OBJECTIVES:Palbociclib (PBB) is an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for the treatment of HR+/HER2- breast cancer. However, poor adherence and limited tolerability of oral administration often compromise its therapeutic effectiveness, especially in palliative care for metastatic conditions. Dose reductions are frequently required to manage toxicity, but lower doses can still provide effective tumour control with reduced neutropenia risk, thereby improving quality of life and progression-free survival. Developing a long-acting injectable (LAI) formulation of PBB offers significant advantages for sustained therapy in advanced-stage cancer management. METHODS:This study focuses on dose selection, release profile optimisation, and the design of sterile PBB-loaded PLGA microsphere suspensions for intramuscular (IM) administration using physiologically based pharmacokinetic (PBPK) modelling and simulations. The PBPK model, developed and validated with data from oral and intravenous routes, enabled the prediction of IM pharmacokinetics. Clinical target product profiles were defined based on IC50 and minimum steady-state concentration (Css, min). KEY FINDINGS:The dose optimisation study revealed that the rational selection of dose for both strengths, with an optimised sustained-release profile (Target 2, showing minimal initial burst and controlled release reaching ~55% by day 10.5 and ~90% by day 21), achieved the desired clinical quality target product profiles. CONCLUSIONS:The developed model will further support polymer selection, specification setting, and drug-to-polymer ratio. Incorporating PBB's physicochemical properties and host response helps guide rational formulation design.

Understanding the drug substance's degradation behaviour is essential for rational selection of formulation strategies, packaging materials, and storage conditions. Forced degradation studies provide critical information on drug degradation and are mandatory for regulatory submissions. Erlotinib hydrochloride (ERL) is a firstgeneration oral tyrosine kinase inhibitor used to manage metastatic non-small cell lung cancer. To date, only a few studies have reported forced degradation and LC-HRMS-based impurity profiling of ERL, and none have described a RP-HPLC method for ERL- Polylactide-co-glycolide (PLGA) systems. A comprehensive forced degradation study of ERL and characterization of impurities were performed using RP-HPLC and LC-HRMS. The RP-HPLC method was developed using a C18 column and 50 mM ammonium acetate: acetonitrile (45:55 % v/v) at a flow rate of 1 mL/min, with detection at 246 nm. The method was validated in accordance with ICH Q2(R2) and successfully applied for ERL-PLGA premixes. LC-HRMS analysis was performed using an ESI source in both positive and negative ion mode with a scan range of 100-2000 m/z. Forced degradation studies revealed significant degradation of ERL under oxidative and acidic conditions. Fourteen impurities were identified, including Impurity 1 (m/z 412.1856) and 3 (m/z 430.1515) from acid, Impurity 2 (m/z 410.1697), 9 (m/z 380.1595), and 10 (m/z 414.1647) from oxidation, while the remaining were process-related impurities. In silico toxicity prediction indicated predominant immunotoxicity (98 %) and respiratory toxicity (96 %) for ERL and impurities. Greenness and blueness assessments using AGREE, Complex-GAPI, and BAGI confirmed moderate environmental impact and high analytical performance for the developed method.

Mesalamine (MES) remains a first-line therapy for the treatment of inflammatory bowel disease; however, its clinical use is limited by poor aqueous solubility in the colon, high dose requirements, variable pharmacokinetics, pill burden, and patient non-compliance. This study aimed to develop and optimise MES nanocrystals (MES NCs) using a top-down ball milling approach using a stabiliser Hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Thirteen different batches were formulated to assess the effects of speed and time of milling, and polymer concentration on particle size, polydispersity index (PDI), morphology, crystallinity, thermal properties, and dissolution. The B11 batch was evaluated for its biological activity using PMA-differentiated THP 1 cell line treated with LPS using inflammatory markers: IL-4, IL-6, TNFα, and TGF-β. The first reproducibility batches (0.1/400/40; B9-B15) exhibited an intra-batch average particle size of 537.3 ± 139.2 nm with a PDI of 0.5 ± 0.1. SEM analysis confirmed a uniform plate-like morphology. PXRD analysis revealed partial peak shifts and broadening, suggesting lattice strain in the milled NCs. Dissolution studies demonstrated pH-dependent release of MES-NCs. FTIR confirmed drug-polymer compatibility. Cytotoxicity testing in PMA-differentiated THP-1 macrophage-like cells showed > 64

