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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5320_Библиотеки_им_академика_М_И_Перельмана
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Pharmaceutical Dosage Forms and Drug Delivery
• The compound is nurtured through different stages of clinical trials and commercialization, during
which process it evolves into a drug product.
• The drug product is commercialized, it gains widespread acceptance and use, and the sponsor can
recoup the investment in the compound through exclusive commercialization for the duration of
the patent life.
•
pound then depend on market conditions such as the disease state, other molecules or therapies
available, and patients’ needs.
The R&D efforts post- commercialization of an NCE or NME are targeted at improving the value prop-
osition of the compound to increase patent life. These could include, for example:
• Improving some aspects of the drug product that increase the value proposition, such as higher
bioavailability or reduction in variability in drug absorption. For example, an improvement in the
drug product, such as micronization of the drug, that overcomes the effect of food or gastric pH on
oral absorption.
• Different routes of administration. For example, conversion of a previous IV route of administra-
ability to self- administer the drug in an outpatient setting.
• The combination of drug products with other compounds leads to synergism in therapy. For
example, amoxicillin is often coadministered with clavulanic acid, saxagliptin is coadministered
with metformin, and several antihypertensive drugs are coadministered in a single- dosage unit.
•
• Increasing label claims to include coverage of additional disease states. For example, an oncology
drug approved for a given indication can increase its market by seeking approval for additional
Review Questions
2.1 Which of the following is true for the drug development and regulatory process?
A A drug’s sponsor must submit an IND application before an FIH trial of a drug
B An IND application must precede an NDA submission to the FDA
C An NDA approval must precede a corresponding ANDA submission
D All of the above
E None of the above
2.2 Indicate which of the following statements is TRUE and which is FALSE.
A The FDA can approve new formulations without phase III clinical trials.
B In phase III clinical trials, only a small number of patients are enrolled.
C New drug substances are extracted from plants or animals or synthesized in laboratories.
D The CDER is responsible for approving vaccines.
E The ANDA requires full clinical and nonclinical testing.
F
G The BLA is approved by the CBER, whereas the NDA is approved by the CDER.
2.3
A
B List the different steps involved in the drug development and approval process.
C In which phase of drug development are healthy subjects evaluated?
2.4
A
B What information does the FDA require in an IND application?
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Drug Development
C What are the goals of phase I, II, and III trials?
D Why is the postmarketing surveillance necessary?
2.5 What are the three key components of pharmaceutical development?
A Bioavailability: To ensure the drug has reproducible and clinically desired bioavailability
from a dosage form.
B Stability: To ensure that the drug product is stable at the labeled storage conditions for the
duration of its assigned shelf life.
C Manufacturability: To ensure that the drug product can be manufactured reproducibly and
robustly at a commercial scale.
D
adverse effects.
E All of the above
Match the stage of drug development in the left column with the key deliverables of that stage in
the right column. Write the letter of the row in the left column instead of the corresponding row
in the right column.
Stage of drug development Key deliverables of this stage
1 Preclinical A
of the new drug product in
a wide patient population
(number of subjects usually
in 1000s)
2 Clinical: Phase I B Conversion of a drug
substance to a drug product
with the assurance of
stability, bioavailability, and
manufacturability at scales
needed for the given stage of
product development
3 Clinical: Phase II C
ways to enhance the value of
an existing commercial drug
product, such as by coming up
with a new dosage form, route
of administration, combination
drug product, indication, or
intellectual property
4 Clinical: Phase III D First- in- human (FIH) safety
studies in a limited number of
subjects
5 Pharmaceutical development E
in a larger patient population
(number of subjects usually
in 100s)
Life cycle management F Physicochemical characteriza-
-
cacy studies in animal species
in preparation for the FIH
dosing of a drug candidate
37
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38
Pharmaceutical Dosage Forms and Drug Delivery
2.7 Interspecies dose scaling for small- molecule compounds is generally carried out using which
metric?
A Body weight
B Body surface area
C
D Muscle weight
E Fat tissue weight
2.8
A Phase I
B Phase II
C Phase III
D Phase IV
2.9 Which of the following may not be a typical post- commercialization activity?
A
B
C First phase III clinical trial to support commercialization of an NCE
D Investigation of an approved drug’s ability to treat a new disease indication
FURTHER READINGS
Allen L.V., Popovich N.G., and Ansel H.C. (2005) Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems, 8th ed. New York: Lippincott Williams & Wilkins.
