Legrand Philippe, Lesieur Sylviane, Bochot Amélie, Gref Ruxandra, Raatjes Wouter, Barratt Gillian, Vauthier Christine
University Paris Sud, UMR CNRS 8612, IFR 141, Châtenay Malabry, F-92296, France.
Int J Pharm. 2007 Nov 1;344(1-2):33-43. doi: 10.1016/j.ijpharm.2007.05.054. Epub 2007 May 31.
The aim of this study was to define the parameters determining an optimized yield of monodisperse, nanosized particles after nanoprecipitation of a biodegradable polymer, with a view to industrial scale-up the process. Poly(d,l)-lactides (PLAs) from a homologous series of different molar masses were nanoprecipitated at different initial polymer concentrations from two organic solvents, acetone and tetrahydrofuran (THF), into water without surfactant according to a standardized procedure. Quasi-elastic light scattering and gel permeation chromatography with universal detection were used respectively to size the particles and to determine the molar mass distribution of the polymeric chains forming both nanoparticles and bulk aggregates. The intrinsic viscosity of the polymers as a function of molar mass and solvent were determined by kinematic viscosity measurements in organic solutions. High yields of small nanoparticles were obtained with polymers of lower molar mass (22600 and 32100 g/mol). For a given polymer concentration in organic solution, the particle diameter was always lower from acetone than from THF. For initial molar masses higher than 32100 g/mol, only dilute organic solutions gave significant yields of nanoparticles. Furthermore, polymer mass fractionation occurred with increasing initial molar mass and/or concentration: the nanoparticles were formed by polymeric chains of molar masses significantly lower than the average initial one. In general, nanoparticle production was satisfactory when the initial organic solution of polymer was in the dilute rather than the semi-dilute regime. Moreover, acetone, which acted as a theta solvent for PLA, always led to smaller particles and better yields than THF.
本研究的目的是确定在可生物降解聚合物纳米沉淀后决定单分散纳米颗粒优化产率的参数，以期将该工艺扩大到工业规模。按照标准化程序，将不同摩尔质量同系物系列的聚（d，l）-丙交酯（PLA）在不同的初始聚合物浓度下从两种有机溶剂丙酮和四氢呋喃（THF）中纳米沉淀到无表面活性剂的水中。分别使用准弹性光散射和通用检测凝胶渗透色谱法对颗粒进行尺寸测定，并确定形成纳米颗粒和本体聚集体的聚合物链的摩尔质量分布。通过在有机溶液中进行运动粘度测量来确定聚合物的特性粘度作为摩尔质量和溶剂的函数。较低摩尔质量（22600和32100 g/mol）的聚合物可获得高产率的小纳米颗粒。对于有机溶液中给定的聚合物浓度，丙酮形成的颗粒直径总是低于THF形成的颗粒直径。对于高于32100 g/mol的初始摩尔质量，只有稀有机溶液能产生可观产率的纳米颗粒。此外，随着初始摩尔质量和/或浓度的增加，聚合物发生质量分级：纳米颗粒由摩尔质量明显低于平均初始摩尔质量的聚合物链形成。一般来说，当初始聚合物有机溶液处于稀溶液而非半稀溶液状态时，纳米颗粒的生产效果令人满意。此外，作为PLA的θ溶剂的丙酮总是比THF产生更小的颗粒和更高的产率。
