Principles of dosage form design

Drugs are rarely administered as pure chemical substances alone and are almost always given as formulated preparations or medicines. These can vary from relatively simple solutions to complex drug delivery systems through the use of appropriate additives or excipients in the formulations. The excipients provide varied and specialized pharmaceutical functions. It is the formulation additives that, amongst other things, solubilize, suspend, thicken, preserve, emulsify, modify dissolution, improve the compactability and flavour drug substances to form various medicines or dosage forms.

The principal objective of dosage form design is to achieve a predictable therapeutic response to a drug included in a formulation which is capable of large-scale manufacture with reproducible product quality. To ensure product quality, numerous features are required: chemical and physical stability, with suitable preservation against microbial contamination if appropriate, uniformity of dose of drug, acceptability to users, including both prescriber and patient, as well as suitable packaging and labelling. Ideally, dosage forms should also be independent of patient-to-patient variation, although in practice, this feature remains difficult to achieve. However, recent developments are beginning to accommodate this requirement. These include drug delivery systems that rely on the specific metabolic activity of individual patients and implants that respond, for example, to externally applied sound or magnetic fields to trigger a drug delivery function.

Consideration should be given to differences in the bioavailability of drugs and their bio-fate in patients between apparently similar formulations and possible causative reasons. In recent years, increasing attention has therefore been directed towards eliminating variation in bioavailability characteristics, particularly for medicinal products containing an equivalent dose of a drug substance, as it is recognized that formulation factors can influence their therapeutic performance. To optimize the bioavailability of drug substances, it is often necessary to carefully select the most appropriate chemical form of the drug. For example, such selection should address solubility requirements, drug particle size and physical form and consider appropriate additives and manufacturing aids coupled to selecting the most appropriate administration route(s) and dosage form(s). Additionally, suitable manufacturing processes, labelling and packaging are required.

There are numerous dosage forms into which a drug substance can be incorporated for the convenient and efficacious treatment of a disease. Dosage forms can be designed for administration by alternative delivery routes to maximize therapeutic response. Preparations can be taken orally or injected, as well as being applied to the skin or inhaled, and Table 1.1 lists the range of dosage forms which can be used to deliver drugs by the various administration routes. However, it is necessary to relate the drug substance to the clinical indication being treated before the correct combination of drug and dosage form can be made, since each disease or illness often requires a specific type of drug therapy. In addition, factors governing choice of administration route and the specific requirements of that route which affect drug absorption need to be taken into account when designing dosage forms.

Many drugs are formulated into several dosage forms of varying strengths, each having selected pharmaceutical characteristics which are suitable for a specific application. One such drug is the glucocorticoid prednisolone used in the suppression of inflammatory and allergic disorders. Through the use of different chemical forms and formulation additives, a range of effective anti-inflammatory preparations is available, including tablet, enteric-coated tablet, injections, eye drops and enema. The extremely low aqueous solubility of the base prednisolone and acetate salt makes these forms useful in tablet and slowly absorbed intramuscular suspension injection forms, whilst the soluble sodium phosphate salt enables a soluble tablet form and solutions for eye and ear drops, enema and intravenous injection to be prepared. The analgesic paracetamol is also available in a range of dosage forms and strengths to meet the specific needs of the user, including tablets, dispersible tablets, paediatric soluble tablets, paediatric oral solution, sugar-free oral solution, oral suspension, double-strength oral suspension and suppositories.

In addition, whilst many new drugs based on low molecular weight organic compounds continue to be discovered and transformed into medicinal products, the development of drugs from biotechnology is increasing and the importance of these therapeutic agents is growing. Such active compounds are macromolecular and of relatively large molecular weight, and these include materials such as peptides, proteins and viral components. These drug substances present different and complex challenges in their formulation and processing into medicines due to their alternative biological, chemical and structural properties. Nevertheless, the underlying principles of dosage form design remain applicable. At present, these therapeutic agents are principally formulated into parenteral and respiratory dosage forms although other routes of administration are being considered and researched. Delivery of these biotechnologically-based drug substances via these routes of administration imposes additional constraints upon the selection of appropriate formulation excipients.

It is therefore apparent that before a drug substance can be successfully formulated into a dosage form, many factors must be considered. These can be broadly grouped into three categories:

High-quality and efficacious medicines will be formulated and prepared only when all these factors are considered and related to each other. This is the underlying principle of dosage form design.

Biopharmaceutical aspects of dosage form design

Biopharmaceutics can be regarded as the study of the relationship between the physical, chemical and biological sciences applied to drugs, dosage forms and drug action. Clearly, understanding the principles of this subject is important in dosage form design, particularly with regard to drug absorption, as well as drug distribution, metabolism and excretion. In general, a drug substance must be in solution before it can be absorbed via absorbing membranes and epithelia of the skin, gastrointestinal tract and lungs into body fluids. Drugs are absorbed in two general ways: by passive diffusion and by carrier mediated transport mechanisms. In passive diffusion, which is thought to control the absorption of many drugs, the process is driven by the concentration gradient existing across the cellular barrier, with drug molecules passing from regions of high to low concentration. Lipid solubility and degree of ionization of the drug at the absorbing site influence the rate of diffusion. Recent research into carrier mediated transport mechanisms has provided much information and knowledge, providing guidance in some cases for the design of new drug molecules. Several specialized transport mechanisms are postulated, including active and facilitated transport. Once absorbed, the drug can exert a therapeutic effect either locally or at a site of action remote from the site of administration. In the latter case, the drug has to be transported in body fluids (as shown in Fig. 1.1).

When the dosage form is designed to deliver drugs via the buccal, respiratory, rectal, intramuscular or subcutaneous routes, the drug passes directly into the circulation blood from absorbing tissues, whilst the intravenous route provides the most direct route of all. When delivered by the oral route, onset of drug action will be delayed because of required transit time in the gastrointestinal tract prior to absorption, the absorption process and factors associated with hepatoenteric blood circulation. The physical form of the oral dosage form will also influence absorption rate and onset of action, with solutions acting faster than suspensions, which in turn generally act faster than capsules and tablets. Dosage forms can thus be listed in order of time of onset of therapeutic effect (see Table 1.2). However, all drugs irrespective of their delivery route remain foreign substances to the human body and distribution, metabolic and elimination processes commence immediately following drug absorption until the drug is eliminated from the body via the urine, faeces, saliva, skin or lungs in unchanged or metabolized form.