Crystallographic and spectroscopic assessment of pharmaceutical material mechanics

Among the various dosage forms available on the market, oral solid dosage forms (tablets, capsules) are the most common means of formulating a drug substance. General unit operations involved in manufacturing these dosage forms include blending, granulation, compression and coating. Compression of solid dosage forms plays an important role in achieving a quality drug product. The compression properties of materials depend on various factors, of which the crystal structure i.e. how molecules organize themselves in a given material plays a pivotal role. Therefore, understanding the various elements of crystal structure is of paramount interest to material scientists to identify materials with good compression properties. One element of interest is the strength and distribution of intermolecular forces and its connection to compaction performance. Although there are tools available to measure the strength and distribution, they either provide incomplete or biased information. The objective of this study is to introduce a new spectroscopic technique Brillouin Light Scattering (BLS) to address the above deficiency. BLS is based on the interaction of light with the sound waves propagating in a material. Faster the sound waves, greater is the interaction strength and vice versa. We extended BLS to particulates in order to obtain the mechanical properties of materials and tried to connect the crystal structure, mechanical properties to the compaction performance of our model systems. Our model systems include single component (PABA esters, X-NBA) and two component systems (CAF and THY cocrystals). The selection of these model systems is based on modulating the strength and distribution of intermolecular forces. For example, we modulate the strength of dispersive and weak hydrogen bonds in PABA and X-NBA systems respectively. In the CAF and THY cocrystals, we modulate the overall organization of intermolecular forces relative to CAF and THY alone. Our hypothesis is that the reorganization of intermolecular forces would modulate mechanical properties, anisotropy and ultimately compaction performance.

Our results indicated that materials with similar crystal structures either exhibit similar or different compaction performance depending on the anisotropy and mechanical properties. Among various motifs, the layered structures displayed greater ease of deformation based on mechanical properties, presence of slip planes (weakly held planes, low yield pressures). Materials with a quasi-isotropic distribution of strong forces either showed deteriorated compaction performance or greater resistance to deformation (high yield pressures). Materials with greater ease of deformation displayed low Young’s and shear moduli. Cocrystallization enhanced tabletability in the case of caffeine (CAF) and compromised performance for THY. Overall, the mechanical properties measured using BLS were in good agreement with the observed compaction performance for all the model systems studied. These results highlight that intermolecular forces, their strength and distribution can lead to better understanding of materials and may be useful in implementing a Quality-by-design approach for the development of drug products.