(298a) Carrier Based Dry Powder Inhaler Formulation – a Particle Engineering Perspective | AIChE

(298a) Carrier Based Dry Powder Inhaler Formulation – a Particle Engineering Perspective


Zellnitz, S., Research Center Pharmaceutical Engineering GmbH
Roblegg, E., University of Graz
Paudel, A., European Consortium on Continuous Pharmaceutical Manufacturing (ECCPM)

Dry powder inhalers (DPI) are the preferred devices among orally inhaled drug products due to their ease of handling and administration as well as superior product stability1. They deliver a dry powder of the active pharmaceutical ingredient (API) either in the presence or absence of larger size excipient particles (usually a sugar) as the carrier. Carrier-based DPIs are manufactured via adhesive dry mixing of the fine drug particles (1-5 µm) with the coarse excipient particles. A delicate balance of the inter-particle forces is necessary to guarantee a stable homogeneous mixture during processability (e.g. capsule filling, transport, and storage) and eventually to allow API detachment from the carrier during delivery. Rational engineering of particles can offer an invaluable opportunity to tailor API and carrier with the desired physicochemical characteristics and thereby enable fine-tuning the inter-particle cohesive-adhesive balance (CAB). Thus, the present work intends to explore diverse particles engineering approaches for API and carrier and evaluate the impacts on particle properties and product performance.

API particle engineering

Salbutamol sulphate (SS) (Selectchemie) was chosen as a model API and engineered to the inhalable size using spray drying (Nano Spray Dryer B-90, Büchi Labortechnick AG) and jet-milling (AS50 Air Spiral jet mill, Hosokawa Alpine AG) The samples were stored and characterized immediately, 7, 14 and 21 days after production with respect to their solid-state, micromeritics and surface properties. Spray drying resulted into rugged spherical amorphous SS particles (Dv0.5= 3.75 ± 0.08 µm) that were able to form strong agglomerates through “amorphous bridging”. On the other hand, jet-milling produced smaller (Dv0.5 = 2.06 ± 0.08 µm), crystalline, irregular shaped particles with a very large surface area (11.04 ± 0.10 m2/g) that, over time, formed looser particle aggregates of decreasing size.

API particle performance

The SS particles generated by different engineering routes were further formulated into carrier-based DPIs to evaluate their performance. Both spray dried SS (SDSS) and jet-milled SS (JMSS) particles were mixed with α-lactose monohydrate (Lactohale® 100, DFE Pharma) to yield adhesive blends at low (1%) and high (10%) drug loads. By increasing the drug load, propagation of API particle properties effects on blending (Turbula blender TC2, Willy A. Bachofen Maschinenfabrik), capsule filling (Labby, MG2) and in vitro aerosolization performance (Next Generation Impactor – NGI, Copley Scientific) could be evaluated.

Adhesive mixing

Notable differences were found between CAB values of JMSS and SDSS particles. SDSS particles present a greater tendency to attach as agglomerates to the “active sites” within the carrier surface compared to JMSS counterpart. Moreover, it was also apparent that smoother lactose particles were seemingly unable to bind the SDSS to their surfaces, reinforcing the hypothesis that cohesive forces of SDSS particles (drug-drug) are higher than their adhesive ones (drug-carrier)2. Consequently, it is proposed that under the same formulation conditions, (i.e. API-carrier pair and blending process), when compared to JMSS, SDSS particles adhere more poorly to the carrier being more prone to detachment during powder handling.

Capsule filling

Capsule filling results supported blending observations revealing larger differences in blend uniformity for the SDSS mixtures, being that this was particularly evident at low loads and smaller powder bed heights, where drug content and powder densification effects were minimized. It is hypothesized that during processing, the SDSS particles are able to detach very easily from the carrier surface resulting in rapid segregation of the powder bed. It is well-known that the interaction forces between the drug and excipient host particles are beneficial with respect to handling of the powder blend as they reduce the risk of segregation3. Thus, as expected when compared to the JMSS blends API detachment in SDSS mixtures resulted in capsules filled with a highly variable amount of the targeted drug content.

In vitro aerosolization performance

In vitro aerosolization also supports SDSS poor attachment to carrier surface as demonstrated by the extensive deposition in mouth and throat. In opposition the JMSS blends where greater losses were seen in the pre-separator. It is known that the higher fraction of free API particles (not adhered to carrier surface) can lead to larger drug deposition in the mouth and throat than in the pre-separator4 . Finally, it was also evident that the SDSS agglomerates are aerosolized as such resulting in a significant larger mean median aerodynamic diameter (MMAD) when compared to their JMSS counter-parts.

