(170c) Surface Dynamics of Micronized Active Particles

Surface Dynamics of Micronized Active
Particles

Vibha Puri¹, Jagdeep Shur², Robert Price² & Ajit Narang¹

¹Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way,
South San Francisco, CA 94080, USA

²Nanopharm Ltd., Cavendish House, Newport NP10 8FY, UK

ABSTRACT

Purpose

The performance of pharmaceutical powders in drug products, such as dry
powder inhalations (DPIs), is predominantly governed by the interfacial
interactions of the particles in  multi-component
powder blends. The particle size targeted for lung delivery of drugs is in the
range of 1 to 5 micron. Air jet micronization is
commonly used for particle size reduction of synthetic, crystalline APIs.
However, this high energy process can induce structural and surface disorder in
the micronized API. Furthermore, this mechanically activated API on storage can
undergo relaxation (surface stabilization) that can alter the material’s
surface properties. Often a conditioning or resting step is introduced
to allow the energized, micronized API to stabilize. Hence, there is a need for
better understanding of the surface of micronized API and development of a
conceptual framework for selection of conditioning environment for the
micronized API.

The objective of the study was to investigate
the molecular and particle level changes occurring during storage of a model
micronized API (compound A), and their impact on interparticle
interactions. A multitude of techniques were used to investigate surface
structural disorder, surface energetics, and interparticle
interactions.

Materials and methods

Micronized API (Compound A) produced by air jet milling was stored under
different temperature and relative humidity conditions of 20°C/30%RH, 60°C/30%
RH,  20°C/80%RH, and 60°C/80% RH, and characterized at 0, 3, 6, and 9 week
time period. The structural disorder in the micronized API was measured by
RH-perfusion microcalorimetry (using a thermal
activity monior (TAM), TA Instruments, USA). Surface
free energy (SFE) was measured by inverse gas chromatography (using surface
energy analyser, SMS Instruments, USA). The interparticle
forces between drug-drug (cohesive) and drug-lactose (Respitose
SV003, DFE Pharma, USA) (adhesive) particles were measured by atomic force microscopy
(AFM) (Nanoscope IIIa, CA,
USA). The slope of plots of force of cohesion versus adhesion was denoted as
the cohesive-adhesive balance (CAB). Changes in the specific surface area,
particle size, and crystallinity were also monitored.

Results and discussion

Compound A is non-hygroscopic with <0.3% water uptake at 25°C/90% RH.
Complementary use of melting peak characterization (by differential scanning
calorimeter) and thermodynamics of sorption-desorption isotherm (by TAM) showed
that the structural disorder due to micronization was
predominantly at the surface. The TAM profiles indicated that all stored
samples underwent structural relaxation over time (Figure 1). The effect of
high temperature (60°C/30% RH) and high relative humidity (20°C/80%RH) in lowering
the structural disorder was comparable. Maximum relaxation was achieved under
combined conditions of high temperature and relative humidity (60°C/80%RH).

The freshly micronized API showed total, dispersive, and specific (acid-base)
surface energies of 64.0±1.2, 58.9±0.9, and 5.1±0.5 mJ/m²,
respectively, at the surface coverage of 0.01 n/n_m.
The dispersive component of the SFE was the major contributor to the total SFE,
and showed quantitative lowering in the stored samples (Figure 2). At the
9-week time point, all the samples showed lowering of SFE to similar extent.
However, the kinetics was significantly fast at high temperature and high
relative humidity condition (60°C/80%RH), and the samples showed greater
heterogeneity.

The SFE profiles determined for API and lactose
monohydrate were collectively used to compute work of cohesion (drug-drug) and
adhesion (drug-lactose). The freshly micronized API had IGC-CAB of 1.16,
suggesting the material was cohesive. The SFE change was most rapid at extreme
stress condition of 60°C/80% RH and the CAB value lowered to 1.04, both, for
the 3- and 9-week samples. However, the remaining three storage conditions
showed a staggered fall over the 3- and 9-week periods, with CAB value lowering
to about 1.11, followed by reduction to 1.04.

The AFM studies provided a direct measurement
of interparticle forces (Figure 3). The freshly
micronized API sample displayed a CAB value of 1.35 suggesting that the
drug-drug cohesion was higher than the drug-lactose adhesion. On storage, the
CAB values showed a trend to reduce and fall below 1. At the stress condition
of high temperature-high humidity (60°C/80%RH), the CAB value reached 0.65 at
9-week time point, which indicated that the drug-lactose adhesion forces were
~1.5 fold higher than the drug-drug cohesion forces. Comparing the percent
change in CAB across the four storage conditions, the low temperature-low
humidity (20°C/30%RH) environment showed least change (CAB of 1.18).

The powder samples showed lowering of the specific
surface area over the period of storage, with maximum reduction seen for high
temperature-high relative humidity condition (60°C/80%RH).

Conclusion

The study highlights the use of surface specific techniques to
quantitatively measure changes in the micronized API. Micronization
of pharmaceutical powders can induce structural disorder in the constituent
particles. These materials continue to undergo surface re-construction on
storage, which can then impact their physicochemical properties.  

Compound A changed in molecular and particle level properties upon
storage under different temperature and humidity conditions. Surface structural
disorder, surface energy, and specific surface area lowered on storage. The CAB
of micronized API changed from being cohesive (CAB>1) to adhesive (CAB<1)
on exposure to stress conditions over time.

The study shows that the extent of change in
structural disorder, surface energy, particle features (such as specific
surface area), and the overall interparticle forces
were at different scales for the different environmental conditions. The higher
stress conditions showed faster kinetics of change in material properties along
with the greater heterogeneity. Hence, the selection of conditioning
environment for the micronized API can impact the overall drug product
performance.