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eye on Unfortunately, powders in the range of 1 to 5 µm are characterized by high cohesive and adhesive proper- ties that make processing them rather difficult [2]. One approach to over- coming this obstacle is to mix the micronized API with coarser excipient particles. The larger size of these car- rier particles—usually in the range of 50 to 200 µm—improves powder flow and thereby improves powder dosing and dispersing. Additionally, the excipient acts as a diluent and thereby increases the amount of powder that must be dosed from the microgram range to the milligram range, a scale that makes dosing more feasible. The design of most commercial DPI devices presumes that alpha- lactose monohydrate will be the for- mulation's excipient. Reasons for using lactose as a carrier are as much histori- cal as practical. There is a long history of using lactose in pulmonary drug delivery, and the excipient has "gener- ally recognized as safe" (GRAS) status [3]. It is also physically and chemically stable and compatible with most APIs, and different grades with different par- ticle sizes for DPI applications are available. Lactose grades intended for use in DPI formulations have better characterized particle size distributions and tighter microbial limits compared to the conventional pharmaceutical grades of lactose for use in oral formu- lations. However, the role of lactose in a DPI formulation is not only to facili- tate metering and filling. The excipi- ent also influences the performance of the DPI significantly, usually in terms of in vitro parameters, such as the emitted dose, content uniformity, and FPF. The FPF represents the percent- age of API particles smaller than 5 µm that are released from the device. That percentage, it is believed, corresponds to the fraction of the API available for lung deposition in vivo. The efficiency of a DPI formulation is the result of a complex interaction of different para- meters, as summarized in Figure 1. Changes in processing the bulk pow- der, the device itself, and the physical or chemical properties of the API or the excipient will lead to changes in the uniformity of the delivered dose, the impactor stage of deposition, and the resulting FPF. API-carrier interaction Due to their strong adhesive nature, the micronized API particles join the coarser excipient particles to form an adhesive mixture, meaning the API will adhere to the surface of the excipi- ent. This is the typical carrier function of lactose, as illustrated in Figure 2. These adhesive API-carrier combina- tions form homogenous and stable mixtures. Because the amount of API is usually comparatively small, the carrier is the primary influence on the flow properties [4,5]. However, as men- tioned above, only particles between 1 and 5 µm are suitable for delivery to the lungs. This means, in order to reach their target, the API particles must detach from the carrier surface during the inhalation maneuver of the patient. This detachment, or deaggre- gation, takes place mainly inside the device. In general, three different Tablets & Capsules October 2016 41 Sabine Hauptstein, Mirjam Kobler, Eva Littringer, and Eugen Schwarz Meggle Excipients and Technology excipients This edition of the column focuses on lactose for use in dry powder inhaler (DPI) formu- lations and specifically on how the particle size distribution and the device influence the performance of the finished dosage form. The aims of DPI process develop- ment are often diverse. For generic products, the aim is to copy a disper- sion profile. For formulations that include new chemical entities, the aim is to show high and stable fine-particle fractions (FPFs) that maximize the therapeutic effect. Most challenges to developing DPI formulations can be overcome by selecting the right excipient. Lactose monohydrate, by far the most used carrier, is an omnipresent excipient and available in many different forms, each optimized for a different applica- tion. Even within portfolios of "lactose for dry powder inhalers," however, there are several different grades and they are not interchangeable. The interplay of excipient, active pharma- ceutical ingredient (API), and inhala- tion device influences the performance of the finished dosage form, as illus- trated in Figure 1. Particle size and carrier selection In order to deliver API particles to the lung, they must have an aerody- namic particle size, between 1 and 5 microns (µm). Particles of this size are presumed to offer efficient delivery to the respiratory tract and to deposit there. Larger particles will only reach the oropharyngeal region due to their inertia. Particles smaller than 1 µm are more likely to be exhaled than deposited [1]. Figure 1 Important parameters in DPI formulation development and the performance of the finished dosage form Formulation Device Mixing Filling Removal forces Type •Capsule •Blister •Reservoir Process Lactose API DPI development