Bashaw E.D. (2004) Drug and dosage form development: Regulatory perspectives. In Ghosh T.K. and Jasti
B.R. (Eds.) Theory and Practice of Contemporary Pharmaceutics, Boca Raton, FL: CRC Press, pp.
www.fda.gov/
Narang A.S., and Desai D.D. (2009) Anticancer drug development: Unique aspects of pharmaceutical
development. In Mahato R.I. and Lu Y. (Eds.) Pharmaceutical Perspectives of Cancer Therapeutics,
New York: AAPS- Springer Publishing Program.
Pandit N.K. (2007) Introduction to the Pharmaceutical Sciences, Philladelphia, PA: Lippincott Williams &
Wilkins.
The Drug Development Process, New York: Marcel
Dekker.
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3
Pharmaceutical Considerations
LEARNING OBJECTIVES
On completion of this chapter, the students should be able to
1. Describe the pH- partition theory as it applies to drug absorption.
2.
3.
4. Describe the pH- partition theory and its limitations.
3.1 Introduction
ation with one or more nonmedical agents (known as pharmaceutical ingredients or excipients) that serve
varied and specialized pharmaceutical functions. Commonly used pharmaceutical ingredients are listed
in Table 3.1. Pharmaceutical ingredients solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve,
Drug absorption depends on its lipid solubility, formulation, and the route of administration. The
proper design and formulation of a dosage form require a thorough understanding of the physical, chemical, and biologic characteristics of the drug substances as well as that of the pharmaceutical ingredients
to be used in fabricating the product. The drug and pharmaceutical ingredients must be compatible with
3.2 Advantages of Pharmaceutical Dosage Forms
A pharmaceutical dosage form is the entity that is administered to patients so that they receive an effective
dose of a drug. Some common examples are tablets, capsules, suppositories, injections, suspensions, and
transdermal patches. Besides providing the mechanism for the safe and convenient delivery of accurate
dosage, pharmaceutical dosage forms are needed for the following additional reasons:
•
(coated tablets).
•
(enteric- coated tablets).
• To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets,
and avored syrup).
• To provide liquid preparations of substances that are either insoluble or unstable in the desired
vehicle (suspensions).
DOI: 10.1201/9781003389378-4
39
D
RT
r
πη
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TABLE 3.1
Pharmaceutical Dosage Forms and Drug Delivery
List of Pharmaceutical Ingredients
Ingredients Denition Examples
Antifungal preservatives Used in liquid and semisolid
formulations to prevent the growth
of fungi
Antimicrobial preservatives Used in liquid and semisolid
formulations to prevent the growth of
microorganisms
Antioxidant Used to prevent oxidation Ascorbic acid, ascorbyl palmitate,
Emulsifying agent Used to promote and maintain
of a liquid in a vehicle in which it is
immiscible
Surfactant Used to reduce surface or interfacial
tension
Plasticizer Used to enhance coat spread over
tablets, beads, and granules
Suspending agent Used to reduce sedimentation rate of
drug particles dispersed throughout a
vehicle in which they are not soluble
Benzoic acid, butylparaben,
ethylparaben, sodium benzoate, and
sodium propionate
Benzalkonium chloride, benzyl alcohol,
cetylpyridinium chloride, phenylethyl
alcohol
Acacia, cetyl alcohol, glyceryl
monostearate, sorbitan monostearate
Polysorbate 80, sodium lauryl sulfate,
sorbitan monopalmitate
Glycerin, diethyl palmitate
Carbopol, hydroxymethyl cellu-
lose, hydroxypropyl cellulose,
methylcellulose, tragacanth
• To provide rate- controlled drug action (various controlled- release tablets, capsules, and
suspensions).
•
• To target the drug at the desired site of action (e.g., nanoparticulate systems, liposomes, etc.).
3.3 Influential Factors in Dosage Form Design
Each drug substance has intrinsic chemical and physical characteristics that must be considered before
the development of its pharmaceutical formulation. These characteristics are the particle size, surface
factors are discussed below, except the particle size and dissolution rate, which will be discussed in the
next chapter.
3.3.1 Molecular Size and Volume
Molecular size and volume have important implications for drug absorption. Tight junctions can block
the passage of even relatively small molecules, whereas gap junctions are looser. Molecules up to 1,200
=
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Pharmaceutical Considerations
41
where DR is the gas constant = 8.313 J K molT
η
r is the solvated radius of diffusing solute.
Since volume (Vr3, the above equation suggests that drug diffusivity is inversely proportional to the molecular volume. Molecular volume is dependent on molecular weight, conformation, and
heteroatom content. Molecules with a compact conformation will have a lower molecular volume and
thus a higher diffusivity. As shown in Figure 3.1, the diffusion and permeability of the endothelial monolayer to molecules decreased with increasing molecular weight.
