Solid Crystal structure and external appearance

Solid Crystal structure and external appearance

• All crystals are constructed from repeating units called unit cells.
• All unit cells in a specific crystal are the same size and contain the same number of molecules or ions arranged in the same way.
• There are seven primitive unit cells cubic, hexagonal, trigonal, tetragonal, orthorhombic, monoclinic and triclinic. Certain of these may also be endcentred (monoclinic and orthorhombic), body-centred (cubic, tetragonal and orthorhombic) or face-centred (cubic and orthorhombic), making a total of 14 possible unit cells called Bravais lattices.
• It is possible to describe the various planes of a crystal using the system of Miller indices . The general rules for applying this system are:

                   – Determine the intercepts of the plane on the a, b, and c axes in terms of unit cell lengths.
                   – Take the reciprocals of the intercepts.
                   – Clear any fractions by multiplying by the lowest common denominator.
                   – Reduce the numbers to the lowest terms.
                   – Replace negative numbers with a bar above the number.
                   – Express the result as three numbers
The external appearance of a crystal is described by its overall shape or habit, for
example, acicular (needle-like), prismatic or tabular. The crystal habit affects:

• the ability to inject a suspension containing a drug in crystal form – platelike crystals are easier to inject through a fi ne needle than needle-like crystals
• the flow properties of the drug in the solid state – equidimensional crystals have better fl ow properties and compaction characteristics than needle-like crystals, making them more suitable for tableting.
• The crystal habit depends on the conditions of crystallisation, such as solvent used, the temperature, and the concentration and presence of impurities. Surfactants in the solvent medium used for crystal growth can alter crystal form by adsorbing onto growing faces during crystal growth.

Polymorphism

When polymorphism occurs, the molecules arrange themselves in two or more different ways in the crystal; either they may be packed differently in the crystal lattice or there may be differences in the orientation or conformation of the molecules at the lattice sites.
                                                              Polymorphs of the same drug have different X-ray diffraction patterns, may have different melting points and solubilities and also usually exist in different habits. Certain classes of drug are particularly susceptible to polymorphism; for example, about 65% of the commercial sulfonamides and 70% of the barbiturates used medicinally are known to exist in several polymorphic forms.
                                                             The particular polymorph formed by a drug depends on the conditions of crystallisation; for example, the solvent used, the rate
of crystallisation and the temperature.

Under a given set of conditions the polymorphic form with the lowest free energy will be the most stable, and other polymorphs will tend to transform into it.

Polymorphism has the following pharmaceutical implications:
Formulation problems

•  Polymorphs with certain crystal habits may be difficult to inject in suspension form or to formulate as tablets .

• Transformation between polymorphic forms during storage can cause changes in crystal size in suspensions and their eventual caking.

•  Crystal growth in creams as a result of phase transformation can cause the cream to become gritty.

•  Changes in polymorphic forms of vehicles such as theobroma oil, used to make suppositories, could cause products with different and unacceptable melting characteristics.

Analytical issues

• Difficulties in identification arise when samples that are thought to be the same substance give different infrared spectra in the solid state because they exist in different polymorphic forms.

•  Change in polymorphic form can be caused by grinding with potassium bromide when samples are being prepared for infrared analysis.

•  Changes in crystal form can also be induced by solvent extraction methods used for isolation of drugs from formulations prior to examination by infrared spectroscopy – these can be avoided by converting both samples and reference material into the same form by recrystallisation from the same solvent.

Bioavailability differences

• The difference in the bioavailability of different polymorphic forms of a drug is usually insignificant but is a problem in the case of the chloramphenicol palmitate, one (form A) of the three polymorphic forms of which is poorly absorbed.

Crystal hydrates

When some compounds crystallise they may entrap solvent in the crystal. Crystals that contain solvent of crystallisation are called crystal solvates, or crystal hydrates when water is the solvent of crystallisation. Crystals that contain no water of crystallisation are
termed anhydrates.

There are two main types of crystal solvate:

 1. Polymorphic solvates are very stable and are difficult to desolvate because solvent plays key role in holding the crystal together. When these crystals lose their solvent they collapse and recrystallise in a new crystal form.

2. Pseudopolymorphic solvates lose their solvent more readily and desolvation does not destroy the crystal lattice. In these solvates the solvent is not part of the crystal bonding and merely occupies voids in the crystal.

The particular solvate formed by a drug depends on the conditions of crystallisation, particularly the solvent used. The solvated forms of a drug have different physicochemical
properties to the anhydrous form:

•  The melting point of the anhydrous crystal is usually higher than that of the hydrate.
• Anhydrous crystals usually have higher aqueous solubilities than hydrates.
• The rates of dissolution of various solvated forms of a drug differ but are generally higher than that of the anhydrous form.
•  There may be measurable differences in bioavailabilities of the solvates of a particular drug; for example, the monoethanol solvate of prednisolone tertiary butyl acetate has an absorption rate in vivo which is nearly five times greater than that of the anhydrous form of this drug.

Wetting of solid surfaces and powders

The wetting of a solid when a liquid spreads over

its surface is referred to as spreading wetting. Read more>>