(T1030-04-22) Structure-Mechanical Property Relationship in Molecular Crystals for Predicting Tabletability

Purpose: Most active pharmaceutical ingredients (APIs) for the manufacturing of oral drugs, such as tablets and capsules, are molecular crystals. During milling, size reduction takes place by crystal fracturing, usually along specific crystallographic planes. During compaction, a tablet is formed by the plastic deformation of particles and formation of bonded contacts between particles. Thus, the knowledge of hardness, fracture toughness, and propensity for deformation on slip planes in contrast to fracture on cleavage planes is critical in understanding how crystals deform and identifying crystals that possess sufficient brittleness for milling and enough plasticity for tableting. Therefore, this work aims to fill the knowledge gap by quantifying the mechanical properties of succinic acid (SA) and L-alanine (LA) using nanoindentation. The obtained mechanical properties are correlated with crystal structures to identify key factors that contribute towards plasticity or fracture in a crystal. Furthermore, this work focuses on correlating the single crystal mechanical properties and structure with their bulk powder tableting performance to define the optimum range of hardness, elastic modulus, and fracture toughness for adequate tabletability of APIs.

Methods: Single crystal synthesis- Single crystals of succinic acid (C₄H₆O₄) and L-alanine (C₃H₇NO₂) were synthesized by cooling method. Supersaturated solutions were prepared by heating and cooling the suspensions of succinic acid and L-alanine in de-ionized water. Seeds were introduced to shorten the crystallization duration. Crystal face indexing- Crystal faces for indentation were indexed with Bruker D8 Discover using monochromatic Co-Ka (1.79 Å) radiation at 40 kV voltage and 35 mA current. 3. Nanoindentation- Nanoindentation data were collected using a nanoindenter at ambient conditions and analyzed using the Oliver-Pharr method. A diamond Berkovich indenter was used for probing the mechanical properties (modulus and hardness) of the crystals. Indentations were conducted in the load-controlled mode with a partial load-unload function having 1 s load, 5 s hold, and 0.5 s unload segments with a peak load of 1000 mN. Calculation of energy framework- The intermolecular interaction energies in SA and LA were calculated using CrystalExplorer with the B3LYP-D2/6-31G(d,p) molecular wavefunction. Molecular packing features were analyzed using VESTA 3.5.7. Visualization of crystallographic planes and directions parallel to the indentation axis aided in correlating structural features with mechanical properties.

Results: Crystal morphology and face indexing- The experimentally grown SA crystal has a hexagonal shape with (100) face being the largest and, thus, the most accessible to indent. The grown LA crystal possesses a trapezoidal morphology and the largest crystal face was (120) (Figure 1). The crystals of SA and LA were cleaved with a sharp razor to access other faces for indentation. Mechanical property analysis- When measuring modulus and hardness, partial load-unload function was used as it has an advantage of measuring depth-dependent properties. As indentation progresses deeper into the material, the modulus and hardness values become independent of the displacement and attains a plateau (Figure 1). Thus, the property values were averaged in this plateau region for each of the tests. Molecular structure analysis- Calculation of interaction energy between (020) planes in succinic acid revealed that it is lower between planes (-98.2 kJ/mol) than that within the plane (-134.2 kJ/mol). Due to these weak interaction energies between the adjacent layers of (020), sliding between the planes become energetically favorable (Figure 2). Thus, energy framework model supports the assignment of (020) as the slip plane in SA and shows presence of directional bonding, which makes plastic deformation facile and renders lower modulus and hardness in SA. Much higher intermolecular interaction energies (-421.1 kJ/mol), shown by the thicker cylinders in the energy framework, are observed along all the directions of LA (Figure 2). There exist weaker bonding interactions (23.5 kJ/mol) across the (020) layers, making it the most probable slip plane in LA. Due to three- dimensional hydrogen bonding network, plastic deformation is restricted in L-alanine causing higher modulus and hardness than SA. Correlation of structure-property with tabletability- Succinic acid, possessing lower modulus and hardness and directional bonding, undergoes greater deformation under compressive loading and forms higher bonding area and bonding strength. This makes robust succinic acid tablets with a tensile strength of 0.45 MPa at a compaction pressure of 200 MPa. On the contrary, L-alanine exhibits higher modulus, hardness, and brittleness index, leading to poor tabletability with a very low tensile strength of 0.03 MPa at a compaction pressure of 200 MPa.

Conclusion: The mechanical properties of succinic acid and L-alanine can be strongly correlated with their underlying molecular arrangement. Tabletability has been successfully linked via this structure-property correlation, which shows that a crystal with higher directional bonding and lower modulus, hardness, and brittleness index forms tablets with higher tensile strength. On the other hand, a crystal having higher modulus, hardness, brittleness index resist plastic deformation and forms fragile tablets.

References: 1. Varughese, S., Kiran, M.S.R.N., Ramamurty, U. and Desiraju, G.R., 2013. Nanoindentation in crystal engineering: quantifying mechanical properties of molecular crystals. Angewandte Chemie International Edition, 52(10), pp.2701-2712.
2. Majumder, S., Sun, C.C. and Mara, N.A., 2022. Nanomechanical testing in drug delivery: Theory, applications, and emerging trends. Advanced Drug Delivery Reviews, 183, p.114167.
3. Ramamurty, U. and Jang, J.I., 2014. Nanoindentation for probing the mechanical behavior of molecular crystals–a review of the technique and how to use it. CrystEngComm, 16(1), pp.12-23.

Acknowledgements: We thank the National Science Foundation for support through the Industry University Collaborative Research Center grant IIP-2137264, Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP). We also thank the Characterization Facility at the University of Minnesota for the access to their advanced equipment.


Fig 1. Modulus and hardness plots of the crystals obtained from nanoindentation


Fig 2. Energy framework model for succinic acid and L-alanine in analyzing the intermolecular interactions along the indentation direction


Table 1. Summary of mechanical properties of succinic acid (SA) and L-alanine (LA)