Laboratory of Biophysics and Surface Analysis, School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
Int J Pharm. 2010 May 31;391(1-2):98-106. doi: 10.1016/j.ijpharm.2010.02.024. Epub 2010 Feb 23.
The aims of this study were to investigate and characterize the physico-chemical properties of beclomethasone dipropionate (BDP) crystallized from tricholoromonofluoromethane (CFC-11). Physical interactions in a model pressurised metered dose inhaler (pMDI) system and changes in surface energy after size reduction (micronization) were determined. Although CFC-11 has largely been phased out of use in pMDIs due to its ozone depletion potential, the BDP CFC-11 clathrate is a stable entity and thus suitable as a model for our initial investigations. In addition, although propellant clathrates have been known for sometime, as far as the authors are aware, their surface energies and adhesive interactions have not been reported. The structure of the clathrate was investigated using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (X-RPD). In addition, atomic force microscopy (AFM) was employed to determine the dispersive surface free energy (SE) and force of adhesion (F(adh)) of the BDP CFC-11 clathrate with different pMDI components in a model propellant (decafluoropentane). The dispersive surface free energies for anhydrous BDP (micronized), the CFC-11 clathrate and ball-milled BDP CFC-11 clathrate are (47.5+/-4.9) mJ m(-2), (11.3+/-4.1) mJ m(-2) and (15.2+/-1.3) mJ m(-2) respectively. Force of adhesion results shows that BDP CFC-11 clathrates, even after being ball-milled for 2.5h, have a lower F(adh) compared to micronized anhydrous BDP with different pMDI components. This shows that the formation of the crystalline CFC-11 clathrate is advantageous when compared to the micronized anhydrous form, in terms of its surface energy and potential interactions within a suspension MDI formulation. In the wider context, this work has implications for the future development of HFA formulations with APIs which are prone to the formation of propellant clathrates.
本研究的目的是研究和表征从三氯一氟甲烷（CFC-11）结晶的倍氯米松二丙酸酯（BDP）的物理化学性质。在模型压力定量吸入器（pMDI）系统中确定了物理相互作用和粒径减小（微米化）后表面能的变化。尽管由于其消耗臭氧层的潜力，CFC-11 已在很大程度上从 pMDI 中淘汰，但 BDP CFC-11 包合物是一种稳定的实体，因此适合作为我们初步研究的模型。此外，尽管推进剂包合物已经存在了一段时间，但据作者所知，它们的表面能和粘附相互作用尚未报道。使用扫描电子显微镜（SEM）、X 射线光电子能谱（XPS）和 X 射线粉末衍射（X-RPD）研究了包合物的结构。此外，原子力显微镜（AFM）用于确定不同 pMDI 成分在模型推进剂（十氟戊烷）中与 BDP CFC-11 包合物的分散表面自由能（SE）和粘附力（F（adh））。无水 BDP（微米化）、CFC-11 包合物和球磨 BDP CFC-11 包合物的分散表面自由能分别为（47.5+/-4.9）mJ m（-2）、（11.3+/-4.1）mJ m（-2）和（15.2+/-1.3）mJ m（-2）。粘附力结果表明，即使经过 2.5 小时的球磨，BDP CFC-11 包合物的 F（adh）也低于不同 pMDI 成分的微米化无水 BDP。这表明，与微米化无水形式相比，形成结晶 CFC-11 包合物在悬浮 MDI 制剂中的表面能和潜在相互作用方面具有优势。从更广泛的角度来看，这项工作对未来开发容易形成推进剂包合物的 API 的 HFA 制剂具有影响。
