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SIMS21, Poland 2017 - Mark Nicholas abstract

Mark Nicholas oral presentation (OA3-Tue2-3-1)

Lactose friends and phobes: cohesive/adhesive balance measurements by TOF-SIMS of fast blends of 20 mg of micronized drugs or coating agents with 980 mg of micronized lactose

Mark Nicholas1, Esther Mézière2

1 AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden
2 École européenne de chimie, polymères et matériaux, 25 Rue Becquerel, 67087 Strasbourg, France

Inhalation powders put high demands on control of powder stickiness. Since the powders are micron-sized (1-5 µm for best lung deposition), the surface-to-volume ratio is relatively high, and the aggregate properties of the particles are very dependent upon their stickiness. Their stickiness is, in turn, dependent upon their surface composition and roughness.

The aggregate properties of the most interest are powder flow (for filling inhalers) and deaggregation (upon inhalation). It does no good if the particles which are intended to reach the lungs are originally in the desired 1-5 µm size range, but instead leave the inhaler as aggregates larger than 5 µm.

In inhalation, lactose is a common excipient (inactive ingredient) blended with the active pharmaceutical ingredient (API). Lactose is added either as a large carrier (typically 50-200 µm) to improve powder flow for filling the inhaler or as fines (i.e. micronized) to form 1-5 µm aggregates with the API or both. Thus, the relative stickiness of API particles to lactose or to themselves is of great importance in predicting the aggregation/deaggregation behavior of lactose/API blends.

This cohesive/adhesive balance for lactose/API blends has been investigated by AFM.1 The technique is onerous. One measures the relative stickiness of a single API particle on the AFM tip to a surface of lactose and a surface of the API. This is repeated several times.

In this work, we developed a novel method to measure the cohesive-adhesive balance (CAB) between lactose and APIs using 20 mg of micronized API, 980 mg of lactose fines, and fast, reproducible blending methods followed by TOF-SIMS. Surprisingly, there was not a continuum of CAB behavior. Our test method revealed that the APIs grouped into three groups as regards their abilities to coat lactose. Knowledge of to which group an API belongs is important information when determining how hard to blend the APIs and excipients.

Another level of complexity in inhalation powder formulation adds coating agents to the blend of API and lactose. The intent here is to “paint over” the differences in CAB values for different APIs. In principle this would work perfectly if by blending the coating agent with the API, the API were completely covered by the coating agent. We did not test the coatability of the 16 APIs tested, but we did apply our CAB test method to blends of common coating agents with lactose. The coating agents coat the lactose to varying degrees and are worse at coating lactose than many APIs! Furthermore, longer blending times do not always give higher degrees of coating!

1Begat, Pharmaceutical Research, 2004 21(9):1591-1597