Achieving therapeutic intraluminal Mesalamine (MES) concentration at colonic lesion sites is influenced by variable gastrointestinal (GI) pH, buffer capacity (β), fluid volume, viscosity, and transit time. Conventional dissolution tests often overpredict in vivo performance, limiting their relevance for pharmacokinetic prediction. The present study focuses on understanding the impact of pH, molarities, and β on the dissolution behaviour of the MES products and generics. This study evaluates the effect of dissolution media on Prolonged-release granules (PRGs) and Multi-Matrix (MMX®) tablets, and their generics, using product-specific guidance (PSG) protocols across dissolution media and buffer strengths (25, 50, and 160 mM). PRGs showed slower release in low molarity media. It was observed that there was no β effect on the drug release profile in acetate media, where MES remains a poorly soluble zwitterion at pH 4.3. MMX® tablets were sensitive to buffer molarity; 25 mM phosphate buffer caused slower release, revealing differences that were masked under high-molarity Quality Control (QC) media. In 160 mM phosphate buffer, MMX® generics were similar to the reference, but did not meet the f₂ criteria in 25 mM buffer, demonstrating the discriminatory power of low-β media. Overall, molarity, β and pH critically influence MES release, suggesting that different dissolution methods for MES formulations with respect to their discriminatory power should be a valuable tool to mitigate bioequivalence failures in generic development.

Solid-state pharmaceutical properties play a pivotal role in determining product performance, manufacturing consistency, and clinical outcomes, especially for high-dose active pharmaceutical ingredients (APIs). Mesalamine (MES), a BCS class IV drug, has the highest unit dose of 4000 mg and is available as prolonged-release granules for oral administration. MES delayed-release tablets are available in different strengths of 400, 800, and 1200 mg. In this study, five MES API samples from various manufacturers were evaluated for crystal morphology, bulk properties, crystallinity, thermal behaviour, solubility, wettability, and dissolution performance. No significant difference was observed in particle size (Dv 50 ranging from 38.2 to 63.7 µm). Crystals, including needles, rectangular bars, and mixed morphologies, were observed in APIs from different manufacturers, resulting in distinct surface and packing characteristics. The rectangular bar crystal habit of API D likely results in parallel packing during compaction, exposing basal faces on the tablet surface. The higher contact angle of 53.0 ± 0.6° was observed with API D. In contrast to contact angle, it was observed that the high saturation solubility (3.4 mg/mL in pH 7.2 and 7.4) and higher extent of dissolution (95.3 ± 2.3

Furosemide, a diuretic for managing edema in premature neonates and infants with congestive heart failure, is often formulated with alcohol and preservatives, posing risks like neurotoxicity and cardiovascular complications. This study aimed to develop a safe, alcohol-and preservative-free micellar liquid formulation of furosemide for pediatric use. Drug-loaded micelles were prepared using Kolliphor RH 40 (polyoxyl 40 hydrogenated castor oil) as a surfactant and hydroxypropyl-beta-cyclodextrin as a solubiliser and characterized for size, morphology, zeta potential, polydispersity, critical micelle concentration, stability, and microbiological quality. Of the twelve formulations, F11 and F12 were selected for their visual clarity and physical properties. The optimised batch (F11) formed nanosized micelles (19.16 ± 0.06 nm) with uniform distribution (PDI 0.292 ± 0.02) and steric stabilisation (zeta potential −0.43 ± 0.01 mV). Entrapment efficiency exceeded 98 %, and transmittance was >97 %, confirming high clarity. The formulation remained stable in SGF and SIF for 12 h with >99 % assay retention and complies with the stability protocol. The data obtained from stability studies indicate the physical, pharmaceutical, and microbial stability of the developed formulation. This alcohol- and preservative-free micellar formulation may offer a safe and effective treatment option for paediatric populations.