A drug must diffuse through various biological membranes after administration into the body. In addition, drugs in many controlled- release systems must diffuse through a rate- controlling membrane or
matrix. The ability of a drug to diffuse through membranes is a function of its molecular size and volume.
For drugs with a molecular weight greater than 500, diffusion in many polymeric matrices is very small.
Lipinski devised the so- called Rule of 5, which refers to the drug- like properties of molecules. It states
that poor oral absorption is more likely when the drug molecule has:
•
• A molecular weight greater than 800.
• A log P > 5.
• More than 10H- bond acceptors.
However, this rule is not applicable to the compounds that are substrates for transporters.
FIGURE 3.1 Diffusion (a) and permeability (b) of compounds with different molecular weights across an endothelial
Fo
T
SS
K
=+
()
−
0
Fo
T
ppH
SS
K
=+
−
0
)
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42
3.3.2 Drug Solubility and pH
Pharmaceutical Dosage Forms and Drug Delivery
Therefore, a drug substance must possess some aqueous solubility for systemic absorption and therapeutic response. Enhanced aqueous solubility may be achieved by forming salts or esters, by chemical
complexation, by reducing the drug’s particle size (i.e., micronization), or by creating an amorphous
solid. One of the most important factors in the formulation process is pH, which affects the solubility and
stability of weakly acidic or basic compounds. Changes in pH can lead to ionization or salt formation.
Adjustment in pH is often used to increase the solubility of ionizable drugs because the ionized molecular
species have higher water solubility than their neutral species. According to Equations (3.1) and (3.2),
the total solubility, ST, is the function of intrinsic solubility, S0, and the difference between the molecule’s
pKa and the solution pH. The intrinsic solubility is the solubility of the neutral species. Weak acids can
be solubilized at pHs below their acidic pKa, whereas weak bases can be solubilized at pHs above their
basic pKa. For every pH unit away from the pKa
solubility can be achieved as long as the formulation pH is at least 3 units away from the pKa. Adjusting
solution pH is the simplest and most common method to increase water solubility in injectable products.
raweak acid
raweak base (1 10
110
pH p
a
a
(3.1)
(3.2)
Unlike a weak acid or base, the solubility of a strong acid or base is less affected by pH. The drugs
without ionizable groups are often solubilized by the combination of an aqueous solution and a watersoluble organic solvent/ surfactant. Frequently, a solute is more soluble in a mixture of solvents than
in one solvent alone. This phenomenon is known as cosolvency, and the solvents that in combination
increase the solubility of the solute are called cosolvents. Adding a cosolvent can increase the solubility
of hydrophobic molecules by reducing the dielectric constant
on the energy needed to separate two oppositely charged bodies. Some of the cosolvents commonly
used in pharmaceutical formulations include ethyl alcohol, glycerin, sorbitol, propylene glycol, and polyethylene glycols (PEGs). Polyethylene glycol 300 or 400, propylene glycol, glycerin, dimethylacetamide
(DMA), N- methyl- 2- pyrrolidone (NMP), dimethyl sulfoxide (DMSO), Cremophor, and polysorbate 80
are often used for solubilization of drugs that have no ionizable groups. As shown in Figure 3.2, the solu-
compared with one of these solvents alone. However, the use of cosolvents often leads to the precipitation
of the drug on dilution during the administration of the drug solution into the body, resulting in pain or
tissue damage.
molecule in a noncovalent manner, lower the chemical potential of the molecules in solution. These
noncovalent solubility- enhancing interactions are the basis of the phenomenon that like dissolves like
tain cases, favorable electromagnetic interactions. Solutes dissolve better in solvents of similar polarity.
Therefore, to dissolve a highly polar or ionic compound, one should use a solvent that is highly polar or
has a high dielectric constant. On the contrary, to dissolve a drug that is nonpolar, one should use a solvent
that is relatively nonpolar or has a low dielectric constant.
prodrugs.
A prodrug is a drug that is therapeutically inactive when administered but becomes activated in the
body by chemical or enzymatic processing. Adding polar groups, such as carboxylic acids, ketones,
interaction between the drug molecule and the water molecules. Table 3.2 lists different substituents that
-
ence its effect.
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Pharmaceutical Considerations
43
FIGURE 3.2
(Reproduced from Krause, G.M. and Gross, J.M., J. Am. Pharm. Assoc. Ed., 40, 137, 1951. With permission.)
