Hydrogen Bonding Principle-Based Molecular Design of a Polymer Excipient and Impacts on Hydrophobic Drug Properties: Molecular Simulation and Experiment.

Although some commercial excipients for improving the solubility of highly crystalline drugs are widely used, they still cannot cover all types of hydrophobic drugs. In this regard, with phenytoin as the target drug, related molecular structures of polymer excipients were designed. The optimal repeating units of NiPAm and HEAm were screened out through quantum mechanical simulation and Monte Carlo simulation methods, and the copolymerization ratio was also determined. Using molecular dynamics simulation technology, it was confirmed that the dispersibility and intermolecular hydrogen bonds of phenytoin in the designed copolymer were better than those in the commercial PVP materials. At the same time, the designed copolymers and solid dispersions were also prepared during the experiment, and the improvement of their solubility was confirmed, which is in accordance with the simulation predictions. The new ideas and simulation technology may be used for drug modification and development.

[1]  P. A. Williams,et al.  An experimental and theoretical charge density study of theophylline and malonic acid cocrystallization , 2022, RSC advances.

[2]  J. Meng,et al.  Study on the Effect of Polymer Excipients on the Dispersibility, Interaction, Solubility, and Scavenging Reactive Oxygen Species of Myricetin Solid Dispersion: Experiment and Molecular Simulation , 2022, ACS omega.

[3]  P. Jeemon,et al.  Malformation risk of new anti-epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP) , 2021, Seizure.

[4]  James H. Wang,et al.  Polyvinyl Butyral with Different Acetalization Degrees: Synthesis and Solubility Parameters , 2021, Journal of Macromolecular Science, Part B.

[5]  F. Bates,et al.  Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness. , 2021, ACS macro letters.

[6]  Linan Liu,et al.  Automated PET-RAFT Polymerization Towards Pharmaceutical Amorphous Solid Dispersion Development. , 2021, ACS applied polymer materials.

[7]  Sizhu Wu,et al.  Study on the mechanisms of the lubricating oil antioxidants: Experimental and molecular simulation , 2021 .

[8]  K. Kontogiannopoulos,et al.  Evaluation of rivaroxaban amorphous solid dispersions physical stability via molecular mobility studies and molecular simulations. , 2020, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[9]  T. Lodge,et al.  Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles. , 2020, ACS applied bio materials.

[10]  Sonal V. Bhujbal,et al.  Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach , 2020, International journal of pharmaceutics: X.

[11]  K. Kontogiannopoulos,et al.  Experimental, thermodynamic and molecular modelling evaluation of amorphous simvastatin-poly(vinylpyrrolidone) solid dispersions. , 2020, Molecular pharmaceutics.

[12]  Sizhu Wu,et al.  High-efficiency and selective adsorption of organic pollutants by magnetic CoFe2O4/graphene oxide adsorbents: Experimental and molecular dynamics simulation study , 2020 .

[13]  Ping I. Lee,et al.  Evolution of Supersaturation from Amorphous Solid Dispersions in Water-Insoluble Polymer Carriers: Effects of Swelling Capacity and Interplay between Partition and Diffusion. , 2020, International journal of pharmaceutics.

[14]  L. S. Taylor,et al.  Congruent release of drug and polymer from amorphous solid dispersions: insights into the role of drug-polymer hydrogen bonding, surface crystallization and glass transition. , 2020, Molecular pharmaceutics.

[15]  Sizhu Wu,et al.  Antioxidation behavior of bonded primary-secondary antioxidant/styrene-butadiene rubber composite: Experimental and molecular simulation investigations , 2020 .

[16]  Sizhu Wu,et al.  Influencing factors for vulcanization induction period of accelerator / natural rubber composites: Molecular simulation and experimental study , 2019 .

[17]  Yujie Zhu,et al.  Solid dispersions of telaprevir with improved solubility prepared by co-milling: formulation, physicochemical characterization, and cytotoxicity evaluation. , 2019, Materials science & engineering. C, Materials for biological applications.

[18]  M. Hillmyer,et al.  Critical Excipient Properties for the Dissolution Enhancement of Phenytoin , 2019, ACS omega.

[19]  Sizhu Wu,et al.  Synergistic effects of antioxidant and silica on enhancing thermo-oxidative resistance of natural rubber: Insights from experiments and molecular simulations , 2019, Materials & Design.

[20]  Hua-lin Liao,et al.  Molecular dynamics study of the intercalation and conformational transition of poly (N-vinyl caprolactam), a thermosensitive polymer in hydrated Na-montmorillonite , 2019, Polymer.

[21]  E. Venuti,et al.  Surface Induced Phenytoin Polymorph. 2. Structure Validation by Comparing Experimental and Density Functional Theory Raman Spectra , 2019, Crystal growth & design.

