(252c) Controlling the Particle Morphology of Spray Dried Poly(methacrylic acid-co-methyl methacrylate) (Eudragit L100) Polymer

Title: Controlling the particle morphology of spray dried poly(methacrylic
acid-co-methyl methacrylate) (Eudragit L100) polymer

Authors: Kimberly B. Shepard and Michael M. Morgen

Purpose: Poly(methacrylic acid-co-methyl methacrylate)
(PMMAMA, or trade name Eudragit L100) is an enteric random co-polymer of
methacrylic acid and methyl methacrylate with a high glass transition
temperature (~190°C). Spray dried amorphous dispersions (SDDs, left figure)
which use PMMAMA as a matrix polymer leverage these properties and often have
excellent physical stability, limited gastric release, and fast dissolution
rate at intestinal pH. In previous work, we have demonstrated that SDDs of
PMMAMA, HPMC and a rapidly crystallizing drug can be formulated to achieve
rapid dissolution and sustained supersaturation during in vitro dissolution testing. However, during scale-up of PMMAMA SDD
manufacture, poor powder properties lead to very low yields, which complicate
formulation and process development. In particular, clusters of string-like
structures were found throughout the SDDs (see center Figure). In this work, we
investigate a process and formulation space in which string formation can be
minimized or eliminated.

Methods: PMMAMA SDDs were prepared on small scale (1-100g) or
lab scale (100g-10kg) custom spray drying equipment from either 97/3
acetone/water or pure methanol solutions, with solids loading varying from
3-12%wt. Process parameters, such as inlet and outlet temperature (80-140°C,
and 35-65°C), liquid atomization pressure (100-600psi), atomization gas
pressure (5-30psi), nozzle type (e.g. 2-fluid or pressure swirl), solution
temperature, were varied.  SDDs were
characterized via scanning electron microscopy (SEM).

Results: During a typical pressure-swirl atomization process,
droplets are generated when the liquid sheet exiting the nozzle first breaks up
to form long one-dimensional “filaments,” which in turn de-stabilize and break
up to form droplets. During spray drying, liquid droplets dry into particles
via a skinning process, i.e. solvent evaporates rapidly from the surface of the
droplet, leaving behind a solid-like polymer skin on the surface of the droplet
that occurs at a critical concentration. We hypothesize that PMMAMA string
structures form when polymer skinning occurs before the filaments fully atomize
into droplets. SEM images show examples of “bead on a string” structures, where
skinning occurred in the midst of droplet breakup (see right Figure). In these
experiments, string formation was reduced by either increasing the time for
droplets to skin (e.g. decreasing drying kinetics or decreasing solution
concentration) or decreasing the time to droplet formation (e.g. increasing
atomization pressure).

We
have identified a robust processing space on both small-scale and lab-scale
spray dryers where string formation is avoided. Decreasing the outlet
temperature from 65°C to 35°C results in adequate drying while eliminating
strings. By spray drying from a more dilute solution, the time to skinning can
be significantly increased. A solids loading of 3% and 5% in 97/3 acetone/water
shows negligible string formation. Increased atomization pressure reduces the
time to droplet breakup and subsequent string formation for pressure-swirl and
2-fluid nozzles. Utilizing a slower-drying solvent, such as methanol, or
reducing the temperature of the spray solution can also reduce string formation.

Conclusions: By controlling the spray solution solids loading,
drying temperature, atomization conditions and other parameters, we identified
a process space where PMMAMA SDDs can be manufactured without string formation
and with acceptable particle properties (i.e. lack of strings). Stability and performance implications of this processing
strategy are currently being evaluated. This process is applicable to other
polymer systems in which string formation during spray drying is observed.