Introduction to pharmaceutics

Introduction to pharmaceutics

One of the earliest impressions that many new pharmacy and pharmaceutical science students have
of their chosen subject is the large number of long and sometimes unusual-sounding names that are used
to describe the various subject areas within pharmacy and the pharmaceutical sciences.

The aim of this article is to explain to the reader what is meant by just one of them – ‘pharmaceutics’.

It describes how the term has been interpreted for the purpose of
this book and how pharmaceutics fits into the overall scheme of pharmaceutical science and the process
of designing and manufacturing a new medicine.

This note also leads the reader through the organization of this book and explains the reasons why an understanding of the material contained in its chapters is important in the design of modern drug delivery
systems.

The word ‘pharmaceutics’ is used in pharmacy and the pharmaceutical sciences to encompass a wide
range of subject areas that are all associated with the steps to which a drug is subjected towards the end of its development. It encompasses the stages that follow on from the discovery or synthesis of the drug, its isolation and purification, and its testing for
beneficial pharmacological effects and absence of serious toxicological problems.

Put at its simplest – pharmaceutics converts a drug into a medicine.
Just a comment here about the word ‘drug’.

This is the pharmacologically active ingredient in a medicine. ‘Drug’ is the correct word, but because the word has been somewhat hijacked as the
common term for a substance of misuse, alternatives are frequently used, such as ‘medicinal agent’, ‘pharmacological agent’, ‘active principle’, ‘active
ingredient’, or increasingly ‘active pharmaceutical ingredient (API)’, etc.

The article and the blog at large uses the simpler and still correct word, ‘drug’.

Phrases like ‘active ingredient’ can suggest that the other ingredients of
a medicine have no function at all. This book will teach you loud and clear that this is not the case.

Pharmaceutics, and therefore this book, is concerned with the scientific and technological aspects of the design and manufacture of dosage forms. Arguably,
it is the most diverse of all the subject areas in the pharmaceutical sciences and encompasses:

  • an understanding of the basic physical chemistry necessary for the effective design of dosage forms (physical pharmaceutics)
  • an understanding of relevant body systems and how drugs arrive there following administration
    (biopharmaceutics)
  • the design and formulation of medicines (dosage form design)
  • the manufacture of these medicines on a small (compounding), intermediate (pilot-scale) and large (manufacturing) scale
  • the avoidance and elimination of
    microorganisms in medicines (pharmaceutical microbiology, sterilization), and
  • product performance testing (physical testing, drug release, stability testing).

Medicines are drug-delivery systems.

That is, they are a means of administering drugs to the body in a
safe, effective, accurate, reproducible and convenient manner. The article and the blog at large discusses the overall considerations that must be made so that the conversion of a drug to a medicine can take place.

It emphasizes the fact that medicines are very rarely drugs alone but require
additives (termed excipients) to make them into dosage forms, and this in turn introduces the concept of formulation.

The blog explains that there are three
major considerations in the design of dosage forms:

  1. the physicochemical properties of the drug itself
  2. biopharmaceutical considerations, such as how the administration route and formulation of a
    dosage form affect the rate and extent of drug absorption into the body, and
  3. therapeutic considerations of the disease state and patient to be treated, which in turn determine the most suitable type of dosage
    form, possible routes of administration and the
    most suitable duration of action and dose frequency for the drug in question.

This introduction of pharmaceutics provides an excellent introduction
to the subject matter of the blog as a whole and clearly justifies the need for the pharmacist and formulation scientist to understand the science
contained in this website (blog).

New readers are encouraged to read this introductory article first, thoroughly and carefully, so that they can grasp the basics of the subject before
proceeding onto the more detailed information here (other articles).

For many reasons, which are discussed in the blog, the vast majority of dosage forms are administered via the mouth in the form of solid products, such as
tablets and capsules. This means that one of the most important stages in drug administration is the dissolution of solid particles to form a solution in the
gastrointestinal tract.

The formulation scientist therefore needs knowledge of both liquid and solid
materials, in particular the properties of drugs in solution and the factors influencing their dissolution
from solid particles.

