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PHM1153 Physical Pharmacy /11 Kausar Ahmad Kulliyyah of Pharmacy

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1 PHM1153 Physical Pharmacy 1 2010/11 Kausar Ahmad Kulliyyah of Pharmacy
Solids Kausar Ahmad Kulliyyah of Pharmacy PHM1153 Physical Pharmacy /12

2 Contents General properties Types of solids Amorphous Crystalline
Crystal structure Crystallisation Crystal growth PHM1153 Physical Pharmacy /12

3 What is solid… pharmacy?
Majority of drugs and excipients exist as solids Various dosage forms are prepared e.g. tablets, emulsions Types of solids affect Processing Efficacy PHM1153 Physical Pharmacy /12

4 General Properties Maintain shape Not fluid
Molecules/atoms/ions are held closely by intermolecular interatomic ionic forces PHM1153 Physical Pharmacy /12

5 Intermolecular forces
PHM1153 Physical Pharmacy /11 Intermolecular forces Van der Waals forces Dipole-dipole (Keesom) e.g. HCl Dipole-induced dipole (Debye) Induced dipole-induced dipole (London) Ion dipole and ion-induced dipole forces Hydrogen bonds e.g. H2O In solids, average kinetic energy << strength of intermolecular forces Hence, each molecule can only move short distances around a fixed position. Exercise Describe in your own words the action of each force above and give examples. Arrange the forces in decreasing strength. Dipole-Induced Dipole Forces A dipole-induced dipole attraction is a weak attraction that results when a polar molecule induces a dipole in an atom or in a nonpolar molecule by disturbing the arrangement of electrons in the nonpolar species. Ion-Induced Dipole Forces An ion-induced dipole attraction is a weak attraction that results when the approach of an ion induces a dipole in an atom or in a nonpolar molecule by disturbing the arrangement of electrons in the nonpolar species. PHM1153 Physical Pharmacy /12

6 Classification of Solids
PHM1153 Physical Pharmacy /11 Classification of Solids Amorphous Crystalline PHM1153 Physical Pharmacy /12

7 Amorphous Solids E.g. silica gel, synthetic plastics/polymers
Irregular shape - molecules are arranged in a random manner No definite melting point - no crystal lattice to break Exhibit characteristic glass transition temperature, Tg Flow when subject to pressure over time Isotropic i.e. same properties in all direction Affect therapeutic activity e.g. amorphous antibiotic novobiocin is readily absorbed and therapeutically active compared to the crystalline form PHM1153 Physical Pharmacy /12

8 Crystalline Solids E.g. diamond, graphite
Regular shape i.e. fixed geometric patterns Incompressible Definite /specific boiling points Diffract X-rays PHM1153 Physical Pharmacy /12

9 PHM1153 Physical Pharmacy 1 2010/11
Crystal Structure Crystals contain highly ordered molecules or atoms held together by non-covalent interactions E.g. NaCl has the cubic structure But the cubic structure in 3D can be further classified into symmetrical lattices i.e. it may be face centred, body centred or simply a primitive cube. What is meant by a primitive cube? This is basically the most simple form of a cube. During crystal growth, depending on the crystallisation conditions, the Na+ and Cl- ions may arrange themselves in a different manner. Why? Let’s say the crystallisation takes place at a high temperature. We would expect that the ions would have far greater kinetic energy compared to crystallisation that takes place at lower temperature. In this instance, there would be a higher possibility for the ions to arrange themselves in the lattice in a way that would not obstruct their movement that much. Hence, the primitive cubic structure is dominant. If the crystallisation temperature is very low, the ions would be able to arrange themselves neatly in the cubic structure, in a more dense fashion , which would give the face centred cubic structure. You will appreciate this more when you do the experiment on the polymorphism of L-glutamic acid in Dosage Design 1. Source: PHM1153 Physical Pharmacy /12

