Inhalable Ipratropium Bromide Particle Engineering with Multicriteria Optimization.

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 27-3 screening 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 R 2 = 0.9938), span (p = 0.0278, adjusted R 2 = 0.7912), yield (p = 0.0020, adjusted R 2 = 0.9320), and OT (p = 0.0082, adjusted R 2 = 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.

[A new method for technical synthesis of tertiary and quaternary d,1-tropic acid esters of some N-subsituted nortropan- and granatan-3-oles (author's transl)]. / Eine neue Methode zur technischen Darstellung von tertiären und quartären d,1-Tropasäureestern einiger N-substituierter Nortropan- bzw. Granatan-3-ole

A new technically feasible method for synthesizing atropine is described. This method can also be applied to N-substituted nortropan- and granatan-3-oles. The quaternization of these basic tropic acid ester yields new substances which have a pharmacological profile different from that of atropine. The stereoselectivity of the quanternization reaction is discussed.