Once solutions are formed, the
formulation scientist must understand the properties of these solutions. The reader will see later in the blog(other articles) how drug release from the dosage form and absorption of the drug into the body across biological barriers are strongly dependent on the properties of the drug in solution, such as the degree of ionisation and speed of diffusion of the drug molecules.

The properties of surfaces and interfaces will be described in our next article. These are important to an understanding of adsorption onto solid surfaces, and are involved in the dissolution of solid particles and the study of disperse systems, such as colloids, suspensions and emulsions.

The scientific background to the systems
mentioned is also discussed. Knowledge of the flow properties of liquids (whether solutions, suspensions or emulsions) and semisolids is useful in solving certain
problems relating to the manufacture, performance and stability of liquid and semi-solid dosage forms.

This Part ends with an explanation of the kinetics of many different processes. As the article explains, the mathematics of these processes has importance in a large number of areas of product design, manufacture, storage and drug delivery.

Relevant processes include:

  • dissolution
  • microbiological growth and
    destruction,
  • biopharmaceutics (including drug absorption, distribution, metabolism and excretion), preformulation, the rate of drug release from dosage forms, and the decomposition of medicinal compounds and products.

By far the majority of drugs are solid (mainly crystalline) powders and, unfortunately, most of these particulate
solids have numerous adverse characteristics that must be overcome or controlled during the design
of medicines to enable their satisfactory manufacture and subsequent performance in dosage forms.

The blog therefore explains the concept of the solid state and how the internal and surface properties of solids are important and need to be characterized.

This is followed by an explanation of the more macroscopic properties of powders that influence their performance during the design and manufacture of dosage forms – particle size and its measurement, size reduction, and the separation of powders with the desired size characteristics from those of other
sizes.

There follows an explanation of the many problems associated with the mixing and flow of powders. In large-scale tablet and capsule production,
for example, powders must contain a satisfactory mix of all the ingredients in order to achieve uniformity of dosage in every dosage unit manufactured.

The powder must have fast and uniform powder flow in high-speed tableting and encapsulation machines. For convenience, the mixing of liquids and semisolids is also discussed here as the basic theory is the same.

Another extremely important area that must be understood before a satisfactory dosage form can be designed and manufactured is the microbiological
aspects of medicines development and production.

It is necessary to control or eliminate viable microorganisms from the product both before and during manufacture.

Microbiology is a very wide-ranging
subject. This blog concentrates only on those aspects of microbiology that are directly relevant to the design, production and distribution of dosage forms.

This mainly involves avoiding (asepsis) and eliminating (sterilization) the presence (contamination) of viable
microorganisms in medicines, and preventing the growth of any microorganism which might enter the
product during storage and use of the medicine (preservation). Techniques for testing that these intentions have been achieved are also described.

It is not possible to begin to design a satisfactory dosage form without knowledge and understanding
of how drugs are absorbed into the body, the various routes that can be used for this purpose and the fate of the drugs once they enter the body and reach
their site(s) of action.

A couple of examples illustrate
this:

  • Whilst an immediate-release capsule of nifedipine has a dosing frequency of three times a day, formulation of the drug in a
    modified-release capsule permits once-daily dosing, with an improved drug plasma profile
    and increased patient convenience and adherence.
  • A cream formulation of a sunscreen applied to the skin restricts the active component(s) to the skin surface, whilst a gel formulation of
    estradiol, also applied to the skin surface, is formulated so as to ensure effective penetration
    of drug through the skin and into the systemic circulation.

The first stage of designing and manufacturing a dosage form is known as preformulation. This, as
the name implies, is a consideration of the steps that need to be performed before formulation proper
can begin.

Preformulation involves a full understanding of the physicochemical properties of drugs and other ingredients (excipients) in a dosage form and
how they may interact. An early grasp of this knowledge is of great use to the formulation scientist as the data gathered in these early stages will influence strongly the design of the future dosage form.

Results of tests carried out at this stage of development can give a much clearer indication of the possible (and
indeed impossible) dosage forms for a new drug candidate.

The properties of these
dosage forms can be modified dependent on the properties of the drug, excipients included, the route of drug administration and specific patient needs.

Appropriate formulation of emulsions results in more structured semi-solid creams, most frequently used for application to the skin.

These dosage forms may be administered by a number of routes, and their formulation requirements will vary dependent on the route of administration.

