Issue link: https://www.e-digitaleditions.com/i/1276475
24 August 2020 Inhalation Combination approaches for complex situations In certain complex situations, like an API with a ten- dency to agglomerate in a micronized state and low solubility in suitable solvents for spray drying, com- bination approaches offer almost limitless engineer- ing possibilities. In particular, milling followed by suspension spray drying enables the creation of core- shell structures in which a crystalline API core may be coated with a thin layer of an excipient to alter the sur- face chemistry. 11, 12 is alteration could be performed to improve the aerosolization process or to stabilize the powder to prevent fusing. Additionally, this approach also provides a means of re-isolating the milled API from a wet media milling process. While there are many advantages to jet milling, achiev- ing sub-micron particle size may not be possible in a jet milling process. If sub-micron particles are required to achieve sufficient bioavailability of a low aqueous solu- bility API, then wet media milling may be most appro- priate. During process design for wet media milling, an appropriate anti-solvent and stabilizing excipients to limit Ostwald ripening must be evaluated. 13 If a stable sub-micron suspension can be formed (such as by a flow-through wet media mill or by a batch-style reso- nant acoustic mixer), then spray drying offers a means to reproducibly isolate and collect the milled material from the suspension. While a combination approach may allow additional degrees of freedom in particle engineering, it adds complexity and costs to the manufacture of these parti- cles. Before using them, drug manufacturers will likely benefit from evaluating whether these approaches are required or provide significant benefits that a simpler approach would not be able to achieve. Choosing the correct particle engineering approach for speed to clinic and patient Many factors influence the development speed for a new drug product. Understanding the options and limitations of the API is a crucial first step. While all the approaches previously mentioned can produce powder with ideal pulmonary delivery characteristics, under- standing the advantages and limitations of multiple approaches early on could save time and money. For instance, if milling and spray drying result in similar powder attributes, milling could be a clear choice for a simpler, high-throughput path forward. It may be ben- eficial to consider a concurrent approach while evalu- ating particle engineering techniques at the feasibility stage, as compared to a step-wise approach. Other milling approaches, like ball milling, rely on collisions between a hard grinding media and the product. In this case, some care must be taken to ensure no contamination of the product with the mill- ing media as well as to separate the product from the media. Due to the jet mill's reliance on particle/parti- cle collisions in air, the risk of contamination is lower and product losses in the machinery or on the grind- ing media are minimized. 10 Jet milling is amenable to size reduction for respirable powder manufacturing but under certain circum- stances it may not be the ideal approach. While the technique is most appropriate when a material can be reproducibly crystallized with a relatively high melt temperature, if the starting crystallinity or crystallite size of the API is variable, then the resulting milled particle size may be more dependent on ingoing attributes than on milling process parameters. is outcome can then present scale-up and/or lot-to-lot variability challenges. If the melt temperature is too low, the likelihood of producing amorphous material while milling increases. e formation of amorphous material may not prohibit commercial product devel- opment, but the risk of future form change can be considered by assessing whether the amorphous mate- rial will re-crystallize on stability, whether recrystalli- zation results in particle fusing, if amorphous material is more susceptible to degradation and whether bio- availability is significantly affected due to changes in dissolution. By considering risks like these based on prior knowledge of the API or specifically designed studies, researchers can determine whether jet milling is the right engineering approach. Overall, jet milling offers the advantages of a continuous, scaleable pro- cess for micronizing many different types of material with no solubility requirements. In top-down approaches, API aerosol formation and powder flowability can be further modified after mill- ing by blending the micronized API with excipients such as carriers (e.g., lactose) or surface modifying agents (e.g., magnesium stearate). ere are a variety of lactose carrier grades, from coarse particles to fine particles, that can be used to adjust the balance of adhesion between carrier and API particles. Blending also provides a benefit for indications with low-dose requirements (i.e., < 5 mg API). In these cases, it may be possible to improve powder handling in dose-filling operations, which, in turn, improves the consistency of dose delivery to the lungs. In cases of low interac- tion forces between particles, it may be possible to dose the micronized API without excipients, thereby enabling higher active content per dose while also circumventing concerns about powder blend content uniformity. Initial feasibility studies would evaluate the neat API without the use of excipients before addi- tional formulation approaches were taken.