The Role of Carriers in DPI Capsules

Choice of carrier can have a significant impact on the capsule filling process as well as the performance of the DPI formulation.
May 02, 2018
Volume 42, Issue 5, pg 30–33

Sherry Yates Young/shutterstock.comThe use of capsules loaded into a dry powder inhaler (DPI) to deliver drugs to the lungs is a well-established method for the treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Developing a capsule formulation for inhalation, however, is not nearly the same as an orally administered capsule. For DPI capsules, powder properties not only affect the manufacturing process but also drug delivery to the lungs. Experts from DFE Pharma—Mohit Mehta, scientist; Gerald Hebbink, scientist; and Harry Peters, lactose inhalation specialist—spoke to Pharmaceutical Technologyabout the importance of carrier selection and how the capsule filling process can affect DPI performance. 

The role of carrier in DPI formulations

PharmTech:Can you tell us about the role of carriers in DPI formulations?

DFE Pharma:DPI formulations contain micronized drugs. The aerodynamic particle size of these micronized drugs typically ranges between 1–5 μm. The majority of the drugs used for treatment of asthma and chronic obstructive pulmonary disease (COPD) are either beta agonist, anticholinergic, or corticosteroids, which can be formulated in combinations. These drugs have very low doses, usually in the microgram range. The carrier, therefore, provides the bulk, which enables ease of handling during dispensing, manufacturing, and delivery through the device (1). A carrier is an important component of the DPI formulation. Because micronized drugs have poor flow properties, mixing the drug with a suitable carrier enhances the flow behavior and thus improves dosing accuracy and consistency. Furthermore, the carrier facilitates the dispersion of the cohesive micronized drug during the inhalation event. Any change in the physiochemical properties of the carrier has potential to alter the product performance and drug deposition in the lungs; therefore, selecting and optimizing the right carrier is an important step in developing a suitable DPI formulation.

Excipients used as carriers

PharmTech:What excipients are commonly used as carriers?

DFE Pharma:Due to the lack of toxicological data concerning the potential hazard of carriers to lung tissue, the primary carrier currently approved or certified safe by FDA remains limited to lactose. Mannitol has been investigated as a carrier. However, mannitol can trigger issues related to bronchoconstriction, and using it as a carrier for treatment of asthma and COPD could be a regulatory challenge (2). Based on their functional role, there are other excipients, such as magnesium stearate, distearyl phoshatidylcholine (DSPC), and fumaryl diketopiperazine (FDKP), that have also been approved to be used for inhalations. The major commercially available formulations are, however, manufactured using lactose as the carrier (3). Lactose has been thoroughly investigated and described for this purpose. Mostly alpha-monohydrate lactose is used, although there are existing formulations that use beta-anhydrous lactose. 

Selecting a carrier

PharmTech:What are the key considerations when selecting a carrier for a DPI formulation? What are the properties required in a carrier?

DFE Pharma:Selection of a carrier is typically based on: 

  • Functionality: powder flow and dispersion during inhalation
  • Stability: physicochemical stability, biocompatibility, biodegradability, and compatibility with the drug substance 
  • Safety: it must be inert and non-toxic to lung tissues. 

Consequently, it has been stated that the efficiency of a DPI formulation is extremely dependent on the carrier characteristics, and the selection of carrier is a crucial determinant of the overall DPI performance (1). In case of DPI formulations, most of the micronized drug particles adhere to the surface of coarse carrier particles. During inhalation maneuvering, based on the velocity of inspired air flow, these drug particles are detached from the surface of the carrier particles. The larger carrier particles are deposited in the upper airways, while the small drug particles can reach the lower parts of the lungs (1). Detachment of drug from the carrier is based on the balance between inter-particulate adhesive forces and air flow velocity (4). The right cohesive and adhesive balance is, therefore, required between the drug and carrier to produce a stable formulation that at the same time allows easy separation during inhalation.

Often the question is raised to a lactose producer as to what grade of inhalation lactose should be used. There is, however, no single grade lactose that fits all purposes. One has to determine what kind of functionality needs to be addressed with the lactose. Is it the filling of the device, the mixing of the powder, the metering of the device, the deposition of the drug, or a combination of these?

