{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:07:57Z","timestamp":1788772077785,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: In this study, two cocrystals of diclofenac acid (DCA) with the coformers theophylline (THEO) and isonicotinamide (ISNT) were prepared. Subsequently, nanococrystals were generated from these cocrystals using a top-down wet media milling approach. Methods: Critical process parameters such as milling time, milling volume, drug loading percentage, bead volume, and dispersion media were optimized to achieve the desired particle size distribution. The nanococrystals were characterized using dynamic light scattering (DLS), polarized light microscopy (PLM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results: In vitro dissolution studies revealed that nanococrystals of DCA-ISNT (DE0\u2013120 = 22.5% at pH 1.2 and DE0\u2013120 = 58.7% at pH 4.5) and DCA-THEO (DE0\u2013120 = 18.5% at pH 1.2 and DE0\u2013120 = 48.2% at pH 4.5) exhibited superior dissolution performance compared to DCA nanocrystals (DE0\u2013120 = 12.5% at pH 1.2 and DE0\u2013120 = 39.0% at pH 4.5), with the dissolution advantage decreasing as the pH of the medium increased. The improved dissolution behaviour was a complex interplay of factors including particle size distribution, surface wetting kinetics, exposure of hydrophilic\/hydrophobic functional groups during dissolution, nanococrystal microenvironmental pH, DCA\u2019s ionization behaviour, lattice energy, and intermolecular interaction strengths. Additionally, nanococrystals exhibited a significantly higher flux rate in simultaneous gastric transfer dissolution and flux studies compared with DCA, likely due to higher apparent solubility and superior diffusion through the unstirred water layer (UWL). Pharmacokinetic studies confirmed that nanococrystals DCA-ISNT NCC (AUC0\u2013\u221e = 3062.65 \u00b1 526.91 ng\/mL\u00b7h) outperformed DCA nanocrystals (AUC0\u2013\u221e = 2352.53 \u00b1 537.78 ng\/mL\u00b7h), DCA-THEO NCC (AUC0\u2013\u221e = 2222.96 \u00b1 151.19 ng\/mL\u00b7h) and the cocrystals in terms of pharmacokinetic performance. Conclusions: The findings indicate that DCA-ISNT NCC exhibited superior pharmacokinetic performance and, together with the enhanced dissolution and flux properties of the nanococrystals, demonstrates their potential for enhanced therapeutic efficacy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091119","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nanococrystals of Diclofenac Acid to Improve Biopharmaceutical Performance: Understanding the Key Drivers"],"prefix":"10.3390","volume":"18","author":[{"given":"Katangur Vishruth","family":"Reddy","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumalya","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourav","family":"Chougule","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Pariskar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2245-4401","authenticated-orcid":false,"given":"Rohit Y.","family":"Sathe","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, Institute of Chemical Technology, Matunga, Mumbai 400019, Maharashtra, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Dangi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasad V.","family":"Bharatam","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-6680","authenticated-orcid":false,"given":"Arvind K.","family":"Bansal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar 160062, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1111\/j.2042-7158.2010.01030.x","article-title":"Pharmaceutical applications of cyclodextrins: Basic science and product development","volume":"62","author":"Loftsson","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.1016\/j.apsb.2024.08.027","article-title":"Solubilization techniques used for poorly water-soluble drugs","volume":"14","author":"Xie","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/S1359-6446(04)03171-X","article-title":"Application of formulation technologies in lead candidate selection and optimization","volume":"9","author":"Chaubal","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s11814-010-0520-0","article-title":"Solid forms of pharmaceuticals: Polymorphs, salts and cocrystals","volume":"28","author":"Sarma","year":"2011","journal-title":"Korean J. Chem. Eng."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.addr.2007.05.010","article-title":"Salt formation to improve drug solubility","volume":"59","author":"Serajuddin","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ijpharm.2017.10.051","article-title":"Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery\u2014An update","volume":"535","author":"Jermain","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.addr.2007.05.011","article-title":"Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates","volume":"59","author":"Blagden","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","unstructured":"U.S. Food and Drug Administration (2018). Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry (Revision 1)."