Salcaprozate sodium (SNAC) is an FDA GRAS-listed permeation enhancer used in oral semaglutide and vitamin B12 formulations. Although its rapid and reversible membrane-perturbing effects are well recognised, it’s in vivo performance is highly variable. Since effective membrane fluidisation requires permeation enhancers to remain as monomers, the critical micelle concentration (CMC) is a key determinant of efficacy. This study investigated the micellization behaviour of SNAC under physiologically relevant conditions. The CMC of SNAC was determined across physiologically relevant pH buffers using complementary techniques, including conductometry, tensiometry, microvolume UV/Visible spectroscopy, and fluorescence spectroscopy. The effects of electrolytes, bile salts, and selected coadministered drugs on SNAC micellization were evaluated. SNAC did not form micelles under gastric conditions due to increased protonation and low solubility. In contrast, SNAC micellized at intestinal pH 6.8 with a CMC of 6.26 ± 0.38 mM. Physiological factors strongly influenced micellization, particularly under intestinal conditions. The presence of electrolytes significantly reduced the CMC to 3.36 ± 0.03 mM, due to reduced electrostatic repulsion and a counter-ion effect. Bile salts showed a biphasic effect, increasing the CMC at low concentrations and promoting mixed micellization at higher concentrations. Coadministered drugs, including aspirin, metformin, nimesulide, ciprofloxacin, and semaglutide, significantly altered SNAC CMC values. Semaglutide showed a non-monotonic effect, decreasing the CMC at low concentrations but increasing it at higher concentrations due to oligomerisation. These findings provide mechanistic insights into SNAC micellization under physiologically relevant conditions and offer a rational basis for optimising SNAC-based oral drug delivery systems.

Palbociclib (PLB) is a selective inhibitor of cyclin-dependent kinase 4/6, widely used in the care of breast cancer. Assessment of its stability and degradation behavior is important for ensuring drug safety and supporting formulation development, storage, and shelf-life for novel formulations. Forced degradation studies are essential for evaluating intrinsic drug stability, characterizing potential impurities, and elucidating degradation pathways, which shall be used to control the impurities. This study focuses on developing and validating a stability-indicating reversed-phase high-performance liquid chromatography (RP–HPLC) method for the PLB quantification and on investigating its degradation pathways, along with impurity profiling using liquid chromatography high-resolution mass spectrometry (LC–HRMS). Chromatographic separation was performed on a C18 column in isocratic mode using 0.03 M ammonium acetate buffer containing 0.1% triethylamine (pH 6.5) and acetonitrile (55:45, v/v) at a flow rate of 0.8 mL/min, with detection at 265 nm. A forced degradation study was performed under acidic, alkaline, oxidative, thermal, and photolytic conditions. LC–HRMS analysis enabled the accurate mass determination of the drug substance and its degradation products, and ten impurities were identified, including oxidative, hydrolytic, and process-related species. Oxidation is the predominant degradation pathway, followed by hydrolysis, which resulted in a few impurities. The developed RP–HPLC and LC–HRMS approach proved effective for comprehensive stability assessment and impurity profiling. Further, fragmentation of impurities using Tandem Mass Spectrometry (MS/MS) data analysis confirms their identification and degradation pathways. Toxicity prediction suggested potential safety of impurities, while greenness assessment confirmed the method's environmental acceptability.

Reverse engineering (RE) of reference-listed drugs (RLD) plays a major role in developing cost- and time-effective, high-quality generic products for affordable therapies without compromising healthcare quality. The present study attempted to develop the RE protocol using Pentasa™- Mesalamine prolonged-release granules (PRGs) as a model drug product. RE of three different RLD lots was carried out using analytical techniques such as UV spectroscopy, moisture content using water activity and IR moisture balance, High Performance Liquid Chromatography – Reverse Phase (HPLC) for assay, Fourier-Transform Infrared spectroscopy (FT-IR), Raman Spectroscopy- 532 nm (RS- 532), Proton Nuclear Magnetic Resonance Spectroscopy – 500 MHz (NMR) for drug excipient compatibility/interaction studies, Optical and Scanning Electron Microscopy (SEM) for surface morphology, Raman Chemical Imaging (RCI) and Focal Plane Array-FTIR (FPA-FTIR) chemical imaging for drug and excipient distribution in intact granules, surface area and porosity by BET, thermal analysis by DSC, crystallinity using PXRD, metallic impurities using LC Inductively Coupled Plasma Mass Spectrometry (LC ICP-MS) and particle size by laser diffraction, Head Space Gas Chromatography-Mass spectrometry (HS GC–MS) for residual solvents, size exclusion chromatography for molecular weight determination of PVP and ethyl cellulose, texture analysis for deformation studies, packaging evaluation, and in vitro multimedia dissolution using validated USP method. The resulting data was useful in finalising qualitative and quantitative compositions, selecting the technical grade of excipients, understanding the innovator manufacturing process, establishing QTPP, FMEA, and packaging material selection. This work shall serve as a model protocol for RE of RLD formulation for developing complex generic products.

