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Open research questions in Drug Solubulity and Delivery Systems

42 unresolved questions extracted from the limitations and future-work sections of 435 Drug Solubulity and Delivery Systems papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • This study initiates the validation of P1 and P2 polymers for a new application, as these materials have not been previously studied as stabilizers in oral NS formulations.

    Formulation and Evaluation of Indomethacin Nanosuspensions Stabilized by Poly(2-oxazine) and Poly(2-oxazoline)-Based Polymers for Solubility Enhancement · 2026 · DOI

  • Despite advantages, GRDDS also presents limitations: • Variable gastric emptying • Dependence on food intake • Sensitivity to gastric pH • Risk of dose dumping • Complex formulation development Researchers continue exploring advanced polymers and improved delivery these technologies limitations and achieve more predictable gastric retention. (Menon et al., 1994; Billa et al., 2000).

    Anchored Healing: Innovative Gastroretentive Platforms for Prolonged Peptic Ulcer Therapy · 2026 · DOI

  • a major important of IJDDT, Volume 16 Issue 45s, 2026 Page 639 Anchored Healing: Innovative Gastroretentive Platforms for Prolonged Peptic Ulcer Therapy scientific guidance, ACKNOWLEDGMENT The authors express sincere gratitude to everyone who contributed to the completion of this work. Valuable discussions, constructive feedback greatly improved the quality of the manuscript.

    Anchored Healing: Innovative Gastroretentive Platforms for Prolonged Peptic Ulcer Therapy · 2026 · DOI

  • ASD has been a successful technique for addressing poor water solubility in pharma- ceutical compounds; however, the manufacturing processes employed for ASD are quite challenging, requiring the knowledge of various process- related activities related parameters and product- especially with regard to PVPVA. While several marketed products are formulated with PVPVA, it appears that PVPVA is a current industry preference for solving solubility challenges for oral delivery using ASD using SD and HME techniques that are used for thermolabile drugs and upgrading the drug loading. The increasing number of PVPVA ASD on the market demonstrates that PVPVA is successful for both solubilization as well as stabilizing poorly soluble drugs. Over the past few years, it is proven that PVPVA-based ASD are and will continue to be a significant topic of research in the field of formulation development owing to its demonstrated capacity to enhance the oral absorption of poorly soluble drugs. Prediction of drug release from PVPVA ASD requires a thorough knowledge of in vitro dissolution testing, deeper understanding of dissolution performance, drug and polymer properties. Utilization of absorption models to capture both gastric and intestinal environments are most useful for PVPVA-based ASDs. Translation from an in vitro dissolution profile to in vivo oral bioavailability is still a challenge for PVPVA ASDs. Limited research has been conducted in the literature that dealt with this issue. To anticipate in vivo performance of PVPVA ASDs, for instance, physiologically based pharmacokinetic (PBPK) modelling or IVIVC (in vitro–in vivo cor-relation) techniques should be applied. In addition, a deeper mechanistic knowledge of the absorption of APIs in biological systems is beneficial for translational methods. Furthermore, establishing robust and reliable strategies for predicting in vivo exposure from PVPVA-based ASDs will be an important area in research and development. AUTHOR CONTRIBUTIONS Pathak V: literature review, manuscript writing, data curation; Jangra K: reference verification, manuscript review; Redhu R: figure preparation, data compilation; Kushwah V: conceptualization, peer review; Yadav A: data organization, formatting; Kumar C: conceptualization, supervision, peer review, final editing. CONFLICT OF INTEREST The authors declare no conflict of interest. ACKNOWLEDGEMENTS The authors acknowledge the support of Geeta Institute of Pharmacy, Geeta University, Naultha, Panipat, Haryana, India for providing the necessary resources and facilities for the completion of this review. REFERENCES 1. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business Sinica B. prospects. Acta 2015;5(5):442-53.