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1016\/j.apsb.2025.12.003","article-title":"Crystal engineering for poorly water-soluble drugs: From design to applications","volume":"16","author":"Chen","year":"2026","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105422","DOI":"10.1016\/j.ejps.2020.105422","article-title":"The role of pH and dose\/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation","volume":"152","author":"Machado","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1021\/acs.cgd.1c00950","article-title":"Bioavailability-Enhancing Cocrystals: Screening, In Vivo Predictive Dissolution, and Supersaturation Maintenance","volume":"22","author":"Chen","year":"2022","journal-title":"Cryst. Growth Des."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6719","DOI":"10.1021\/acs.cgd.6b01434","article-title":"Harvesting Potential Dissolution Advantages of Soluble Cocrystals by Depressing Precipitation Using the Common Coformer Effect","volume":"16","author":"Yamashita","year":"2016","journal-title":"Cryst. Growth Des."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6370","DOI":"10.1021\/acs.cgd.8b00933","article-title":"Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and Applications","volume":"18","author":"Padrela","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.ejps.2015.06.006","article-title":"Novel nanosized formulations of two diclofenac acid polymorphs to improve topical bioavailability","volume":"77","author":"Pireddu","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1007\/s11095-022-03243-9","article-title":"Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs","volume":"39","author":"Huang","year":"2022","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"121536","DOI":"10.1016\/j.ijpharm.2022.121536","article-title":"Kinetic solubility improvement and influence of polymers on controlled supersaturation of itraconazole-succinic acid nano-co-crystals","volume":"616","author":"Huang","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejpb.2016.07.006","article-title":"A novel solubilization technique for poorly soluble drugs through the integration of nanocrystal and cocrystal technologies","volume":"107","author":"Karashima","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125172","DOI":"10.1016\/j.ijpharm.2025.125172","article-title":"Simultaneously improving tabletability and solubility of diclofenac by cocrystallization with picolinamide","volume":"670","author":"Wu","year":"2025","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/jps.24647","article-title":"Gastrointestinal Behavior of Weakly Acidic BCS Class II Drugs in Man\u2014Case Study of Diclofenac Potassium","volume":"105","author":"Brouwers","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/ijcp.12359","article-title":"Comparison of intramuscular compound betamethasone and oral diclofenac sodium in the treatment of acute attacks of gout","volume":"68","author":"Zhang","year":"2014","journal-title":"Int. J. Clin. Pract."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105654","DOI":"10.1016\/j.ejps.2020.105654","article-title":"Anti-inflammatory drug nanocrystals: State of art and regulatory perspective","volume":"158","author":"Macedo","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jadhav, S., Kaur, A., and Bansal, A.K. (2020). Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12111015"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1016\/j.xphs.2020.08.002","article-title":"Composing Novel Diclofenac Potassium and l-Proline Salt Cocrystal as a Strategy to Increase Solubility and Dissolution","volume":"109","author":"Nugrahani","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0378-5173(03)00315-6","article-title":"The use of solid self-emulsifying systems in the delivery of diclofenac","volume":"262","author":"Attama","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ijpharm.2009.01.024","article-title":"Diclofenac nanosuspensions: Influence of preparation procedure and crystal form on drug dissolution behaviour","volume":"373","author":"Lai","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e04864","DOI":"10.1016\/j.heliyon.2020.e04864","article-title":"Diclofenac-proline nano-co-crystal development, characterization, in vitro dissolution and diffusion study","volume":"6","author":"Nugrahani","year":"2020","journal-title":"Heliyon"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.2042-7158.1975.tb09378.x","article-title":"The concept of dissolution efficiency","volume":"27","author":"Khan","year":"1975","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107294","DOI":"10.1016\/j.ejps.2025.107294","article-title":"Excipient variability critically impacts crystallization propensity of spray-dried amorphous solid dispersions","volume":"216","author":"Bhadoriya","year":"2026","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5226","DOI":"10.1021\/acs.molpharmaceut.3c00646","article-title":"Study on Sulfamethoxazole\u2013Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties","volume":"20","author":"Roy","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1002\/jps.20932","article-title":"Microenvironmental