Whilst drugs in the solid state can be administered as simple powders, they are more usually formulated
as solid dosage forms, namely tablets (currently the most commonly encountered solid dosage form) and
capsules. Several chapters in this Part describe the various stages in the processing of a powder required
to manufacture tablets: granulation (formation of drug-excipient aggregates), drying, compaction and coating. Tablet formulation and manufacture requires
inclusion of several excipients, including fillers, disintegrants, binders, glidants, lubricants and antiadherents.

The purposes of these are described,
together with their impact on product quality and performance. The strategies to modify the release of drug from solid dosage forms include: production of monolithic matrix systems, the use of a ratecontrolling membrane or osmotic pump systems.

For all dosage forms, drug must be released at an appropriate rate at the appropriate site for drug action and/
or absorption to occur. This is particularly pertinent for solid peroral dosage forms, which must permit
dissolution of drug at an appropriate rate and at an appropriate site within the gastrointestinal tract.

Bioavailability (i.e. the amount of drug that is absorbedbinto the bloodstream) may be limited by the rate of
drug dissolution, whilst the pH range in the gastrointestinal tract (pH 1–8) may adversely affect the absorption of ionizable drugs.

Consequently, dissolution testing is a key quality control test and is considered in detail here.

Solid dosage forms are administered predominantly (though not exclusively) by the oral route. Whilst the oral route is the most common way of administering drugs, many other routes for administration exist and are necessary.

Each of these is considered in
detail. Such routes include parenteral administration (injections, infusions, implants), pulmonary (aerosols),
nasal (sprays, drops, semisolids, powders), ocular (drops, semisolids, injection, implants), topical and
transdermal (semisolids, patches, liquids, powders), ungual (nail lacquers, liquids), rectal (suppositories, tablets, capsules, semisolids, liquids, foams) and
vaginal (pessaries, semisolids, films, rings, tampons).

For each route, consideration is given to the nature of the administration site and the formulation requirements either to localize drug action, or to control absorption, as appropriate. The dosage forms available for delivering drugs by each route are outlined and
particular aspects regarding their formulation and manufacture are highlighted.

The methods used to characterize and test these dosage forms, for formulation development and quality assurance purposes are also detailed.

Drugs of natural (plant) origin are discussed. Unlike conventional dosage forms these comprise plant extracts
that have many complex components with potentially variable composition.

Certain biotechnology products, for instance insulin, are long established, whilst others such as nucleic acids for gene therapy offer exciting therapeutic possibilities for the future.

All are relatively large macromolecules and present particular formulation and drug delivery challenges. To meet some of the challenges associated with delivery of biotechnology products, pharmaceutical nanotechnology has
become established in recent years as a means of iimproving solubility and dissolution rate, protecting
drugs from hostile environments, minimizing adverse effects and delivering drugs to specific therapeutic
targets.

The preparation and properties of various nanomedicines, including antibodies, polymer-drug conjugates, liposomes, nanoparticles and dendrimers are considered.

Some specific patient groups (in particular the elderly and young children) have particular needs
(difficulty swallowing, subdivision of commercially available doses, etc.) and the formulation consequences
are discussed.

Before finalizing the formulation and packaging of the dosage form, there must be a clear understanding of the stability of the drug(s) and other additives in a pharmaceutical product with respect to the reasons why, and the rates at which, they may degrade during storage.

The product pack and any possible interactions between it and the drug or medicine it contains are so vitally linked that the final pack should not be
considered as an afterthought. Instead, packaging considerations should be uppermost in the minds of formulators as soon as they receive the drug substance on which to work.

No product will be stable indefinitely, and so mechanisms (i.e. the fundamental chemistry) and kinetics of degradation must be understood so that a safe and realistic shelf-life for every product can be determined.

It is shown how the presence of antimicrobial preservatives in the medicine can minimize the consequences of such contamination.

However, such preservatives must be
nontoxic by the route of administration and should not interact with components of the drug product or its packaging

At this point the product is considered to be of appropriate quality for patient use and, once approved by regulatory authorities, the pharmaceutical technologist passes the product on to another aspect of pharmacy – the interface with the patient, i.e. dispensing and pharmacy practic

Leave a Reply