 0:44 4:49 ± 1:03 3.3 Disintegration Stability – Conventional Shell Controls (FC1–FC6) Conventional gelatin controls showed a progressive and ultimately non-compliant deterioration in disintegration performance (Table 7 ). FC6 failed USP at the 2-month accelerated station — the earliest failure recorded. FC2, FC4, and FC5 failed at 3 months accelerated, and FC1 and FC3 at 6 months accelerated. Under intermediate conditions (30°C/65% RH), FC3, FC4, and FC5 also failed at 6 months. Even under long-term conditions (25°C/60% RH), mean disintegration at 6 months reached 25 min 21 sec — only ~ 4.6 minutes below the compliance limit, representing a critically narrow margin. Table 7 Disintegration stability data — Conventional Shell Controls (FC1–FC6). n = 6; values expressed as mean (mm:ss ± SD); FAILS = disintegration > 30 min; USP compliance limit ≤ 30 min. Conventional Shell Controls (FC1–FC6) – Disintegration Time (mm:ss) Trial/ Formulation Initial 1M (40°C) 2M (40°C) 3M (40°C) 6M (40°C) 3M (30°C) 6M (30°C) 3M (25°C) 6M (25°C) FC1 (Conventional) 7:51 10:48 15:34 26:53 FAILS 13:38 22:18 9:29 16:15 FC2 (Conventional) 10:34 16:24 26:32 FAILS FAILS 14:09 25:26 14:18 22:29 FC3 (Conventional) 8:28 12:19 22:44 27:31 FAILS 11:13 FAILS 19:27 27:14 FC4 (Conventional) 12:30 13:17 28:51 FAILS FAILS 14:29 FAILS 21:15 28:30 FC5 (Conventional) 12:30 13:17 28:51 FAILS FAILS 14:29 FAILS 21:15 28:30 FC6 (Conventional) 9:15 17:18 FAILS FAILS FAILS 16:11 FAILS 25:21 29:10 Mean ± SD 10:11 ± 2:00 13:54 ± 2:28 20:25 ± 11:11 FAILS FAILS 14:01 ± 1:37 FAILS 18:31 ± 5:41 25:21 ± 5:05 4. Accelerated Methods for Evaluating Cross-Linking Several chemical species are known to induce gelatin cross-linking either through direct nucleophilic addition to reactive groups or via oxidative free-radical mechanisms. Common promoters documented in the literature include aldehydes (furfural, acrolein, formaldehyde, glutaraldehyde, glyceraldehyde), reducing sugars (aldoses via Maillard reaction), hydrogen peroxide, inorganic salts, and polyfunctional amines [ 5 , 25 , 28 ]. In pharmaceutical development, accelerated stress methods are employed to artificially induce and compare cross-linking susceptibility across shell formulations under reproducible conditions. 4.1 Formaldehyde Treatment Formaldehyde forms stable Schiff base (aldimine) intermediates with ε-amino groups of lysine residues on gelatin chains, representing the prototypical aldehyde cross-linking mechanism [ 25 , 26 ]. In the present study, formaldehyde challenge resulted in markedly different responses between modified and conventional shells. FT4 (Povidone K30) consistently produced post-treatment disintegration times of 11–12 minutes, indicating that the PVP network effectively competes with gelatin amino groups for aldehyde reactivity, or physically occludes the inter-chain space. All modified formulations passed the 30-minute limit post-treatment, while several conventional controls did not. 4.2 Gamma Irradiation Gamma irradiation (⁶⁰Co) generates hydroxyl radicals that abstract hydrogen from carbon-hydrogen bonds within the gelatin backbone, initiating chain radical propagation and subsequent inter-chain C–C or C–N bond formation [ 27 ]. This mechanism is orthogonal to aldehyde-driven cross-linking and provided a complementary mechanistic challenge. Modified shells, particularly FT4 and FT6, maintained acceptable disintegration post-irradiation, while conventional controls showed significant impairment. Direct quantification of cross-link density (TNBS assay, FTIR, DSC) was beyond the scope of this investigation but is planned for future work. 5. Proposed Mechanism of Drug Release from Cross-Linked Softgel Capsules A three-phase mechanistic model for drug release from modified cross-linked shells is proposed based on the disintegration trends observed and established gelatin chemistry principles. Figure 4 illustrates this mechanism schematically. In Phase 1 (intact storage), the gelatin shell containing incorporated water-soluble polymers maintains structural integrity. Polymer chains occupy interstitial spaces within the gelatin network and may physically shield reactive amino acid residues from incoming cross-linking agents diffusing from the fill. In Phase 2 (dissolution contact), water penetrates the shell and rapidly hydrates the polymer components. HPMC, Povidone K30, and Klucel LF dissolve or swell, generating macroscopic channels and pores within the gelatin matrix. This pore network is functionally critical: even where partial gelatin cross-linking has occurred, the channels provide pathways for both water ingress and fill medicament egress. In Phase 3 (drug release), the fill medicament diffuses or flows through the pore network and is released into the dissolution medium. In severely cross-linked conventional shells lacking these pore-forming agents, the cross-linked gelatin network remains largely intact, restricting both water ingress and fill egress and accounting for the observed disintegration failures. This model is consistent with prior reports on HPMC-modified capsule shells and provides a rational basis for the observed performance ranking: excipients that dissolve most readily (PVP > HPMC > HPC > MCC) generate the most immediate pore-formation benefit [ 6 , 15 ]. 6. Discussion The central finding of this study — that all six modified shell formulations maintained pharmacopeial disintegration compliance over six months under all three ICH stability conditions, while all six conventional controls failed under accelerated storage — provides clear and reproducible evidence that excipient-based gelatin shell modification is an effective strategy for cross-linking management in softgel dosage form development. The practical advantage of this approach over full gelatin replacement is its compatibility with established rotary die infrastructure. None of the modified formulations required modification to encapsulation equipment or process parameters, as confirmed by the process data in Table 4 . All excipients employed — HPMC, Povidone K30, HPC, MCC — are pharmacopoeially approved with extensive regulatory precedent in oral dosage forms, supporting straightforward inclusion in ANDA or CTD Module 3.2.P documentation. The performance hierarchy observed across the modified formulations offers practical guidance for excipient selection. FT4 (Povidone K30, 2% w/w) demonstrated the most consistent protection for amino acid-containing fills (L-Arginine), producing disintegration times below 12 minutes even after formaldehyde challenge at 6 months accelerated. PVP's effectiveness in this context is attributable to its strong hydrogen-bonding capacity, documented ability to complex with reactive carbonyl species [ 15 ], and high aqueous solubility, which facilitates rapid pore formation upon dissolution medium contact. FT5 (Klucel LF, 2% w/w) showed superior performance for oil-based capsules (omega-3 fills) relative to the L-Arginine-containing FT5 group, suggesting that the protective mechanism is more physical (pore formation) than chemical (reactive-species scavenging) for this system. The guanidinium group of L-Arginine is particularly reactive with gelatin amino groups, and the Klucel LF system appears to offer insufficient chemical competition at 2% w/w to match PVP's performance in this context. FT6 (PVP + MCC) showed an intermediate profile: combining two mechanistically distinct excipients (a reactive-species competitor and a pore-forming particulate) did not produce fully additive protection at the concentrations tested, possibly because the higher total polymer load introduced a viscosity effect that slightly slowed initial shell dissolution, reflected in FT6's higher baseline disintegration time (3:04 vs 1:40 for FT4). Systematic optimisation of the PVP:MCC ratio in FT6-type systems represents a logical next step. Limitations of this study include the indirect assessment of cross-link density through functional disintegration testing rather than direct chemical quantification. Future studies should incorporate TNBS assay (free amino group titration), FTIR spectroscopy (amide bond shifts), and DSC (denaturation temperature analysis) to directly quantify cross-link density and establish the quantitative relationship between polymer concentration and cross-link inhibition. Dissolution profiling (USP Apparatus I or II) would additionally characterise the impact of modified shell performance on drug release kinetics for representative active substances. The platform technology described here carries implications beyond anti-cross-linking functionality. HPMC- and HPC-modified shells offer enhanced elasticity suitable for twist-off softgel formats and chewable applications. The improved seal integrity in FT4-type formulations is particularly advantageous for highly viscous fill matrices that place high mechanical stress on capsule seams. Cosmetic and nutraceutical applications, where pearlescent pigments and flavouring agents are routinely incorporated into shells, may similarly benefit from the enhanced flexibility conferred by these excipient systems. 