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FIGURE 3.3 Relationship between drug absorption and log P. A decrease in the drug absorption beyond a certain log P
value is probably due to its binding to plasma proteins, reduction in free drug levels, or its binding to extraneous sites.
Pharmaceutical Dosage Forms and Drug Delivery
FIGURE 3.4 Hydrolysis of aspirin. Acetylsalicylic acid (aspirin) is hydrolyzed to salicylic acid and acetic acid.
3.3.5 Stability
The chemical and physical stability of a drug substance alone and when combined with formulation
components is critical to preparing a successful pharmaceutical product. Drugs containing one of the
following functional groups are liable to undergo hydrolytic degradation: ester, amide, lactose, lactam,
imide, or carbamate. Drugs that contain ester linkages include acetylsalicylic acid, physostigmine,
methyldopa, tetracaine, and procaine. For example, the hydrolysis of acetylsalicylic acid (commercially
known as aspirin) is represented in Figure 3.4. Aspirin is hydrolyzed to salicylic acid and acetic acid.
Nitrazepam, chlordiazepoxide, penicillins, and cephalosporins are also susceptible to hydrolysis.
Several methods are available to stabilize drug solutions that are susceptible to hydrolysis. For example,
protection against moisture in formulation, processing, and packaging may prevent decomposition.
Suspending drugs in nonaqueous solvents such as alcohol, glycerin, or propylene glycol may also reduce
hydrolysis.
After hydrolysis, oxidation is the next most common pathway for drug degradation. Drugs that undergo
oxidative degradation include morphine, dopamine, adrenaline, steroids, antibiotics, and vitamins.
of the oxygen from a container, antioxidants are often added to formulations to prevent oxidation.
HA HA↔+
+−
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Pharmaceutical Considerations
47
Excipients used to prepare a solid dosage can also affect the drug’s stability, possibly by increasing the
moisture content of the preparation. Excipients, such as starch and povidone, have very high- water content. Povidone contains about 28% equilibrium moisture at 75% relative humidity. However, the effect of
this high moisture content on the stability of a drug will depend on how strongly it is bound and whether
the moisture can come in contact with the drug. The effects of tablet excipients on drug decomposition
are widely reported in the literature. For example, magnesium trisilicate is known to cause increased
hydrolysis of aspirin in the tablet because of its high moisture content.
3.3.6 pKa/ Dissociation Constants
Many drug substances are either weak acids or weak bases and thus undergo a phenomenon known as dissociation when dissolved in a liquid medium. Suppose this dissociation involves a separation of charges.
In that case, there is a change in the electrical charge distribution on the species and a separation into
two or more charged particles, or ionization. The extent of ionization of a drug has an important effect
dependent on the pH of the medium containing the drug. Table 3.4 lists the normal pHs of some organs
in vivo. In a for-
mulation, the vehicle is often adjusted to a certain pH to obtain a certain level of ionization of the drug for
solubility and stability. The extent of ionization of a drug has a strong effect on its extent of absorption,
distribution, and elimination.
Acids donate protons to a system at a pH greater than 7 and bases accept protons when added to an
acidic system (i.e., at pH < 7). Many drugs are weak acids or bases and therefore exist in both unionized
solution is given by the dissociation constant (Ka) of the drug. Such dissociation constants are conveniently expressed in terms of pKa values for both acidic and basic drugs. For a weak acidic drug, HA (e.g.,
aspirin and phenylbutazone), the equilibrium is presented by:
According to the Bronsted– Lowry theory of acids and bases, an acid is a substance that will donate a
TABLE 3.4
Nominal pH Values of Some Body Fluids and Sites
Sites Nominal pH
Aqueous humor 7.21
Blood 7.40
7.35
Duodenum 7.35
Ileum 8.00
Colon
7.4
Saliva
Semen 7.2
Stomach
Urine
Vaginal secretions, pre- menopause 4.5
Vaginal secretions, postmenopause 7.0
K K
12
]↔
+−
Or
HA
K
[][]
[]
+−
lo
a
K =+
][
−
][
+−
−=−−
][
+
][
+−
a
K
+
[]
[]
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48
Pharmaceutical Dosage Forms and Drug Delivery
proton and a base is a substance that will accept a proton. Based on this theory, the conjugate base A may
accept a proton and revert to the free acid. Therefore, the dissociation constant for this reaction is:
[HA] [H ][A
1
K
==
a
K
HA
2
Taking logarithms of both sides:
glog Hlog Alog HA
The signs in this equation may be reversed to give the following equation:
loglog Hlog Alog HA
pH logHA
=
p
K
a
−
A
This is a general equation applicable to any weakly acidic drugs.
