Polymorphic Forms: Physical Stability - University of Sunderland PDF

MPharm Programme Physical stability: Polymorphic forms Prof. Amal Ali Elkordy Professor of Pharmaceutics Slide 1 of 23 MPharm Polymorphic forms  OVERVIEW Basic crystallographic properties...

MPharm Programme Physical stability: Polymorphic forms Prof. Amal Ali Elkordy Professor of Pharmaceutics Slide 1 of 23 MPharm Polymorphic forms  OVERVIEW Basic crystallographic properties of crystalline The unit cell and as non-crystalline geometric descript of materials crystallinity Crystal lattice systems: Classificati of crystal systems Crystal habit Polymorphism of 23MPharm Slide 2 Polymorphic forms  Polymorphic forms: Basic Crystallographic Properties of Crystalline and Non-crystalline Materials Properties of crystals: atoms and molecules are packed in a high Heat degree of order Crystals sharp transition from the solid into the liquid state (melting) Examples: sodium chloride, ibuprofen 222°C Slide 3 of 23 MPharm 230°C Polymorphic forms  Properties of amorphous materials: atoms and molecules are arranged in a random order Heat Amorphous substance softening and then formation of a highly viscous liquid Examples: glass, spray-dried lactose monohydrate 231°C 245 °C Slide 4 of 23 MPharm Polymorphic forms  The unit cell as geometric descriptor of crystallinity Crystallographic structure: Due to the high degree of order in crystals, a periodic reoccurrence of atoms and molecules can take place in all three dimensions in space. This crystallographic structure can be described as three- dimensional Unit cell: is the lattice, buildingin which blockthe of the crystal. unit cell is theMany of the building repeating unit. blocks packed together to fill the space of the crystal. Description of the unit cell is depend on Slide 5geometry of 23 MPharm (see below). Polymorphic forms  The unit cell as geometric descriptor of crystallinity Unit cell: described by three dimensions (the length of the axes of the unit cell and the three angles between The dimensions these axes) and angles describing a unit cell: a, b and c are lengths of axes. a, b and g are Slide 6 of 23 angles MPharm Polymorphic forms  Crystal lattice systems Classification of crystal systems: - depending on geometric description, there are seven, 7, possible unit cells (basic crystal systems) that give all possible degrees of order of atoms and molecules being only at each corner of the unit cell. - Advanced crystallography classifies the crystal systems into fourteen, 14, Bravais-lattices, which consider the possibility of presence of centre atoms inside Slide 7 of 23 MPharm the unit cell or at edges of faces Polymorphic forms  Basic crystal lattice systems triclinic monoclinic orthorhombic trigonal hexagonal tetragonal The unit cells ofcubic the seven basic crystal lattice Slide 8 of 23 MPharm Polymorphic forms systems  Examples for basic crystal Crystal Proportionlattices Proportion Example lattices of axes of angles Slide 9 of 23 MPharm Polymorphic forms  Crystal habit - describes the overall shape of the crystal - results of different rates of growth in Two crystals (orthorombic) each with same habit may have dimension different combinations of faces. (Florence and Attwood, 2006 Crystals with same combinations of crystallographic forms may have different c crystal habits: a- b prismatic, a b- Slide 10 isometric, of 23 MPharm c- tabular Polymorphic forms  Crystal habit modification - Crystal habit can be modified by adding impurities - Example: Presence of surfactants, in the crystallisation solution, can change crystal habit by adsorbing onto crystal faces during crystal growth e.g. influence of anionic and cationic surfactants - Anionic on crystal habit of adipic - Cationic acid. surfactant surfactant results in thin results in thin long needle flaky plates Slide 11 of 23 MPharm Polymorphic forms  Polymorphis m substance can form - Polymorphic crystal forms with different order of molecules or atoms - for the inner order, not for the crystal shape - Polymorphic forms can have same type of crystal lattice (e.g. triclinic) however different proportions of axes and angles - Because polymorphic forms have different order of elements, therefore there Slide 12 of 23 will be MPharm different Polymorphic forms attraction forces  Polymorphis m - have different thermodynamic stability - have different free energies - have different fundamental physical properties: (melting point, vapour pressure, solubility) - have effect on the manufacture of dosage forms - have effect on pharmacological activity of dosage forms - have effect on drug bioavailability Slide 13 of 23 MPharm Polymorphic forms  Effect of polymorphic forms on bioavailability of chloramphenicol palmitate Slide 14 of 23 MPharm Polymorphic forms  Transition between polymorphic forms - by heat or pressure - “enantropic transition”: transition between all forms - “monotropic transition”: transition from one form to another and not vice versa in other words: transition from metastable form into stable form; metastable forms are higher energy polymorphs - stable polymorphic form has: - lowest free energy - highest melting point -MPharm Slide 15 of 23 usually, lowest Polymorphic formssolubility.  Transition between polymorphic forms - Nomenclature of polymorphic forms: Roman numbers (I, II,….etc), in the order of highest melting point - Example: testosterone - polymorphic form I: stable form (MP=155°C) - Polymorphic - in drug delivery,forms II-IV: to it is better havemetastable metastableforms (MP=148, forms; 144 they have and solubility, better 143°C, respectively) they give better dissolution and bioavaialbility (see the Slide 16 of 23 previous MPharm Figure) Polymorphic forms  Polymorphism of paracetamol Polymorph I Polymorph II (monoclinic) (orthorombic) (Florence and Attwood, 2006) Polymorph I &II Polymorph I at Slide 17 of 23 room temperature MPharm Polymorphic forms after 30  Crystal solvates and crystal hydrates - during crystallisation, some materials may entrap solvent in the crystal: - Crystal solvates: crystals contain solvent of crystallisation - Crystal hydrates: water is the solvent of crystallisation - Anhydrates: crystals with no water of crystallisation - polymorphic solvate: solvent interact Slide 18 of 23 MPharm with crystal Polymorphic forms structure  Crystal solvates and crystal hydrates - pseudopolymorphic solvate: no interaction between the solvent and crystal bonding; when crystal solvates lose the solvent, crystal lattice will not be destroyed - crystal hydrate and anhydrate of a drug have different solubility and melting point and hence different pharmaceutical - hydrates are properties less soluble and thermodynamically more stable Slide 19 of 23 MPharm Polymorphic forms  Bioavailability of ampicillin in anhydrate and trihydrate forms Slide 20 of MPharm 23 Polymorphic forms  Crystal defects – Point defects - Due to: - missing - impurity replacing atom the original atom - defect can influence the physical properties of the crystals Slide 21 of 23 MPharm Polymorphic forms  Summary - Understanding the meaning of unit cell and crystal lattice - knowledge about crystal habit and polymorphism - ability to differentiate between crysta hydrates and solvates Slide 22 of 23 MPharm Polymorphic forms  Recommended reading - Particle Science and Powder Technology, Part 2 (2017). In: Aulton, M.E., Taylor K.M.G (eds.), Aulton’s Pharmaceutics, The Design and Manufacture of Medicines. 5th Ed., Elsevier Publisher, pages: 129-137. - Florence A.T., Attwood, D., 2006. Physicochemical Principles of Pharmacy. 4th Edition, Pharmaceutical Press, London, pp. 8-22. Slide 23 of 23 MPharm Polymorphic forms THANK YOU FOR YOUR ATTENTION MPharm Polymorphic forms