7. Conclusions Targeted incorporation of water-soluble polymers into soft gelatin capsule shells provides an effective, scalable, and mechanistically supported strategy for mitigating cross-linking under pharmaceutical storage conditions. All six modified formulations demonstrated USP disintegration compliance over six months of ICH stability testing including accelerated conditions (40°C/75% RH), in direct contrast to conventional gelatin controls that failed within two months under equivalent stress. FT4 (Povidone K30, 2% w/w) offered the most robust cross-linking protection for amino acid-containing fills, with disintegration times consistently below 12 minutes after formaldehyde challenge at 6 months accelerated. HPMC-based formulations (FT1, FT2) performed reliably for oxidised lipid fills. The proposed mechanism — polymer dissolution creating pore channels that maintain drug release pathways through a cross-linked gelatin network — provides a rational and practically actionable basis for shell design. Future work should focus on direct quantification of cross-link density by TNBS assay, FTIR, and DSC; systematic polymer concentration optimisation; and comparative dissolution profiling to fully characterise the impact of modified shell performance on drug release kinetics. Translation of these findings to commercial scale will extend the applicability of this platform across conventional and advanced oral delivery formats. Abbreviations AEE Acid Ethyl Ester ALA Alpha-Linolenic Acid ANDA Abbreviated New Drug Application API Active Pharmaceutical Ingredient BCS Biopharmaceutics Classification System CTD Common Technical Document DHA Docosahexaenoic Acid DSC Differential Scanning Calorimetry EPA Eicosapentaenoic Acid FTIR Fourier-Transform Infrared Spectroscopy HCl Hydrochloric Acid HDPE High-Density Polyethylene HPC Hydroxypropyl Cellulose HPMC Hydroxypropyl Methylcellulose ICH International Council for Harmonisation IPA Isopropyl Alcohol MCC Microcrystalline Cellulose PVP Polyvinylpyrrolidone QbD Quality by Design RH Relative Humidity RPM Revolutions Per Minute SD Standard Deviation SGC Soft Gelatin Capsule SS Stainless Steel TG Triglycerides TNBS Trinitrobenzenesulfonic Acid USP United States Pharmacopeia. Declarations Conflicts of Interest The authors declare no conflicts of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution All authors read and approved of the final manuscript. Acknowledgements The authors gratefully acknowledge the Research and Development department of Jamjoom Pharmaceuticals, Jeddah 21442, Kingdom of Saudi Arabia, for providing laboratory facilities, equipment, and raw materials. The authors also thank Sri Ramachandra Institute of Higher Education and Research (SRIHER-DU), Chennai, India, for institutional and academic support. Data Availability The datasets generated and analysed during the present study are available from the corresponding author upon reasonable written request. References Gullapalli RP. Soft gelatin capsules (softgels). J Pharm Sci. 2010;99(10):4107–48. Gullapalli RP, Mazzitelli CL. Gelatin and non-gelatin capsule dosage forms. J Pharm Sci. 2017;106(6):1453–65. Damian F, Harati M, Schwartzenhauer J, Van Cauwenberghe O, Wettig SD. Challenges of dissolution methods development for soft gelatin capsules. Pharmaceutics. 2021;13(2):214. Tesconi MS, Bramer SL, Yalkowsky SH. The preparation of soft gelatin capsules for a radioactive tracer study. Pharm Dev Technol. 1999;4(4):507–13. Digenis GA, Gold TB, Shah VP. Cross-linking of gelatin capsules and its relevance to their in vitro–in vivo performance. J Pharm Sci. 1994;83(7):915–21. Jones BE, Podczeck F. Pharmaceutical Capsules. London: Pharmaceutical; 2004. pp. 210–3. Lai JY, Li YT. Influence of cross-linker concentration on the functionality of carbodiimide cross-linked gelatin membranes. J Biomater Sci Polym Ed. 2011;22(1–3):277–95. Naharros-Molinero A, Caballo-González MÁ, de la Mata FJ, García-Gallego S. Shell formulation in soft gelatin capsules: design and characterization. Adv Healthc Mater. 2023:e2302250. Al-Tabakha MM, Arida AI, Fahelelbom KM, et al. Influence of capsule shell composition on the performance indicators of hypromellose capsule. Drug Dev Ind Pharm. 2015;41(10):1726–37. Hutchison K. Encapsulation in softgels for pharmaceutical advantage. In: Karsa DR, Stephenson RA, editors. Encapsulation and Controlled Release. Cambridge: Woodhead; 2005. pp. 86–97. Kuentz M, Rothenhäusler B, Röthlisberger D. Time domain 1H NMR to monitor softening of gelatin and HPMC capsule shells. Drug Dev Ind Pharm. 2006;32(10):1165–73. Al-Tabakha MM. HPMC capsules: current status and future prospects. J Pharm Pharm Sci. 2010;13(3):428–42. Mikhailov OV. Gelatin as it is: history and modernity. Int J Mol Sci. 2023;24(4):3583. Lai JY. The role of bloom index of gelatin on the interaction with retinal pigment epithelial cells. Int J Mol Sci. 2009;10(8):3442–56. Yang M, Xie S, Li Q, et al. Effects of polyvinylpyrrolidone as binder and pore-former on the release of topiramate from ethylcellulose coated pellets. Int J Pharm. 2014;465(1–2):187–96. Hassan EM, Fatmi AA, Chidambaram N. Enteric soft capsules. US Patent US9433585. 2016. Paul S, Sun CC. Modulating sticking propensity of pharmaceuticals through excipient selection. Pharm Res. 2018;35(6):113. Chen L, Ding X, He Z, et al. Surface engineered excipients: improved functional properties of fine grade microcrystalline cellulose. Int J Pharm. 2018;536(1):127–37. Watson H, Mitra S, Croden FC, et al. A randomised trial of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota. Gut. 2018;67(11):1974–83. Ward ED, Thomasson K, Fischer KR. Analysis of omega-3 fatty acid content in fish oil products. J Pharm Pract. 2022;35(6):870–3. Koppo K, Taes YE, Pottier A, et al. Dietary arginine supplementation speeds pulmonary VO2 kinetics during cycle exercise. Med Sci Sports Exerc. 2009;41(8):1626–32. McConell GK. Effects of L-arginine supplementation on exercise metabolism. Curr Opin Clin Nutr Metab Care. 2007;10(1):46–51. Jerosch J. Effects of glucosamine and chondroitin sulfate on cartilage metabolism in OA. Int J Rheumatol. 2011;2011:969012. Jiang SJ, Zhao XH. Cross-linking and glucosamine conjugation of casein by transglutaminase. Int J Food Prop. 2012;15(6):1286–99. Tayri-Wilk T, Slavin M, Zamel J, et al. Mass spectrometry reveals the chemistry of formaldehyde cross-linking in structured proteins. Nat Commun. 2020;11:3128. Bhutani U, Ronghe A, Majumdar S. Piperine as a placebo: stability of gelatin capsules without a cross-linker. ACS Appl Bio Mater. 2018;1(5):1244–53. Islam MM, Zaman A, Islam MS, Khan MA, Rahman MM. Physico-chemical characteristics of gamma-irradiated gelatin. Prog Biomater. 2014;3(1):21. Glube N, Moos LV, Duchateau G. Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract. Results Pharma Sci. 2013;3:1–6. Chiwele I, Jones BE, Podczeck F. The shell dissolution of various empty hard capsules. Chem Pharm Bull (Tokyo). 2000;48(7):951–6. Wu Y, Zhao F, Paborji M. Effect of fill weight, capsule shell, and sinker design on dissolution behavior. Pharm Dev Technol. 2003;8(4):379–83. Zhou K, Yang Y, Zheng B, et al. Enhancing pullulan soft capsules with a mixture of glycerol and sorbitol plasticizers. Polym (Basel). 2023;15(10):2247. He C, Feng W, Cao L, Fan L. Crosslinking of poly(L-lactide) nanofibers with triallyl isocyanurate by gamma-irradiation. J Biomed Mater Res A. 2011;99(4):655–65. Wu Y, Parrish C, Micklavzina BL, et al. Flow behavior of concentrated tricalcium phosphate suspensions in oil for softgel encapsulation. Int J Pharm. 2021;601:120562. De Temmerman ML, Demeester J, De Vos F, De Smedt SC. Encapsulation performance of layer-by-layer microcapsules for proteins. Biomacromolecules. 2011;12(4):1283–9. Marucci M, Ragnarsson G, von Corswant C, et al. Polymer leaching from film coating: effects on transport properties. Int J Pharm. 2011;411(1–2):43–8. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9346787","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":637073836,"identity":"ce86aad7-eac2-445f-9d47-60b429494be1","order_by":0,"name":"Kaliyamoorthy Senthilraja","email":"","orcid":"","institution":"Sriramachandra Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Kaliyamoorthy","middleName":"","lastName":"Senthilraja","suffix":""},{"id":637073838,"identity":"fe8fdea7-faed-4517-aa09-924a38ba7175","order_by":1,"name":"AT Rajasekhar","email":"","orcid":"","institution":"Sriramachandra Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"AT","middleName":"","lastName":"Rajasekhar","suffix":""},{"id":637073839,"identity":"9ff1fc46-8453-4db8-b716-025bf4f2857d","order_by":2,"name":"Un-Nabi Sheikh Shafiq","email":"","orcid":"","institution":"Jamjoom Pharmaceutical company factory","correspondingAuthor":false,"prefix":"","firstName":"Un-Nabi","middleName":"Sheikh","lastName":"Shafiq","suffix":""},{"id":637073840,"identity":"42270859-4d90-4a6a-b0cd-73568eb77f30","order_by":3,"name":"D Anusha","email":"","orcid":"","institution":"Sriramachandra Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"D","middleName":"","lastName":"Anusha","suffix":""},{"id":637073841,"identity":"5cdc12fd-038d-4157-bf86-8f38ef0f0c38","order_by":4,"name":"Nagalakshmi S","email":"data:image/png;base64,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","orcid":"","institution":"Sriramachandra Higher Education and Research","correspondingAuthor":true,"prefix":"","firstName":"Nagalakshmi","middleName":"","lastName":"S","suffix":""}],"badges":[],"createdAt":"2026-04-07 14:54:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9346787/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9346787/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108998132,"identity":"074ff934-eb95-4273-8096-572b4e75cdff","added_by":"auto","created_at":"2026-05-11 14:30:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":271425,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eEncapsulation equipment used in this study. (A) GIC Engineering SUPRA BT/044-06 Soft Gelatin Encapsulation Machine; (B) 50-litre jacketed Gelatin Manufacturing Tank (Pharma Tech Pvt. Ltd.).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9346787/v1/7c22b10aed4f1a571cb0d9fd.png"},{"id":108998176,"identity":"7c259195-eb02-436d-ba36-82e569d02199","added_by":"auto","created_at":"2026-05-11 14:30:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35471,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eProcess flow chart for modified gelatin shell (gel mass) preparation. The sequence covers water–glycerin blending, gelatin dissolution, vacuum degassing, polymer hydration and incorporation, and gel maturation prior to encapsulation.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9346787/v1/fde6e8fc557ad6e1cf6d6b73.png"},{"id":108998265,"identity":"1e5436ea-a1ba-41a9-aa4d-693837213677","added_by":"auto","created_at":"2026-05-11 14:30:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":527966,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eRepresentative photographs of dried soft gelatin capsules from each modified shell trial formulation. FT1 (HPMC 6 cps), FT2 (HPMC 3 cps), FT3 (blended gelatin + MCC PH105), FT4 (Povidone K30), FT5 (Klucel LF), FT6 (Povidone K30 + MCC PH105). All capsules showed acceptable organoleptic properties; FT3 and FT6 exhibited slight opacity attributable to dispersed MCC particles.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9346787/v1/1cfef9df1bedb48f38b81f2d.png"},{"id":108998177,"identity":"449553b0-3975-4108-a709-24eae019fa02","added_by":"auto","created_at":"2026-05-11 14:30:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":179028,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eProposed mechanism of drug release from modified cross-linked soft gelatin capsules. (A) Intact shell with dispersed water-soluble polymer network (HPMC, PVP, HPC, MCC) and encapsulated fill medicament. (B) Upon exposure to dissolution medium, water-soluble polymers dissolve or swell, creating pore channels within the gelatin matrix even when gelatin is partially cross-linked. (C) Fill medicament releases through the pore network, maintaining functional drug delivery despite cross-linking.