pH Modulation in Solid Dosage Forms","volume":"96","author":"Badawy","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106037","DOI":"10.1016\/j.ejps.2021.106037","article-title":"Is equilibrium slurry pH a good surrogate for solid surface pH during drug dissolution?","volume":"168","author":"Uekusa","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1007\/s11095-008-9679-z","article-title":"Miniaturized Rotating Disk Intrinsic Dissolution Rate Measurement: Effects of Buffer Capacity in Comparisons to Traditional Wood\u2019s Apparatus","volume":"25","author":"Avdeef","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1007\/s11095-005-2504-z","article-title":"Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH","volume":"22","author":"Li","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1002\/jps.21052","article-title":"Measurement of Surface pH of Pharmaceutical Solids: A Critical Evaluation of Indicator Dye-Sorption Method and its Comparison with Slurry pH Method","volume":"97","author":"Pudipeddi","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/jps.2600740208","article-title":"Effect of Diffusion Layer pH and Solubility on the Dissolution Rate of Pharmaceutical Bases and their Hydrochloride Salts I: Phenazopyridine","volume":"74","author":"Serajuddin","year":"1985","journal-title":"J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00894-016-2909-0","article-title":"COMPASS II: Extended coverage for polymer and drug-like molecule databases","volume":"22","author":"Sun","year":"2016","journal-title":"J. Mol. Model."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1023\/B:JCAM.0000035186.90683.f2","article-title":"VEGA\u2014An open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming","volume":"18","author":"Pedretti","year":"2004","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1023\/A:1016024005429","article-title":"Lipophilicity in Molecular Modeling","volume":"13","author":"Testa","year":"1996","journal-title":"Pharm. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1107\/S1600576721002910","article-title":"CrystalExplorer: A program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals","volume":"54","author":"Spackman","year":"2021","journal-title":"J. Appl. Crystallogr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1021\/acs.molpharmaceut.9b00406","article-title":"Prediction of Bioequivalence and Food Effect Using Flux- and Solubility-Based Methods","volume":"16","author":"Tsinman","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_41","first-page":"365","article-title":"PAMPA\u2014A drug absorption in vitro model: 11. Matching the in vivo unstirred water layer thickness by individual-well stirring in microtitre plates","volume":"22","author":"Avdeef","year":"2004","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18565","DOI":"10.1039\/C7CP01372H","article-title":"Enhanced steady-state dissolution flux in reactive convective dissolution","volume":"19","author":"Loodts","year":"2017","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1208\/s12248-021-00668-9","article-title":"Flux-Based Formulation Development\u2014A Proof of Concept Study","volume":"24","author":"Nagy","year":"2022","journal-title":"AAPS J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.1021\/mp5004652","article-title":"Pharmaceutical Cocrystals of Diflunisal and Diclofenac with Theophylline","volume":"11","author":"Surov","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1021\/cg100670k","article-title":"Pharmaceutical Co-crystals with Isonicotinamide\u2014Vitamin B3, Clofibric Acid, and Diclofenac\u2014And Two Isonicotinamide Hydrates","volume":"11","author":"Lemmerer","year":"2011","journal-title":"Cryst. Growth Des."},{"key":"ref_46","first-page":"84","article-title":"Anisotropic surface chemistry of crystalline pharmaceutical solids","volume":"7","author":"Heng","year":"2014","journal-title":"AAPS PharmSciTech"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1208\/s12249-021-02182-9","article-title":"Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution","volume":"23","author":"Jagia","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4610","DOI":"10.1021\/acs.molpharmaceut.9b00716","article-title":"Role of Structure, Microenvironmental pH, and Speciation to Understand the Formation and Properties of Febuxostat Eutectics","volume":"16","author":"Jagia","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nrd1280","article-title":"Crystal structures of drugs: Advances in determination, prediction and engineering","volume":"3","author":"Datta","year":"2004","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1119\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:11:07Z","timestamp":1788768667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,6]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["pharmaceutics18091119"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18091119","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,6]]}}}