+ = BH
+
∴ pKa = pH + log[BH+ ]/ [B] for a weakly basic drug.
TABLE 3.5
pKa Values of Typical Acidic and Basic Drugs
Drugs pK
Acidic drugs
Acetylsalicylic acid 3.5
Barbital 7.9
Phenobarbital 7.4
Penicillin G 2.8
Phenytoin 8.3
Theophylline
Tolbutamide 5.3
Basic Drugs
Amphetamine 9.8
Atropine 9.7
4.2, 8.8
Codeine 7.9
Morphine 7.9
Procaine 9.0
Verapamil 8.8
Source: Martindale, W. and Reynolds, J.E.F.
(1993) Martindale: The Extra
Pharmacopeia, 30th ed., London, UK: The
Pharmaceutical Press.
a
p
[]
lo
i
C
15..
C
i
1
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Pharmaceutical Considerations
49
These equations are known as Henderson– Hasselbalch equations. This equation describes the derivation of pH as a measure of acidity (using pKa) in biologic and chemical systems. The equation is
reactions. Bracketed quantities such as [Base] and [Acid] denote the molar concentration of the quantity enclosed. Based on these equations, it is apparent that the pKa equals the pH when the concentration of the ionized and nonionized species is equal (i.e., log1 = 0). It is therefore important to realize
that a compound is only 50% ionized when the pKa is equal to the pH. Ionization constants are usually
expressed in terms of pKa values for both acidic and basic drugs. The strength of acid is inversely
related to the magnitude of its pKa. The lower is the pKa, the stronger is the acid. Conversely, the
strength of a base is directly related to the magnitude of its pKa. The pKa of a strong base is high. The
pKa values of a series of drugs are listed in Table 3.5. Acidic drugs are completely unionized at pHs
up to 2 units below their pKa and are completely ionized at pHs greater than 2 units above their pKa.
Conversely, basic drugs are completely ionized at pH up to 2 units below their pKa and are completely
unionized when the pH is greater than 2 units above their pKa. Both types of drugs are exactly 50%
ionized at their pKa values. Some drugs can donate or accept more than one proton, and so, they may
have several pKa values.
For either weak acid or base, the ionized species, BH+ and A, have very low solubility and are virtually
of the uncharged drugs will depend on the physicochemical properties of the drug.
2) groups. The pKa values of ioniz
they are isolated in solution. Therefore, these compounds are often referred to as amphoteric in nature.
The pH of a solution determines the net charge on the molecule and ultimately the solubility. Since water
is a polar solvent and ionic species are more water soluble than the nonionic ones, a conjugate acid (BH+ )
and a conjugate base (A) are generally more water soluble than the corresponding free base (B) or free
acid (HA).
EXAMPLE 3.1
The pKa value of aspirin, which is a weak acid, is about 3.5. What are the ratios of unionized and
ionized forms of this drug in the stomach (pH 2) and in the plasma (pH 7.4)? Why does aspirin
often cause gastric bleeding?
Answer:
u
gppH 3.5
C
pH log
K =+
a
K=−=− =20
a
[HA]
−
A
where Cu is the concentration of unionized drug and Ci is the concentration of ionized drug.
u
antilog1.5 31.62:
C
i
C
..
.:11
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50
Pharmaceutical Dosage Forms and Drug Delivery
In the plasma,
u
C
C
logppH 3.5
K
=−=−=−
C
u
a
i
=−=×
antilog ()1.259 10
39
74 39
−
4
Therefore, most of the administered aspirin remains unionized in the stomach, and thus, it is
rapidly taken up by the stomach, leading to gastric bleeding.