    PVP/VA Based Amorphous Solid Dispersions: A Comprehensive Review on Manufacturing Techniques, Marketed Products, Clinical Perspectives and Recent Patents · 2026 · DOI

  • the industry," Pharmaceutical in 30. Dias RJ, Mali KK, Ghorpade VS, Havaldar VD, Mohite VR. Formulation and Evaluation of Carbamazepine Liquisolid Compacts Using Novel Carriers. Indian Journal of Pharmaceutical Education and Research. 2017;51(2S): S69-S78 D. 31. Fahmy RH, Kassem MA. Enhancement of famotidine dissolution rate through liquisolid tablets formulation: In vitro and in vivo evaluation. Eur J Pharm Biopharm. 2008;69(3):993-1003. 32. Spireas S, Wang T, Grover R. Effect of powder substrate on the dissolution properties of methyclothiazide liquisolid compacts. Drug Dev Ind Pharm.1999;25(2):163-8. 33. Spireas S. Liquidsolid system and method of same U.S.Patent 6423339B1, preparing 2002R. 34.. El Maziri, "The choice of excipients in the composition of tablets with ranitidine," 2023. 35.. W. Style, R. Tutika, J. Y. Kim, et al., "Solid– liquid composites for soft multifunctional materials," *Advanced Functional Materials*, vol. 31, no. 6, 2021. 36. Davis DA Jr, Thakkar R, Su Y, Williams RO III. Selective laser sintering three-dimensional printing as a single-step process to prepare amorphous solid dispersion dosage forms for improved solubility and dissolution. Journal of Pharmaceutical Sciences,2021. 37. E. O. Kissi, R. Nilsson, L. P. Nogueira, A. Larsson et al., "Influence of drug load on the printability and solid-state properties of 3Dprinted naproxen-based amorphous solid dispersion," Molecules, 2021. 38. T. W. Jarrells and E. J. Munson, powder Xray diffraction, and solid-state nuclear magnetic for measuring crystallinity in amorphous solid spectroscopy resonance INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES 4375 | P a g e Lakshya Veer Singh, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 4357-4383 | Review dispersions-application to drug-in" Journal of Pharmaceutical Sciences, 2022. Intensity Acoustic Vibration," Processes, 2023. 39. S. Sareen, G. Mathew, and L. Joseph, "Improvement in solubility of poor watersoluble drugs by solid dispersion," 2012. 40. Elkordy AA, Essa EA, Elshafeey AH. Influence of carrier and coating particle size on the release of furosemide from liquisolid compacts. Eur J Pharm Biopharm. 2012;80(2):480-6. 41. Javadzadeh Y, Siahi MR, Asnaashari S, Nokhodchi A. Liquisolid compacts: The effect of excipient particle size and type on dissolution rate of poorly water-soluble drugs. J Pharm Sci. 2007;96(4):1141-50. reduction 42. R. Kumar, A. K. Thakur, P. Chaudhari, "Particle size techniques of the pharmaceutical for enhancement of their dissolution rate and bioavailability," Journal of Pharmaceutical, vol. 2022, Springer. compounds 43. Kassem MA, Mohsen AM, Ahmed RS. The effect of particle size reduction and liquisolid technique on dissolution enhancement of hydrophobic drugs. J Drug Deliv Sci Technol. 2017;39:25-33. 44. Khan I, Khan MI, Khan U.

    Liquid-Solid Compacts: Approach for Improving Drug Solubility and Bioavailability · 2026 · DOI

  • Looking ahead, cyclodextrins are expected to play an increasingly important role in advanced cosmetic formulations. Their combination with nanotechnology-based systems offers promising opportunities for improving skin penetration and enabling more precise control over the release of active ingredients (Ribeiro et al., 2020). They are also likely to find broader use in herbal and natural formulations, where challenges related to solubility and stability are particularly common (Astray et al., 2009). In targeted skincare applications, especially in anti-aging products, cyclodextrins may help www.wjpr.net │ Vol 15, Issue 10, 2026. │ ISO 9001: 2015 Certified Journal │ 507 Astha et al. World Journal of Pharmaceutical Research enhance the delivery of actives while reducing irritation. Continued research into modified and polymer- based systems is expected to further expand their potential in this area.

    CYCLODEXTRINS IN COSMETIC FORMULATIONS: EMERGING ROLE AS SOLUBILITY ENHANCERS, STABILIZERS AND FUNCTIONAL CARRIERS · 2026 · DOI