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-9346787/v1/b4b04e20deda6ec7f31bd08a.png"},{"id":108998427,"identity":"cb3e4d33-b81f-43bd-b908-0dbfe60d5377","added_by":"auto","created_at":"2026-05-11 14:31:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1918404,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9346787/v1/3617ae71-e743-46bb-8806-5b351cf71819.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Platform Technology and Alternative Strategies for Mitigating Cross-Linking in Soft Gelatin Capsules: Development, Evaluation, and Mechanistic Insights","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003eModified gelatin shells with water-soluble polymers resist cross-linking during stability\u003c/li\u003e\n \u003cli\u003eAll six modified formulations passed USP \u0026lt;701\u0026gt; disintegration over 6-month ICH studies\u003c/li\u003e\n \u003cli\u003ePovidone K30 offered strongest protection in amino acid (L-Arginine) fill systems\u003c/li\u003e\n \u003cli\u003eConventional gelatin controls failed as early as 2 months under accelerated conditions\u003c/li\u003e\n \u003cli\u003ePlatform is compatible with standard rotary die manufacturing at industrial scale\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eSoft gelatin capsules (softgels) represent one of the most commercially established and technically sophisticated oral dosage forms for the delivery of lipophilic, poorly water-soluble, and BCS Class II/IV drug substances [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Their capacity to encapsulate liquid, semi-liquid, and suspension-based matrices within a hermetically sealed shell confers important biopharmaceutical advantages: improved dissolution rate, enhanced gastric dispersibility, and superior dose-uniformity relative to solid oral forms. These attributes have made softgels the preferred choice for a growing range of nutraceutical, over-the-counter, and prescription products [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite these advantages, the gelatin shell \u0026mdash; a film of hydrolysed collagen protein plasticised with glycerin \u0026mdash; is inherently susceptible to cross-linking reactions during storage. Cross-linking involves the formation of covalent bonds between adjacent polypeptide chains of gelatin, most commonly via nucleophilic addition of ε-amino groups (lysine residues) and N-terminal amines to carbonyl-bearing species [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The resulting network densification reduces shell hydrophilicity, restricts water uptake, and ultimately impairs or prevents disintegration and drug release \u0026mdash; a phenomenon with direct clinical implications for formulations in which the drug's absorption is rate-limited by dissolution [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTwo mechanistically distinct classes of cross-linking are recognised in softgel systems. Chemically induced cross-linking is driven by reactive species migrating from the fill material or packaging environment into the gelatin shell; these include saturated and unsaturated aldehydes generated from lipid peroxidation (furfural, acrolein, malondialdehyde), free amino acids (L-Arginine, glucosamine, chondroitin), and reducing sugars [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Self-induced (autogenous) cross-linking arises from the intrinsic reactivity of gelatin chains under elevated temperature and humidity conditions. In practice, both pathways may operate simultaneously and are difficult to deconvolute without specific physicochemical analysis.\u003c/p\u003e \u003cp\u003eSeveral mitigation strategies have been explored previously, including reduction of fill peroxide value, addition of antioxidants to fill formulations, selection of low-permeability packaging films, and complete substitution of gelatin with alternative polymers such as hydroxypropyl methylcellulose (HPMC), pullulan, or modified starch [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. While effective, alternative shell materials typically require specialised encapsulation conditions and carry higher raw material cost, and their regulatory acceptance pathways differ from those for conventional gelatin. A formulation-based strategy that preserves gelatin as the primary shell material while incorporating selected excipients to counteract cross-linking would therefore offer a practical and commercially attractive alternative [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present study was designed around this hypothesis. We incorporated water-soluble polymers \u0026mdash; HPMC (two viscosity grades), Povidone K30, Hydroxypropyl Cellulose (Klucel LF), and Microcrystalline Cellulose \u0026mdash; into the gelatin shell at defined concentrations, prepared capsules filled with deliberately reactive model fills representing worst-case cross-linking scenarios, and evaluated the resulting formulations under a full ICH stability programme. Accelerated chemical stress models (formaldehyde treatment and gamma irradiation) were additionally employed to probe the mechanistic basis of observed protection. The findings reported herein establish a robust, scalable, and mechanistically coherent platform for cross-linking management in soft gelatin capsule development.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Materials\u003c/h2\u003e \u003cp\u003eAll materials were of pharmaceutical or analytical grade. Gelatin (GELITA\u0026reg; Bovine Bone Gelatine, 110 bloom and 160 bloom) was sourced from Gelita AG, Eberbach, Germany. Glycerin was obtained from Vance Bio Energy Sdn. Bhd., Malaysia. HPMC grades 6 cps and 3 cps (Methocel E6 and E3 Premium LV) were supplied by Dow Chemical Company Ltd., USA. Microcrystalline Cellulose PH105 (Avicel\u0026reg; PH-105) was from FMC International Health and Nutrition. Povidone K30 (Plasdone K-29/32) and HPC LF (Klucel LF) were from Ashland, Texas City, USA. Fill materials included aged Omega-3 Acid Ethyl Esters (EPA 36%/DHA 24%; Huatai, China), Flaxseed Oil 50% ALA (Sanmark Ltd.), Omega-3 Triglycerides DHA 50 TG (Kinomega, China), L-Arginine (Shanghai Kyowa Amino Acid Co. Ltd., China), Glucosamine Hydrochloride (Coastal Laboratories), Chondroitin Sulfate Sodium (BioGen Extracts), White Beeswax (Poth Hille \u0026amp; Co. Ltd., UK), Soybean Lecithin (Bperfect India Ltd.), Hydrogenated Vegetable Oil BBS-C NF Type-II (Abitec Corporation, USA), and Soybean Oil (AOS Products Pvt. Ltd., India). Full material details including batch numbers are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMaterial resource details.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS.No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMaterial Name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTrade Name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBatch No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eManufacturer / Supplier\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGelatin 110 bloom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGELITA\u0026reg; Bovine Bone Gelatine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e646918\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGelita AG, Eberbach, Germany\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGelatin 160 bloom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGELITA\u0026reg; Bovine Bone Gelatine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e641317\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGelita AG, Eberbach, Germany\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlycerin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRefined Glycerine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD210726-13-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVance Bio Energy Sdn. Bhd., Malaysia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPMC 6 cps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMethocel E6 Premium LV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD011G7PL02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDow Chemical Company Ltd., USA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPMC 3 cps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMethocel E3 Premium LV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD011K52L02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDow Chemical Company Ltd., USA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMCC PH105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAvicel\u0026reg; PH-105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51529C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFMC International Health and Nutrition\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePovidone K30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlasdone K-29/32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0002663456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAshland, Texas City, USA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPC LF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKlucel LF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e229477\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAshland, Texas City, USA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePurified Water\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIn-house\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOmega-3 AEE (EPA-36%/DHA-24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOmega-3 Fatty Acid Esters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEE3624-200902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHuatai Biopharmaceuticals, China\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFlaxseed Oil 50% ALA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFL020112-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSanmark Ltd.