Lactose for inhaled formulations

PharmTech:Can you discuss the differences between lactose for inhaled formulations versus lactose used in oral formulations? 

DFE Pharma:Lactose for oral formulations is primarily selected based on the manufacturing process, the dosage form (whether tablets, capsules, or sachets), and the nature of the API (e.g., moisture sensitivity). In the case of lactose for inhalation, selection is based on filling of the device, device design, and deposition of drug into the lungs. In both solid oral and inhalation dosage forms, important characteristics to be considered when selecting a lactose are particle size and flow properties. However, in case of inhalation formulations, the particle size of the lactose plays a crucial role in determining drug deposition into the lungs and its pharmacokinetic behavior. For inhalation-grade lactose, health authorities require extra testing and controls, especially for some parameters, where tighter limits are required compared to pharmaceutical-grade lactose. Inhalation-grade lactose has to be manufactured specifically to meet the stringent specifications.

DPI performance

PharmTech:Can you elaborate on how capsule filling affects DPI performance, and what’s the best way to ensure reproducibility and consistency of DPI performance?

DFE Pharma:Capsules play an important role in delivery of drugs in the case of capsule-based DPIs. The capsule has a significant impact on powder deagglomeration and the detachment of the micronized drug from the carrier during inhalation. Capsule selection should, therefore, be an integral part of DPI product development. In comparison to solid oral formulations, DPI capsules have low fill weights, and hence, it is often more challenging to fill the dry powders with accuracy and consistency. Filling of these powders often requires specialized filling equipment with built-in systems for in-process checks and the ability to reject under- or over-filled capsules based on the required quality specifications. 

Temperature and humidity play a crucial role. It is important to avoid moisture uptake, as it may lead to powder aggregation and variability in the filling process (5). For accurate powder dosing, there are several mechanisms available, which include dosator filling, vacuum drum filler, and tamping pins. Generally, the filling mechanism is selected based on the amount and the characteristics of powder blend to be filled. Powder flow properties are one of the important parameters of the dry powder blends that can affect capsule filling and the DPI performance. It is important to have a thorough understanding of powder flow properties in combination with the mechanism of filling to optimize the filling parameters, which govern reproducibility and consistency of DPI performance. 

Scaling up

PharmTech:What are the challenges of scaling up DPI capsule production and how do you address them? 

DFE Pharma:There are several unit operations involved in DPI capsule manufacturing. However, the most important unit operations during scale up are blending and capsule filling. Blending is well established in the pharmaceutical industry, and manufacturing scale-up from bench to factory is generally well understood. However, blending is an important unit operation that plays a crucial role in determining the detachment of micronized drug from the carrier particles. In the case of a capsule filling operation, the major challenge is the unavailability of a defined scalability factor from laboratory scale to commercial scale. Hence, the whole process needs to be optimized based on the batch size, the filling equipment, and powder flow properties at commercial scale. To address these issues, the best approach is to have proper risk assessment done before optimizing the process. Risk assessment should take into consideration powder flow properties, filling process parameters, environmental conditions, storage after filling, and further packaging into blisters.


1. G. Pilcer, N. Wauthoz, and K. Amighi, Adv. Drug Deliv. Rev. 64 (3) 233–256 (2012).
2. S. Anderson, Breathe 8 (1) 53–60 (2011).
3. P. Tingting et al., Acta Pharmaceutica Sinica B. 6 (4) 308–318 (2016).
4. H. Hamishehka, Y. Rahimpour, and Y. Javadzadeh, “The Role of Carrier in Dry Powder Inhaler,” in Recent Advances in Novel Drug Carrier Systems, A.D. Sezer Ed. (InTech, Rijeka, Croatia, 2012), pp. 39–66.
5. D. Edwards, Therapeutic Delivery 1 (1) 195–201 (2010).   

Article Details

Pharmaceutical Technology
Vol. 42, No. 5
May 2018
Pages: 30–33


When referring to this article, please cite it as A. Siew, "The Role of Carriers in DPI Capsules," Pharmaceutical Technology 42 (5) 2018.

lorem ipsum