The applications of rheology in pharmaceutical formulation

The components used to make a formulation may not only affect the physical and release characteristics
of the product but may also guide it to the site of absorption.

In some cases, it may be possible to exploit the properties of the excipients such that the dosage form is retained at a specific location in the body.

This approach is often necessary for locally acting products which are used to treat or prevent diseases of, for example, the eye and the skin.

To treat conditions in the eye, an aqueous solution of the drug is delivered to the precorneal area by means of a
dropper.

If the solution is Newtonian and of low viscosity, then it will be rapidly cleared from the eye as a result of reflex tear production and blinking.

The resultant short residence time means that an effective concentration will only be attained for brief periods following dosing, so that treatment is pulsatile.

However, if a water-soluble polymer is
added to the formulation, such that the viscosity is within the range of 15 mPa s to 30 mPa s, then the residence time increases, as does the bioavailability.

Addition of excipients that make the product pseudoplastic will facilitate blinking, and this may improve acceptance and adherence by the patient.

If the product can be made viscoelastic, then solutions of higher consistency may be tolerated.

This can be achieved in the eye if a polymeric solution is designed to be Newtonian when it is instilled but then undergoes a sol–gel transition in situ in reaction to the change in environment such as temperature, pH or ion content.

Poly(vinyl alcohol), cellulose ethers and
esters and sodium alginate are all examples of polymers which have been used as viscolysers in eye drops.

Polyacrylic acid and cellulose acetate phthalate have been claimed to produce reactive systems.

The ointments and creams which are applied to the skin to deliver a drug which has a local action, such as a corticosteroid or anti-infective agent, are
usually semisolids.

Their rheological properties need
to be assessed after manufacture and during the shelf life in order to ensure that the product is physically stable; this is important because the rate of release of the drug and the concentration at the site of action are related to the apparent viscosity.

Also, since these products are normally packaged in flexible tubes, rheological measurements will also indicate whether
the product can be readily removed from the container.

Knowledge of the flow properties of a product such as a gel for topical application can be used to predict patient acceptability, since humans can detect
small changes in viscosity during activities such as rubbing an ointment on the skin, shaking ketchup from a bottle or squeezing toothpaste from a tube.

Since the ability of the body to act as a rheometer involves the unconscious coordination of a number of senses, the term psychorheology has been adopted
by workers in this field.

All three situations provide examples of the advantages of designing a formulation which has a yield stress and exhibits plastic or pseudoplastic behaviour so that the patient only has
to apply the appropriate shear rate.

Transdermal delivery systems (often referred to as patches) are used to deliver drug across the skin at a rate which means that they can be left on the skin for periods of up to a week.

The drug can either be incorporated in a reservoir or be dissolved in the layer
of adhesive which holds the device on the skin.

The rheological properties of the adhesive can therefore be used to predict and control not only the adhesion but also the rate of drug absorption.

The latter can be used to estimate the length of time that the device needs to be applied to the skin.

When a dosage form is intended to be administered perorally, so that the active ingredient can be absorbed from the gastrointestinal tract, then the gastrointestinal tract transit time plays a major role in the extent and amount of drug which appears in the bloodstream.

The first phase of gastrointestinal tract transit is gastric emptying, which is in part dictated by the rise in viscosity of the stomach contents in the presence of food.

The consequential increase in gastric residence time and decrease in the dissolution rate of the active ingredient can lead to a reduction in the rate, but not necessarily the extent, of absorption.

Such effects can be exploited by the pharmaceutical formulator, for example, by including a gel-forming polymer in the formulation, since this can simulate in vivo the effect exerted by food.

However, its use as a means of prolonging the duration of action of an orally administered medicine needs to be thoroughly understood particularly in relation to the effect of the presence and nature of food, since any benefit could be lost by, for example, administration of the dosage form following a high-fat meal.

Many solid sustained-release dosage forms depend on the inclusion of high molecular weight polymers for their mode of action, and the viscosity of a particular polymer both in dilute solution and as a swollen gel is used to aid the selection of the most suitable candidate.

A final example of the application of rheology in the design and use of dosage forms is the administration of medicines by intramuscular injection.

These are formulated as either aqueous or lipophilic (oily) solutions or suspensions.

Following injection, the active ingredient is absorbed more quickly from an aqueous formulation than its lipophilic counterpart.

The incorporation of the active ingredient as a suspension in either type of base offers a further opportunity
of slowing the rate of release.

The influence that the nature of the solvent has on the rate of drug release
is in part due to its compatibility with the tissue, but its viscosity is also of importance.

Although it may be possible to extend the dosing interval by further increasing the viscosity of the oil, it has to be borne in mind that the product needs to be able to be drawn into a syringe via a needle, the diameter of which must not be so large as to alarm or discomfort the patient.

Furthermore, adding other excipients
such as polymers to the formulation or even just altering the particle size of the suspended particles can induce marked alterations in the rheological properties such that the injection may become plastic, pseudoplastic or dilatant.

If it does become plastic, then provided that the yield value is not too high, it
may be possible for it to pass through a syringe needle by application of a force which it is reasonable to achieve with a syringe.

Quite obviously this will not be the case if the suspension becomes dilatant since as the applied force is increased the product will become more solid.

Often the ideal formulation is one which is pseudoplastic because as the force is increased so the apparent viscosity will fall, making it easier for the injection to flow through the needle.

Ideally the product should also be truly thixotropic because once it has been injected into the muscle, the reduction in shear rate will mean that the bolus
will gel and thus form a depot, from which release of the drug may be expected to be delayed.

The use of appropriate rheological techniques in the development of such products can be beneficial not only to predict their performance in vivo but
also to monitor changes in characteristics on storage.

This is especially true for suspension formulations, since fine particles have a notorious and, sometimes, malevolent capacity for increasing in size on storage,
and if as a result a pseudoplastic product becomes dilatant, then it will be impossible to administer it to the patient.

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