title: Mechanistic Design of Chemically Diverse Polymers with Applications in Oral Drug Delivery.
abstract: Polymers play a key role in stabilizing amorphous drug formulations, a recent strategy employed to improve solubility and bioavailability of drugs delivered orally. However, the molecular mechanism of stabilization is unclear, therefore, the rational design of new crystallization-inhibiting excipients remains a substantial challenge. This article presents a combined experimental and computational approach to elucidate the molecular features that improve the effectiveness of cellulose polymers as solution crystallization inhibitors, a crucial first step toward their rational design. Polymers with chemically diverse substituents including carboxylic acids, esters, ethers, alcohols, amides, amines, and sulfides were synthesized. Measurements of nucleation induction times of the model drug, telaprevir, show that the only effective polymers contained carboxylate groups in combination with an optimal hydrocarbon chain length. Computational results indicate that polymer conformation as well as solvation free energy are important determinants of effectiveness at inhibiting crystallization and show that simulations are a promising predictive tool in the screening of polymers. This study suggests that polymers need to have an adequate hydrophilicity to promote solvation in an aqueous environment, and sufficient hydrophobic regions to drive interactions with the drug. Particularly, the right balance between key substituent groups and lengths of hydrocarbon side chains is needed to create effective materials.
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana, United States.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Mosquera-Giraldo
authors.affiliation: Department of Chemistry, College of Science, Purdue University , West Lafayette, Indiana, United States.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Borca
authors.affiliation: Department of Sustainable Biomaterials, College of Natural Resources and Environment, Virginia Tech , Blacksburg, Virginia, United States.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Sustainable Biomaterials, College of Natural Resources and Environment, Virginia Tech , Blacksburg, Virginia, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Edgar
authors.affiliation: Department of Chemistry, College of Science, Purdue University , West Lafayette, Indiana, United States.
authors.forename: Lyudmila V
authors.initials: LV
authors.lastname: Slipchenko
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana, United States.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
mesh_terms: D000284:Administration, Oral; D002482:Cellulose / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D016503:Drug Delivery Systems; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D012996:Solutions / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D011108:Polymers; D012996:Solutions; D014867:Water; D002482:Cellulose