Overcoming Solid State Formulation Challenges (Polymorphs and co-crystals) Introduction to solid state formulation challenges Drug approval and development process Drug approval and development process Introduction to solid state formulation challenges Biopharmaceutics Classification System for “small molecules” oral delivery Biopharmaceutics Classification System for “small molecules” oral delivery High solubility High Permeability Low solubility High Permeability Class III Class IV High solubility Low Permeability Low solubility Low Permeability Anti-viral Anti-cancer Solubility Highest Dose dissolves in less than 250 mL 90% intestinal absorption Class II Permeability Class I Introduction to solid state formulation challenges Solid forms S o l i d fo r m s Crystalline (ordered supra-molecular structure) Pure substance crystals Multicomponent crystals Amorphous (disordered supra-molecular structure) Pure substance Multicomponent solid dispersion Introduction to solid state formulation challenges Solid forms S o l i d fo r m s Polymorphism in the Pharmaceutical Industry, Solid Form and Drug Development , Rolf Hilfiker, Markus von Raumer Crystal Engineering Polymorphism – when structure is a “game changer” Pure substance polymorphism Coal and diamonds… Crystal Engineering Polymorphism equilibrium and kinetics Polymorphism equilibrium and kinetics Polymorphism of water crystals Equilibrium Ice Ih Ice III liquid Crystallization of snow flakes Crystal Engineering Polymorphism equilibrium and kinetics Polymorphism equilibrium and kinetics Rodrigues et al. Mannitol Crystallization at Sub-Zero Temperatures J Phys Chem Lett. . 2021 Feb 11;12(5):1453-1460. doi: 10.1021/acs.jpclett.0c03680. Case study 1: Crystallization of mannitol Three anhydrous polymorphs (α, β, δ) and a hemihydrate (HH) Which polymorphs form when cooling a solution with 20% manitol? Crystal Engineering Polymorphism equilibrium and kinetics Polymorphism equilibrium and kinetics Kinetics will define the phase Many unstable (non-equilibrium) forms can exist and crystallize European Pharmacopoeia 180 molecules (study) Polymorphism in the Pharmaceutical Industry, Solid Form and Drug Development , Rolf Hilfiker, Markus von Raumer Crystal Engineering Polymorphism equilibrium and kinetics Polymorphism equilibrium and kinetics Kinetics will define the phase Many unstable (non-equilibrium) forms can exist and crystallize “When leaving a given state and in transforming to another state, the state that is sought out is not the thermodynamically stable one, but the state nearest in stability to the original state” Ostwald rule of stages The Ostwald rule of stages serves as a guidance on the evolution of a system initially far from equilibrium. With a probability better than 95%, this rule (not a law!) fits well with observations. Rodriguez-Navarro et al. Nonclassical crystallization in vivo et in vitro J Struct Biology. . 2016 Nov 196:260-287 doi: 10.1016/j.jsb.2016.09.005 Crystal Engineering Polymorphism equilibrium and kinetics Polymorphism equilibrium and kinetics Polymorphism control (crystal nucleation) Seeding model Assuming: Crystallization is only by crystal growth No aggregation or breakage Minimal secondary nucleation id e al O aumento de massa é proporcional ao cubo da dimensão característica Ls is the mean size of the final crystals Lp is the mean size of the seed crystals Cs is the seed loading ms is the mass of the seeds mp is mass of final crystals Which case represents agglomeration? What phenomena could explain the triangles? Polymorphism in the Pharmaceutical Industry, Solid Form and Drug Development , Rolf Hilfiker, Markus von Raumer Crystal Engineering Polymorphism equilibrium and kinetics Polymorphism equilibrium and kinetics How to seed Polymorphism control (crystal nucleation) To seed or not to seed? 1 . The product crystal is more stable Seeding improves process control but does not control polymorphic form Stable metastable 2 . The product is more stable but can nucleate as a metastable form Seeding improves process control and avoids crystal impurities of the metastable form (if done at low supersaturation) 3 . The product crystal is metastable and is the first to nucleate Seeding can improve the control, but there is a high risk of polymorph transformation because supersaturation is higher for the more stable polymorph Supersaturation limit (high probability of spontaneous nucleation) Solubility 4 . The product is metastable but the first to nucleate is the stable form (exception to the Ostwald rule) FORGET SEEDING… Polymorphism in the Pharmaceutical Industry, Solid Form and Drug Development , Rolf Hilfiker, Markus von Raumer Crystal Engineering Polymorphism equilibrium and kinetics Application Case study 2: Crystallization of paracetamol in different polymorphs Monoclinic; Tfus = 167 ºC Orthorhombic; Tfus = 154 ºC Which do you consider to be form I and form II judging by their temperature of fusion (see solubility curve)? Which form is easier to crystallize (justify)? How can you produce Form I without contamination from form II? How can you produce Form II avoiding contamination from form I? Study the influence of particle size of 1 g of seeds, that can precipitate 100 kg of paracetamol? Crystal Engineering Polymorphism Important to know Case study 3: Crystallization of Ritonavir – the worst case scenario Ritonavir (Norvir) Influence of polymorphism on properties (the issues) How it was controlled
