General Methods of Preparation of Topical Systems

Irrespective of whether the scale of preparation is large or small, ointments, pastes, and creams tend to be produced by one or the other of two general methods. Some are made at high temperature by blending liquid and melted-solid components together and then dispersing all other ingredients within the hot, oily melt. Alternatively, drug and/or adjuvants can be dispersed or dissolved within one of the phases or a fraction of one of the phases of an emulsion prior to forming the emulsion. The drug can be mixed into a freshly formed, still molten emulsion while it is still warm. Finally, a drug can be incorporated into an already solidified base via cold incorporation. As earlier pointed out, the first of these methods is commonly used to make o/w creams of the vanishing cream type. The fusion method is used to prepare many ointments as well. Cold incorporation comes into play in large-scale manufacture when the systems in preparation contain heat-labile drugs. In this instance, the drug is first crudely worked into an ointment or cream base by serial dilution and then distributed uniformly with the aid of a roller mill. Cold incorporation is also necessary when a base is destroyed by heat, as happens with Plastibase (Squibb).

In the fusion method for ointments, mineral oil, petrolatum, waxes, and other ingredients as belong in the formulation are heated together to somewhere between 60°C and 80°C, depending on the components, and mixed to a uniform composition while in the fluidized state. Cooling is then effected using some sort of a heat exchanger. To prevent decomposition, drugs and certain delicate adjuvants are added sometime during the cooling process. If insoluble solids need to be dispersed, the system is put through a milling process (colloid mill, homogenizer, ultrasonic mixer, etc.) to disperse them fully. A hand homogenizer works well at the prescription counter for small volume, extemporaneously prepared systems. Systems in preparation are always cooled with mild stirring until they are close to solidification. The rate of cooling is important, for rapid cooling, as mentioned, imparts a finer, more rigid structure. Stirring should be set to minimize vortexing and thereby prevent air incorporation into the solidifying system. Representative formulations with more system-specific, detailed directions are given in Table 6 for ointments and the other semisolid systems of note.

The fusion method for preparing creams is a bit more complex. In this instance, the aqueous and oil phases are heated separately to somewhere between 60°C and 80°C. As a general rule, the oil phase is heated to 5°C above the melting point of the highest-melting waxy ingredient and the water phase is heated to 5°C above the temperature of the oil phase, the latter to prevent premature solidification during the emulsification process. Water-soluble ingredients are dissolved in the heated aqueous phase and oil-soluble ingredients are dissolved in the oily melt, but only as long as they are heat stable and not too volatile. If an o/w system is to be made, the emulsifiers are added to the aqueous phase, and the emulsion is formed by slow addition of the oil phase. In the industry, the crude emulsion is then passed through a high-shear mixer to form a finely divided emulsion state. Following this, the emulsion is cooled with gentle stirring until congealed, again taking care not to whip air into the formulation. Typically, the emulsions solidify between 40°C and 50°C. If a w/o emulsion is to be made, the addition steps are usually reversed. Therefore, and generally, the discontinuous phase is added to the continuous, external phase containing the emulsifier. However, methods vary here, and for a particular formula the reverse order of addition may work best. Any means that reliably leads to a good emulsion is obviously acceptable.

As outlined when discussing absorption bases, the drug may also be dissolved in water to form a solution to be levigated into an ointment base or cream. Such addition softens creams even to the point of converting them to thick lotions. The chosen vehicle, of course, must have an inherent capacity to emulsify or otherwise take up the solution. Aromatic materials such as essential oils, perfume oils, camphor, and menthol, which volatilize if added when the base is hot, are incorporated into these semisolids while they are still being mixed but near the temperature where a particular system starts to congeal. Volatile materials are often introduced into the formulation as hydroalcoholic solutions.

The preparation of gels can involve high-temperature processing too. It is easier to disperse methylcellulose in hot than in cold water, for instance. The polymer then goes into solution and thickens or sets up as the temperature is lowered. Adding the hot methylcellulose dispersion to ice water gets one quickly to the final equilibrium state. Tragacanth gels, on the other hand, must be prepared at room temperature because of the extreme heat lability of this natural gum. A little alcohol or propylene glycol can be mixed into this gum before adding water to it to facilitate wetting of the gum prior to its dispersion. By way of contrast, Carbopol-containing systems are gelled by neutralizing the medium they have been dispersed in with alkali. Neutralization induces carboxyl groups found on the polymer backbone to ionize, instantaneously drawing these polymers into solution. Organic solvents can be gelled with Carbopol polymers as well, in such instances using soluble amines for the neutralization step.

Several prototype gel formulations are given in Table 6 to illustrate general compositional requirements and manufacturing methods. The design of specific systems tailored to meet predetermined, demanding performance criteria, particularly with respect to bioavailability, generally requires modification of published formulations or a totally original approach.

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