L5. Particle and Crystal Engineering.pdf

PR5214 Advances in Solid Pharmaceutical Formulations L5. Engineering: Particle and Crystal Design DUN JIANGNAN, Ph.D. AY24/25.S1 10-SEP-2024 Review session Learning Outcomes Understand the structure-property relationship, especially for the impacts of crystal str...

PR5214 Advances in Solid Pharmaceutical Formulations L5. Engineering: Particle and Crystal Design DUN JIANGNAN, Ph.D. AY24/25.S1 10-SEP-2024 Review session Learning Outcomes Understand the structure-property relationship, especially for the impacts of crystal structures on their mechanical properties. Be able to compare the mechanical properties based on a given set of crystal structures. Familiar with the applications of crystal engineering to the development of solid oral dosage forms; Understand the impacts of roller compaction on the mechanical properties of tablets. Understand the changes in particle/granule size on the mechanical properties of tablets. © J.D., NUS Engineering in Formulation Development If you recall…majorities of the APIs have deficient properties, which make them not suitable for pharmaceutical development as a tablet. Poor mechanical properties Poor chemical stability Low solubility/bioavailability Bitter taste Poor photostability … How to x the problem? © J.D., NUS fi The Material Science Tetrahedron (MST) Process Engineering Crystal Engineering （API) Material Sciences Performance Particle engineering (excipients) Structure-property relationship Structure Property © J.D., NUS Crystal Engineering “The understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties.” – G.R. Desiraju What’s the di erence between crystal engineering and organic synthesis? Non-covalent bonding Crystal Covalent bonding New molecule © J.D., NUS To change the structure of API ff The Structure-Property Relationship Graphite Diamond Mohs Hardness Scale Soft Hard © J.D., NUS The Slip System in Crystal Structure How to assess a slip system qualitatively? Flat parallel layers Individual column structures Layers that are not parallel but have no interlock How to assess a slip system quantitatively? Calculation based on the energy framework Force The presence of a slip system in a crystal lattice enhances the plastic deformation, thus increasing the BA. © J.D., NUS Acetaminophen What’s the tabletability of Acetaminophen (Form I)? 2.0 Tablet Acetaminophen HCl tensile Parallel layers strength (MPa) Acetaminophen Interlocked layers Compaction pressure (MPa) © J.D., NUS  Sulfamerazine Now, let’s continue with the sulfamerazine Why I > II ? Type I Type II Sun and Grant, 2001, Pharm. Res. 18:274-280 © J.D., NUS The Structure-Property Relationship “Layer by layer: “3D cross-link” Graphite Diamond Mohs Hardness Scale Soft Hard © J.D., NUS Cocrystals A distinct class of novel, crystalline materials which could alter the physicochemical properties of the compound. Pharmaceutical cocrystals have been de ned as cocrystals, which contained an API as one component and another component as a coformer in a stoichiometric ratio. Cocrystal vs Salt? Proton transfer © J.D., NUS fi Baicalein (BAI) 5.00 Scutellaria baicalensis Tablet tensile strength (MPa) 3.79 2.57 The tensile strength of BAI is less than 1 MPa for Poor API tabletability all compaction pressures ranging from 50-300MPa. 1.36 0.14 0.00 75.00 150.00 225.00 300.00 Compac on pressure (MPa) © J.D., NUS ti Tabletability of BAI Cocrystals BAI-NCT BAI-CAF Why the physical mixture between BAI and NCT/or CAF does not e ectively change the tabletability? © J.D., NUS ff Crystal structure of BAI Zigzag BAI crystal packing obstructs the possible slips when compressed, therefore reduces the plasticity. 15 © J.D., NUS Crystal structure of BAI Stacking wavelike layers parallel to the bc plane through an extensive H-bonding network. Isotropic rigid 3D H-bonding prohibits possible slips under external force. 