Jin, Zheng
(2010)
The micro and nano scale characterization and identification of tablet formulations.
PhD thesis, University of Nottingham.
Abstract
The aim of this project was to characterize the surface properties of materials used in tablet formulations with sub-micron resolution by the techniques of Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), Scanning Thermal Microscopy (SThM), Nano-TA system, Differential Scanning Calorimeter (DSC), Attenuated Total Reflectance Infrared (ATR-IR), Near-Infrared Spectroscopy (NIR) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). In particular, the work aimed to develop new AFM based methodologies to advance this method both in terms of quantification and mapping. AFM was employed to investigate properties of solid materials such as surface free energy, Young’s modulus, melting point and phase transition temperatures from pharmaceutical materials in blend mixtures with the nanoscale resolution. These approaches developed here provide new tools to understand the process induced changes and stability issues in solid dosage forms such as tablets and inhalation formulations from minute amounts of materials.
The surface free energy values of solid materials obtained from AFM adhesion force measurements were described in Chapter 3. The adhesion forces obtained with AFM in low relative humidity environments were used to derive the surface free energy values using the Hertzian and JKR based models. The surface free energy was proposed to be close to the so called dispersion surface free energy since the adhesion forces at low relative humidity mainly resulted from van der Waals forces in the systems studied here. The comparison of surface free energy between AFM and those derived from a contact angle method showed that the dispersion surface free energy values derived from the contact angle method were generally higher than those from AFM. For example, the surface free energy value derived from AFM adhesion force measurements for lactose monohydrate was 33.0 mJ/m2, while from contact angle method the value was 46.8 mJ/m2. Whilst in reasonable agreement, the variation was believed to result from the differences in probe substance (liquid in contact angle and solid in AFM method), scale of measurements (contact area 200 nm2 in AFM, several mm2 in contact angle) and possible polar interactions. However, the surface free energy values derived from direct solid-solid interactions in AFM adhesion force measurements may have more relevances in applications that relate to solid-solid interactions, such as in pharmaceuticals.
The influence of polar interaction in AFM adhesion force measurements at low relative humidity was further investigated in Chapter 4. The techniques of colloid probe and plasma polymerized coating were employed: Plasma polymerized hexane and allylamine were coated on the surfaces of glass beads mounted on AFM cantilevers. Plasma Polymerized Hexane had only a dispersion surface free energy while plasma polymerized allylamine had both dispersion and polar surface free energy components. The differences in normalized adhesion forces between these two kinds of colloid probes can reveal the influence of polar interactions at low relative humidity in AFM adhesion force measurements. For most samples, the experimental adhesion forces with plasma polymerized allylamine colloid probes were smaller than the theoretical values calculated from dispersion interactions. The polar interactions in such conditions were repulsive so they had decreased the experimental adhesion forces. So in AFM adhesion force measurements, the polar interactions existed even at very low humidity. However the relative magnitude of polar interactions were smaller than the dispersion interactions and for silicon sample the polar interactions were negligible.
In Chapter 5, properties including Young’s modulus, melting points and phase transition temperature were measured at the nanoscale with AFM, SThM and the nano-TA system. The variation of Young’s modulus with temperature, for the excipients hydroxypropylmethylcellulose (HPMC), dibasic calcium phosphate dihydrate (DCPD) was studied. The differences in Young’s modulus between DCPD and its anhydrous form were revealed with AFM measurements. The melting point and phase transition temperature were measured by nano-TA system with sub-100 nm spatial resolution. The thermal properties obtained from nano-TA system were consistent with those from bulk measurements using DSC: e.g. the dehydration of lactose monohydrate (150 ºC) was confirmed by nano-TA system and DSC measurements.
In Chapter 6, the methods to derive surface free energy and thermal properties described in previous chapters were employed to spatially locate and characterize an API (AZD 3409 malate salt) and excipient (lactose monohydrate) on the surface of a model tablet at the nanoscale using AFM and the nano-TA system. The API and excipient were mixed with the ratio of 20:80. 50:50 and 80:20 w/w and compressed into discs to create the model tablets. The surfaces of model tablets were first characterized by ATR-IR, NIR and ToF-SIMS. Then AFM adhesion force measurements were carried out to map the location of each component in the mixed discs. In addition, in situ topography AFM images of the discs were recorded. At the position of force mapping, the nano-TA system was employed to correlate the thermal properties including the melting points of both materials and the dehydration of the lactose monohydrate with surface free energy information from force mapping. The surface free energy and thermal properties data were consistent with bulk measurements in previous chapters. In situ correlation between AFM force mapping (surface energy) and nano-TA system (thermal properties) at 5 differences positions on a model disc surface showed consistent identification of the two materials. This proof of principal work can be extended to more complex formulations and has the potential to be employed in early stage solid state stability testing to identify the appearance of new species at surfaces or solid-solid interfaces.
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