  • The future of GRDDS is expected to evolve into intelligent and personalized medicine. The main prospects are as follows: 14.1. Digital Integration: The real-time monitoring of the gastric retention and physiologic data could be done by integrating small ingestible sensors within smart pills, providing information to clinicians about medication adherence and performance.[117] 14.2. AI-Driven Formulation: GRDDS development requires analysis of complex data that can be easily done by using AI and Machine Learning models, which saves time and cost required to develop an optimized and effective dosage form.[106] 14.3. Delivery of Biologics: The delivery of biologics like peptides, proteins and nucleic acids involves designing the protective gastric depot having permeation enhancers and enzyme inhibitors.[118] 14.4. Advanced Manufacturing: 4D printing will be used to fabricate devices that change shape inside the stomach in response to gastric stimuli, ensuring mechanical retention followed by safe disintegration. [119] 15. Identified Research Gaps and Future Directions Despite the substantial progress, many critical research gaps persist and offer an opportunity for further investigation: 15.1. IVIVC Gap: The most important challenge today, however, is the absence of in vitro dissolution and retention studies that are capable of predicting the dynamic, biologically active conditions found within the human stomach concerning its contraction and motility pattern, shear forces, and fluctuating pH and volume. The development of more biorelevant and mechanically dynamic in vitro apparatuses is considered highly crucial to enhance the predictive power of pre-clinical studies and reduce the high failure rates in clinical development. 15.2. Safety of Long-term Gastric Retention: There is a paucity of long-term toxicological data on the continuous exposure of the gastric mucosa to high concentrations of drugs and polymeric excipients from GRDDS. Systematic studies are needed to evaluate the potential for chronic irritation, mucosal damage, or unforeseen complications, particularly for drugs meant for lifelong management of chronic diseases. 15.3. Standardization and Robustness for Clinical Translation: The performance of many gastroretentive drug delivery systems is variable and influenced by factors such as prandial state and individual physiological differences. The formation of harmonized regulatory frameworks and strong bioequivalence protocols for generic GRDDSs continues to be one of the important challenges.

    Conquering Gastric Transit: A Comprehensive Review of Gastroretentive Drug Delivery Systems - From Mechanistic Foundations to AI-Driven Innovations · 2026 · DOI

  • Section 10.2 asserts that floating microspheres are particularly effective for drugs acting locally in the stomach (gastritis, gastric ulcers, acid-related diseases) by maintaining prolonged gastric retention, but does not provide comparative efficacy data or head-to-head clinical trials comparing floating microsphere formulations to existing gastroretentive therapies (e.g., sucralfate suspension, bismuth compounds) in these disease states.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • The paper discusses pharmacokinetic studies using animal models (rats, rabbits, dogs) and human volunteers with blood sampling at predetermined intervals analyzed by HPLC, LC-MS/MS, or UV spectroscopy, but does not specify the recommended sampling intervals, total study duration, or inter-species translation factors required to predict human pharmacokinetics of floating microspheres from preclinical animal data.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • Nano floating microspheres are introduced as a recent advance combining nanotechnology with gastroretentive drug delivery (Section 11.1), but the excerpt is truncated and does not specify the size range, buoyancy mechanisms, or comparative advantages of nano floating microspheres versus conventional microspheres (typically 50-300 μm) in terms of gastric retention, drug release kinetics, or bioavailability enhancement.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • The paper emphasizes that floating microspheres enhance H. pylori eradication by maintaining high local antibiotic concentrations and improving mucus layer penetration, but does not provide specific data on whether current floating microsphere formulations can achieve sufficient penetration depth through the gastric mucus layer to reach H. pylori residing in deep mucosal folds or under biofilm structures.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • Table 8 lists levodopa, riboflavin, furosemide, metformin, and ciprofloxacin as candidate drugs for floating microspheres with narrow absorption windows, but the paper lacks quantitative data on the minimum gastric retention time required for each drug to achieve clinically meaningful improvements in bioavailability or AUC compared to conventional formulations.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • The paper discusses IVIVC establishment for floating microspheres by correlating in-vitro dissolution profiles with in-vivo plasma concentration-time data, but does not specify which Level (I, II, III, or IV) IVIVC classifications have been successfully established for different drug classes or polymer matrices used in gastroretentive microsphere formulations.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • Gamma scintigraphy with technetium-99m radiolabeling is identified as the gold standard for assessing gastroretentive floating microspheres, but the paper does not specify comparative studies evaluating radiation exposure risks versus alternative imaging modalities (MRI, ultrasonography) for long-term or repeated pharmacokinetic monitoring in human volunteers.

    <b>Gastroretentive Floating Microspheres: A Promising Approach for Site-Specific and Controlled Drug Delivery.</b> · 2026 · DOI

  • The study demonstrates that EZE exhibits more variable release governed by mixed diffusion-matrix relaxation mechanisms compared to ROS (dominantly diffusion-driven), but the specific molecular interactions or localization differences within the PLGA core versus lipid shell that govern these distinct release mechanisms in the lipid-polymer hybrid nanoparticles remain mechanistically unclear.

