(14b) Connecting the Product-Process-Performance Interplay for Improved Understanding in Development of a Spray Dried Dispersion Drug Product

The pharmaceutical industry has faced a shift in the physicochemical properties of pre-clinical drug candidates rendering them less soluble and bioavailable. Spray drying has become an important unit operation in the pharmaceutical industry to produce spray dried amorphous dispersions (SDD) which can improve apparent solubility versus the crystalline drug as well as dissolution rate, thus improvingthe bioavailability of poorly soluble active pharmaceutical ingredients (API). The development of drug products consisting of spray dried solid dispersions is complex as it involves the need for strengthened understanding of the solid dispersion and drug product formulation attributes as they relate to enhancement of drug dissolution rate and maintenance thereof in the drug product. In contrast to standard drug particle erosion as main dissolution mechanism in conventional crystalline API formulation, solid dispersions can release drug in various types of species ranging from free drug, nano-particles, bile salt micelles, precipitated drug, and so on¹. The characteristic dissolution mechanisms are impacted by API physiochemical properties and formulation as well as the process conditions utilized to make them.

This work will cover: 1. different mechanisms of dissolution and species formed for various APIs, 2. how the spray drying process influences dissolution and amorphous product stability, 3. utility of novel spectroscopic and other characterization techniques to study dispersion quality and performance, 4. influence of dispersion and drug product formulation properties on dissolution and tablet properties, 5. end to end considerations for ensuring how key quality and performance attributes are designed in and maintained in the drug product.

Spray dried dispersion particles and powders were manufactured on various scales ranging from single particle levitation, ProCepT 4M8, GEA mobile minor and GEA PSD-2 spray dryers. Multiple process conditions resulting in a range of drying rates were studied and will be presented. The resulting powders will be characterized by standard techniques such as modulated differential scanning calorimetry (mDSC) and x-ray powder diffraction (XRPD) to evaluate bulk amorphous dispersion uniformity. In several cases, additional techniques such as focused ion beam scanning electron calorimetry (FIB-SEM), x-ray photoelectron spectroscopy (XPS), and energy dispersive x-ray spectroscopy (EDX) were utilized to look a particle level homogeneity. Drug product formulations were made by standard tumble blenders, dry granulated, lubricated and compressed into tablets. Discriminating dissolution methodologies were used to study drug release from the dispersions and tablet formulations. Environmental stressing was conducted to look at stability and impact on drug release from tablets.

The choice of polymers and surfactants that make up the SDD composition was shown to have a significant impact on the amorphous quality, particle level uniformity, resulting phase stability and dissolution behavior. The choice of solvent composition and spray drying conditions was shown to have a modest to profound impact on these quality attributes. This was shown through dissolution studies coupled with human PK data as well as phase uniformity issues discovered immediately following manufacture or after post-process stressing. The API has inherent physio-chemical properties that tend to give rise to characteristic speciation behavior during dissolution of SDD powder. The rate of release of overall drug into these entities was negatively impacted as the dispersion load in the tablet increases, tablet void fraction exceeded critical levels, and tablet disintegrant system was not properly designed.

In conclusion, spray dried dispersion based drug products require end to end study and understanding of the API behavior, formulation and process components, characterization methodology for amorphous quality and dissolution methodology and environmental stresses to be successful. Discriminating dissolution methodologies can help understand the specific mechanisms of dissolution enhancement and novel characterization methods can be useful in characterizing and ensuring maintenance of amorphous quality in the SDD and final drug product.

References:

1: D.T Friesen et al. Hydroxypropyl Methylcellulose Acetate Succinate-Based

Spray-Dried Dispersions: An Overview. Molecular Pharmaceutics. 2008. VOL. 5, NO. 6, pg. 1003–1019