Issue link: http://www.e-digitaleditions.com/i/552614
process dependent on formulation requirements. A decision to include excipients without precedence must be carefully evaluated as additional toxicology studies may be required which adds risk to the overall develop- ment program. 9 Some compounds can be sprayed neat without the addition of any excipients—a "formula- tion" concept worth considering for certain stability pro- file and dose requirements. In the albuterol case study, lactose—with an approximate aqueous solubility to the active ingredient—provided a high dry state Tg for the resulting product. Spray dried powder manufacture and analytical characterization It is imperative to perform rigorous solid-state character- ization of spray dried powders in order to understand and anticipate performance and stability. Analysis should be performed under best-case conditions, often approximating the anticipated storage conditions of the final drug product as well as anticipated extreme condi- tions, which short term informal stability studies can mimic. Table 1 summarizes and highlights a standard battery of solid-state analytical tests performed at Cap- sugel Dosage Form Solutions/Bend Research for the development of inhalation spray dried powders. As shown using the case study, albuterol powder charac- teristics were similar across scale and formulation. One small difference between the formulations was observed by modulated differential scanning calorimetry (mDSC) analysis as increasing active ingredient decreased glass transition temperature (Tg). This was expected as the Tg of amorphous albuterol sulfate is approximately 60°C and, as a result, by increasing the albuterol content, a reduction in glass transition temperature of an amorphous dispersion would be expected. Water content of the final spray dried product is an important parameter to under- stand, especially with regard to inhalation and protein therapeutics, as water content not only impacts molecular mobility and thermal tolerances (Tg), but also impacts particle aggregation and protein stability. Generally, the powder is processed at spray dryer conditions designed to meet water contents between 1-5 weight %. The geometric particle size of the spray dried particles was consistent across all four batches which, given differ- ences in manufacturing scale of some of these powders, highlighted the robustness of the current process approach. SEM analysis revealed that each of the dry powder formulations was comprised of wrinkled spheres with rough surfaces independent of active loadings and spray dryer scales (Figure 2). Surface roughness (rugos- ity) is often desirable for powders destined for the lung, in that static and water capillary forces between the par- ticles are often decreased and entrainment into the air- flow is increased, which when combined enables "declumping" and more efficient delivery of powders during inhalation. Encapsulation considerations and process Capsules were filled with varying weights of powder using the Xcelodose filling system. Consistent fill weights were observed at 5 mg, 10 mg and 20 mg of total powder; relative standard deviations (RSDs) were between 1.7 mg and 2.3 mg, decreasing as fill weights increased. These fill weights were selected, as they approximately match fill weights for capsule-based inhalation drug products and exhibit almost three orders of magnitude dose ranges achievable with this process. Aerosol evaluation of spray dried powders Along with solid-state characterization approaches, aerosol characteristics using an NGI were studied to bet- ter understand the impact of albuterol loading and scale 10 AUGUST 2015 Inhalation Figure 1 Highly Crystalline API e.g. corticosteroids, LAMA's 400 350 300 250 200 150 100 50 0 • Disperse/flow enhancing surface • Excipient binder/diluent • Sub-micron API crystals • Disperse/flow enhancing surface • Excipient binder/diluent • Amorphous dispersion of API and excipient 0 1 2 3 4 5 6 Amorphous API e.g. albuterol, biotherapeutics 5µm 5µm 3.98µm 2.45µm Melting Point (°C) LogP Drug property characteristics that may drive formulation and process approaches. Crystalline or amorphous drug forms may be present in spray dried particles depending on API melting points.