Hierarchical Mass Transfer Analysis of Drug Particle Dissolution, Highlighting the Hydrodynamics, pH, Particle Size and Buffer Effects for Dissolution of Ionizable and non-Ionizable Drugs in a Compendial Dissolution Vessel.
Hierarchical Mass Transfer Analysis of Drug Particle Dissolution, Highlighting the Hydrodynamics, pH, Particle Size and Buffer Effects for Dissolution of Ionizable and non-Ionizable Drugs in a Compendial Dissolution Vessel.
复制标题
药物颗粒溶出度的分层传质分析，强调药典溶出容器中可电离和不可电离药物溶出的流体动力学、pH、粒径和缓冲液效应。
作者：
Niloufar Salehi;J. Al;Deanna M. Mudie;G. Amidon;R. Ziff;G. Amidon
溶出度是制剂口服给药的关键过程。在通过上皮细胞膜吸收到达体循环之前，药物必须首先溶解在人胃肠道（GI）中。由于体内和体外溶出度依赖于药物的理化、制剂和GI生理特性，因此体内和体外溶出度较为复杂。然而，了解这一过程对于开发耐用的制剂至关重要。为了增强我们对体内和体外溶出度的理解，开发了考虑药物性质、GI流体性质和流体流体动力学的分级传质（HMT）模型。关键药物性质包括固有溶解度、酸/碱特性、pKa、粒度和颗粒多分散性。GI流体性质包括本体pH、缓冲物质浓度、流体剪切速率和流体对流。为了证实该模型，在美国药典（USP）2溶出仪中进行体外溶出实验。弱酸性（布洛芬），弱碱性（氟哌啶醇），和非离子化（非洛地平）的药物被用来研究酸/碱的字符，pKa和固有溶解度的溶出度的影响。使用900 ml pH 6.5和37 ℃的5 mM碳酸氢盐和磷酸盐缓冲液研究缓冲液种类对药物溶出度的影响。为了研究流体剪切速率和对流的影响，该装置在不同的叶轮转速下操作。此外，采用不同平均粒径的布洛芬颗粒，考察粒径对药物溶出度的影响。体外实验表明，由于界面缓冲能力较低，本研究中使用的两种可电离化合物在碳酸氢盐缓冲液中的溶出速率比在相同缓冲液浓度的磷酸盐缓冲液中慢，这是碳酸氢盐缓冲液的独特行为。因此，使用代理（即，50 mM磷酸盐）用于生物相关体外溶出试验的碳酸氢盐缓冲液可能高估可电离药物的体内溶出速率。模型模拟表明，在建模时假设单分散粒度，溶出度可能高估多分散粒度分布的溶出速率。与体内情况相比，USP 2装置在不同转速下的体外条件下的流体动力学参数（最大剪切速率和流体速度）高出几个数量级。体内和体外药物溶出流体动力学条件之间的不一致可能导致高估体外条件下的溶出速率。体外溶出度数据支持HMT用于药物溶出度的准确度。这是第一个药物溶出模型，它结合了本体pH值和缓冲液浓度对界面药物颗粒溶解度的电离化合物与介质流体动力学效应（扩散，对流，剪切和限制组件），和药物粒度分布的影响。
Dissolution is a crucial process for the oral delivery of drug products. Before being absorbed through epithelial cell membranes to reach systemic circulation, drugs must first dissolve in the human gastrointestinal (GI) tract. In vivo and in vitro dissolution is complex due to its dependency upon drug physicochemical, drug product, and GI physiological properties. However, an understanding of this process is critical for the development of robust drug products. To enhance our understanding of in vivo and in vitro dissolution, a hierarchical mass transfer (HMT) model was developed that considers drug properties, GI fluid properties, and fluid hydrodynamics. Key drug properties include intrinsic solubility, acid/base character, pKa, particle size, and particle polydispersity. GI fluid properties include bulk pH, buffer species concentration, fluid shear rate, and fluid convection. To corroborate the model in vitro dissolution experiments were conducted in the United States Pharmacopeia (USP) 2 dissolution apparatus. A weakly acidic (ibuprofen), a weakly basic (haloperidol), and a non-ionizable (felodipine) drug were used to study the effects of acid/base character, pKa and intrinsic solubility on dissolution. 900 ml of 5 mM bicarbonate and phosphate buffers at pH 6.5 and 37 0C were used to study the impact of buffer species on drug dissolution. To investigate the impacts of fluid shear rate and convection, the apparatus was operated at different impeller rotational speeds. Moreover, pre-sieved ibuprofen particles with different average diameters were used to investigate the effect of particle size on drug dissolution. In vitro experiments demonstrate that dissolution rates of both ionizable compounds used in this study were slower in bicarbonate buffer than in a phosphate buffer with the same buffer concentration due to lower interfacial buffer capacity, a unique behavior of bicarbonate buffer. Therefore, using surrogates (i.e., 50 mM phosphate) for bicarbonate buffer for biorelevant in in vitro dissolution testing may overestimate in vivo dissolution rate for ionizable drugs. Model simulations demonstrated that assuming a monodisperse particle size when modeling, dissolution may overestimate the dissolution rate for polydisperse particle size distributions. The hydrodynamic parameters (maximum shear rate and fluid velocity) under in vitro conditions in USP 2 apparatus under different rotational speeds are orders of magnitude higher compared to the in vivo situation. The inconsistencies between the in vivo and in vitro drug dissolution hydrodynamic conditions may cause an overestimation of the dissolution rate under in vitro conditions. The in vitro dissolution data supported the accuracy of the HMT for drug dissolution. This is the first drug dissolution model that incorporates the effect of the bulk pH and buffer concentration on the interfacial drug particle solubility of ionizable compounds combined with the medium hydrodynamics effect (diffusion, convection, shear, and confinement components), and drug particle-size distribution.
影响因子：
4.9
作者：
Mudie DM;Amidon GL;Amidon GE
通讯作者：
Amidon GE