Carrier particle engineering

Using an integrated approach, lactose was spray dried in the presence of polyethylene glycol (PEG) 200. Anomeric composition of lactose in lactose-PEG 200 feed solutions of variable compositions was analyzed via polarimetry at different temperatures. These results were correlated with the solid state and anomeric composition of the resulting spray dried particles. Characterization of the dried powders revealed that crystalline (in an anomeric ratio 0.8:1 of α to β) spherical particles with a median particle size (Dv0.5) of 50.9 ± 0.4 µm could be produced. In addition, the surface of these particles was composed of a plate like structure of PEG 200 and segregated β-lactose.

Carrier particle performance

A blend of lactose-PEG 200 composite particles with JMSS was produced and the role of carrier properties on DPI efficiency assessed. For this, the performance of the composites blend was compared with a series of other adhesive mixtures containing distinct lactose grades with different anomeric compositions and/or physical properties. This way, it was possible to deconvolute the contribution of solid state, surface chemistry and morphology of carrier particles on the dry adhesive mixing (Turbula blender TC2, Willy A. Bachofen Maschinenfabrik) and in vitro aerosolization performance (Next Generation Impactor – NGI, Copley Scientific).

Adhesive mixing

Blending of spray dried lactose-PEG 200 composite particles with JMSS resulted in the presence of a notable number of drug agglomerates. For instance, it has been reported that particles with lower shape coefficients (SC), a coefficient representing the surface area, density and aspect ratio of the particle, achieve mixing homogeneity faster, but tend to show higher segregation propensity5. Considering the lower density, regular shape (spherical) and smoother surface of the lactose-PEG 200 composites, the aforementioned provided a rationale behind the observed results.

In vitro aerosolization performance

Comparison of the blends containing carriers composed of α-lactose monohydrate evidenced the impact of particle morphology on DPI performance. More precisely, blends containing the spherical α-lactose monohydrate resulted in a poorer in vitro aerosolization performance of JMSS when compared to their tomahawk shaped counterparts. It is known that powder bed fluidization behavior can be affected by particle shape; for intance, spherical particles tend to pack more uniformly, resulting in powder beds with higher tensile strengths 6 and more difficult to fluidize via airflow. These powder beds are often lifted as plugs or fractures 7 thatresult in an inferior and variable lung deposition of fine drug particles.


API and carrier particles engineered by different routes yield distinct physicochemical properties. Assessment and understanding of particle properties and process interplay can enable tuning of DPI product performance. Thus, an integrated understanding of particle characteristics in relation to their processability and intended performance is necessary to develop DPI products capable of tailored drug delivery.


(1) Telko, M. J.; Hickey, A. J. Dry Powder Inhaler Formulation. Respir. Care 2005, 50 (9), 1209–1227.

(2) Pinto, J. T.; Radivojev, S.; Zellnitz, S.; Roblegg, E.; Paudel, A. How Does Secondary Processing Affect the Physicochemical Properties of Inhalable Salbutamol Sulphate Particles? A Temporal Investigation. Int. J. Pharm. 2017, 528 (1-2), 416–428.

(3) De Boer, A. H.; Chan, H. K.; Price, R. A Critical View on Lactose-Based Drug Formulation and Device Studies for Dry Powder Inhalation: Which Are Relevant and What Interactions to Expect? Advanced Drug Delivery Reviews. 2012, pp 257–274.

(4) Kumon, M.; Suzuki, M.; Kusai, A.; Yonemochi, E.; Terada, K. Novel Approach to DPI Carrier Lactose with Mechanofusion Process with Additives and Evaluation by IGC. Chem. Pharm. Bull. (Tokyo). 2006, 54 (11), 1508–1514.

(5) Wong, L. W.; Pilpel, N. Effect of Particle Shape on the Mixing of Powders. J. Pharm. Pharmacol. 1990, 42 (1), 1–6.

(6) Fukunaka, T.; Sawaguchi, K.; Golman, B.; Shinohara, K. Effect of Particle Shape of Active Pharmaceutical Ingredients Prepared by Fluidized-Bed Jet-Milling on Cohesiveness. J. Pharm. Sci. 2005, 94 (5), 1004–1012.

(7) Kaialy, W.; Nokhodchi, A. Freeze-Dried Mannitol for Superior Pulmonary Drug Delivery via Dry Powder Inhaler. Pharm Res 2013, 30 (2), 458–477.