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2.2 Utilization of Pharmacokinetic Data to Determine Bioavailability…
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Fig. 2.3 Exemplary pharmacokinetic parameters derived from plotting drug concentration
versus time
17
to the drug. The concentration-time prole before the C
is a function of how
max
quickly the drug enters the systemic circulation (i.e., the absorption rate), whereas
the concentration-time prole after the C
is a function of how quickly the drug is
max
eliminated from the central compartment.
2.2 Utilization ofPharmacokinetic Data toDetermine
Bioavailability andBioequivalence
Bioavailability studies are designed to quantify both the rate and extent of drug
absorption. These are dened using the plasma C
Absolute bioavailability is determined by comparing the plasma concentration-time
prole of the drug administered via an extravascular route compared to intravascular delivery. In this case, the drug administered via the intravascular route is assumed
to be 100% bioavailable. Mathematically, absolute bioavailability is described
according to the following equation:
AUC
extravascularIV
AUC
IV extravascular
D
where F
F
abs
refers to the absolute bioavailability of the extravascular dosage form
abs
(e.g., oral dosage form); AUC refers to the area under the curve of intravascular (IV)
, T
max
D
, and AUC of the drug.
max
100
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2 Overview of Biopharmaceutics and Regulatory Concepts Relevant to Drug Product…
and extravascular dosage forms, respectively; and D refers to the dose of the intravascular and extravascular dosage forms, respectively. Factors that may reduce the
bioavailability of the drug prior to entering the systemic circulation include insufcient or incomplete release of the drug from the drug product, poor absorption,
drug degradation in the physiological environment, or metabolism of the drug.
Relative bioavailability refers to the comparison of the exposure following
administration of two different extravascular dosage forms. For example, a relative
bioavailability study may compare a drug administered via the intramuscular versus
subcutaneous administration, or compare two different oral formulations. From a
regulatory perspective, relative bioavailability studies are important for establishing
bioequivalence of drug products. Bioequivalence is dened by the FDA as the
absence of a signicant difference in the rate and extent to which the active ingredient/moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes
available at the site of action when administered at the same molar dose under similar conditions in an appropriately designed study. Establishing bioequivalence is
important for bridging changes made in the drug product during clinical trials, as
well as in the approval of generic drug products. The FDA describes a generic drug
as a medication created to be the same as an already marketed brand-name drug in
dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. These similarities help to demonstrate bioequivalence,
which means that a generic medicine works in the same way and provides the same
clinical benet as the brand-name medicine. Relative bioavailability can be mathematically dened using the following equation:
AUC
F
rel
AUC
D
AB
100
D
BA
where A and B refer to the drug products being compared.
2.3 Biopharmaceutics Classication System
The Biopharmaceutics Classication System (BCS) is used to characterize the oral
absorption of a drug based on its solubility and permeability. The reader is referred
to Chap. 3, Sect. 3.2.6 of this textbook for a complete description of the BCS system
as relevant to dosage form design and development.
2.4 Overview oftheRegulatory Pathways forDrug
Product Approval
The regulatory process for drug product approval is a complex, rigorous, and lengthy
process. In the United States, the Center for Drug Evaluation and Research (CDER)
branch of the FDA regulates the approval, manufacturing, and marketing of
2.4 Overview oftheRegulatory Pathways forDrug Product Approval
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19
over-the-counter and prescription drugs, including biological therapeutics and
generic drugs, whereas the Center for Biologics Evaluation and Research (CBER)
regulates FDA-licensed allergenic, cellular and gene therapy, hematologic, and vaccine products. Development of a new drug product can be divided into preclinical
(i.e., before human use) and clinical stages (i.e., human use in patients and volunteers, depending on phase of study). Prior to initiating clinical trials, drug manufacturers must rst submit an Investigational New Drug (IND) application. Approval
of an IND application by the FDA allows the drug to be distributed across state
lines, which is generally necessary to conduct clinical trials. At this stage of development, the FDA is primarily concerned about the safety of the drug product in
humans. The FDA denes the drug product as the nished dosage form that con-
tains a drug substance, generally, but not necessarily in association with other active
or inactive ingredients and drug (i.e., drug substance, active ingredient) means the
specic chemical entity in the drug product that is intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease. Likewise, the FDA denes
dosage form as the physical form in which a drug is produced and dispensed, such
as a table, a capsule, or an injectable. As such, the IND application contains information related to three broad areas:
1. Animal pharmacology and toxicology studies, which are designed to de-risk the
potential for toxicity in humans.
