Mpharm Program: Physical Stability of Two-Phase Systems PDF

MPharm Programme Physical stability: Two phase systems Prof. Amal Ali Elkordy Professor of Pharmaceutics Slide 1 of 23 MPharm Two phase systems OVERVIEW - What? Physical stability and two phase systems (solid-liquid prospective) - What? Crystalline and amorphous states - Why? Solid state is importan...

MPharm Programme Physical stability: Two phase systems Prof. Amal Ali Elkordy Professor of Pharmaceutics Slide 1 of 23 MPharm Two phase systems OVERVIEW - What? Physical stability and two phase systems (solid-liquid prospective) - What? Crystalline and amorphous states - Why? Solid state is important in pharmaceutical formulations - How? Methods of crystallisation - What? Supercritical fluid technology Slide 2 of 23 MPharm Two phase systems Physical properties Slide 3 of 23 Particle size and surface area Solubility Dissolution Crystal properties, polymorphism Stability Organoleptic (taste, odour, colour,..) MPharm Two phase systems Physical stability Mostly refers to visual and organoleptic appearances. Excessive temperatures, pH, moisture, oxidation are the greatest threats to chemical and physical drug lives. Change in physical stability is mostly an indirect effect of chemical stability. Two phase systems (solid-liquid phases) Slide 4 of 23 MPharm Two phase systems What? Crystalline and amorphous states Definitions - Crystal: “clear ice”. Crystals are chemically well defined; they have a high degree of order for atoms and molecules. - Ideal crystals: perfect arrays in which the building blocks are arranged according to well defined symmetries into unit cells that are repeated in the three dimensions by translations. The ideal solid body is crystalline - Amorphous material: atoms and molecules are arranged in a random manner, disordered state, e.g. glass. Slide 5 of 23 MPharm Two phase systems Crystallisation from solution: - Crystallisation: Transition of a chemical from the liquid solution state into a solid crystalline state. Accordingly, physical conditions (solute concentration, pressure and temperature) should consider the phase transition boundary - Solute: A chemical that is in the liquid solution state - Solvent: A liquid in which the solute is dissolved - Anti-solvent: A liquid in which the solute is insoluble Slide 6 of 23 MPharm Two phase systems http://departments.kings.edu/chemlab/animation/ Amorphous Slide 7 of 23 MPharm Two phase systems Crystalline Basic Processes of Crystallisation from Solution - Supersaturation of the solution (by cooling; evaporation; addition of anti-solvent; or addition of a precipitant) - Nucleation: formation of a small mass (crystal nuclei) - Homogeneous nucleation: pure molecules of solute crystallise - Heterogeneous nucleation: catalytic formation of the crystal around an impurity (seed crystals) - Crystal growth: addition of more solute molecules to the formed nuclei Slide 8 of 23 MPharm Two phase systems Saturation Solubility Curve Slide 9 of 23 MPharm Two phase systems Why? Solid State is Important in Pharmaceutical Formulations - Solid state: shape, particle size, polymorphism, hydration, solvation: - flowability - tableting - dissolution - bioavailability - disintegration - route of drug administration Slide 10 of 23 MPharm Two phase systems How? Methods of Crystallisation Cooling Crystallisation Slide 11 of 23 MPharm Two phase systems Evaporation Crystallisation Slide 12 of 23 MPharm Two phase systems Crystallisation by addition of anti-solvent A: is a solvent for a drug B: is anti-solvent for the drug The solvent and anti-solvent are miscible The drug is sparingly soluble, or insoluble in the solvent/anti-solvent mixture Slide 13 of 23 MPharm Two phase systems Crystallisation by precipitation Change of the pH of the solution Addition of precipitating agent Slide 14 of 23 MPharm Two phase systems Supercritical Fluid Technology - Supercritical fluids are substances above their critical temperature and pressure - Supercritical fluids combine properties between gas and liquid:  viscosity and dispersion (gas)  density (liquid) - Supercritical fluids:  Have a high dissolution capacity for many substances, because of their high density  Supply a rapid mass transfer, because of their low viscosity Slide 15 of 23 MPharm Two phase systems Supercritical Fluid Technology Pressure Supercritical fluid region Solid Liquid Gas Temperature A pressure-temperature phase diagram showing the supercritical fluid region Slide 16 of 23 MPharm Two phase systems - Critical properties of some solvents: Tc(°C) Pc(bar)  CO2: 31 37.8  N2: -147 39  Ethylene: 9 50 Introduction to Supercritical Fluids Slide 17 of 23 MPharm Two phase systems 1- Rapid Expansion of Supercritical Solutions (RESS) Pre-heater CO2 Extractor Solute Extraction unit (T, P) Vacuum/ pressure Heated nozzle, pre-expansion Precipitation unit (T, P) RESS technique RESS involves the precipitation of a solute from the supercritical fluid by reducing the solvent density through a rapid expansion Slide 18 of 23 MPharm Two phase systems 2- Supercritical Anti-Solvent (SAS) SAS technique Slide 19 of 23 MPharm Two phase systems 2- Supercritical Anti-Solvent (SAS) In SAS technique, A solution is sprayed into the supercritical fluid, which acts as anti-solvent for the drug. The drug particles precipitate and the solvent of the solution is extracted into the supercritical fluid Slide 20 of 23 MPharm Two phase systems Particles produced by supercritical fluid technology A B A Nicotinic acid, A- before processing, B- after processing (York, P., 1999, PSTT, 2, 430-440) Slide 21 of 23 MPharm Two phase systems B Lysozyme, A- before processing, B- after processing Summary - Understanding the physical principles and basic processes of crystallisation - Demonstration of the methods used in crystallisation - Understanding the basic procedures used in the supercritical fluid technology Slide 22 of 23 MPharm Two phase systems Recommended reading - Chapter 8: Solid state properties: crystallization, 2021. In: Aulton's Pharmaceutics, The Design and Manufacture of Medicines. 6th Ed., Elsevier. - Florence A.T., Attwood, D., 2006. Physicochemical Principles of Pharmacy. 4th Edition, Pharmaceutical Press, London, pp. 8-13. - York, P. 1999. Strategies for particle design using supercritical fluid technologies. Pharm. Sci. Tech. Today, 2, 430-440. (Access via Science Direct Website). Slide 23 of 23 MPharm Two phase systems THANK YOU FOR YOUR ATTENTION Slide 22 of 23 MPharm Two phase systems