Rheology and the Formulations of Drugs

¶ … Liquid Dosage Forms

Rheology is the study of the deformation and flow of matter, focusing on "the viscosity characteristics of powders, fluids and semisolids" (Adesina "Rheology" 2). As such, it is this branch of physics that enables pharmacists to determine the proper mix and flow of materials used in the treatment of patients. Everything from the way in which a drug is packaged to how it is poured, squeezed, or injected must be considered by the pharmacist trained in the art of rheology prior to the drug's serving as an effective intervention. This paper will discuss that factors that would be considered when prepping a liquid dosage form and explain the relationships between these factors and the desired effects or outcomes that the drug form should possess.

There are various types of liquid dosage forms -- pharmaceutical solutions (liquid preparations that have chemical substances in them) and sterile dosage forms. Types of the former include syrups, elixirs, spirits, aromatic waters, tinctures, injections and fluidextracts (Adesina "Oral Solutions" 2). When prepping a liquid dosage form, numerous factors have to be considered -- for example, the nature of the form's flow (Newtonian or non-Newtonian), the purpose of the dosage, and the application. Newtonian flow forms consist of simple liquids -- water, alcohol, organic solvents (Adesina "Rheology" 18). Non-Newtonian flow forms comprise the majority of pharmaceutical solutions and these solutions consist of three different classes: pseudoplastic flow, dilatants flow and plastic flow.

Pseudoplastic flows are used in liquid dosage forms when colloidal systems are required (typically polymer-based solutions) -- i.e., solutions that become more fluid the more they are stirred or shaken -- an event known as shear thinning (Adesina "Rheology" 21). Such solutions are necessary when the pharmaceutical solution is desired to retain the solution's integrity over time.

Dilatants flows is the opposite of pseudoplastic flows in that these are solutions that are fluid when free of stress but that become more viscous when they are shaken. They are, in other words, shear thickening solutions. The deflocculated particles within the mixture bunch up when the solution is stirred or stressed.

Plastic flows have a concentrated amount of flocculated particles in the suspensions; the particles are bunched and flow cannot occur until this bunching effect is overcome. Such flows are also desirous for pharmaceutical applications that have limited shelf-life periods or in solutions that require aqueous additives (because in aqueous solution that are too unstable) in order to facilitate ingestion (Adesina "Oral Solutions" 13).

These three types of flow describe the various pharmaceutical solutions that are used by consumers for diverse interventions -- from the easing of symptoms of cold or flu to healing (burns, cuts, rashes, etc.). Depending on the type of form that is preferred by the consumer -- spray (aerosol), cream, or ingestible -- the manufacturers of the pharmaceutical solution will have to consider the type of flows that are conducive to the end product and then formulate the product's ingredients accordingly.

To prepare a liquid dosage form, one of the key factors to consider would be whether or not an antimicrobial agent such as alcohol will need to be added to the solution. Topical solutions or tinctures often utilize alcohol for this reason in their liquid dosages (Adesina "Oral Solutions" 35). Other considerations that must be made depend on the type of solution in question.

For instance, co-solvents are used when needed to support stability and/or solubility. Sometimes preservatives are added if the solution is not self-preserving. For a liquid dosage that is to be sprayed, the solution must be broken up into small particles that are conducive to a Newtonian flow. Antiseptics, local anesthetics, and skin protectants are all types of liquid solutions that would benefit from a spray type of application. Fungal infections, such as athlete's foot or ringworm (jock itch) can be treated in a similar manner.

Likewise, the manner in which the liquid form is to be applied is a consideration that the drug manufacturer must make. If the solution is to be applied in medicinal drops, a small bottle with an applicator would be the preferred packaging, for example. If the liquid dosage is to be sprayed, a spray bottle or medicinal atomizer would be the desired packaging.

Pharmacists must also consider use. Sterile dosage forms, for instance, require special treatment and "must be exceptionally pure and free from physical, chemical and biological contaminants" (Adesina "Sterile Dosage Forms" 2). These forms are commonly administered to patients parenterally so as to allow the patient and physician to avoid problems related to drug degradation via oral administration (Adesina "Sterile Dosage Forms" 3). Additionally, if a drug is particularly irritating to a patient's gut or causes nausea, the sterile dosage form can be given parenterally. Thus, how a drug is intended to be used will be another factor that is taken into consideration when the pharmacist is manufacturing the drug.

Not every form is desirable or even practical. Some have their limitations and this has to be considered as well. The extent to which a liquid form is applicable for particular patients is something that has to be addressed by the manufacturer and research plus experience help to provide the manufacturer with this information. For instance, the limitations of parenteral administration of sterile dosage forms is that it is a typical inconvenient dosage form because it cannot be taken by the individual alone but requires specially trained personnel to administer the form to the patient (Adesina "Sterile Dosage Forms" 4). Likewise, oral liquid dosage forms have disadvantages, such as the fact that they are more liable to degradation, can be difficult to flavor (as a result of the bitterness of the drug itself, are susceptible to bacterial contamination, and often create bulky packaging demands that add complications to transportation. Thus, the limitations of the forms themselves contain ramifications that go beyond the mere administration of the drug itself.

On the other hand, some forms have benefits above and beyond others. For example, thixotropy is a very desirable property for liquid pharmaceutical forms because such a suspension does not settle in the container. A simple shake of the container in which the form is kept will be sufficient in giving the form the proper fluidity so that an adequate dose can be dispensed and administered to the patient. In fact, the inverse of this form -- antithixotropy -- is rarely desirable in pharmaceutical liquid formulations as such a solution is not conducive to the kinds of flow that a patient requires for self-medication.

Ultimately the major formulation considerations of parentally administrated solutions depend upon the nature of the drug and the type of therapy that is to be delivered. As Adesina notes, "the nature of the drug (i.e. physical and chemical characteristics) and certain therapeutic considerations determine the form in which a drug is prepared" ("Sterile Dosage Forms" 11). These considerations include whether or not the drug is unstable in solution (if it is, the form can be prepped as a dry powder and reconstituted through aqueous additives when it is to be administered); whether the drug is insoluble in water (if it is, the product can be prepped "as an aqueous suspension or as a solution of the drug" in a solvent) (Adesina "Sterile Dosage Forms" 11). The chemical makeup of the drug must also be considered as this will affect the drug's onset and duration of activity.