Deconstructing HPMCAS: Excipient Design to Tailor Polymer–Drug Interactions for Oral Drug Delivery

Abstract

Spray-dried dispersions (SDDs) are fascinating polymer−drug mixtures that exploit the amorphous state of a drug to dramatically elevate its apparent aqueous solubility above equilibrium. For practical usage in oral delivery, understanding how polymers mechanistically provide physical stability during storage and prevent supersaturated drugs from succumbing to precipitation during dissolution remains a formidable challenge. To this end, we developed a versatile polymeric platform with functional groups analogous to hydroxypropyl methyl cellulose acetate succinate (HPMCAS, a heterogeneous leading excipient candidate for SDDs) and studied its interactions with Biopharmaceutical Classification System Class II drug models probucol, danazol, and phenytoin at various dosages. By conducting reversible addition−fragmentation chain transfer polymerizations with monomeric components chemically analogous to HPMCAS, we synthetically dismantled the highly polydisperse architecture of HPMCAS into well-defined polymer systems (i.e., targetable M n , Đ < 1.3, tunable T g ). In the powdered SDD form, by wide-angle X-ray diffraction all HPMCAS analogs yielded amorphous danazol and phenytoin up to 50 wt % loading, whereas for probucol, hydrophobic methoxy functionality and high polymeric T g were key to inhibit immediate partitioning into crystalline domains. Nonsink in vitro dissolution tests revealed distinct release profiles. The polymer containing only acetyl and succinoyl substituents spray-dried with probucol increased the area under the dissolution curve by a factor of 180, 112, and 26 over pure drug at 10, 25, and 50 wt % loading, respectively. For crystallization-prone danazol and phenytoin, we observed that the water-soluble polymer with hydroxyl groups inhibited crystal growth and enabled high burst release and supersaturation maintenance. Our findings provide fundamental insight into how excipient microstructures can complex with drugs for excipient formulation applications.

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

“…Polymers function by slowing down the process of nucleation and crystal growth through interaction with the dissolved API molecules and interaction with and adsorption onto growing crystals . Given the kinetic nature of this effect, the thermodynamic equilibrium solubility is usually not affected by the polymer, except in a number of limited cases, where polymers can have a co‐solvent effect as well . Kinetic inhibition of nucleation relies on molecular interactions between the polymer and the drug, that is hydrogen bonds, polar, or dispersion forces .…”

“…Each of these interactions may contribute to varying degrees, especially when considering the impact of water. This is an area that has seen increasing interest in the literature lately but more work is required to resolve the exact contributions and nature of the PI‐API interaction. More generally, such interactions can be influenced by temperature, molecular weight, polarity and hydrogen bonding capabilities of both the drug and the polymer.…”

“…The first example of such an approach was published by Ting et al ., who synthesised co‐polymers inspired by HPMCAS using reversible addition–fragmentation chain transfer (RAFT) polymerisation. These novel polymers were then used in SDDs and studied for interactions with probucol, danazol and phenytoin, to determine which structural motifs were important for inhibition of precipitation.…”

“…This was supported by FTIR spectroscopy. In the FTIR spectra, –OH stretching absorptions of danazol shifted and broadened in the presence of polymers with high proportions of –OH functionality, indicating the presence of hydrogen bond interactions …”

High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals

“…Conversely, HPMCAS was effective in supersaturating nilutamide at 10 wt %; we speculate that its ionized state and amphilicity imparted favorable interactions to nilutamide, akin to other drugs we have previously studied. 18 For the poly(NIPAm- co -DMA) systems with both drugs, at low NIPAm incorporations, excipients were more hydrophilic and abandoned drug molecules due to insufficient inhibitor sites. At the 70 mol % NIPAm composition, solid dispersion dissolution achieved full apparent solubilization at 10 wt % and high drug stabilization at 25 wt %.…”