[22]  F. Bates,et al.  Polymer Nanogels as Reservoirs To Inhibit Hydrophobic Drug Crystallization. , 2019, ACS nano.

[23]  K. O'Donnell,et al.  Rheology of Cellulose Ether Excipients Designed for Hot Melt Extrusion. , 2018, Biomacromolecules.

[24]  Sizhu Wu,et al.  Thermodynamic analyses of the hydrogen bond dissociation reaction and their effects on damping and compatibility capacities of polar small molecule/nitrile-butadiene rubber systems: Molecular simulation and experimental study , 2018, Polymer.

[25]  Jeffrey M. Ting,et al.  Advances in Polymer Design for Enhancing Oral Drug Solubility and Delivery. , 2018, Bioconjugate chemistry.

[26]  R. Suryanarayanan,et al.  Drug-Excipient Interactions: Effect on Molecular Mobility and Physical Stability of Ketoconazole-Organic Acid Coamorphous Systems. , 2018, Molecular pharmaceutics.

[27]  Wenjing Sun,et al.  Molecular insight into the enhancement of benzene-carbon nanotube interactions by surface modification for drug delivery systems (DDS) , 2017 .

[28]  R. Larson,et al.  Multiscale Computational Modeling of the Nanostructure of Solid Dispersions of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) and Phenytoin. , 2017, Molecular pharmaceutics.

[29]  G. Borodi,et al.  Solid dispersions of Myricetin with enhanced solubility: Formulation, characterization and crystal structure of stability-impeding Myricetin monohydrate crystals , 2017 .

[30]  J. Lubach,et al.  A rational approach towards development of amorphous solid dispersions: Experimental and computational techniques. , 2017, International journal of pharmaceutics.

[31]  F. Bates,et al.  Impact of Polymer Excipient Molar Mass and End Groups on Hydrophobic Drug Solubility Enhancement , 2017 .

[32]  M. Fischer,et al.  Benchmarking DFT-GGA calculations for the structure optimisation of neutral-framework zeotypes , 2016, Theoretical Chemistry Accounts.

[33]  L. Slipchenko,et al.  Mechanistic Design of Chemically Diverse Polymers with Applications in Oral Drug Delivery. , 2016, Biomacromolecules.

[34]  R. Pandey,et al.  Stability and Electronic Properties of 2D Nanomaterials Conjugated with Pyrazinamide Chemotherapeutic: A First-Principles Cluster Study , 2016 .

[35]  Shrawan Baghel,et al.  Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. , 2016, Journal of pharmaceutical sciences.

[36]  T. Reineke,et al.  Dissolution and Solubility Enhancement of the Highly Lipophilic Drug Phenytoin via Interaction with Poly(N-isopropylacrylamide-co-vinylpyrrolidone) Excipients. , 2015, Molecular pharmaceutics.

[37]  Jeffrey M. Ting,et al.  Design of Tunable Multicomponent Polymers as Modular Vehicles To Solubilize Highly Lipophilic Drugs , 2014 .

[38]  R. Larson,et al.  Assessing the efficiency of polymeric excipients by atomistic molecular dynamics simulations. , 2014, Molecular pharmaceutics.

[39]  C. Figueirêdo,et al.  Solid dispersion of efavirenz in PVP K-30 by conventional solvent and kneading methods. , 2014, Carbohydrate polymers.

[40]  T. Reineke,et al.  Solution-state polymer assemblies influence BCS class II drug dissolution and supersaturation maintenance. , 2014, Biomacromolecules.

[41]  Jeffrey M. Ting,et al.  Precise Compositional Control and Systematic Preparation of Multimonomeric Statistical Copolymers. , 2013, ACS macro letters.

[42]  Hywel D Williams,et al.  Strategies to Address Low Drug Solubility in Discovery and Development , 2013, Pharmacological Reviews.

[43]  Toshiyuki Niwa,et al.  Development of a novel ultra cryo-milling technique for a poorly water-soluble drug using dry ice beads and liquid nitrogen. , 2012, International journal of pharmaceutics.

[44]  Koichi Wada,et al.  Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. , 2011, International journal of pharmaceutics.

[45]  B. Delley.  Ground-state enthalpies: evaluation of electronic structure approaches with emphasis on the density functional method. , 2006, The journal of physical chemistry. A.

[46]  M. Minch.  An Introduction to Hydrogen Bonding (Jeffrey, George A.) , 1999 .

[47]  Jeremy N. S. Evans,et al.  The Fukui Function: A Key Concept Linking Frontier Molecular Orbital Theory and the Hard-Soft-Acid-Base Principle , 1995 .