(172d) Fundamental Insights into Breakage of Organic Molecular Crystals

There are several reports in the literature that deal with predicting the morphology and mechanical properties of organic crystals. There are fewer studies that translate these predictions into an understanding of the macroscopic properties such as the strength of crystals. Though it seems intuitive that intermolecular interactions within a single crystal would influence mechanical properties and dominate the response of the bulk material to external stresses, proving this hypothesis is non-trivial. The first difficulty is that rarely do macroscopic events depend solely on the properties of single crystals. In typical pharmaceutical operations like compacting or tableting, the behavior of the material is determined by the bulk mechanical properties of the polycrystalline material and the characteristics of the applied external stresses. Secondly, the strength of a polycrystalline sample depends primarily on the relative orientation of lattice/cleavage planes with respect to the external stress and on the presence of defects in crystalline particles such as cracks and improperly grown sides and edges. However, during mechanical operations, it is the crystals themselves that ultimately deform and break, and hence the properties of single crystals are also relevant in understanding the performance of such crystals in unit operations, especially dry or wet-milling. In milling processes, particle-particle and particle-wall contacts are primarily responsible for breakage.

Fundamental mechanical properties such as the elastic moduli of crystals and molecular parameters such as attachment and surface energies of crystal faces can also provide insight into pharmaceutical formulation issues such as the behavior of particles in a compaction process, and compressibility which is the ability of a material to undergo volume reduction under pressure. The bulk characteristics of a powder sample, such as the tendency of the particles to agglomerate which could depend on the surface properties of particles, the direction and distribution of applied stresses and the plasticity of the particles, play a defining role in determining compactibility and compressibility. The traditional method to study and understand these properties has been to use a compaction simulator. Extensive studies have been carried out to understand the bulk compaction behavior of active pharmaceutical ingredients using the simulator. These studies while offering insights into the role played by morphology, packing of crystals and strain rate sensitivity in material performance during compaction, do not offer a predictive framework to delineate the roles of molecular structure, crystalline organization and other fundamental solid-state and mechanical properties in determining bulk performance.

This study adds to previous investigations on computing attachment energies of single crystals but also includes computation of mechanical properties of these crystals. It further describes how these fundamental quantities could play a role in determining the response of the crystals to bulk processing operations such as milling and compaction. In addition, since computation of surface energies is an integral part of the modeling, insight can also be obtained into surface-sensitive phenomena such as aggregation.

To understand the role of crystal structure and energetics on particle size reduction, molecular simulations of crystal structure, morphology and crystal growth energies were carried out. Specifically, in order to probe the influence of crystal strength on the degree of particle size reduction and morphology produced upon milling, molecular modeling studies were carried out on single crystals of Compounds A, B, C, and D. The crystal structures of the compounds were used as a starting point for molecular simulations. The single crystal structures were optimized using molecular mechanics with suitable forcefields ensuring minimal distortion of the unit cell structures. The attachment energy - E(att) - was computed using the Hartman-Perdok methodology as implemented in CERIUS2 and was used in the computation of the growth morphology of the crystals. E(att) is defined as the energy released when a growth slice is added to a growing crystal front. The HP method relies on the concept that the stability of a crystal is driven by the strong bonds formed between growth units. This method identifies strong bonds (periodic bond chains) within and between planes parallel to crystal faces. The HP module determines the bond energy between two growth units by placing them in a temporary model with the same distance and orientation as in the crystal and calculating the difference between the total energies of the separated units. The lattice energy is calculated as the summation of bond energies over all bonds in a crystal. The stable growth planes are those that contain 2D connected nets of strong bonds. These planes are characterized by a low attachment energy. The calculated attachment energies for every plane in the crystal can then be analyzed to identify planes of weak interactions within the crystals.

Certain crystals have the propensity to break along well-defined planes when subjected to external stresses that exceed the strength of the crystal across those planes. This process is referred to as cleavage and the strength across the plane is quantified by the attachment energy. Specific (anisotropic) and dispersion interactions within the crystal lattice, which determine the attachment energy, play a major role in defining the habit or shape of the crystal fragments produced upon cleavage of a large crystal. Another mechanism of particle disruption is plastic deformation that is attributable to kinking, twinning or glide. The slip plane in this process is usually identified as the plane that possesses the lowest attachment energy. Thus, knowledge of the morphology, intermolecular interactions, attachment energies and cleavage planes together can help in understanding why it is easier to break certain crystals compared to others.

This presentation summarizes the results of the molecular modeling studies, the lowest attachment energy for each crystal, the predicted and experimental morphology, the milling operation and the morphology of the particles obtained after the milling operation. In all cases there was very good agreement between the predicted and experimental morphologies. The habit of Compound A is rhomboid and the 001 plane has the lowest attachment energy (-8.22 kcal/mol). The lowest attachment energy for Compound B is -5.7 kcal/mol, attributed to the 010 plane and that for Compound C, -28 kcal/mol for the 001 plane. The morphologies of these crystals are predicted reasonably well by modeling. It was also seen that the milling performance of these three compounds is quite similar in that the profile of particle size reduction with shear frequency is not very different for the three compounds. The attachment energies of the first two compounds are very close to each other while that for Compound C is slightly higher.

Compound D is a hydrate and the predicted morphology of elongated prisms agrees well with the experimental morphology. The 002 plane is associated with the lowest attachment energy of ?56.3 kcal/mol. These results predict that a higher energy input is probably required for particle size reduction of this compound compared to A, B and C. The lab and pilot scale milling data support the model predictions. The mv particle size for Compound D after 100 recycles through a slurry mill was significantly higher (by ~10-15 um) compared to compounds A, B and C. In addition, the micrographs show that little mass fracture had occurred. Instead, the particle size reduction was mainly due to breakage of agglomerated plates and attrition along the edges, resulting in a mixture of round plates and large numbers of fines. The milled morphology suggests that the external stresses generated by the surrounding liquid are not powerful enough to overcome the attachment energies of Compound D and induce fracture. Alternative milling methods with higher energies and different mechanisms may be required to reduce the particle size of compounds with high attachment energies. When Compound D was milled with a media (bead) mill instead, the collisions between the beads and the crystals succeeded in fracturing the crystals into smaller units of similar morphology.

Based on these results, similar computations were carried out with several other compounds and a database of attachment energies was created to correlate breakage with fundamental single crystal properties of compounds A-H. In general it was observed that ease of milling correlated inversely with attachment energy ? it was difficult to break particles of higher attachment energy with the same force/stress compared to those with lower attachment energies. It is expected that these methods could be incorporated in macroscopic computations such as population balance modeling or in conjunction with single crystal experiments, used in predicting breakage phenomena for a wider class of crystals.

Finally, the aspect ratio of crystals is an important factor that could play a significant role in determining the initial stages of breakage where the dominant mechanism is brittle fracture. Ways in which such effects could be incorporated in the methodology will be discussed in the presentation.