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Inhalation June 2022 25 material. is may pose a risk to the drug product, impacting both chemical degradation and physical changes. Ideally, therefore, full crystallinity of the API should be restored in a so-called "condition- ing" process, e.g., by exposing the micronized drug to controlled relative humidity (RH) [4], or alterna- tively to ethanol vapor. By thorough method devel- opment and tight control of RH or ethanol activity (RE), particle growth during the conditioning pro- cess can be kept to a minimum. Spray-drying of API-containing solutions or suspen- sions is another route to the production of inhalable particles [2, 5]. Spray-drying for inhalation is becom- ing increasingly popular and is often the preferred route for biomolecular drugs. However, we will not discuss spray-dried particles in detail here because they may not be the first choice for formulating adhesive mixtures. e micronized API consists of fractured irregular particles that, in most cases, are extremely cohesive, which is why formulation approaches are needed. Particle size distribution is the most critical API property, as it directly relates to the fraction of API that is able to reach to the lungs, but other import- ant API parameters have also been investigated [6]. For example, the shape and surfaces of micronized particles may vary considerably among APIs and such differences will strongly influence dispersion behavior. Despite extensive research, including work in the fields of solid state and material sciences, it is still not possible to predict the dispersibility of a micronized API. Attempts include methods based on atomic force microscopy (AFM) to measure the force between the API and (carrier) lactose [7, 8]. AFM can also be used for assessment of the cohesive- adhesive balance (CAB) [9]. Several other properties of the micronized API contribute to dispersibility, for example, frictional properties [10]. Additional API properties that should merit attention include mechanical properties, which will be discussed in the processing section of this article. A way to circumvent the challenge of assessing the cohesiveness and dispersibility of the API is to per- form pre-formulation studies using relevant excipi- ents, compositions and mixing conditions. Analysis of FPF data may then enable calculation of the "appar- ent dispersibility" of the API in the relevant type of formulation [11, 12]. The excipients Lactose carrier e main excipient, by weight, in the adhesive mix- ture will always be the carrier. Within the carrier size range of approximately 50-300 µm, there are mul- tiple grades of lactose for inhalation from which to select. e choice of carrier has a major impact on formulation performance and a range of carrier particle fraction (FPF). Besides dispersibility, the stability of the inhaled product (both chemical and physical stability) is critical and must be monitored continuously during development work. at discus- sion is, however, outside the scope of this article. Key pharmaceutical requirements Apart from standard pharmaceutical requirements for assay, degradation products, appearance, homo- geneity and uniformity of dose, a key requirement for inhalation products is that the formulation is dis- persed in the inhaled air stream in an efficient, robust and reliable way. e fine particle dose (FPD), nor- mally defined as the amount of drug in the aerosol cloud in particles with an aerodynamic particle size less than 5.0 µm, is a key measure, as this is the API dose that can reach the lungs. e fine particle frac- tion (FPF) is defined as the fine particle dose divided by the delivered dose and is therefore a quality mea- sure, as it directly relates to the efficacy of the inhaled product. e challenge for a developer is that FPF is not easy to understand nor to control, as it is affected by a range of formulation factors as well as other con- siderations. is also means that if changes in FPF occur during scale-up or running production, it can be challenging to make adjustments and reestablish the product performance. The active pharmaceutical ingredient (API) In most cases, the fine API particles are produced by the micronization process of jet milling [2]. is process is well suited for production of particles in the size range of 1-5 µm, the optimal size range for inhaled delivery. e API particles should preferably be crystalline with a narrow particle size distribution. But as microniza- tion can be a very harsh process, the micronized API often contains considerable amounts of amorphous Figure 2 Schematic illustration of an adhesive mixture consisting of carrier particles with attached fine API particles (left). During inhalation, the fine drug particles must detach from the carrier particles and disperse in the inhaled air stream (right) to be able to reach to the lungs.