3.3.7 Degree of Ionization and pH- Partition Theory
For a drug to cross a membrane barrier, it must normally be lipid soluble to get into the biological
-
erentially permeable to the latter species. Thus, an increase in the fraction of a drug that is unionized
will increase the rate of drug transport across the lipid membrane. This phenomenon can be explained
by the pH- partition theory, which states that drugs are absorbed from biological membranes by passive
diffusion, depending on the fraction of the unionized form of the drug at the pH of that biological membrane. Based on the Henderson– Hasselbalch equation, the degree of ionization of a drug will depend on
both its pKa value and the solution’s pH.
The gastrointestinal (GI) tract acts as a lipophilic barrier, and thus, ionized drugs, which will be more
hydrophilic, will have minimal membrane transport compared with the unionized form of the drug. The
pI of the molecule is
-
dominate at a pH lower than the pKa, and the conjugate base form will be present at a pH higher than the pKa.
3.3.7.1 Limitations of pH- Partition Theory
Although the pH- partition theory is useful, it often does not hold true. For example, most weak acids are
well absorbed from the small intestine, which is contrary to the prediction of the pH- partition hypothesis.
Similarly, quaternary ammonium compounds are ionized at all pHs but are readily absorbed from the GI
tract. These discrepancies arise because pH- partition theory does not take into account the following:
• The small intestine has a large epithelial surface area for drug absorption to take place. This large
epithelial area results from mucosa, villi, and microvilli (Figure 3.5). The large mucosal surface
area compensates for ionization effects.
FIGURE 3.5 Drug absorption across small intestine. The small intestine has a large epithelial surface area due to mucosa,
villi, and microvilli. This large surface area compensates the effect of drug ionization on its absorption across the small intestine and invalidates pH- partition theory of drug absorption.
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Pharmaceutical Considerations
51
• Drugs have a relatively long residence time in the small intestine, which also compensates for ionization effects.
• Charged drugs, such as quaternary ammonium compounds and tetracyclines, may interact with
oppositely charged organic ions, resulting in a neutral species, which is absorbable.
• Some drugs are absorbed via active pathways.
• Many more.
Review Questions
3.1 Which of the following statements is FALSE?
A
B Absorption of a weak electrolyte drug does not depend on the extent to which it exists in its
unionized form at the absorption site.
C Amorphous forms of drug have faster dissolution rates than crystalline forms.
D All of the above.
3.2 The pH of a buffer system can be calculated with:
A
B
C
D Yang’s equation
E All of the above
3.3 Indicate which of the following statements are TRUE and which are FALSE:
A
of pharmaceutical suspensions.
B The passive diffusion rate of hydrophobic drugs across biological membranes is higher than
that of hydrophilic compounds.
C -
Ka values.
D Drug solubility can be enhanced by salt formation, use of cosolvent, complex formation, and
micronization.
3.4
A What is the difference between drug adsorption and drug absorption?
B Describe the pH- partition theory and its limitation in relation to drug absorption across the
GI tract.
C Compare any two compounds differing in the following characteristics and suggest which one
i A water- insoluble compound versus a highly soluble compound.
ii A low molecular weight compound versus a high molecular weight compound.
3.5
A Why do we need to formulate a drug into a pharmaceutical dosage form?
B P.
C
A Enlist eight intrinsic characteristics of a drug substance that must be considered before the
development of its pharmaceutical formulation.
B Enlist two limitations of pH- partition theory.
3.7 Ka value of aspirin, which is a weak acid, is about 3.5. What are
the ratios of ionized and unionized forms of the drug in the stomach (pH 2) and in the plasma (pH
7.4)? Why does aspirin often cause gastric bleeding?
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52
Pharmaceutical Dosage Forms and Drug Delivery
3.8 -
chemical properties be improved to increase drug absorption?
3.9 The pKa
3.10 Calculate the percentage of cocaine existing as the free base in a solution of cocaine hydro-
chloride at pH 4.5 and pH 8.0. The pKa
3.11 For a weak acid with a pKa
FURTHER READINGS
Allen L.V., Popovich N.G., and Ansel H.C. (Eds.) (2005) Ansel’s Pharmaceutical Dosage Forms and Drug
Delivery Systems, 8th ed., New York: Lippincott Williams & Wilkins.
Aulton M.E. (Ed.) (1988) Pharmaceutics: The Science of Dosage Form Design, New York: Churchill
Livingstone.
Banker G.S. and Rhodes C.T. (Eds.) (2002) Modern Pharmaceutics, 4th ed., New York: Marcel Dekker.
Block L.H. and Collins C.C. (2001) Biopharmaceutics and drug delivery systems. In Shargel L., Mutnick
A.H., Souney P.H., and Swanson L.N. (Eds.) Comprehensive Pharmacy Review, New York: Lippincott
Block L.H. and Yu A.B.C. (2001) Pharmaceutical principles and drug dosage forms. In Shargel L., Mutnick
A.H., Souney P.H., and Swanson L.N. (Eds.) Comprehensive Pharmacy Review, New York: Lippincott
Cooper and Gunn’s Tutorial Pharmacy. New Delhi, India: CBS Publishers & Distributors.
Physicochemical Principles of Pharmacy, 4th ed., London:
Pharmaceutical Press.
Gennaro A. (Ed.) (2000) Reminton’s The Science and Practice of Pharmacy, 20th ed., Easton, PA: Lippincott,
Williams and Wilkins.
Hillery A.M. . (2001) Advanced drug delivery and targeting: An introduction. In Hillery A.M., Lloyd A.W.,
and Swarbrick J. (Eds.), Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists,
Hogben C.A.M., Tocco D.J., Brodie B.B. and Schanker L.S. (1959) On the mechanism of intestinal absorption
of drugs. J Pharmacol Exp Ther 125
Mahato R.I. (2005) Dosage forms and drug delivery systems, In Gourley D.R. (Ed.) APhA’s Complete Review
for Pharmacy
Shore P.A., Brodie B.B. and Hogben C.A.M. (1957) The gastric secretion of drugs. A pH partition hypothesis.
J Pharmacol Exp Ther 119
Martin’s Physical Pharmacy and Pharmaceutical Sciences, 5th ed., New York: Lippincott
Williams & Wilkins.
Strickley R.G. (2004) Solubilizing excipients in oral and injectable formulations. Pharm Res 21
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4
Biopharmaceutical Considerations
On completion of this chapter, the students should be able to understand
1. Fick’s laws of diffusion and their application.
2.
3. The concepts of steady state and sink conditions.
4. The interrelationship among diffusion, dissolution, and absorption.
5. Pore diffusion.
4.1 Introduction
To achieve an optimal drug response from a dosage form, a drug should be delivered to its site of action at
a concentration that minimizes its side effects and maximizes its therapeutic effects. The drug concentration at its target site depends on the dose of the drug administered and the rate and extent of its absorption,
distribution, metabolism, and elimination (ADME/ pharmacokinetics). For a drug molecule to exert its
-
logical membrane barriers, penetrate in adequate concentration to the sites of action (distribution), escape
to cause the desired alteration of cellular function (pharmacodynamics).
The biological effect of a drug depends on three components:
LEARNING OBJECTIVES
1. Biopharmaceutical factors
a. Dose and dosing frequency
b. Route of administration
c. Drug release from the delivery system
2. Pharmacokinetic factors (what the body does to the drug)
a. Absorption
b. Distribution
c. Metabolism
d. Elimination
3. Pharmacodynamic factors (what the drug does to the body)
a.
b.
All these factors must be taken into consideration when making decisions on dosage form. For example,
a high- dose drug may not be a suitable candidate for an oral sustained- release dosage form due to tablet
DOI: 10.1201/9781003389378-5
53
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54
Pharmaceutical Dosage Forms and Drug Delivery
size restrictions. Similarly, a drug with a long plasma elimination half- life and low frequency of dosing,
such as once a day, would not be considered a good candidate for a sustained- release oral dosage form.
Physicochemical properties of the drug K
), pKa value,
o/ w
diffusion rate, and intrinsic dissolution rate, primarily determine the biopharmaceutical aspects of dosage
form design. In this chapter, we will discuss these aspects, with an emphasis on oral solid dosage forms,
such as tablets, since these are the most commonly used drug delivery systems. We will discuss drug
release from the dosage form (diffusion and dissolution) and absorption across the biological membranes.
4.2 Diffusion
4.2.1 Drug Transport across a Polymeric Barrier
Drug transport through a polymeric or biological barrier may occur by simple molecular permeation
known as molecular diffusion or by movement through pores and channels known as pore diffusion
(Figure 4.1).
4.2.1.1 Molecular Diffusion
The transport of a drug molecule through a polymeric membrane that involves the dissolution of the drug
in the matrix of the membrane, followed by its diffusive transport to the surrounding bulk liquid, is an
example of simple molecular diffusion (Figure 4.1a). The release rate of the drug by diffusive transport
through the polymeric matrix depends on the size and shape of the diffusing molecules, drug solubility
liquid, and the degree of stirring of the bulk liquid at the interface.
4.2.1.2 Pore Diffusion
(Figure 4.1b). In pore diffusion, the release rate of dissolved drug is affected by the porosity of the membrane, pore structure, surface functional groups (e.g., hydrophobic or hydrophilic), tortuosity, and length
of pores.
The molecules may also pass through the tortuous gaps between the overlapping strands of the polymer
(Figure 4.1c). In both molecular and pore diffusion cases, the drug must be available in a dissolved state.
This would be the case if the drug product is formulated as a drug solution in the polymer. If a formulation
consists of a suspension of drug particles in the polymer, another kinetic step of dissolving the drug into
the polymer or the solvent is involved. The rate of dissolution of a drug would depend on the degree of
-
tation in the system. Drug dissolution from its particles will be discussed in the next section.
FIGURE 4.1
J
M
tS
=×
d
J
C
x
d
d
d
d
d
d
M
t
C
x
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Biopharmaceutical Considerations
4.2.1.3 Matrix Erosion
55
In addition to molecular diffusion and pore diffusion, erosion of the polymeric matrix may often be
involved in the case of biodegradable polymers. The kinetic contribution of matrix erosion to the drug
release rate would depend on the relative rates of drug dissolution, polymer erosion, drug dissolution in
the polymer, drug dissolution in the bulk solvent, molecular diffusion, and pore diffusion.
4.2.2 Principles of Diffusion
Passive diffusion leads to changes in concentration in a region over a period of time and space. Fick’s
laws of diffusion quantitate the amount of solute diffusing per unit of time and area as a function of a
concentration gradient of solute in the direction of diffusion. These laws also relate the changes in solute
concentration in a given region over time to the change in the concentration gradient of the solute in that
region.
4.2.2.1 Fick’s First Law
Fick’s law of diffusion postulates that the diffusing molecules go from regions of high concentration to
regions of low concentration. The rate of diffusion, the amount of material (M
cross- section (S) of a barrier in unit time (tJ). Flux is related to the concentration
gradient (dC = C1C2) between the donor region at a higher concentration (C1) and the receiving region
at a lower concentration (C2) per unit distance (x) by the following expression:
d
1
(4.1)
where J2 s), S is the cross- section of the barrier, in cm2, dM/ dt = rate of diffusion, in
g/ s (MtC/ dx:
D
=− ×
(4.2)
where D2/ s, C is the concentration, in g/ cm3 or g/ mL, x is
the distance perpendicular to the surface of the barrier, in cm
Thus,
DS
=− ××
D, or diffusivity,
often called, appears to be a proportionality constant, it does not remain constant. It is affected by changes
in concentration, temperature, pressure, solvent properties, molecular weight, and the chemical nature of
4.2.2.2 Fick’s Second Law
Fick’s second law predicts changes in solute concentration over time caused by diffusion. It states that the
change in concentration with time in a particular region is proportional to the change in the concentration
gradient at that region in the system. The concentration of solute or diffusant, C, in the volume of the
region, x
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