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOmega-3 TG (DHA 50 TG)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKinOmega 1050TG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e231031-1050TG-0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKinomega, China\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eL-Arginine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20053209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eShanghai Kyowa Amino Acid Co. Ltd., China\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucosamine HCl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCL02032223161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCoastal Laboratories\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChondroitin Sulfate Sodium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCS1015045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBioGen Extracts\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhite Beeswax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePoth Hille \u0026amp; Company Ltd., UK\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSoybean Lecithin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCSL Lot 2301-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBperfect India Ltd.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHydrogenated Vegetable Oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBBS-C NF Type-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e223A2C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAbitec Corporation, USA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSoybean Oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSoya Oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSOY/14112022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAOS Products Pvt. Ltd., India\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Equipment\u003c/h2\u003e \u003cp\u003eEncapsulation was performed on a GIC Engineering SUPRA BT/044\u0026thinsp;\u0026minus;\u0026thinsp;06 rotary die machine (USA). Gelatin preparation was carried out in a 50-litre jacketed stainless-steel gelatin melting tank (Pharma Tech Pvt. Ltd., India) equipped with a vacuum degassing system. Disintegration testing was conducted using an Electrolab EDI-2SA basket-rack assembly per USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026gt;.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Methods\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1 Gel Mass Preparation\u003c/h2\u003e \u003cp\u003eAll gel formulations were prepared using a standardised protocol. Purified water (plus 5% extra volume to compensate for evaporation) and glycerin were blended manually in a stainless-steel container and transferred to the preheated gelatin melting tank. The measured gelatin (single or blended bloom type) was added and heated to 70\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u0026deg;C over 30\u0026ndash;45 minutes under continuous stirring until fully dissolved. Vacuum (\u0026minus;\u0026thinsp;20 to \u0026minus;\u0026thinsp;30 in Hg) was applied to remove entrapped air, with periodic visual inspection against a white LED background.\u003c/p\u003e \u003cp\u003eFor polymer-containing formulations, HPMC, Povidone K30, or Klucel LF was hydrated separately in a portion of purified water under slow mechanical stirring (\u0026asymp;\u0026thinsp;250 RPM) for 3\u0026ndash;5 hours to produce a lump-free solution. MCC PH105 was dispersed in water prior to incorporation. Hydrated polymer solutions were added to the hot gelatin mass and mixed under vacuum for 30 minutes to ensure homogeneity. The final gel mass was transferred to a preheated holding tank at 52\u0026deg;C and matured for \u0026ge;\u0026thinsp;4 hours before encapsulation. Formulation-specific excipient selections and concentrations are described in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The preparation workflow is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGel mass formulation compositions (% w/w; batch size 15 kg).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS.No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIngredient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFT1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFT2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFT3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFT4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFT5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFT6\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGelatin 110 bloom (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e25.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGelatin 160 bloom (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlycerin (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e21.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPMC 6 cps (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPMC 3 cps (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMCC PH105 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePovidone K30 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPC \u0026ndash; Klucel LF (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePurified Water (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e35.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2 Fill Medicament Preparation\u003c/h2\u003e \u003cp\u003eReactive fills were deliberately selected or conditioned to generate worst-case cross-linking challenges across different chemical classes:\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT1 \u0026ndash; Aged Omega-3 Ethyl Esters\u003c/strong\u003e \u003cp\u003eRancid, aged omega-3 fatty acid ethyl esters (EPA 36%/DHA 24%) with elevated peroxide value, simulating oxidatively degraded lipid fills [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT2 \u0026ndash; Expired Flaxseed Oil\u003c/strong\u003e \u003cp\u003eExpired flaxseed oil with peroxide value 15.0 meq/kg, representing a high primary oxidation product scenario [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT3 \u0026ndash; Aged Omega-3 Triglycerides\u003c/strong\u003e \u003cp\u003eOld rancid omega-3 TG (DHA 50 TG) containing both primary and secondary lipid oxidation byproducts [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT4 and FT5 \u0026ndash; L-Arginine Suspension\u003c/strong\u003e \u003cp\u003eL-Arginine (150 mg/capsule) dispersed in soybean oil\u0026ndash;lecithin\u0026ndash;beeswax\u0026ndash;hydrogenated vegetable oil matrix. The wax components were melted at 65\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u0026deg;C, cooled to \u0026lt;\u0026thinsp;40\u0026deg;C, combined with the oil\u0026ndash;lecithin phase, and L-Arginine incorporated under stirring prior to deaeration [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT6 \u0026ndash; Glucosamine\u0026ndash;Chondroitin System\u003c/strong\u003e \u003cp\u003eGlucosamine HCl (125 mg) and Chondroitin Sulfate Sodium (107.8 mg) dispersed in soybean oil\u0026ndash;lecithin\u0026ndash;beeswax matrix by the same melt-disperse-deaerate protocol [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFill medicament compositions (mg per capsule; batch size 3000 capsules).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS.No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIngredient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFT1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFT2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFT3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFT4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFT5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFT6\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOmega-3 AEE (EPA-36%/DHA-24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e350.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFlaxseed Oil 50% ALA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e550.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOmega-3 TG (DHA 50 TG)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e350.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eL-Arginine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e150.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e150.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucosamine Hydrochloride\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e125.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChondroitin Sulfate Sodium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e107.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhite Beeswax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSoybean Lecithin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHydrogenated Vegetable Oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSoybean Oil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e323.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e323.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e170.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFill weight (mg/capsule)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e350.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e550.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e350.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e500.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e500.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e420.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.3.3 Encapsulation\u003c/h2\u003e \u003cp\u003eCapsules were manufactured on a GIC SUPRA BT/044\u0026thinsp;\u0026minus;\u0026thinsp;06 rotary die machine. Matured gel mass was transferred to the preheated spreader box under air pressure, spread over chilled casting drums to form gelatin ribbons of 32\u0026ndash;34 thou thickness, and simultaneously filled and sealed at the die roll assembly via a rotary pump. Key process parameters are provided in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEncapsulation process parameters.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS.No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLimit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFT1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFT2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFT3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFT4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFT5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eFT6\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDie Size (minim)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDie Shape\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOval/Round\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRound\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpreader Box Temp (\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u0026ndash;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e58.