title: Structural insight into the physical stability of amorphous Simvastatin dispersed in pHPMA: enhanced dynamics and local clustering as evidenced by solid-state NMR and Raman spectroscopy.
abstract: New drug formulations are sought for poorly water-soluble substances because there is a risk of compromised bioavailability if such substances are administered orally. Such active pharmaceutical ingredients can be reformulated as solid dispersions with suitable water-soluble polymers. In this contribution, formulation of a novel and physically stable dispersion of Simvastatin in poly(2-hydroxypropyl) methacrylamide (pHPMA) is demonstrated. Due to the limited water sorption of pHPMA and a high Tg, the prepared dispersion is more suited for oral administration and storage compared with neat amorphous Simvastatin. Surprisingly, the rate of global reorientation and the internal motion of Simvastatin molecules were enhanced and exhibited dynamical heterogeneities when incorporated into the pHPMA matrix. As revealed by solid-state nuclear magnetic resonance combined with Raman spectroscopy exploiting the fluorescence phenomenon the mobility of the ester and lactone components increased considerably, whereas the naphthalene ring remained rigid. Furthermore, the solid dispersion was found to be nano-heterogeneous with nanometer-sized Simvastatin domains. The presence of these clusters had no impact on the dynamics of the rigid pHPMA chains. Thus, the diffusion of Simvastatin molecules through the glassy pHPMA walls and the subsequent transformation of the clusters into larger crystallites were prevented. No crystallization was detected for more than two years.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Czech Republic. Electronic address: urbanova@imc.cas.cz.
authors.forename: Martina
authors.initials: M
authors.lastname: Urbanova
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Czech Republic. Electronic address: sturcova@imc.cas.cz.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sturcova
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Czech Republic. Electronic address: kredatusova@imc.cas.cz.
authors.forename: Jana
authors.initials: J
authors.lastname: Kredatusova
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Czech Republic. Electronic address: brus@imc.cas.cz.
authors.forename: Jiri
authors.initials: J
authors.lastname: Brus
mesh_terms: D000327:Adsorption; D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011109:Polymethacrylic Acids / Q000737:chemistry*; D019821:Simvastatin / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D014867:Water / Q000737:chemistry
chemical_list: D011109:Polymethacrylic Acids; D014867:Water; C011533:Duxon; D019821:Simvastatin
keywords: Fluorescence; Pharmaceuticals; Raman spectroscopy; Simvastatin; Solid dispersions; Solid-state NMR