2. Chemistry, Manufacturing, and Controls (CMC) for the drug product. This
includes the composition and specications for the drug product, site of manufacture, drug product stability, and quality control measures in place for the
manufacturing.
3. Clinical protocols and investigator information, which includes the location and
design of the clinical studies and qualications of the clinical investigators.
For new drug products, clinical trials are generally conducted in three phases, which
if successful, culminates in the ling of a New Drug Application (NDA) with the
FDA.Phase I clinical trials are conducted in a small number of healthy participants
(e.g., 20–100). They are designed to determine safety and dosage in humans.
Participants are generally exposed to single or multiple doses of the drug product at
varying levels. The drug concentrations in the body are measured, and the tolerability or presence of side effects is observed. Phase II clinical trials utilize several
hundred participants with the disease or condition that the drug product is designed
to treat. These trials are designed to gather additional safety data and to rene the
protocol and research methods that will be used in future clinical studies. It is
important to note the number of participants in Phase II trials is generally too low to
statistically demonstrate efcacy. Phase III clinical trials are typically much larger,
can consist of several hundred to several thousand participants with the disease or
condition, and are typically conducted across multiple different clinical sites. Their
purpose is to demonstrate whether the drug product denitively offers a treatment
benet in a specic patient population and to provide additional safety data. The
data gathered through the preclinical animal studies and the human clinical trials of
the Investigational New Drug, along with the information regarding the ingredients
2 Overview of Biopharmaceutics and Regulatory Concepts Relevant to Drug Product…
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20
of the drug product and how the drug product is manufactured, processed, and packaged, become part of the NDA. The NDA is the vehicle by which the drug sponsor
formally proposes that the FDA approve a new drug product for sale and marketing
in the United States. Following approval, the FDA typically requires a Phase IV
clinical trial, which utilizes several thousand participants for continued evaluation
of safety and efcacy of the drug product. The FDA-approved label is the ofcial
description of an approved drug product that includes the following:
• Indication (i.e., what the drug is used for)
• Who should take it
• Adverse events (i.e., side effects)
• Instructions for uses in pregnancy, children, and other populations
• Safety information for the patient
As compared to a new molecular entity, which the FDA denes as an active
ingredient that contains no active moiety that has been previously approved by the
Agency in an application or has been previously marketed as a drug in the United
States, the FDA describes a generic drug as the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use. Generic
drug products are approved by the FDA through the abbreviated new drug applica-
tion (ANDA) pathway. In this pathway, bioequivalence studies are used in place of
the efcacy and bioavailability studies required in the NDA pathway (Table 2.1).
This substantially shortens the development timeline of generic versus novel drug
products. All approved innovator and generic drug products are listed in the FDA’s
Approved Drug Products with Therapeutic Equivalence Evaluations (also known as
the Orange Book). As noted by the FDA, the Orange Book serves to identify drug
products approved on the basis of safety and effectiveness by the FDA and related
patent and exclusivity information.
Bioequivalence can be established through appropriately designed pharmacokinetic studies. These studies are typically conducted using a cross-over design, in
which the same subject receives both the reference and test product with an
Table 2.1 Example generic drug approval requirements—new drug application versus abbreviated
new drug application
NDA (new drug application)
Labeling Labeling
Pharmacology/toxicology Pharmacology/toxicology
Chemistry, manufacturing, and controls
(CMC)
Microbiology Microbiology
Inspection/testing Inspection/testing
Preclinical (animal) studies Bioequivalence studies
Clinical (human) safety and efcacy
studies
Bioavailability studies
ANDA (abbreviated new drug application)—
generic drugs
Chemistry, manufacturing, and controls (CMC)
Further Reading
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appropriate washout period to minimize variability. AUC, C
max,
and T
are deter-
max
mined for the test (e.g., generic) and reference (e.g., innovator) products. In certain
cases, invivo bioequivalence studies may be exempted if an assumption of equivalence in invivo performance can be justied by satisfactory invitro data. The FDA
provides “Product-Specic Guidances for Generic Drug Development,” which
details the agency’s expectations on how to develop generic drug products therapeutically equivalent to specic reference listed drugs.
