title: An investigation into the role of polymeric carriers on crystal growth within amorphous solid dispersion systems.
abstract: Using phase diagrams derived from Flory-Huggins theory, we defined the thermodynamic state of amorphous felodipine within three different polymeric carriers. Variation in the solubility and miscibility of felodipine within different polymeric materials (using F-H theory) has been identified and used to select the most suitable polymeric carriers for the production of amorphous drug-polymer solid dispersions. With this information, amorphous felodipine solid dispersions were manufactured using three different polymeric materials (HPMCAS-HF, Soluplus, and PVPK15) at predefined drug loadings, and the crystal growth rates of felodipine from these solid dispersions were investigated. Crystallization of amorphous felodipine was studied using Raman spectral imaging and polarized light microscopy. Using this data, we examined the correlation among several characteristics of solid dispersions to the crystal growth rate of felodipine. An exponential relationship was found to exist between drug loading and crystal growth rate. Moreover, crystal growth within all selected amorphous drug-polymer solid dispersion systems were viscosity dependent (η(-ξ)). The exponent, ξ, was estimated to be 1.36 at a temperature of 80 °C. Values of ξ exceeding 1 may indicate strong viscosity dependent crystal growth in the amorphous drug-polymer solid dispersion systems. We argue that the elevated exponent value (ξ > 1) is a result of drug-polymer mixing which leads to a less fragile amorphous drug-polymer solid dispersion system. All systems investigated displayed an upper critical solution temperature, and the solid-liquid boundary was always higher than the spinodal decomposition curve. Furthermore, for PVP-FD amorphous dispersions at drug loadings exceeding 0.6 volume ratio, the mechanism of phase separation within the metastable zone was found to be driven by nucleation and growth rather than liquid-liquid separation.
authors.affiliation: The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Tian
authors.affiliation: The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
authors.forename: David S
authors.initials: DS
authors.lastname: Jones
authors.affiliation: The Drug Delivery and Biomaterials Group, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Andrews
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D004337:Drug Carriers; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D004355:Drug Stability; D015736:Felodipine / Q000008:administration & dosage*; D005898:Glass; D006358:Hot Temperature; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry; D012995:Solubility; D013059:Spectrum Analysis, Raman; D013816:Thermodynamics; D014783:Viscosity
chemical_list: D004337:Drug Carriers; D011108:Polymers; D011145:Polyvinyls; C488580:poly(vinyl phenyl ketone); C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D015736:Felodipine
keywords: Flory−Huggins; HPMCAS; PVP; Raman spectral mapping; Soluplus; amorphous; crystal growth kinetics; felodipine; nucleation and growth; solid dispersions; viscosity