Elkady O.A.Tadros M.I.El-laithy H.M.Department of PharmaceuticsFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)Giza11787Egypt; Department of Pharmaceutics and Industrial PharmacyFaculty of PharmacyCairo UniversityKasr El-Aini StreetCairo11562Egypt2020-01-092020-01-09202015309932https://doi.org/10.1208/s12249-019-1561-2PubMed ID 31807950https://link.springer.com/article/10.1208/s12249-019-1561-2ScopusRisedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate chitosan (RS-CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 - 3.39 mV) discrete, spherical microspheres (3.47 - 0.16 ?m) having a high EE% (94.58 - 0.19%) and prolonged RS release over 12 h (Q12 h, 89.70 - 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 - 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS-CS crosslinker-free nebulizable microspheres. 2019, American Association of Pharmaceutical Scientists.EnglishOctober University for Modern Sciences and Artsجامعة أكتوبر للعلوم الحديثة والآدابUniversity of Modern Sciences and ArtsMSA Universitychitosancrosslinker-freemicrospheresquality by design (QbD)risedronate sodiumcesium ionchitosanmicrosphererisedronic acidsurfactantanimal experimentanimal tissueArticledrug releaseFourier transform infrared spectroscopygelationin vivo studylunglung alveolusmalenonhumanparticle sizepriority journalratrisk assessmentrisk factorstatic electricitytemperatureX ray diffractionzeta potentialArticlehttps://doi.org/10.1208/s12249-019-1561-2PubMed ID 31807950