Erlotinib is an orally administered tyrosine kinase inhibitor used in the treatment of EGFR-positive non-small cell lung cancer. However, poor tolerability and suboptimal patient adherence often limit its clinical efficacy. Furthermore, lower doses are recommended for elderly patients, those with EGFR-sensitising mutations, and cutaneous toxicities. A PLGA-based long-acting injectable formulation may offer significant advantages for metastatic NSCLC by enhancing treatment compliance. This study aims to develop a physiologically based pharmacokinetic model to support dose selection, optimisation of release profiles, and dosage form design.The semimechanistic ERL PBPK model was first developed and validated for oral formulations and subsequently extended to intramuscular depots. The IM model was used to determine the optimal dose and release profile to maintain plasma drug concentrations above the IC50 and Css min targets.A monthly dose of 750 mg with an intermediate-release profile able to maintain the drug concentration above the Css, min. When targeting the IC50, the prototype formulations required a monthly dose of 300 mg and a three-month dose of 1200 mg, both with intermediate-release profiles.The semimechanistic PBPK model successfully predicted the optimal dose and release profile. The results provided valuable insights for polymer grade selection and drug-to-polymer ratio optimisation.

Semaglutide (SEM) is a GLP-1 analogue, administered subcutaneously or orally. Due to its large molecular structure, it has poor oral absorption and bioavailability. The reported oral bioavailability is 0.4% to 1% in the fasting state. Sodium N-[8-{2-hydroxybenzoyl} amino] caprylate (SNAC) is used as a permeation enhancer to improve gastric permeability and oral bioavailability.This study developed a semi-mechanistic pharmacokinetic (PK) model to predict the steady-state pharmacokinetics of oral SEM, primarily using published clinical data and literature-derived parameters. The present study investigated the impact of SNAC on the gastric absorption of SEM.The semi-mechanistic PK model was developed for the intravenous (IV) and oral formulations. The oral absorption model was developed for SEM at different single doses with varying amounts of SNAC. The dose, SNAC concentration, gastrointestinal permeability, and intestinal first-pass effect impact the PK of the oral SEM. Steady-state PK studies were used to validate the single-dose oral PK model. IV, single-dose, and multiple-dose oral PK models were developed and validated.The developed semi-mechanistic model could be useful for further development of mechanistic, physiologically based pharmacokinetic (PBPK) models for formulation development, drug interactions, and the influence of pharmacokinetics in special populations.

Semaglutide (SMG), a clinically relevant peptide-based therapeutic whose physical and chemical stability are critical concerns during manufacturing and storage. Although the stability of SMG in solution has been extensively studied, its solid-state behaviour remains unclear. This study aimed to systematically evaluate the impact of thermal stress on the solid-state physicochemical stability of SMG. The solid-state stability of SMG was assessed using complementary analytical techniques, including Fourier transform-infrared (FT-IR) spectroscopy, circular dichroism (CD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), reverse-phase high-performance liquid chromatography (RP-HPLC), and liquid chromatography–high-resolution mass spectrometry (LC-HRMS). FT-IR and CD analyses demonstrated that SMG retains its native α-helical conformation up to 60°C. However, the α-helical content decreased from 49.07

The dissolution behaviour of sub-micronized nanocrystals, especially for poorly soluble drugs, is quite unpredictable. Mesalamine (MES) is a high-dose, poorly soluble drug with two pKa and four ionic forms. The fabrication of sub-micronized nanocrystals reduces the dose, pill burden, and improves the therapeutic adherence. The present study investigates the dissolution behaviour of sub-micronized mesalamine (SMES), also known as nanocrystals, micronized crystals, suspension, and tablets, using different dissolution methods and the USP dissolution apparatus. The method parameters, including the choice of apparatus, hydrodynamics, buffer capacity, pH, and volume of the media, were optimized to achieve the optimal dissolution method for discriminating particle sizes. The particle size discriminatory powder dissolution method (method 5) was developed using the 1 mm beads in the USP Type I apparatus. The dissolution efficacy of MES and SMES was found to be 31.2

