title: Inhalable Ipratropium Bromide Particle Engineering with Multicriteria Optimization.
abstract: Spray-dried ipratropium bromide (IPB) microspheres for oral inhalation were engineered using Quality by Design. The interrogation of material properties, process parameters, and critical product quality attributes interplay enabled rational product design. A 27-3screening design exhibited the Maillard reaction between L-leucine (LL) and lactose at studied outlet temperatures (OT) >130°C. A response surface custom design was used in conjunction with multicriteria optimization to determine the operating design space to achieve inhalable microparticles. Statistically significant predictive models were developed for volume median diameter (p = 0.0001, adjusted R2= 0.9938), span (p = 0.0278, adjusted R2= 0.7912), yield (p = 0.0020, adjusted R2= 0.9320), and OT (p = 0.0082, adjusted R2= 0.8768). An independent verification batch confirmed the model's predictive capability. The prediction and actual values were in good agreement. Particle size and span were 3.32 ± 0.09 μm and 1.71 ± 0.18, which were 4.7 and 5.3% higher than the predicted values. The process yield was 50.3%, compared to the predicted value of 65.3%. The OT was 100°C versus the predicted value of 105°C. The label strength of IPB microparticles was 99.0 to 105.9% w/w suggesting that enrichment occurred during the spray-drying process. The present study can be utilized to initiate the design of the first commercial IPB dry powder inhaler.
authors.affiliation: College of Pharmacy & Health Sciences, Department of Pharmaceutical Sciences, Campbell University, Buies Creek, North Carolina, USA.|Tergus Pharma LLC, Durham, North Carolina, USA.
authors.forename: Bhavani Prasad
authors.initials: BP
authors.lastname: Vinjamuri
authors.affiliation: College of Pharmacy & Health Sciences, Department of Pharmaceutical Sciences, Campbell University, Buies Creek, North Carolina, USA.
authors.forename: Rahul V
authors.initials: RV
authors.lastname: Haware
authors.affiliation: College of Pharmacy & Health Sciences, Department of Pharmaceutical Sciences, Campbell University, Buies Creek, North Carolina, USA. stagnerw@campbell.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Stagner
mesh_terms: D000280:Administration, Inhalation; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D002616:Chemical Engineering / Q000379:methods*; D003890:Desiccation; D058995:Dry Powder Inhalers / Q000379:methods; D009241:Ipratropium / Q000008:administration & dosage / Q000138:chemical synthesis*; D007785:Lactose / Q000008:administration & dosage / Q000138:chemical synthesis; D010316:Particle Size; D011208:Powders; D013696:Temperature; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D001993:Bronchodilator Agents; D011208:Powders; D009241:Ipratropium; D007785:Lactose
keywords: design of experiments; dry powder inhaler; ipratropium bromide; multicriteria optimization; quality by design; spray drying