Category: Formulation and Quality
Purpose: Amorphous solid dispersions (ASDs) are important bioavailability enhancing formulations for poorly water-soluble drug substances. To achieve safety, efficacy and shelf-life, ASDs must be physically and chemically stable, achieve the target pharmacokinetic profile in the gastrointestinal tract and have robust manufacturability. In this work, we demonstrate how ASD particles can be engineered using the spray drying process to influence mechanical and flow properties critical to tableting.
Methods: A 20% loading of felodipine dispersed in the polymer, PVP VA64, was spray-dried on a PSD-1 spray dryer using acetone as a spray solvent. Four different processing conditions were used to produce small or large droplets with slow or fast drying kinetics. Resulting powder properties were characterized, including particle size distribution via laser diffraction (Malvern Mastersizer 2000), morphology via scanning electron microscopy (Hitachi S-3400N microscope), Brunauer-Emmett-Teller specific surface area (SSA) (ASAP 2020, Micromeritics), true density (Micromeritics AccuPyc helium pycnometer), bulk density and tapped density. Mechanical properties were measured, including Compactability, Tabletability, Compressibility (CTC) profiles (TA.HD Plus Texture Analyzer) and Hiestand dimensionless tableting (HDT) indices using square test specimens produced on a triaxial tablet press. Flowability was measured via flow function coefficient (ffc) (Schulze Ring Shear Tester) and Carr’s Compressibility Index (CI).
Results: Spray dried particle morphologies included intact, collapsed, and fractured hollow spheres, with mean particle sizes ranging from 4–115 µm and bulk densities ranging from 0.05–0.38 g/cm3 (See Table 1). HDT indices and CTC profiles demonstrated a 4-fold difference in tensile strength (TS), a 1.5-fold difference in dynamic hardness (Hd) and a 1.3-fold difference in compression pressure (CP) at a solid fraction (SF) of 0.85 (See Table 1 & Figure 1). The mechanical properties of all four ASDs indicate that they should produce strong tablets (TS >1 MPa) at reasonable solid fractions (SF < 0.85) and at easily achievable compression pressures (CP < 200 MPa). Despite favorable TS for all samples, particle morphology was found to impact TS at a given solid fraction. Small (d[4,3] = 4 µm), collapsed hollow spheres had the highest SSA and highest TS at SF=0.85. However, despite a similar particle size (d[4,3] = 4 µm), and the 2nd highest SSA of all samples, small (non-collapsed) hollow spheres had the lowest TS at SF=0.85. The small, hollow spheres likely had lower TS because the spherical particles have thick walls relative to their small radii that minimized plastic deformation and prevented brittle fracture, resulting in low contact area and therefore TS (See Figure 2). On the other hand, collapsed hollow spheres showed signs of substantial plastic deformation upon compression, wherein individual particles became indiscernible from each other. Flowability results suggested poor flow for three out of four samples, with the large collapsed hollow spheres having the most favorable ffc and CI (See Table 1). FFc trended with particle size. Small particles were “very cohesive”, and larger particles were “easy flowing” according to USP Chapter < 1063 >. CI trended with a combination of particle size, density and morphology. Small, high bulk density hollow spheres and large, high bulk density collapsed hollow spheres had the most favorable CI values. Small, moderate bulk density collapsed hollow spheres and large, low bulk density fractured particles had the poorest CI values.
Conclusion: Particle engineering via spray drying can be used to tune mechanical and flow properties of amorphous solid dispersions (ASDs) to facilitate downstream manufacturability. In this study, we produced ASD particles with a wide range of particle sizes, densities, and morphologies for a single binary ASD composition by varying key processing variables, allowing production of particles well-suited for incorporation into solid dosage forms. Results show optimizing particle properties involves a balance between key attributes. For example, larger particles tend to improve powder flow, but diminish compaction properties. Likewise, collapsed hollow spheres may give more desirable tensile strength than hollow spheres, but the interlocking nature of collapsed spheres can diminish powder flow. Establishing fundamental knowledge relating the process to particle properties to powder performance is important for enabling advanced efficient manufacturing technologies, such as direct compression, which reduce the number of unit operations and the associated manufacturing time and cost.
Deanna Mudie– Principal Scientist, Lonza, Bend, Oregon
Alyssa Ekdahl– Austin, Texas
David Malewski– Vallejo, California
Gregory Amidon– Professor of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan
Aaron Goodwin– Boulder, Colorado