KAUSAR AHMADKULLIYYAH OF PHARMACY

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Solids

http://staff.iium.edu.my/akausar

Contents

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General properties

Types of solids Amorphous Crystalline

Crystal structureCrystallisation

• Crystal growth

What is solid…..to pharmacy?

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Majority of drugs and excipients exist as solids

Various dosage forms are preparede.g. tablets, emulsions

Types of solids affect Processing Efficacy

General Properties

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Maintain shape

Not fluid

Molecules/atoms/ions are held closely by

intermolecular

interatomic

ionic forces

Intermolecular forces

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1. Van der Waals forces

i. Dipole-dipole (Keesom) e.g. HCl

ii. Dipole-induced dipole (Debye)

iii. Induced dipole-induced dipole (London)

2. Ion dipole and ion-induced dipole forces

3. Hydrogen bonds e.g. H2O

In solids, average kinetic energy << strength of intermolecular forcesHence, each molecule can only move short distances around a fixed position.

Classification of Solids

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Amorphous

Crystalline

Amorphous Solids

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E.g. silica gel, synthetic plastics/polymersIrregular shape

- molecules are arranged in a random mannerNo definite melting point

- no crystal lattice to breakExhibit characteristic glass transition temperature, TgFlow when subject to pressure over timeIsotropic i.e. same properties in all directionAffect therapeutic activity e.g. amorphous antibiotic

novobiocin is readily absorbed and therapeutically active compared to the crystalline form

Crystalline Solids

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E.g. diamond, graphite

Regular shape i.e. fixed geometric patterns

Incompressible

Definite /specific boiling points

Diffract X-rays

Crystal Structure

Crystals contain

highly ordered

molecules or atoms

held together by

non-covalent

interactions

E.g. NaCl has the

cubic structure

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Source: http://cst-www.nrl.navy.mil/lattice/spcgrp/cubic.html

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TRICLINICboric acid

MONOCLINICsucrose

ORTHOROMBICiodine

TRIGONAL?

TETRAGONALurea

HEXAGONALiodoform

Crystal Lattices in 3D

Crystal lattice End centred

Side centred

Face centred

Body centred

Bravais/ Total

Cubic 1 1 1 3

Triclinic 1 1

Monoclinic 1 1 2

Orthorhombic 1 1 1 1 4

Hexagonal 1 1

Rhombohedral 1 1

Tetragonal 1 1 2

Total unit cells 7 14

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Lattices for drugs

For drugs, only 3 types:

1. Triclinic

2. Monoclinic

3. Orthorombic

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FCC Structure of NaCl

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Small spheres represent Na+ ions, large spheres represent Cl- ions.

Each sodium ion is octahedrally surrounded by six chloride ions and vice versa.

Binding Forces

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Solid Crystal structure

Binding force

NaCl cubic Electrostatic attraction

Diamond ? Covalent

Graphite hexagonal Covalent

Fatty acids ? Van der Waals & hydrogen bonding

Gold ? ?

Mefenamic acid

? ?

Salicylic acid ? ?

Crystallisation

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Crystallisation steps from solution:-

1. Supersaturation of the solutione.g. cooling, evaporation, addition of precipitant or chemical reaction

2. Formation of crystal nucleie.g. collision of molecules, deliberate seeding

3. Crystal growth around the nuclei

Crystal Growth

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Steps involved:

1. 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

2. Arrangement in the lattice

Precipitation

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1. Induced by altering pH of solution to reach saturation solubility.

2. By chemical reaction to produce precipitate from a homogeneous solution.

The rate of reaction is important in determining habit.

Crystallization of Sodium Acetate end lecture here

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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

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End of lecture 1 of 2

Crystallisation

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Contents - 2

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Properties of solids and implications

Crystal habits

Types of crystal habit

Factors affecting habits

Polymorphism

Methods to characterise solids

Crystal Habits

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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.

Factors affecting types of habits

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Temperature

Solvent/s

Crystal growth ratee.g. at high

rate, acicular form of

phenylsalicylate is formed

Viscositye.g. less viscous media favours

coarse and equidimensional

forms of minerals

Addition of impuritiese.g.sulfonic

acid dyes alter habits of

ammonium, sodium and potassium nitrates

Presence of surfactants

e.g. anionic & cationic

surfactants on adipic acid

crystals

Types of Habits

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ACICULARLong and needle-like, thinner than prismatic but thicker than fibrous. e.g. Natrolite

EQUANTAny 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

PRISMATICCommon crystal habit. Prismatic crystals are "pencil-like", elongated crystals that are thicker than needles.

TABULARBook-like (tablets) that are thicker than platy but not as elongated as bladed. Wulfenite forms crystals that are a good example of tabular crystals.

Sodium Chloride

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Exercise

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How many forms of adipic acid crystals exist?

Refer Florence & Attwood

Polymorphisms

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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.

Example: Polymorphism of Spironolactone

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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

Polymorphs of Spironolactone

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Properties of Spironolactone Polymorphs

Parameters Form 1 Form 2

Unit cell Orthorombic 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

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Polymorphism in Pharmaceutical Compounds

Drugs Crystalline Amorphous

Ampicillin 1 0

Cortisone acetate 8 0

Chloramphenicol palmitate

3 1

Erythromycin 2 0

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Solubility of Chloramphenicol Palmitate

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Form B

Form A

1: 1

Form B

Form A

Characterisation of Solids

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1. Microscopy – polarised light

2. 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

3. X-ray diffraction – powder sample >>polymorphic state

Continue characterisation of solids

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4. Differential scanning calorimetry – Tg, Tc and Tm

5. Infrared spectrometry

6. Melting point – pure solid & liquid in equilibrium normal at 1 atm

7. Heat of fusion ( Hf) – heat required to melt

(increase intermolecular distance) 1 g of solid

8. Solubility

References

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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