Lastly, the FDA denes biological products as a wide range of products including vaccines, blood and blood components, allergenics, somatic cells, gene therapy,
tissues, and recombinant therapeutic proteins, and they can be composed of sugars,
proteins, or nucleic acids or complex combinations of these substances. Biological
products are approved for marketing by a Biologic License Application (BLA),
which requires the company that manufactures a biologic for sale to hold a license
for the product (see Chap. 15 for a more in-depth discussion of biological products).
Further Reading
Suggested readings for the student include the following texts:
Shargel L, Yu AC, Shargel L, Yu AC.In: Shargel L, Yu ABC, editors. Applied biopharmaceutics
& pharmacokinetics, 7e. McGraw Hill; 2016. https://accesspharmacy.mhmedical.com/content.
aspx?bookid=1592§ionid=100668516.
Chapter 3
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Preformulation inDrug Product Design
Abstract This chapter provides an overview of the factors that are considered in
dosage form design, including physicochemical properties of drugs, drug solubility
and dissolution, drug bioavailability, membrane permeability, and solid-state characteristics. Commonly performed preformulation studies including dissolution testing, x-ray diffraction, thermogravimetric analysis, differential scanning calorimetry,
particle size analysis, and drug degradation testing, are discussed.
Keywords Preformulation studies · Physicochemical properties · Dosage-form
design · Bioavailability · Biopharmaceutics classication system · Solid-state
characterization · Drug stability
Learning Objectives
1. Describe the factors that are considered in dosage form design.
2. Describe the physical and chemical properties of drugs that are characterized
during preformulation studies.
3. Explain the importance of solubility to the therapeutic effect of a drug.
4. Explain the relationship between drug ionization and drug bioavailability.
5. Describe what factors affect the dissolution rate of a drug.
6. Describe the importance of the partition coefcient for the distribution of a drug
in the body.
7. Describe the factors that affect the membrane permeability of a drug.
8. Compare and contrast drugs in BCS classes 1, 2, 3, and 4.
9. Compare and contrast crystalline and amorphous forms of solids.
10. Explain the importance of determining if a drug displays polymorphism.
11. Describe different analytical methods used to identify amorphous and crystal-
line morphologies.
12. Explain the importance of melting point in pharmaceutical product development.
13. Explain the concept of particle size distribution.
14. Explain the relationship between particle size and dissolution.
15. Describe the different methods of particle size reduction.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_3
23
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3 Preformulation inDrug Product Design
16. Describe the common mechanisms of drug degradation and how they are
prevented.
17. Explain how hygroscopicity can affect a drug product.
18. Describe the rationale for utilizing prodrugs.
19. Explain a solid dispersion as applied to drug delivery.
20. Describe the spray-drying process and hot-melt extrusion for producing amor-
phous solid dispersions of pharmaceutical compositions.
21. Describe hydroxypropyl methylcellulose acetate succinate as used as a polymer
carrier in amorphous solid dispersions.
Key Concepts
Students should know and be able to describe each of the following concepts as they
review this chapter:
1. Amorphous and amorphous solid dispersions
2. Apparent partition coefcient
3. Arrhenius Equation
4. Bioavailability
5. Biopharmaceutics Classication System
6. Bulk density
7. Chemical stability
8. Crystalline
9. Differential scanning calorimetry
10. Diffusion
11. Dissociation constant
12. Dissolution
13. Donor and receptor compartments
14. Dynamic vapor sorption
15. Enantiomer
16. Epimerization
17. Eutectic
18. Excipients
19. Extrinsic property
20. Fick’s rst law
21. Gibbs free energy
22. Glass transition temperature
23. High performance liquid chromatography
24. Hydrolysis
25. Hygroscopicity
26. Intrinsic property
27. Ionization
28. Lipophilic/hydrophilic
29. Median diameter
30. Melting point
31. