The behavior and action of a drug is ultimately determined by its chemical structure
The structure determines its physicochemical properties, which in turn play a major role in physical, chemical, and biological performance
A critical physicochemical property of a drug is ionization
-This is a process by which a neutral molecule gains or loses a proton and thereby acquires a positive or negative electrical charge
-The charged species which are formed are called ions
-One way of classifying compounds is based on whether, and how much, they ionize in aqueous solutions
Ions can conduct an electrical current, and so substances that form ions in solution are called
A ____________________ is a compound that does not ionize when dissolved in water, and exists solely as the neutral, uncharged species
ex. ethanol, dextrose, and some steroids
Many drug compounds do not ionize under physiological conditions and are considered to be
Compounds with the following functional groups do not generally ionize in aqueous solution
-Alcohols and sugars
-The majority of amides
A strong electrolyte ionizes completely when dissolved in water, and exists solely in the form of positive and negative ions in solution
-An example is sodium chloride (NaCl), which ionizes to form Na+ and Cl− in aqueous solution
-A few drugs are strong electrolytes; examples are KCl (as a potassium supplement) and lithium carbonate (Li2CO3 ) (in the treatment of manic depression).
A weak electrolyte is ionizable, but ionizes partially; a fraction of dissolved molecules remain un-ionized, while others acquire a positive or negative charge
-Simple examples of weak electrolytes are acetic acid and ammonia
-Many drugs and other pharmaceutically important compounds are weak electrolytes
Importance of Ionization of Weak Electrolytes
The properties of ionized (charged) and un-ionized (uncharged) forms of a drug or biologically active compound are dramatically different from each other, even though the only change in structure is the gain or loss of a proton, and the presence or absence of a charge
The charged and uncharged forms of a drug will be
-Absorbed and distributed differently.
-Will bind to receptors differently
-And may be metabolized and eliminated differently
Thus, for a drug that can ionize, the proportion of ionized and un-ionized forms in the body is critical in determining its behavior
The ionization of drugs in the drug product is also important, influencing route of administration and shelf life of the drug product
Indomethacin, an oral anti-inflammatory drug, provides a good example of the importance of ionization in drug design
-On administration, indomethacin (a weak electrolyte) must first dissolve in aqueous contents of the gastrointestinal tract
-The ionized form of the drug dissolves more rapidly and to a greater extent than the un-ionized form
-To enter the bloodstream, however, it needs to cross lipophilic cell barriers, which requires at least some molecules to be in the un-ionized form in the intestines
-Once indomethacin has reached its site of action, only the ionized form binds to the receptor
-Thus, both ionized and un-ionized forms are important for different aspects of ADME (absorption, distribution, metabolism, excretion) and pharmacodynamics of indomethacin
-According to the Bronsted-Lowry theory of acids and bases, an acid is a compound that can donate a proton and a base is one that can accept a proton
-Therefore, there has to be another compound present to receive the proton from the acid, or to provide a proton to the base
-In almost all situations, this other compound is water
Water is the solvent and medium for all living organisms
-Water is also a reactant in many pharmaceutical reactions of interest
-water is critical in determining the configuration of proteins and other biological macromolecules that are important in drug action
Water is a remarkable solvent because it can behave as both an acid and a base
-The water molecule possesses a dipole (two electric charges of equal magnitude but opposite sign, separated by a small distance), giving it the ability to accept or donate a positively charged proton
a substance that can act as either an acid or a base
Water accepts a proton in the following equilibrium
Water can also donate a proton as follows
The ionization product constant of water is Kw
-This relationship says that the product of protons and hydroxide ions in an aqueous solution is always constant
-The value of Kw at 25 C is 10^−14
The pH value is a convenient way to express the acidity of a solution and is defined as follows
-The symbol p is an operator that converts a number into its negative logarithm
-The pH scale has a range from 0 to 14.
-Seven is considered neutral pH where the concentration of hydrogen ions is equal to the concentration of hydroxide ions
-A solution pH below 7 means that the solution is acidic and the concentration of hydrogen ions exceeds the concentration of hydroxide ions
-If the concentration of hydroxide ions is greater than that of hydrogen ions, the solution is basic or alkaline and has a pH greater than 7
-The pH of body fluids ranges between 1 and (approximately) 8
-The stomach is the most acidic region of the body with a pH that varies between 1 and 3
-The normal pH of intestinal fluids is approximately 6 to 7
-The pH of blood is 7.4, which corresponds to a [H+] of approximately 40 nM (This value can only vary from 37 to 43 nM without serious metabolic consequences)
-Local pH in various tissues depends on composition and function of each tissue, and rarely exceeds 8
a drug can be expected to encounter physiological environments that vary between pH 1 and 8, which makes ionization in this pH range of the greatest interest
If a drug does not have a functional group that ionizes in this pH region, it behaves as a nonelectrolyte and remains un-ionized over the entire physiological pH range
From a formulation perspective, it is important to control pH of a product to
-minimize drug degradation
-improve patient comfort and compliance
Dosage forms, particularly liquids (such as solutions, suspensions, and emulsions), may have pH values outside the 1-8 pH range.
-Higher pH values of pharmaceutical liquids are often required to make the drug more soluble, or to maintain good stability and an adequate shelf life
-Thus, in these situations, ionization behavior over a wider pH range has to be understood and considered
Strong acids such as HCl and H2SO4 dissociate completely in water and exist entirely in their ionized form, making them strong electrolytes
-The H+ ion will react with a water molecule to produce the hydronium ion, although for convenience we usually do not write the complete reaction
-when a strong acid is added to water, hydrogen ion concentration in solution increases and pH decreases
-Because a strong acid dissociates completely, the molar concentration of H+ is equal to the molar concentration of acid added for a monoprotic acid (HCl), and twice the molar acid concentration for a diprotic acid (H2SO4).
a strong base like NaOH dissociates completely in water and exists entirely in its ionized form
-The actual base here is hydroxide ion, OH−, which will react with H+ in water
-Consequently, the concentration of H+ will decrease and the solution pH will increase
-The molar decrease in H+ concentration will be equal to the molar concentration of NaOH added
Although strong acids and bases are often used in pharmaceutical products to adjust the pH of liquids
there are no strong acid or strong base drugs
Many drugs can be classified as weak acids or weak bases
-Like strong acids and bases, these compounds can also dissociate in water and donate or accept protons
-The main difference is that weak acids and bases are only partially dissociated in water because of their diminished ability to donate or accept protons
When a weak acid is added to water, the pH decreases
-Only a fraction of acid molecules dissociate to donate protons to water.
-The rest of the weak acid molecules remain un-ionized
-Therefore, weak acids exist in solution in two forms—the uncharged, un-ionized species and negatively charged ions
when a weak base is dissolved in water, only a fraction of molecules accept protons
Weak bases also exist in solution in two forms—the uncharged, un-ionized species and positively charged ions
Typical weak acids have the following functionalities
Ionization of Weak Acids and bases
-Consider the ionization of a weak acid such as acetylsalicylic acid, or aspirin, which has one carboxylic acid group
-acetylsalicylic acid is a weak acid because it donates a proton, and the acetylsalicylate ion is a weak base because it accepts a proton.
-An acid and base that can be represented by an equilibrium in which the two species differ only by a proton is called a conjugate acid-base pair
An acid and base that can be represented by an equilibrium in which the two species differ only by a proton is called a conjugate acid-base pair
In this equilibrium, acetylsalicylic acid is a weak acid because it donates a proton, and the acetylsalicylate ion is a weak base because it accepts a proton
Ka is called the acid dissociation constant
A simplified way of representing dissociation of any weak acid, denoted as HA for convenience, is as follows: Where A− is the conjugate base of the acid HA
The ionization of the weak base benzocaine with one amino group is shown in the following figure
A simplified way of representing ionization equilibrium for any base B is as follows: Here, BH+ is the conjugate acid of the base B
Ionization of the weak base benzocaine in aqueous solution
The equilibrium is now expressed as the dissociation of the conjugate acid of the weak base, with Ka as the corresponding acid dissociation constant
Because ions behave differently from uncharged molecules, we are interested in what proportion of a weak acid or weak base is un-ionized or ionized in a given situation
this will help us understand and predict its behavior
The law of mass action describes the dissociation of a weak acid and of the conjugate acid of a weak base
It states that at equilibrium the product of the concentrations on one side of an equation, when divided by the product of concentrations on the other side of the equation, is a constant regardless of the individual concentrations
-A large value of Ka means that the acid favors giving up protons and dissociates extensively
-Consequently, the reverse reaction is not favored; the conjugate base A− is stable and does not have a high propensity to accept protons
-The larger the Ka, the stronger the acid HA, and the weaker its conjugate base A−
-Therefore, Ka is a property of the conjugate acid-base pair and gives us information about the strengths of both forms
Ka for the conjugate acid of a weak base
-The larger the value of Ka, the more BH+ dissociates to donate protons.
-Therefore, the larger the Ka, the stronger the conjugate acid BH+ is, and the weaker the base B
The negative logarithm of Ka is referred to as the pKa (The symbol p is an operator that converts a number into its negative logarithm)
pKa gets smaller as Ka gets larger.
-In other words, weak acids (or conjugate acids of weak bases) with a large Ka have a small pKa.
-Weak acids with a small Ka have a large pKa.
The pKa value itself does not tell us whether a drug is a weak acid or base
-For example, if a drug has a pKa value of 5, it could be either a weak acid or a weak base.
-One way to tell is to examine the structure of the molecule and identify functional groups that are known to be acidic or basic.
-Another way is to see the types of salts that the compound forms.
The lower the pKa of a compound,
the stronger is the acidic form of the conjugate acid-base pair
ex. a weak acid with a pKa of 3 is a stronger acid than a weak acid with a pKa of 4
the higher the pKa of a compound
the stronger is the basic form of the conjugate acid-base pair
ex. A weak base of pKa 8 is a stronger base than a weak base of pKa 7
Weak acid and base drugs are frequently available as their salts
-For example, the weak acid drug naproxen is also available as its sodium salt, sodium naproxen
-The weak base drug clonidine is also available in its salt form, clonidine hydrochloride
-Salt names can give us information about whether a drug in its un-ionized form is a weak acid or base
The salt of a weak acid is usually obtained by reacting it with a
strong base such as NaOH, which gives the sodium salt
The salt of a weak base is obtained by reacting it with a
strong acid such as HCl, which gives the hydrochloride salt
Some drug salts are also made by combining
Salts themselves are strong electrolytes, in that they dissociate completely into their constituent ions in water
However, the ions generated do not remain completely ionized if one of the components of the salt is a weak acid or base
Pharmaceutical companies often develop the salt form of a drug rather than the original weak acid or base form for several reasons
-Salts can be more readily crystallized into stable, easy to manufacture crystals
-They dissolve faster in aqueous solutions, are more stable on storage, and are easier to handle during processing
In particular, salts of amine drugs are preferred over the weak base form.
-Many amines are volatile and unstable, and have a short shelf life as solids.
-Stability and shelf life improve dramatically if an amine is converted to the hydrochloride salt
The relative concentrations of the ionized and un-ionized forms depend not only on the pKa of the weak acid or base, but also on the
pH of the aqueous solution in which it is dissolved.
-A buffered solution is one that resists changes in its pH when small amounts of acid or base are added, or when the solution is diluted!!
-Buffer solutions contain an acid to react with added OH− and a base to react with added H+.
-These can be any weak acid-weak base pair, but are usually a conjugate acid-conjugate base pair.
The pH of the buffer depends on the pKa of the buffering substance and on the relative concentrations of conjugate acid and base
It can be calculated using the Henderson-Hasselbalch equation.
Acidic buffer solutions (pH <7) are commonly made from a weak acid and one of its salts—often a sodium salt.
-An example is a solution of acetic acid (pKa = 4.75) and sodium acetate
-If the solution contains equimolar concentrations of the acid and salt, it will have a pH of 4.75. The following equilibrium describes this system:
-If additional hydrogen ions are added to this solution, they are consumed in the reaction with CH3COO−, and the equilibrium shifts to the left
-If additional hydroxide ions enter, they react with CH3COOH, producing CH3COO−, and shift the equilibrium to the right
-In this way, the [H+] and thus the pH of the solution remain constant
An alkaline buffer solution (pH >7) is commonly made from a weak base and one of its salts
-An example is a solution of ammonia (pKa = 9.25) and ammonium chloride.
-If these are mixed in equimolar proportions, the solution has a pH of 9.25.
-The ability of a buffer to maintain constant pH is known as its buffer capacity
-defined as the amount of acid or base that can be added to a given volume of the buffer solution before pH changes to an appreciable degree
A buffer system is most useful at a solution pH
-at or close to its pKa, because there are adequate concentrations of both the conjugate acid and base forms of the buffer to neutralize added acid or base.
-Thus, the most effective buffers (with a large buffer capacity) contain the acid and base in large and equal amounts
Pharmaceutical formulations are often buffered to control pH and thus help to
minimize drug degradation, improve patient comfort and compliance, or allow delivery of a sufficient drug dose.
The pH of body fluids can vary from 8 in pancreatic fluid to 1 in the stomach
-The average pH of blood is 7.4, and of cells is 7.0 to 7.3.
-Although there is great variation in pH between fluids in the body, there is little variation within each system.
-For example, blood pH only varies between 7.35 and 7.45 in a healthy individual.
Proteins are the most important buffers in the body
because their amino and carboxylic acid groups act as proton acceptors or donors as hydrogen ions are added or removed from the environment
The phosphate buffer system is also important in maintaining pH of intracellular fluid
-This buffer system consists of dihydrogen phosphate ions (H2PO4−) as proton donor (acid) and hydrogen phosphate ions (HPO42−) as proton acceptor (base)
-These two ions are in equilibrium with each other as indicated by the equation
Selecting a Buffer System or a Compound to Adjust pH
-Ingredients to buffer or adjust pH must be nontoxic for the intended route of administration!
-Agents for any route of administration should be nonirritating at the needed concentration.
-For oral liquid preparations, buffer compounds should not have a disagreeable odor or taste
-Agents used for parenteral preparations must be in sterile form or must be rendered sterile
Sodium Bicarbonate Injection is often used to
raise the pH of some parenteral preparations
For an easily made buffer in the low- to mid-pH range (3.6-5.6)
For preparations to be buffered between pH 6 and 8
Sorenson’s Phosphate Buffer is a useful system
If a concentrated multipurpose buffer solution is desired in the low- to mid-pH range (2.5-6.5),