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e59.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSegment Temp (\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u0026ndash;46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e37.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMachine Speed (RPM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0\u0026ndash;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRibbon Thickness (thou)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u0026ndash;34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCasting Drum Temp (\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u0026ndash;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGelatin Solution Temp (\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u0026ndash;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e54.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e54.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.3.4 Drying, Polishing, and Packaging\u003c/h2\u003e \u003cp\u003eWet capsules were tumble-dried for one hour, transferred to stainless-steel trays, and dried in a controlled room at 25\u0026deg;C and 20\u0026ndash;25% RH until target hardness was reached (typically 48\u0026ndash;72 hours). Dried capsules were weight-sorted, polished with a 70% IPA-moistened lint-free cloth, and packaged in 100 mL HDPE bottles with screw caps and induction seals. No desiccant was included, to prevent masking of moisture-driven cross-linking.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.3.5 Stability Study Design\u003c/h2\u003e \u003cp\u003eStability testing followed ICH Q1A(R2) guidelines over six months under accelerated (40\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C/75\u0026thinsp;\u0026plusmn;\u0026thinsp;5% RH), intermediate (30\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C/65\u0026thinsp;\u0026plusmn;\u0026thinsp;5% RH), and long-term (25\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C/60\u0026thinsp;\u0026plusmn;\u0026thinsp;5% RH) conditions. Evaluation parameters included description/appearance, average fill content, and disintegration time (USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026gt;). The stability protocol is summarised in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStability protocol (ICH Q1A(R2)).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStability Condition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e40\u0026deg;\u0026plusmn;2\u0026deg;C / 75\u0026thinsp;\u0026plusmn;\u0026thinsp;5% RH (Accelerated)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e30\u0026deg;\u0026plusmn;2\u0026deg;C / 65\u0026thinsp;\u0026plusmn;\u0026thinsp;5% RH (Intermediate)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e25\u0026deg;\u0026plusmn;2\u0026deg;C / 60\u0026thinsp;\u0026plusmn;\u0026thinsp;5% RH (Long-term)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest Parameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6M\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDescription / Appearance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage Fill Content (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisintegration Time \u0026ndash; USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026gt; (\u0026le;\u0026thinsp;30 min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e2.3.6 Disintegration Testing\u003c/h2\u003e \u003cp\u003eDisintegration was determined per USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026thinsp;\u0026gt;\u0026thinsp;in purified water at 37\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C using an Electrolab EDI-2SA basket-rack assembly (n\u0026thinsp;=\u0026thinsp;6). Results are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. Capsules not disintegrating within 30 minutes were classified as FAILS.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.3.7 Accelerated Chemical Stress Testing\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eFormaldehyde treatment\u003c/strong\u003e \u003cp\u003eDried capsules were immersed in methanol-based formaldehyde solution at 37\u0026deg;C for 30 minutes, washed in 90% ethanol for 30 minutes, and redried before disintegration testing [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eGamma irradiation\u003c/strong\u003e \u003cp\u003eCapsules were exposed to controlled ⁶⁰Co γ-ray doses as an orthogonal stress model. Irradiation generates free radicals that induce oxidative cross-linking through gelatin side-chain reactions, complementing the aldehyde-driven pathway [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Capsule Appearance\u003c/h2\u003e \u003cp\u003eAll modified shell formulations (FT1\u0026ndash;FT6) and conventional controls were successfully prepared at 15 kg batch scale and produced acceptable capsules (smooth surface, intact seam, uniform colour). FT3 and FT6 (MCC-containing) showed slight opacity relative to the other formulations, consistent with the particulate nature of dispersed MCC within the gelatin film. Capsule photographs for each trial formulation are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Disintegration Stability \u0026ndash; Modified Shell Formulations (FT1\u0026ndash;FT6)\u003c/h2\u003e \u003cp\u003eAll six modified formulations maintained USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026thinsp;\u0026gt;\u0026thinsp;compliance (\u0026le;\u0026thinsp;30 min) throughout the full six-month stability study at all three ICH conditions (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Initial disintegration times ranged from 1 min 40 sec (FT1, FT4) to 3 min 4 sec (FT6). Under accelerated conditions (40\u0026deg;C/75% RH), disintegration times increased progressively, reaching a group mean of 14 min 49 sec at the 6-month station \u0026mdash; remaining comfortably within the pharmacopeial limit. The highest individual value recorded at any time point was 17 min (FT1 at 6M accelerated), still compliant. Under intermediate and long-term conditions, the mean maximum values were 8 min 6 sec (30\u0026deg;C/6M) and 4 min 49 sec (25\u0026deg;C/6M), respectively, confirming that reduced temperature and humidity substantially attenuated the cross-linking drive.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDisintegration stability data \u0026mdash; Modified Shell Formulations (FT1\u0026ndash;FT6). n\u0026thinsp;=\u0026thinsp;6; values expressed as mean (mm:ss\u0026thinsp;\u0026plusmn;\u0026thinsp;SD); USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026thinsp;\u0026gt;\u0026thinsp;compliance limit\u0026thinsp;\u0026le;\u0026thinsp;30 min.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eModified Shell Formulations (FT1\u0026ndash;FT6) \u0026ndash; Disintegration Time (mm:ss)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrial/Formulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInitial\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1M (40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2M (40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3M (40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6M (40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3M (30\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6M (30\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3M (25\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6M (25\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFT1\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(HPMC 6 cps)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3:54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5:42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8:09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4:10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7:37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3:25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3:40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFT2\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(HPMC 3 cps)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4:10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6:13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11:16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5:24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6:20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3:45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4:37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFT3\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(MCC PH105)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3:49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5:22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9:46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13:55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4:39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8:40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3:24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3:33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFT4 (Povidone K30)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4:30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6:45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11:16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5:18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7:43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4:09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5:10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFT5 (Klucel LF)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5:50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7:30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13:48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16:20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6:07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9:08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3:55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5:46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFT6 (PVP\u0026thinsp;+\u0026thinsp;MCC)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5:15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12:05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15:24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6:50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9:21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4:13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6:05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:06\u0026thinsp;\u0026plusmn;\u0026thinsp;0:31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4:35\u0026thinsp;\u0026plusmn;\u0026thinsp;0:48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6:40\u0026thinsp;\u0026plusmn;\u0026thinsp;0:55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10:21\u0026thinsp;\u0026plusmn;\u0026thinsp;2:32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14:49\u0026thinsp;\u0026plusmn;\u0026thinsp;2:02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5:25\u0026thinsp;\u0026plusmn;\u0026thinsp;0:58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8:06\u0026thinsp;\u0026plusmn;\u0026thinsp;1:07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4:06\u0026thinsp;\u0026plusmn;\u0026thinsp;0:44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4:49\u0026thinsp;\u0026plusmn;\u0026thinsp;1:03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Disintegration Stability \u0026ndash; Conventional Shell Controls (FC1\u0026ndash;FC6)\u003c/h2\u003e \u003cp\u003eConventional gelatin controls showed a progressive and ultimately non-compliant deterioration in disintegration performance (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). FC6 failed USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026thinsp;\u0026gt;\u0026thinsp;at the 2-month accelerated station \u0026mdash; the earliest failure recorded. FC2, FC4, and FC5 failed at 3 months accelerated, and FC1 and FC3 at 6 months accelerated. Under intermediate conditions (30\u0026deg;C/65% RH), FC3, FC4, and FC5 also failed at 6 months. Even under long-term conditions (25\u0026deg;C/60% RH), mean disintegration at 6 months reached 25 min 21 sec \u0026mdash; only\u0026thinsp;~\u0026thinsp;4.6 minutes below the compliance limit, representing a critically narrow margin.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDisintegration stability data \u0026mdash; Conventional Shell Controls (FC1\u0026ndash;FC6). n\u0026thinsp;=\u0026thinsp;6; values expressed as mean (mm:ss\u0026thinsp;\u0026plusmn;\u0026thinsp;SD); FAILS\u0026thinsp;=\u0026thinsp;disintegration\u0026thinsp;\u0026gt;\u0026thinsp;30 min; USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026thinsp;\u0026gt;\u0026thinsp;compliance limit\u0026thinsp;\u0026le;\u0026thinsp;30 min.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"11\" nameend=\"c11\" namest=\"c1\"\u003e \u003cp\u003eConventional Shell Controls (FC1\u0026ndash;FC6) \u0026ndash; Disintegration Time (mm:ss)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrial/\u003c/p\u003e \u003cp\u003eFormulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInitial\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1M\u003c/p\u003e \u003cp\u003e(40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2M\u003c/p\u003e \u003cp\u003e(40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3M (40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6M (40\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3M\u003c/p\u003e \u003cp\u003e(30\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6M (30\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3M\u003c/p\u003e \u003cp\u003e(25\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6M\u003c/p\u003e \u003cp\u003e(25\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFC1 (Conventional)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7:51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10:48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15:34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26:53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13:38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e22:18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9:29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e16:15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFC2 (Conventional)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10:34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16:24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26:32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14:09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e25:26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14:18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e22:29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFC3 (Conventional)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8:28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12:19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22:44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27:31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11:13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e19:27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e27:14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFC4 (Conventional)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12:30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13:17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28:51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14:29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21:15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28:30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFC5 (Conventional)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12:30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13:17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28:51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14:29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21:15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28:30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFC6 (Conventional)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9:15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17:18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16:11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e25:21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e29:10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10:11\u0026thinsp;\u0026plusmn;\u0026thinsp;2:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13:54\u0026thinsp;\u0026plusmn;\u0026thinsp;2:28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20:25\u0026thinsp;\u0026plusmn;\u0026thinsp;11:11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14:01\u0026thinsp;\u0026plusmn;\u0026thinsp;1:37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFAILS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e18:31\u0026thinsp;\u0026plusmn;\u0026thinsp;5:41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e25:21\u0026thinsp;\u0026plusmn;\u0026thinsp;5:05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c11\" namest=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Accelerated Methods for Evaluating Cross-Linking","content":"\u003cp\u003eSeveral chemical species are known to induce gelatin cross-linking either through direct nucleophilic addition to reactive groups or via oxidative free-radical mechanisms. Common promoters documented in the literature include aldehydes (furfural, acrolein, formaldehyde, glutaraldehyde, glyceraldehyde), reducing sugars (aldoses via Maillard reaction), hydrogen peroxide, inorganic salts, and polyfunctional amines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In pharmaceutical development, accelerated stress methods are employed to artificially induce and compare cross-linking susceptibility across shell formulations under reproducible conditions.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Formaldehyde Treatment\u003c/h2\u003e \u003cp\u003eFormaldehyde forms stable Schiff base (aldimine) intermediates with ε-amino groups of lysine residues on gelatin chains, representing the prototypical aldehyde cross-linking mechanism [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In the present study, formaldehyde challenge resulted in markedly different responses between modified and conventional shells. FT4 (Povidone K30) consistently produced post-treatment disintegration times of 11\u0026ndash;12 minutes, indicating that the PVP network effectively competes with gelatin amino groups for aldehyde reactivity, or physically occludes the inter-chain space. All modified formulations passed the 30-minute limit post-treatment, while several conventional controls did not.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Gamma Irradiation\u003c/h2\u003e \u003cp\u003eGamma irradiation (⁶⁰Co) generates hydroxyl radicals that abstract hydrogen from carbon-hydrogen bonds within the gelatin backbone, initiating chain radical propagation and subsequent inter-chain C\u0026ndash;C or C\u0026ndash;N bond formation [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This mechanism is orthogonal to aldehyde-driven cross-linking and provided a complementary mechanistic challenge. Modified shells, particularly FT4 and FT6, maintained acceptable disintegration post-irradiation, while conventional controls showed significant impairment. Direct quantification of cross-link density (TNBS assay, FTIR, DSC) was beyond the scope of this investigation but is planned for future work.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Proposed Mechanism of Drug Release from Cross-Linked Softgel Capsules","content":"\u003cp\u003eA three-phase mechanistic model for drug release from modified cross-linked shells is proposed based on the disintegration trends observed and established gelatin chemistry principles. Figure\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates this mechanism schematically.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn Phase 1 (intact storage), the gelatin shell containing incorporated water-soluble polymers maintains structural integrity. Polymer chains occupy interstitial spaces within the gelatin network and may physically shield reactive amino acid residues from incoming cross-linking agents diffusing from the fill.\u003c/p\u003e \u003cp\u003eIn Phase 2 (dissolution contact), water penetrates the shell and rapidly hydrates the polymer components. HPMC, Povidone K30, and Klucel LF dissolve or swell, generating macroscopic channels and pores within the gelatin matrix. This pore network is functionally critical: even where partial gelatin cross-linking has occurred, the channels provide pathways for both water ingress and fill medicament egress.