Introduction: Metformin HCl (MET) is widely used as an oral hypoglycemic agent for the management of type 2 diabetes mellitus. MET is contraindicated for renal compromised patients, so low-dose formulations are recommended for renal failure patients. The alternative approach is to minimize systemic exposure without compromising the therapeutic efficacy using novel site-targeted delayed-release (DR) MET tablets with low bioavailability. Proof-ofconcept studies were conducted to achieve the desired targeted dissolution profile. The manufactured batches failed to attain the desired targeted drug release profile in both acidic as well as buffer media. Methods: MET DR tablets were manufactured using the wet granulation method and subjected to pharmaceutical characterization. The investigation of the dissolution failures was conducted using different orthogonal analytical techniques including Fourier transforminfrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and rheological studies. Results: DSC results revealed reduction in enthalpy values of the drug/polymer physical mixtures and subsequent change in peak transition time of a melting endothermic event. The rheological study results confirmed the loss of viscosity of the rate-controlling polymer in the presence of the drug. There could be a possible interaction between the free acid functional group of the polymer and cationic group of MET. Conclusion: Thermal and rheological analyses were useful analytical tools for investigating dissolution failures during formulation design, submission, and post-approval commercial manufacturing.

The particle size measurement of drug nanocrystals is quite challenging due to solubility, aggregation, Ostwald ripening, non-spherical structure, sedimentation, and polydispersity nature of the particles. Dynamic light scattering (DLS) is frequently used for particle size determination of submicron-sized particles in both research and commercial manufacturing. Despite several advantages, particle size measurement and method development for drug nanocrystals using the DLS technique are limited due to repeatability and reproducibility issues. The present investigation aimed to develop the particle size method for mesalamine (MES) nanocrystals (NCs) using DLS. The method parameters such as solvent, sonication, concentration, temperature, and benchtop stability were screened, and the optimal method parameters were set to get repeatability and reproducibility. Three batches of MES NCs were used for method development, in which one center point batch and two random validation batches were taken. The determined particle size was 453.1 ± 27.1 nm with a polydispersity index (PDI) of 0.32 ± 0.05 for repeatability of the same center point batch. The mean particle size of three different center point batches was 465.4 ± 32.8 nm with a PDI of 0.49 ± 0.08, which revealed the reproducibility of the method and could be applied as a quality control tool in routine commercial manufacturing. The orthogonal microscopic techniques such as field emission scanning electron microscopy (FE SEM) and atomic force microscopy (AFM) were used to validate the DLS method. The results obtained from microscopic methods confirm the validity of the DLS method.

Postoperative ocular inflammation and pain significantly hinder visual recovery, demanding advanced drug delivery systems with enhanced biocompatibility and efficacy. Plant-derived ELNs have emerged as promising nanocarriers due to their natural origin, lipid-rich structure, and inherent safety. This study explores sesame seed-derived ELNs as a novel platform for topical ocular delivery of Nepafenac, a nonsteroidal anti-inflammatory drug (NSAID). ELNs were successfully isolated via ultracentrifugation and characterized for particle size and zeta potential, which was found to be 163.3 +/- 3.05nm and -13.52 +/- 0.89mV, respectively, and protein content was found to be 40.72 mu g/mL at 1mg/mL. Among three loading techniques, sonication yielded the highest drug loading of 19.63 +/- 2.34% and entrapment efficiency of 89.49 +/- 2.26%. In vitro release studies revealed sustained Nepafenac release of 78.2 +/- 5.64% over 24 h, outperforming the marketed formulation, which released 75.11 +/- 2.86% within 6 h. Corneal permeation through excised tissue demonstrated enhanced penetration by the ELNs formulation of 69.75 +/- 2.23% in 2 h versus the marketed suspension, which showed 60.10 +/- 3.43%. Lipidomic profiling and BCA assays confirmed the presence of key biomolecules contributing to the carrier's bioactivity. The isotonicity was confirmed by osmolarity which was found to be 295 +/- 1.3 mOsm/Kg and the viscosity was found to be 1.1 cP that indicates that the formulation behaves as a newtonian fluid, facilitating ease of ocular instillation and rapid spreading over the corneal surface without causing visual blurring or discomfort. Cytocompatibility assessed using the MTT assay in HEK293 and SIRC cells demonstrated excellent cell viability, confirming the safety of the formulation for ocular application. Live/dead confocal imaging further validated the biocompatibility of the formulation in SIRC cells. Collectively, these results validate ELNs as efficient, biocompatible, and sustainable carriers for ophthalmic drug delivery. This ELNs-based approach offers a promising alternative to conventional eye drops, enabling prolonged therapeutic action, improved corneal absorption, and reduced dosing frequency, key features for managing postoperative ocular inflammation.

