Figure 1.7 Crystal habits of a hexagonal crystal.

containing a drug in crystal form will be influenced by the habit: plate-like crystals are easier to inject through a fine needle than are needle-like crystals. The crystal habit can also influence the ease of compression of a tablet and the flow properties of the drug in the solid state. The plate-like crystals of tolbutamide, for example, cause powder bridging in the hopper of the tablet machine and also capping problems during tableting. Neither of these problems occurs with tolbutamide in other crystal habits. The habits acquired depend on the conditions of crystallisation, such as solvent used, the temperature, and the concentration and presence of impurities. Ibuprofen is usually crystallised from hexane as elongated needle-like crystals, which have been found to have poor flow properties; crystallisation from methanol produces equidimensional crystals with better flow properties and compaction characteristics, making them more suitable for tableting. The crystal morphology of the excipients (such as powdered cellulose) included in tablet formulations can also have a significant influence on the strength and disintegration time of tablets.

1.2.1 Crystallisation and factors affecting crystal form2

Crystallisation from solution can be considered to be the result of three successive processes:

• Supersaturation of the solution

• Formation of crystal nuclei

• Crystal growth round the nuclei



Supersaturation can be achieved by cooling, by evaporation, by the addition of a precipitant or by a chemical reaction that changes the nature of the solute. Supersaturation itself is insufficient to cause crystals to form; the crystal embryos must form by collision of molecules of solute in the solution, or sometimes by the addition of seed crystals, or dust particles, or even particles from container walls. Deliberate seeding is often carried out in industrial processes; seed crystals do not necessarily have to be of the substance concerned but may be isomorphous substances (i.e. of the same morphology). As soon as stable nuclei are formed, they begin to grow into visible crystals.

Crystal growth can be considered to be a reverse dissolution process and the diffusion theories of Noyes and Whitney, and of Nernst, consider that matter is deposited continuously on a crystal face at a rate proportional to the difference of concentration between the surface and the bulk solution. So an equation for crystallisation can be proposed in the form dm "di

where m is the mass of solid deposited in time t, A is the surface area of the crystal, cs is the solute concentration at saturation and css is the solute concentration at supersaturation. As km = D/ô (D being the diffusion coefficient of the solute and ô the diffusion layer thickness; see Fig. 1.15), the degree of agitation of the system, which affects ô, also influences crystal growth. Crystals generally dissolve faster than they grow, so growth is not simply the reverse of dissolution. It has been suggested that there are two steps involved in growth in addition to those mentioned earlier, namely transport of the molecules to the surface and their arrangement in an ordered fashion in the lattice. Equation (1.1) turns out to be better written in a modified form:

kg being the overall crystal growth coefficient and n the 'order' of the crystal growth process. For more details reference 2 should be consulted.


Precipitation may be induced by altering the pH of the solution so that the saturation solubility is exceeded. Precipitation may be made to occur from a homogeneous solution by slowly generating the precipitating agent by means of a chemical reaction, a process likely to occur, for example, in intravenous infusion fluids and liquid pharmaceuticals. Precipitation by direct mixing of two reacting solutions sometimes does not bring about immediate nucleation and, as a result, the mixing stage may be followed by an appreciable lag time. The rate of precipitation is an important factor in determining habit, as might be imagined with a dynamic process such as crystallisation, involving nucleation and subsequent crystal growth. The form of phenylsalicylate, for example, depends on rate of crystal growth. Transition to an acicular shape occurs when the rate of growth increases. At low rates of growth, crystals of a more regular shape are obtained. In studies of the effect of solvents on habit it is generally found that less viscous media favour the growth of coarse and more equidimen-sional crystal forms.

Habit modification

Crystal habit can be modified by adding impurities or 'poisons'; for example, sulfonic acid dyes alter the crystal habit of ammonium, sodium and potassium nitrates.

Adipic acid crystals

Adipic acid crystals

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