\u003c/p\u003e \u003cp\u003eIn Phase 3 (drug release), the fill medicament diffuses or flows through the pore network and is released into the dissolution medium. In severely cross-linked conventional shells lacking these pore-forming agents, the cross-linked gelatin network remains largely intact, restricting both water ingress and fill egress and accounting for the observed disintegration failures. This model is consistent with prior reports on HPMC-modified capsule shells and provides a rational basis for the observed performance ranking: excipients that dissolve most readily (PVP\u0026thinsp;\u0026gt;\u0026thinsp;HPMC\u0026thinsp;\u0026gt;\u0026thinsp;HPC\u0026thinsp;\u0026gt;\u0026thinsp;MCC) generate the most immediate pore-formation benefit [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e"},{"header":"6. Discussion","content":"\u003cp\u003eThe central finding of this study \u0026mdash; that all six modified shell formulations maintained pharmacopeial disintegration compliance over six months under all three ICH stability conditions, while all six conventional controls failed under accelerated storage \u0026mdash; provides clear and reproducible evidence that excipient-based gelatin shell modification is an effective strategy for cross-linking management in softgel dosage form development.\u003c/p\u003e \u003cp\u003eThe practical advantage of this approach over full gelatin replacement is its compatibility with established rotary die infrastructure. None of the modified formulations required modification to encapsulation equipment or process parameters, as confirmed by the process data in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. All excipients employed \u0026mdash; HPMC, Povidone K30, HPC, MCC \u0026mdash; are pharmacopoeially approved with extensive regulatory precedent in oral dosage forms, supporting straightforward inclusion in ANDA or CTD Module 3.2.P documentation.\u003c/p\u003e \u003cp\u003eThe performance hierarchy observed across the modified formulations offers practical guidance for excipient selection. FT4 (Povidone K30, 2% w/w) demonstrated the most consistent protection for amino acid-containing fills (L-Arginine), producing disintegration times below 12 minutes even after formaldehyde challenge at 6 months accelerated. PVP's effectiveness in this context is attributable to its strong hydrogen-bonding capacity, documented ability to complex with reactive carbonyl species [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and high aqueous solubility, which facilitates rapid pore formation upon dissolution medium contact.\u003c/p\u003e \u003cp\u003eFT5 (Klucel LF, 2% w/w) showed superior performance for oil-based capsules (omega-3 fills) relative to the L-Arginine-containing FT5 group, suggesting that the protective mechanism is more physical (pore formation) than chemical (reactive-species scavenging) for this system. The guanidinium group of L-Arginine is particularly reactive with gelatin amino groups, and the Klucel LF system appears to offer insufficient chemical competition at 2% w/w to match PVP's performance in this context.\u003c/p\u003e \u003cp\u003eFT6 (PVP\u0026thinsp;+\u0026thinsp;MCC) showed an intermediate profile: combining two mechanistically distinct excipients (a reactive-species competitor and a pore-forming particulate) did not produce fully additive protection at the concentrations tested, possibly because the higher total polymer load introduced a viscosity effect that slightly slowed initial shell dissolution, reflected in FT6's higher baseline disintegration time (3:04 vs 1:40 for FT4). Systematic optimisation of the PVP:MCC ratio in FT6-type systems represents a logical next step.\u003c/p\u003e \u003cp\u003eLimitations of this study include the indirect assessment of cross-link density through functional disintegration testing rather than direct chemical quantification. Future studies should incorporate TNBS assay (free amino group titration), FTIR spectroscopy (amide bond shifts), and DSC (denaturation temperature analysis) to directly quantify cross-link density and establish the quantitative relationship between polymer concentration and cross-link inhibition. Dissolution profiling (USP Apparatus I or II) would additionally characterise the impact of modified shell performance on drug release kinetics for representative active substances.\u003c/p\u003e \u003cp\u003eThe platform technology described here carries implications beyond anti-cross-linking functionality. HPMC- and HPC-modified shells offer enhanced elasticity suitable for twist-off softgel formats and chewable applications. The improved seal integrity in FT4-type formulations is particularly advantageous for highly viscous fill matrices that place high mechanical stress on capsule seams. Cosmetic and nutraceutical applications, where pearlescent pigments and flavouring agents are routinely incorporated into shells, may similarly benefit from the enhanced flexibility conferred by these excipient systems.\u003c/p\u003e"},{"header":"7. Conclusions","content":"\u003cp\u003eTargeted incorporation of water-soluble polymers into soft gelatin capsule shells provides an effective, scalable, and mechanistically supported strategy for mitigating cross-linking under pharmaceutical storage conditions. All six modified formulations demonstrated USP\u0026thinsp;\u0026lt;\u0026thinsp;701\u0026thinsp;\u0026gt;\u0026thinsp;disintegration compliance over six months of ICH stability testing including accelerated conditions (40\u0026deg;C/75% RH), in direct contrast to conventional gelatin controls that failed within two months under equivalent stress.\u003c/p\u003e \u003cp\u003eFT4 (Povidone K30, 2% w/w) offered the most robust cross-linking protection for amino acid-containing fills, with disintegration times consistently below 12 minutes after formaldehyde challenge at 6 months accelerated. HPMC-based formulations (FT1, FT2) performed reliably for oxidised lipid fills. The proposed mechanism \u0026mdash; polymer dissolution creating pore channels that maintain drug release pathways through a cross-linked gelatin network \u0026mdash; provides a rational and practically actionable basis for shell design.\u003c/p\u003e \u003cp\u003eFuture work should focus on direct quantification of cross-link density by TNBS assay, FTIR, and DSC; systematic polymer concentration optimisation; and comparative dissolution profiling to fully characterise the impact of modified shell performance on drug release kinetics. Translation of these findings to commercial scale will extend the applicability of this platform across conventional and advanced oral delivery formats.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAEE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcid Ethyl Ester\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAlpha-Linolenic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eANDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAbbreviated New Drug Application\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eActive Pharmaceutical Ingredient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBiopharmaceutics Classification System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Technical Document\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDHA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDocosahexaenoic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDifferential Scanning Calorimetry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEicosapentaenoic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFTIR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFourier-Transform Infrared Spectroscopy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHCl\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHydrochloric Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHDPE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHigh-Density Polyethylene\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHydroxypropyl Cellulose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPMC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHydroxypropyl Methylcellulose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Council for Harmonisation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIsopropyl Alcohol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMicrocrystalline Cellulose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePVP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolyvinylpyrrolidone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQbD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuality by Design\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRelative Humidity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRPM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRevolutions Per Minute\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSoft Gelatin Capsule\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStainless Steel\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTriglycerides\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNBS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrinitrobenzenesulfonic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUSP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUnited States Pharmacopeia.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors read and approved of the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors gratefully acknowledge the Research and Development department of Jamjoom Pharmaceuticals, Jeddah 21442, Kingdom of Saudi Arabia, for providing laboratory facilities, equipment, and raw materials. The authors also thank Sri Ramachandra Institute of Higher Education and Research (SRIHER-DU), Chennai, India, for institutional and academic support.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analysed during the present study are available from the corresponding author upon reasonable written request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGullapalli RP. Soft gelatin capsules (softgels). J Pharm Sci. 2010;99(10):4107\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGullapalli RP, Mazzitelli CL. Gelatin and non-gelatin capsule dosage forms. J Pharm Sci. 2017;106(6):1453\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamian F, Harati M, Schwartzenhauer J, Van Cauwenberghe O, Wettig SD. Challenges of dissolution methods development for soft gelatin capsules. Pharmaceutics. 2021;13(2):214.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTesconi MS, Bramer SL, Yalkowsky SH. The preparation of soft gelatin capsules for a radioactive tracer study. Pharm Dev Technol. 