10 PHM1153 Physical Pharmacy 1 2010/11
            Crystal Sites: Crystal Home Strukturbericht Designation Pearson Symbol Space Group Prototype Index FAQ References Other Sites NRL Sites: NRL Home MSCT 6000 MSTD 6300 CCMS 6390 Crystal Lattice Structures: Reference Date:  1 Jan 1998 Last Modified: 18 Jan 2003 Index by Space Group Space groups are listed in the order they appear in the Crystallographic Tables. Where it conflicts with the Crystallographic Tables we use the notation in Pearson's Handbook. Space Group generators, Wyckoff positions, etc., are available online via the very useful Bilbao Crystallographic Server, and at the National Research Council of Canada's Generation of standard and alternate settings of the 230 Space Groups page. The easiest way to find information about a given space group is to use the Table of Space Group Symbols. We also have more information on how space groups are presented here. Each class of space groups corresponds to certain Pearson Symbols. Clicking on the appropriate symbol will take you to that part of the Pearson Symbol Index, Space Group Classes: Class Pearson Symbols                   Triclinic Structures (#1-#2) aPn Monoclinic Structures (#3-#15)    mPn    mCn                     Orthorhombic Structures (#16-#74)    oPn    oFn    oIn    oCn    Tetragonal Structures (#75-#142)    tPn    tIn    Trigonal Structures (#143-#167)    hPn    hRn                    Hexagonal Structures (#168-#194)    hPn    Cubic Structures (#195-#230)    cPn    cFn    cIn    Go back to Crystal Lattice Structure page. Structures indexed by: Strukturbericht Designation Pearson Symbol Prototype Current URL: lattice/spcgrp/index.html This page was created at the Naval Research Laboratory Center for Computational Materials Science Send comments and corrections to (Privacy Advisory) PHM1153 Physical Pharmacy /11 TRICLINIC boric acid ORTHOROMBIC iodine MONOCLINIC sucrose In some texts, the crystal structure consists of only six types. The reason is, the trigonal is considered as a part/subset of the hexagonal. The crystal structure is considered a point group. Once the atom, ions or molecules arranged themselves in the lattice, the trigonal structure transforms to a rhombohedral lattice. TRIGONAL ? TETRAGONAL urea HEXAGONAL iodoform PHM1153 Physical Pharmacy /12 The appearance of external hyperlinks does not constitute endorsement by the United States Department of Defense, the United States Department of the Navy, and the Naval Research Laboratory of the linked web sites, or the information, products or serveices contained therein. For other than authorized activities such as military exchanges and Morale, Welfare, and Recreation (MWR) sites, the United States Department of Defense, the Department of the Navy, and the Naval Research Laboratory does not exercise any editorial control over the information you may find at these locations. Such links are provided consistent with the stated purpose of this DoD web site. Return to CCMS home page

11 PHM1153 Physical Pharmacy 1 2010/11
Crystal Lattices in 3D Crystal lattice End centred Side centred Face centred Body centred Bravais/ Total Cubic 1 3 Triclinic Monoclinic 2 Orthorhombic 4 Hexagonal Rhombohedral Tetragonal Total unit cells 7 14 Bravais lattices is a set of space lattices in 3D. PHM1153 Physical Pharmacy /12

12 PHM1153 Physical Pharmacy 1 2010/11
Lattices for drugs For drugs, only 3 types: Triclinic Monoclinic Orthorombic PHM1153 Physical Pharmacy /12

13 FCC Structure of NaCl Small spheres represent Na+ ions, large spheres represent Cl- ions. Each sodium ion is octahedrally surrounded by six chloride ions and vice versa. PHM1153 Physical Pharmacy /12

14 PHM1153 Physical Pharmacy 1 2010/11
Binding Forces Solid Crystal structure Binding force NaCl cubic Electrostatic attraction Diamond ? Covalent Graphite hexagonal Fatty acids Van der Waals & hydrogen bonding Gold Mefenamic acid Salicylic acid Most organic compounds PHM1153 Physical Pharmacy /12

15 Crystallisation Crystallisation steps from solution:-
Supersaturation of the solution e.g. cooling, evaporation, addition of precipitant or chemical reaction Formation of crystal nuclei e.g. collision of molecules, deliberate seeding Crystal growth around the nuclei PHM1153 Physical Pharmacy /12

16 Crystal Growth Steps involved: Transport of molecules to the surface
Degree of agitation in the system affects the diffusion coefficient, thus affects crystal growth. Affinity of solute to solvent Arrangement in the lattice PHM1153 Physical Pharmacy /12

17 Precipitation Induced by altering pH of solution to reach saturation solubility. By chemical reaction to produce precipitate from a homogeneous solution. The rate of reaction is important in determining habit. PHM1153 Physical Pharmacy /12

18 Crystallization of Sodium Acetate end lecture here
Description: A supersaturated solution of sodium acetate is crystallized by pouring it onto a seed crystal, forming a stalagmite-like solid. Heat is radiated from the solid. Source: Shakhashiri, B.Z. Chemical Demonstrations: A Handbook for Teachers of Chemistry PHM1153 Physical Pharmacy /12

19 End of lecture 1 of 2 PHM1153 Physical Pharmacy /12

20 Crystallisation PHM1153 Physical Pharmacy /12

21 Contents - 2 Properties of solids and implications Crystal habits
Types of crystal habit Factors affecting habits Polymorphism Methods to characterise solids PHM1153 Physical Pharmacy /12