Therapeutic peptides' physical and chemical stability is of significant interest to the pharmaceutical industry. This study examines the effects of pH, temperature, and buffer strength on semaglutide (SEMA) stability using two orthogonal stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) methods. The findings aid in designing novel oral and long-acting injectable (LAI) SEMA formulations. Two RP-HPLC methods were developed and validated to separate SEMA and its degradants. Stability studies were conducted at 25°C, 40°C, and 55°C for 24 h in water, with extended studies at 5°C, 25°C, 40°C, 60°C, and 80°C. pH and buffer strength effects were assessed at 25°C and 40°C. SEMA remained stable for 3 h at 80°C. The results obtained from pH-dependent stability studies indicated that SEMA was relatively stable at pH 1.2 at 25°C and 40°C for a day. A higher extent of degradation was observed between the pH of 4.5-5.5; this is due to the isoelectric point of SEMA (pH 5.4), and hence, the finished product pH should be > 7.0. These findings highlight the critical influence of buffer, temperature, and pH on SEMA stability. The results obtained by this study would help develop both oral and LAI SEMA formulations.

The low aqueous solubility limits the therapeutic potential of both new and existing drug molecules. Mesalamine (MES), a primary therapeutic agent for inflammatory bowel diseases, has low aqueous solubility and incomplete dissolution in the colon; hence, it requires a high administered dose (maximum daily dose of 4.8 g/day). This study attempts to improve the dissolution velocity and solubility by designing MES nanocrystals. MES nanocrystals were prepared using the dry ball milling (BM) process. MES nanocrystals (NCs) were prepared using Soluplus as stabilizer, and milling parameters were optimized to obtain the desirable particle size and other pharmaceutical attributes. The prepared MES NCs were characterized to understand the influence of key milling parameters like time, speed, and stabilizer concentration. Variations in these parameters resulted in diverse morphologies, including rectangular bars, elongated hexagons, spheroids, and plates. Batch 29 (40/1/400) exhibited a plate-like crystal habit with a particle size of 435 nm and a PDI of 0.39, demonstrating an improved dissolution efficacy (84

Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), are commonly treated with mesalamine (5-ASA). Among its oral dosage forms, time-dependent prolonged-release granules (PRGs) enable targeted drug delivery throughout the gastrointestinal tract. Developing generic versions of these time-dependent PRGs is challenging due to complex formulation strategies and extensive patent protection. This study functions as a systematic technical diligence, offering a structured patent landscape, clinical data analysis, and design-around strategies to uncover innovation trends, regulatory barriers, and formulation approaches relevant to generic product development. An extensive patent landscape analysis was conducted, and over 50 relevant granted patents, PCT publications, and patent applications (filed between 1983 and 2023) were analysed using major global databases, including USPTO, Espacenet, WIPO, Lens.org, and Google Patents. Granted patents, PCT publications, and patent applications were categorized by legal status, geography, and International Patent Classification (IPC) codes to uncover formulation and process innovation trends. Additionally, 12 clinical studies and formulary data complemented the landscape. The study also examined claim strategies, design-around approaches, and bioequivalence (BE) challenges relevant to generic development. The analysis revealed a progression from early sustained-release tablets to multiparticulate PRGs employing advanced granulation and coating technologies. Innovations in granulation, coating techniques, and excipient selection, such as the use of polymers with defined viscosity grades and optimised curing conditions, pose significant hurdles for generic development. Design-around strategies in non-innovator patents often involved excipient substitutions or process modifications. The development of generic time-dependent 5-ASA PRGs is challenged by complex formulation designs and layered patent protections. This analysis underscores the importance of understanding patent clusters, critical quality attributes, and regulatory timelines. Such insights can guide the formulation of effective design-around and optimization strategies, supporting the development of bioequivalent alternatives and expanding treatment options for IBD.