title: Use of Spray-Dried Dispersions in Early Pharmaceutical Development: Theoretical and Practical Challenges.
abstract: Spray-dried dispersions (SDDs) have become an important formulation technology for the pharmaceutical product development of poorly water-soluble (PWS) compounds. Although this technology is now widely used in the industry, especially in the early-phase development, the lack of mechanistic understanding still causes difficulty in selecting excipients and predicting stability of SDD-based drug products. In this review, the authors aim to discuss several principles of polymer science pertaining to the development of SDDs, in terms of selecting polymers and solvents, optimizing drug loading, as well as assessing physical stability on storage and supersaturation maintenance after dissolution, from both thermodynamic and kinetic considerations. In order to choose compatible solvents with both polymers and active pharmaceutical ingredients (APIs), a symmetric Flory-Huggins interaction (Δχ ∼0) approach was introduced. Regarding spray drying of polymer-API solutions, low critical solution temperature (LCST) was discussed for setting the inlet temperature for drying. In addition, after being exposed to moisture, SDDs are practically converted to ternary systems with asymmetric Flory-Huggins interactions, which are thermodynamically not favored. In this case, the kinetics of phase separation plays a significant role during the storage and dissolution of SDD-based drug products. The impact of polymers on the supersaturation maintenance of APIs in dissolution media was also discussed. Moreover, the nature of SDDs, with reference to solid solution and the notion of solid solubility, was examined in the context of pharmaceutical application. Finally, the importance of robust analytical techniques to characterize the SDD-based drug products was emphasized, considering their complexity.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Co., New Brunswick, New Jersey, 08903, USA. jinjiang.li@bms.com.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Co., New Brunswick, New Jersey, 08903, USA.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Chemical and Synthetic Development, Bristol-Myers Squibb Co., New Brunswick, New Jersey, 08903, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wang
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods*; D013696:Temperature
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D011108:Polymers; D012997:Solvents
keywords: Flory-Huggins interaction parameter; physical stability; polymer and solvent selection; spray drying manufacturing; spray-dried dispersion