Davies Michael, Brindley Anne, Chen Xinyong, Marlow Maria, Doughty Stephen W, Shrubb Ian, Roberts Clive J
Laboratory of Biophysics and Surface Analysis, School of Pharmacy, The University of Nottingham, NG7 2RD, Nottingham, UK.
Pharm Res. 2005 Jul;22(7):1158-66. doi: 10.1007/s11095-005-5647-z. Epub 2005 Jul 22.
Particulate interactions are dominated by aspects such as surface topography, exposed chemical moieties, environmental conditions, and thermodynamic properties such as surface free energy (gamma). The absolute value and relative magnitude of surface energies of a drug and excipients within a formulation can significantly influence manufacture, processing, and use. This study utilizes and compares the potentially complementary analytical techniques of atomic force microscopy (AFM) and inverse gas chromatography (IGC) in the quantitative determination of the surface energy of drug (budesonide) particles (micronized and unmilled) relevant to inhaled delivery. In addition, the study investigates with AFM another important parameter in determining material interactions, the local mechanical properties of the drug.
AFM was used to acquire force of adhesion (Fadh) and related work of adhesion (WA) and surface energy values between individual mironized drug particles and also model substrates (graphite and mica). In addition, AFM probes were used to interrogate the surface energy of unmilled drug particles. Measurement with AFM probes also yielded localized measurements of Young's modulus for the unmilled drug. IGC was also used to probe the surface characteristics of the bulk drug material.
The average values for surface energies acquired from budesonide micronized particle interactions with graphite, mica, and drug particles of the same substance were found to range from 35 to 175, 5 to 40, and 10 to 32 mJ m(-2), respectively. The unmilled material displayed a range of values of 39-88 mJ m(-2) with an average of 60 mJ m(-2). The IGC result for the surface energy of the micronized material was 68.47 +/- 1.60 mJ m(-2). The variability in surface energy from AFM, a feature particularly apparent for the micronized material was attributed to two factors, intrinsic material variations within a single particle and assumptions present within the contact mechanics model used. Here we provide a detailed description of these factors to go some way to rationalize the results. The Young's modulus of the unmilled drug was determined to be approximately 10 GPa.
The range of determined surface energies between the AFM measurement on graphite, mica, and the drug is proposed to reflect the different chemistries displayed by the drug at the single particle level. The maximum values of these ranges can be related to the sites most likely to be involved in adhesion. AFM and IGC yield surface energy estimates in approximate agreement, but clearly are interrogating surfaces in different fashions. This raises questions as to the nature of the measurement being made by these approaches and to the most appropriate time to use these methods in terms of a direct relation to formulation design, manufacture, and drug delivery. Finally, we demonstrate a novel method for assessing the Young's modulus of a drug from a single particle.
颗粒间的相互作用受多种因素主导，如表面形貌、暴露的化学基团、环境条件以及诸如表面自由能（γ）等热力学性质。制剂中药物与辅料的表面能绝对值和相对大小会显著影响制造、加工及使用过程。本研究运用并比较了原子力显微镜（AFM）和反相气相色谱（IGC）这两种具有潜在互补性的分析技术，用于定量测定与吸入给药相关的药物（布地奈德）颗粒（微粉化和未研磨）的表面能。此外，该研究还通过AFM研究了决定材料相互作用的另一个重要参数，即药物的局部力学性能。
使用AFM获取单个微粉化药物颗粒与模型底物（石墨和云母）之间的粘附力（Fadh）、相关粘附功（WA）及表面能值。此外，还使用AFM探针探究未研磨药物颗粒的表面能。利用AFM探针测量还得到了未研磨药物的杨氏模量局部测量值。IGC也被用于探测原料药的表面特性。
从布地奈德微粉化颗粒与石墨、云母以及相同物质的药物颗粒相互作用中获取的表面能平均值，分别为35至175、5至40以及10至32 mJ m(-2)。未研磨材料的表面能值范围为39 - 88 mJ m(-2)，平均值为60 mJ m(-2)。微粉化材料表面能的IGC测量结果为68.47 +/- 1.60 mJ m(-2)。AFM测量得到的表面能存在变异性，这一特征在微粉化材料中尤为明显，其归因于两个因素，即单个颗粒内的固有材料差异以及所使用的接触力学模型中的假设。在此，我们详细描述这些因素，以便在一定程度上合理解释结果。未研磨药物的杨氏模量测定为约10 GPa。
通过AFM在石墨、云母及药物上进行测量所确定的表面能范围，被认为反映了药物在单颗粒水平上呈现的不同化学性质。这些范围的最大值可能与最有可能参与粘附的位点相关。AFM和IGC得出的表面能估计值大致相符，但显然是以不同方式探测表面。这引发了关于这些方法所进行测量的性质以及在与制剂设计、制造和药物递送直接相关方面使用这些方法的最合适时间的问题。最后，我们展示了一种从单个颗粒评估药物杨氏模量的新方法。