16 © J.D., NUS Crystal structure of BAI-NCT Cocrystal ❖ Stacking of columns promotes the slip when compressed, enhances the deformation, and increases the plasticity. 17 © J.D., NUS Crystal structure of BAI-NCT Cocrystal Consists of molecular columns forti ed through multiple hydrogen bonds running along the a axis. Interactions between neighboring columns comprise weak hydrogen bonds. 18 © J.D., NUS fi Crystal structure of BAI-CAF Cocrystal Hexamers are formed, which were further connected to form columns forti ed through hydrogen bonds. The columns are further connected with adjacent columns via hydrogen bonds. These chains are further connected through hydrogen bonds to form thick layers. 19 © J.D., NUS fi  Photostability Cocrystallization could stabilize the Nitrofurantoin Vangala et al., Cryst. Growth Des. (2012) 12:5925−5938 © J.D., NUS  Sweet Berberine Acesulfame potassium Saccharine sodium The formation of sweet salts by the means of crystal engineering is a powerful strategy to improve berberine’s taste. © J.D., NUS Wang et al., Cryst. Growth Des., (2016) 16:933–939 Particle Engineering Coating Particle size adjustment To obtain the optimal particle morphology and surface characteristics; To improve manufacturability, processability, and biopharmaceutical properties. © J.D., NUS Particle Design Unsuccessful tableting Successful tableting © J.D., NUS The Percolation Theory Properties of a mixture of two components with distinct properties, undergo a sudden change when the composition passes through a certain critical point. Cluster – a group of occupied sites that are connected. The probability of a site occupied by a particle is p. As p increases, more clusters and/or larger ones are formed. At a critical concentration, i.e., Percolation threshold (pc), a cluster spanning the entire lattice is formed Below pc, all clusters are nite. Above pc, one in nite cluster is present © J.D., NUS fi fi  Compressible Sands Particle Engineering Sands (Silica) Something compressible? © J.D., NUS Shi & Sun, 2010, J. Pharm. Sci., 99:4458-4462  Acetaminophen Let’s revisit the acetaminophen case… Crystal Engineering - YES Particle Engineering ? Tablet tensile No tablets can be made from pure strengt untreated acetaminophen h (MPa) Acetaminophen Compaction pressure (MPa) © J.D., NUS Shi & Sun, 2011, Pharm. Res. 28:3248-3255 Loss of Reworkability in DG Powder mixture Tablet tensile Granules strength (MPa) The loss of reworkability occurred in the wet granulation Compaction pressure (MPa) © J.D., NUS The “work-hardening” Theory Work hardening, also known as strain hardening, is a process that leads to the strengthening of material through plastic deformation. Once you bend a paper clip, it becomes harder to bend back; If you continue with the bending multiple times, at a certain point, the paper clip will breaks due to mechanical failure. © J.D., NUS Model of Bonding in a Tablet Smaller particle size —> larger surface area Lower porosity —> larger total bonding area (S) H, the average bonding strength per unit bonding area, is a constituent of van der Waals’ force, H-bonding, mechanical interlocking, etc. © J.D., NUS  Effects of Particle Size on Tabletability Sieved powders vs Whole powders within a grade © J.D., NUS Sun & Himmelspach, J. Pharm. Sci. 95:200-206 (2006)  Effects of Granule Sizes on Tabletability The size of granules are more critical than the primary particle size © J.D., NUS Sun & Himmelspach, J. Pharm. Sci. 95:200-206 (2006)  Effects of Multiple RC on Tabletability 44-106 um The work-hardening theory 250-500 um MCCs granulates (roller compacted and milled x1, x2, and x4 times, sieved) © J.D., NUS Sun & Himmelspach, J. Pharm. Sci. 95:200-206 (2006) Effects of Multiple RC on Tabletability Can you interpret this plot? © J.D., NUS Effects of MgSt on inter-granular bonding strength Question: How can you understand more behind the observed tabletability? © J.D., NUS End of the Lecture