Pharmaceutics Remington Education
This text is written to provide students studying for a doctorate in pharmacy with an overview of pharmaceutics that connects this science to the practice of pharmacy. The presentation that follows is a result of the judicious consideration of the subject matter of pharmaceutics in light of what today’s pharmacists do and what future pharmacists will do in their practices. These carefully selected, essential principles are presented in concise form accompanied by examples of their application.
The first six chapters present the fundamental principles relating to the behavior of solids, solutions and dispersed systems, solubility, stability, and the processes that move drugs from the dosage form to the portion of the body where the drug’s receptor is located. The reader is introduced to the scientific basis of generic substitution in the chapter on bioavailability and bioequivalence. The remaining chapters present drug delivery organized by route of administration.
Each chapter reinforces the same basic principles of dosage form design: drug chemistry considerations, materials and methods to prepare a dosage form with the desired qualities and characteristics of the route in which these systems are administered to deliver a drug to its receptors.
I am grateful to my students whose intelligence and enthusiasm have shaped my teaching, and to my husband, Larry Fox, for his energetic support of this project.
i). Introduction to dosage form design
What is pharmaceutics and why do pharmacists study this subject?Historically pharmacists provided two services in the healthcare system: they extracted drugs from their natural sources and prepared or ‘compounded’ the drug into a convenient form for patient use, the dosage form.
ii). Intermolecular forces and the physical and pharmaceutical properties of drugs
As we use solid drugs and pharmaceutical necessities to make dosage forms, we need to be able to mix them to uniformity, push them through tableting machines or capsule fillers and ensure that they release drugs for absorption through dissolution. Powder mixing and flow and the dissolution of solids all depend on the characteristics of the solids used. In this chapter we want to consider the characteristics of solids that affect the preparation and performance of solid dosage forms. These are:
- melting point
- arrangement of the molecules of drug in the solid
- particle size, shape and surface energy
- solubility
- dissolution rate.
iii). Dispersed systems
If we take a solid drug and mix it with water and it ‘disappears’ into the solvent, we say that it has formed a solid in liquid solution. At a molecular level individual molecules of this drug have ceased to interact with one another as they do in a crystal and are surrounded entirely by individual solvent molecules. If we take another solid drug and mix it with water and over time we can still see solid material in the solvent, we have a coarse dispersion that in pharmacy is referred to as a suspension. These hydrophobic drug molecules prefer interacting with each other to interacting with molecules of solvent and this behavior has significant impact on how we formulate and handle suspensions. There is a third set of interactions that can be observed in a mixture between a solid drug or pharmaceutical necessity and a solvent that may be considered intermediate in nature between a molecular solution and a suspension. In these colloidal dispersions we find a network of overlapping solute molecules interacting with molecules of solvent. The behavior of colloidal dispersions can be explained by these simultaneous interactions between colloid and colloid, and colloid and solvent. This chapter focuses on the behavior of colloids and coarse dispersions. Chapter 4 considers molecular solutions in detail.
iv). Properties of solutions and manipulation of solubility
Perhaps the most obvious reason that solubility is important in pharmacy is that many dosage forms are solutions: syrups, elixirs, parenteral solutions or solutions for the eye, ear, nose, respiratory tract or skin. Most of these dosage forms are solutions of drug in water. In the case of parenteral intravenous solutions it is essential to patient safety that the drug remains in solution, meaning that the pharmacist must have a good understanding of the factors that will affect drug solubility.
The second reason that solubility is important in the practice of pharmacy is that those dosage forms that are not solutions must dissolve in aqueous body fluids before they can move across membrane barriers in the body. Formation of a solution, then, is the initial step in delivering many drugs to the site of action, affecting both the rate and extent of drug absorption.
While our initial interest as pharmacists may be in the water solubility of a drug, we will learn that our drug will also need adequate lipid solubility in order to diffuse across the lipid bilayers of the body’s membranes. Thus we find that drug molecules are a collection of compounds whose affinity for water and for lipid fall within a reasonably well-defined range. A highly water soluble drug, that is, a hydrophilic compound, must also have enough lipid solubility to move from the site of administration to the receptors and out of the body through eliminating organs. A lipid soluble drug, that is, a lipophilic compound, must have enough water solubility to dissolve in body fluids at the site of administration and be carried with body fluids to the site of action. It is essential then, to understand what properties of drug molecules contribute to their water and lipid solubilities.
v). Chemical stability of drugs
There are three kinds of stability that we concern ourselves with as formulators and pharmacists: physical stability, microbial stability, and chemical stability. This chapter is focused on the chemical stability of drugs. Physical and microbial stability will be considered as we discuss each class of dosage form.
vi). Drug travel from dosage form to receptor
In this chapter we consider the processes that move drugs from the dosage form to the portion of the body where the drug’s receptor is located, and the factors that influence or limit them. Unless a drug dosage form is an intravenous solution, the drug must be released from the dosage form and dissolve in the body fluids near the site of absorption. The drug must penetrate one or more membranes as it moves into and out of the blood orlymph for distribution. The drug will distribute with the blood flow and will penetrate into other tissues as its chemistry and membrane permeability allow. If the dose of the drug was properly chosen, it will produce the desired effect at the site of action. If the dose was too low, the patient will experience therapeutic failure and if too high, adverse effects. Blood flow will carry the drug to the liver where enzymes may break it into a more polar species, and to the kidneys where the drug or its metabolite will be eliminated. When the amount of drug leaving the body has exceeded the amount of drug coming into the body sufficiently long to drop the concentration at the site of action below the therapeutic threshold, the patient will no longer experience the effects of the drug. Ultimately we seek to understand this aspect of pharmaceutical science in order to predict how fast and how much drug is presented to the site of action. This understanding will enable the pharmacist to answer our patients’ questions about when a medication will begin to improve their condition or when a nurse should evaluate the effect of a dose.
Pharmaceutical scientists have developed efficient approaches to identify drug candidates that have the appropriate biopharmaceutical characteristics to warrant the investment required to bring a drug to market. These same approaches can be used by the practicing pharmacist to make predictions about the rate and extent of travel of drugs in our patients. First the four categories of factors that affect drug travel are reviewed and then their influence is examined as a drug is followed through its liberation, absorption, distribution, metabolism and elimination. The factors that determine how much drug and how quickly a drug is available at the site of action fall into four categories:
- physicochemical factors
- biological factors
- dosage form factors
- patient related factors.
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