    Response0 surface guided design of lipid-polymer hybrid nanoparticles for dual delivery of rosuvastatin and ezetimibe · 2026 · DOI

  • Long-term storage stability was assessed at three months with observed shifts in zeta potential toward more positive values, but the excerpt does not specify the complete characterization of stability parameters (particle size, drug loading retention, crystallinity changes) or extended storage timepoints beyond three months for the rosuvastatin and ezetimibe-loaded LPHNPs.

    Response0 surface guided design of lipid-polymer hybrid nanoparticles for dual delivery of rosuvastatin and ezetimibe · 2026 · DOI

  • The diffusion gradient mechanism governing drug release was inferred from kinetic modeling differences between formulation 1 (lowest DOTAP) and formulation 4 (highest DOTAP), but direct experimental validation of the proposed diffusion gradient hypothesis in lipid-polymer hybrid nanoparticles with varying drug loading and DOTAP content is absent.

    Response0 surface guided design of lipid-polymer hybrid nanoparticles for dual delivery of rosuvastatin and ezetimibe · 2026 · DOI

  • FTIR spectroscopy analysis could not definitively determine which stabilizer (poloxamer 188 or polysorbate 80) is more prominently present on the LPHnp surface; a more quantitative surface characterization technique is needed to precisely identify the composition and spatial distribution of stabilizers in the lipid-polymer hybrid nanoparticle shell.

    Response0 surface guided design of lipid-polymer hybrid nanoparticles for dual delivery of rosuvastatin and ezetimibe · 2026 · DOI

  • The study evaluated drug release profiles in standard pH 6.8 and 7.4 dissolution media, but the authors explicitly note that future evaluation in biorelevant FaSSIF and FeSSIF media mimicking actual gastrointestinal conditions is needed to establish in vitro-in vivo correlation for the rosuvastatin and ezetimibe-loaded lipid-polymer hybrid nanoparticles.

    Response0 surface guided design of lipid-polymer hybrid nanoparticles for dual delivery of rosuvastatin and ezetimibe · 2026 · DOI

  • Systematic and scientific approaches to research and formulation of FDC drugs are necessary to guide pharmaceutical research and development activities and promote rational, safe drug use in clinical practice.

    Fixed-dose Combination Medicinal Products: the Role of Modern Pharmaceutics · 2026 · DOI

  • 3D printing technology for FDC drugs is researched extensively with diverse techniques rather than being applied and deployed for commercial drug manufacturing.

    Fixed-dose Combination Medicinal Products: the Role of Modern Pharmaceutics · 2026 · DOI

  • FDC drugs applying 3D printing technology have not yet been commercialized, with many studies applying the technology to combine multiple active ingredients in various dosage forms rather than industrial production deployment.

    Fixed-dose Combination Medicinal Products: the Role of Modern Pharmaceutics · 2026 · DOI

  • AI/ML models (LASSO, MLP, SVR) correlate solubility with density but require validation across broader drug libraries and diverse physicochemical properties.

    Solubility Enhancement Strategies for Poorly Soluble Drugs: Recent Trends · 2026 · DOI

  • Stability studies are mentioned as evaluating long-term stability and shelf life under varied storage conditions, but specific protocols, acceptable criteria, and comparative data across different FDT formulations are not detailed.

    A Comprehensive Review on Fast Dissolving Tablets · 2026 · DOI

  • than technological. High drug loading or poorly flowing APIs can compromise compressibility and disintegration performance, excipient optimization.2 formulation-driven necessitating careful rather are -Lyophilization yielding exceptionally Lyophilization (freeze-drying) produces highly porous ODTs by sublimation of water from a frozen drug– polymer matrix, rapid disintegration due to capillary action within the sponge- like structure .1,19 While this method achieves superior in-mouth dispersion, its commercial utility is constrained by high production costs, low throughput, and the mechanical fragility of the final dosage form. As a result, lyophilized ODTs require specialized blister packaging and are less suited to large- scale, cost-sensitive markets .1 long cycle times, Overall, conventional technologies are characterized by high regulatory readiness and scalability, but their performance is tightly coupled to excipient selection and formulation design.

    Advances in Orally Disintegrating Tablets (ODTs): Formulation Strategies and Future Prospects · 2026 · DOI

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42 open questions have been extracted from the limitations and future-work passages of 435 Drug Solubulity and Delivery Systems papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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