1999;4(4):507\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDigenis GA, Gold TB, Shah VP. Cross-linking of gelatin capsules and its relevance to their in vitro\u0026ndash;in vivo performance. J Pharm Sci. 1994;83(7):915\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJones BE, Podczeck F. Pharmaceutical Capsules. London: Pharmaceutical; 2004. pp. 210\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLai JY, Li YT. Influence of cross-linker concentration on the functionality of carbodiimide cross-linked gelatin membranes. J Biomater Sci Polym Ed. 2011;22(1\u0026ndash;3):277\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaharros-Molinero A, Caballo-Gonz\u0026aacute;lez M\u0026Aacute;, de la Mata FJ, Garc\u0026iacute;a-Gallego S. Shell formulation in soft gelatin capsules: design and characterization. Adv Healthc Mater. 2023:e2302250.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Tabakha MM, Arida AI, Fahelelbom KM, et al. Influence of capsule shell composition on the performance indicators of hypromellose capsule. Drug Dev Ind Pharm. 2015;41(10):1726\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHutchison K. Encapsulation in softgels for pharmaceutical advantage. In: Karsa DR, Stephenson RA, editors. Encapsulation and Controlled Release. Cambridge: Woodhead; 2005. pp. 86\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuentz M, Rothenh\u0026auml;usler B, R\u0026ouml;thlisberger D. Time domain 1H NMR to monitor softening of gelatin and HPMC capsule shells. Drug Dev Ind Pharm. 2006;32(10):1165\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Tabakha MM. HPMC capsules: current status and future prospects. J Pharm Pharm Sci. 2010;13(3):428\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMikhailov OV. Gelatin as it is: history and modernity. Int J Mol Sci. 2023;24(4):3583.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLai JY. The role of bloom index of gelatin on the interaction with retinal pigment epithelial cells. Int J Mol Sci. 2009;10(8):3442\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang M, Xie S, Li Q, et al. Effects of polyvinylpyrrolidone as binder and pore-former on the release of topiramate from ethylcellulose coated pellets. Int J Pharm. 2014;465(1\u0026ndash;2):187\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHassan EM, Fatmi AA, Chidambaram N. Enteric soft capsules. US Patent US9433585. 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaul S, Sun CC. Modulating sticking propensity of pharmaceuticals through excipient selection. Pharm Res. 2018;35(6):113.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen L, Ding X, He Z, et al. Surface engineered excipients: improved functional properties of fine grade microcrystalline cellulose. Int J Pharm. 2018;536(1):127\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatson H, Mitra S, Croden FC, et al. A randomised trial of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota. Gut. 2018;67(11):1974\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWard ED, Thomasson K, Fischer KR. Analysis of omega-3 fatty acid content in fish oil products. J Pharm Pract. 2022;35(6):870\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoppo K, Taes YE, Pottier A, et al. Dietary arginine supplementation speeds pulmonary VO2 kinetics during cycle exercise. Med Sci Sports Exerc. 2009;41(8):1626\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcConell GK. Effects of L-arginine supplementation on exercise metabolism. Curr Opin Clin Nutr Metab Care. 2007;10(1):46\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJerosch J. Effects of glucosamine and chondroitin sulfate on cartilage metabolism in OA. Int J Rheumatol. 2011;2011:969012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang SJ, Zhao XH. Cross-linking and glucosamine conjugation of casein by transglutaminase. Int J Food Prop. 2012;15(6):1286\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTayri-Wilk T, Slavin M, Zamel J, et al. Mass spectrometry reveals the chemistry of formaldehyde cross-linking in structured proteins. Nat Commun. 2020;11:3128.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhutani U, Ronghe A, Majumdar S. Piperine as a placebo: stability of gelatin capsules without a cross-linker. ACS Appl Bio Mater. 2018;1(5):1244\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIslam MM, Zaman A, Islam MS, Khan MA, Rahman MM. Physico-chemical characteristics of gamma-irradiated gelatin. Prog Biomater. 2014;3(1):21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlube N, Moos LV, Duchateau G. Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract. Results Pharma Sci. 2013;3:1\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChiwele I, Jones BE, Podczeck F. The shell dissolution of various empty hard capsules. Chem Pharm Bull (Tokyo). 2000;48(7):951\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Zhao F, Paborji M. Effect of fill weight, capsule shell, and sinker design on dissolution behavior. Pharm Dev Technol. 2003;8(4):379\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou K, Yang Y, Zheng B, et al. Enhancing pullulan soft capsules with a mixture of glycerol and sorbitol plasticizers. Polym (Basel). 2023;15(10):2247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe C, Feng W, Cao L, Fan L. Crosslinking of poly(L-lactide) nanofibers with triallyl isocyanurate by gamma-irradiation. J Biomed Mater Res A. 2011;99(4):655\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Parrish C, Micklavzina BL, et al. Flow behavior of concentrated tricalcium phosphate suspensions in oil for softgel encapsulation. Int J Pharm. 2021;601:120562.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Temmerman ML, Demeester J, De Vos F, De Smedt SC. Encapsulation performance of layer-by-layer microcapsules for proteins. Biomacromolecules. 2011;12(4):1283\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarucci M, Ragnarsson G, von Corswant C, et al. Polymer leaching from film coating: effects on transport properties. Int J Pharm. 2011;411(1\u0026ndash;2):43\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"soft gelatin capsules, cross-linking, gelatin shell modification, disintegration stability, Povidone K30, HPMC, oral drug delivery, BCS Class IV","lastPublishedDoi":"10.21203/rs.3.rs-9346787/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9346787/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSoft gelatin capsules are widely employed for delivering poorly water-soluble and lipophilic drugs; however, gelatin shells are prone to cross-linking during storage, particularly when fills contain reactive aldehydes, peroxides, or amino acids. Cross-linking impairs shell solubility, delays disintegration, and compromises drug release and bioavailability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003eTo develop and evaluate modified soft gelatin shell formulations incorporating water-soluble polymers and cellulosic excipients for their ability to mitigate cross-linking and maintain pharmacopeial disintegration compliance under real-time and accelerated stability conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eSix modified shell formulations (FT1–FT6) incorporating HPMC, Microcrystalline Cellulose (MCC PH105), Povidone K30, or Hydroxypropyl Cellulose (Klucel LF) were prepared and filled with reactive model fills including aged omega-3 fatty acid esters, flaxseed oil, omega-3 triglycerides, L-Arginine, and glucosamine–chondroitin systems. Six conventional gelatin shells (FC1–FC6) served as controls. Disintegration testing was performed per USP \u0026lt;701\u0026gt; across ICH Q1A(R2) accelerated (40°C/75% RH), intermediate (30°C/65% RH), and long-term (25°C/60% RH) conditions over six months. Accelerated cross-linking stress was applied via formaldehyde treatment and gamma irradiation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAll modified formulations maintained USP \u0026lt;701\u0026gt; compliance (≤30 min) throughout six months under all stability conditions, with a peak mean disintegration of 14 min 49 sec at the 6-month accelerated station. Conventional controls failed as early as the 2-month accelerated time point. FT4 (Povidone K30) showed the most robust protection for L-Arginine fills (≤12 min post-formaldehyde challenge), while HPMC-based formulations (FT1, FT2) performed reliably with oxidised lipid fills.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIncorporation of water-soluble polymers into the gelatin shell matrix provides an effective, scalable, and commercially practicable strategy for cross-linking mitigation. The approach is compatible with conventional rotary die manufacturing and applicable across diverse fill chemistries, supporting the development of robust softgel dosage forms for challenging pharmaceutical candidates.\u003c/p\u003e","manuscriptTitle":"Platform Technology and Alternative Strategies for Mitigating Cross-Linking in Soft Gelatin Capsules: Development, Evaluation, and Mechanistic Insights","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 14:29:09","doi":"10.21203/rs.3.rs-9346787/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"405d3da4-a67c-44c5-8979-1c79e92223fd","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-12T15:57:57+00:00","index":38,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-06T18:26:08+00:00","index":35,"fulltext":""},{"type":"reviewerAgreed","content":"263665027887101496576015082393777997427","date":"2026-05-06T18:17:24+00:00","index":34,"fulltext":""},{"type":"reviewerAgreed","content":"312424812419266150007800369194679416103","date":"2026-05-04T20:53:01+00:00","index":33,"fulltext":""},{"type":"reviewerAgreed","content":"215809230962646613351194304631316715920","date":"2026-05-04T13:59:45+00:00","index":32,"fulltext":""},{"type":"reviewerAgreed","content":"200149741190423566050667953396764362042","date":"2026-05-03T22:48:34+00:00","index":30,"fulltext":""},{"type":"reviewerAgreed","content":"230549784215063419775963194111593252347","date":"2026-05-02T19:03:43+00:00","index":29,"fulltext":""},{"type":"reviewersInvited","content":"20","date":"2026-05-01T18:12:30+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T14:29:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 14:29:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9346787","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9346787","identity":"rs-9346787","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}