22 Crystal Habits Variation in size Number of faces Kind of faces
Habits describe the overall shape of the crystal e.g. acicular (needle), prismatic, pyramidal, tabular, equant, columnar & lamellar types. PHM1153 Physical Pharmacy /12

23 Factors affecting types of habits
Temperature Solvent/s Crystal growth rate e.g. at high rate, acicular form of phenylsalicylate is formed Viscosity e.g. less viscous media favours coarse and equidimensional forms of minerals Addition of impurities e.g.sulfonic acid dyes alter habits of ammonium, sodium and potassium nitrates Presence of surfactants e.g. anionic & cationic surfactants on adipic acid crystals PHM1153 Physical Pharmacy /12

Any three perpendicular axis through the crystal are more or less equal. Can be used to describe rounded as well as angular crystals. e.g. Fluorite ACICULAR Long and needle-like, thinner than prismatic but thicker than fibrous. e.g. Natrolite PRISMATIC Common crystal habit. Prismatic crystals are "pencil-like", elongated crystals that are thicker than needles. TABULAR Book-like (tablets) that are thicker than platy but not as elongated as bladed. Wulfenite forms crystals that are a good example of tabular crystals. PHM1153 Physical Pharmacy /12

25 Sodium Chloride PHM1153 Physical Pharmacy /12

26 Exercise How many forms of adipic acid crystals exist?
Refer Florence & Attwood PHM1153 Physical Pharmacy /12

27 Polymorphisms When compounds crystallise as different polymorphs, properties change. Molecules arrange in two or more ways in the crystal: packed differently in crystal lattice, different orientation, different in conformation of molecules at lattice site. X-ray diffraction patterns change. PHM1153 Physical Pharmacy /12

28 Example: Polymorphism of Spironolactone
A diuretic (no potassium loss) 2 polymorphic forms and 4 solvated crystalline Form 1: spironolactone powder is dissolved in acetone at a temperature near boiling point and cooled to 0 deg. C within a few hours – needle-like Form 2: powder dissolved in acetone or dioxane or chloroform at RT and acetone allowed to evaporate for several weeks - prism PHM1153 Physical Pharmacy /12

29 Polymorphs of Spironolactone
1 PHM1153 Physical Pharmacy /12

30 Properties of Spironolactone Polymorphs
Parameters Form 1 Form 2 Unit cell Orthorombic Dimension of a, b, c axes 0.998, 3.557, 0.623 1.058, 1.900, 1.101 Crystal habit Needle-like Prisms Melting point 205 deg. C 210 deg. C PHM1153 Physical Pharmacy /12

31 Polymorphism in Pharmaceutical Compounds
Drugs Crystalline Amorphous Ampicillin 1 Cortisone acetate 8 Chloramphenicol palmitate 3 Erythromycin 2 PHM1153 Physical Pharmacy /12

32 Solubility of Chloramphenicol Palmitate
Form B Form B 1: 1 Form A Form A PHM1153 Physical Pharmacy /12

33 Characterisation of Solids
Microscopy – polarised light X-ray crystallography - single crystal - on the basis that crystals can diffract X-rays - wavelengths same magnitude as distance between atoms/molecules in crystal - enable the determination of the distances of various planes in crystals. Thus, structures. - e.g. penicillin X-ray diffraction – powder sample >>polymorphic state PHM1153 Physical Pharmacy /12

34 Continue characterisation of solids
Differential scanning calorimetry – Tg, Tc and Tm Infrared spectrometry Melting point – pure solid & liquid in equilibrium normal at 1 atm Heat of fusion ( Hf) – heat required to melt (increase intermolecular distance) 1 g of solid Solubility PHM1153 Physical Pharmacy /12

35 References Atkins, P & de Paula, J. (2002). Atkins’ Physical Chemistry 7th Ed. New York: Oxford. Cartensen, J. T. (2001). Advance Pharmaceutical Solids. New York: Marcel Dekker. Cullity, B. D. & Stock, S. R. (2001). Elements of x-ray diffraction 3rd Ed. New Jersey: Prentice Hall. Florence, A. T. & Attwood, D. (1998). Physicochemical Principles of Pharmacy 3rd. Ed. London: Macmillan. Martin, A. (1993). Physical Pharmacy 4th Ed. Baltimore: Lippincott. Note: The 6th edition is now available. Smart, L. E. & Moore, E. A. (2005). Solid State Chemistry 3rd Ed. Boca Raton: CRC West, A. R. (1999). Basic Solid State Chemistry 2nd Ed. West Sussex: Wiley PHM1153 Physical Pharmacy /12

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