TABLE 3.2
Water Solubility of Different Substituent Groups
Hydrophobic Substituent Groups
3
2
3)
2
3
2CH
Hydrophilic Substituent Groups
3+
3
3
2
2
Concentration oof drug in wateror polar phase
P
()
()
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3.3.3 Lipophilicity and Partition Coefficient
Pharmaceutical Dosage Forms and Drug Delivery
Partitioning is the ability of a compound to distribute in two immiscible liquids. When a weak acid or
base drug is added to two immiscible liquids, some drug goes to the nonpolar phase, and some drug goes
to the aqueous layer. Because like dissolves like, the nonpolar species migrates (partitions) to the nonpolar
layer, and the polar species migrate to the polar aqueous layer.
acts as a lipophilic barrier to many drugs. Since passive diffusion is the predominant mechanism by
which many drugs are transported, the lipophilic nature of the molecules is important. A drug’s partition
P =
Concentrationofdruginoctanol or nonpolar phase
For an ionizable drug, the following equation is applicable:
Concentrationofdruginoctanol or nonpolar phase
=
−
±Concentr1
aationofdruginwater of polar phase
In this equation, α is equal to the degree of ionization. The concentration in the aqueous phase is
estimated by an analytical assay, and the aqueous in octanol or other organic phases is deduced by
of antibiotics from fermentation broth.
P) is known as log P. Log P is a measure of lipophilicity and is
used widely, since many pharmaceutical and biological events depend on lipophilic characteristics. Often,
the log P of a compound is quoted. Table 3.3 lists the log P values of some representative compounds.
For a given drug:
If log P = 0, there is equal drug distribution in both phases.
If log P > 0, the drug is lipid soluble.
If log P < 0, the drug is water soluble.
In general, the higher the log P
the drug passes through the membrane via passive diffusion. However, there is a parabolic relationship
between log P and drug activity when the percentage of drug absorption is plotted against log P values
(Figure 3.3). The parabolic nature of bioactivity and log P values is due to the fact that drugs with high
log P values, protein binding, low solubility, and binding to extraneous sites cause them to have a lower
bioactivity. The decrease in activity is due to the limitation in solubility beyond a certain log P value. If a
drug is too lipophilic, it will remain in the lipid membrane and not partition out again into the underlying
aqueous environment. On the other hand, very polar compounds with very high log P values are not suf-
3.3.4 Polymorphism
The capacity of a substance to exist in more than one solid state form is known as polymorphism, and
the different crystalline forms are called polymorphs. The process is enantiotropic if the change from
one polymorph to another is reversible. However, the system is monotropic if the transition from a meta-
stable to a stable polymorph is unidirectional. Polymorphic forms may exhibit detectable differences
in some or all of the following properties: melting point, dissolution rate, solubility, and stability. Drug
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Pharmaceutical Considerations
TABLE 3.3
45
Log P Values of Representative Drugs
Drug Log P
Acetylsalicylic acid 1.19
Amiodarone
Benzocaine 1.89
Bromocriptine
Bupivacaine 3.4
Caffeine 0.01
Chlorpromazine 5.3
Cortisone 1.47
Desipramine 4.0
Glutethimide 1.9
Haloperidol 1.53
Hydrocortisone 4.3
Indomethacin 3.1
Lidocaine
Methadone 3.9
Misoprostol 2.9
Ondansetron 3.2
Pergolide 3.8
Phenytoin 2.5
Physostigmine 2.2
Prednisone
Sulfadimethoxine
Sulfadiazine 0.12
Sulfathiazole 0.35
Tetracaine
Thiopentone 2.8
Xamoterol 0.5
2.7
substances can be amorphous (i.e., without regular molecular lattice arrangements), crystalline (which
are more oriented or aligned), polymorphic, anhydrous, or solvated. An important form in the formulation
is the crystal or amorphous form of the drug substance. Many drug substances can exist in more than one
crystalline form, with different lattice arrangements. This property is termed polymorphism. Drugs may
undergo a change from one metastable polymorphic form to a more stable polymorphic form. Various
drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). Polymorphic
forms usually exhibit different physicochemical properties, including melting point and solubility, which
can affect the dissolution rate and thus the extent of their absorption. The amorphous form of a compound
is always more soluble than the corresponding crystal form. Changes in crystal characteristics can
example, insulin exhibits a differing degree of activity depending on its state. The amorphous form of
insulin is rapidly absorbed and has a short duration of action. In contrast, the large crystalline product is
more slowly absorbed and has a longer duration of action.
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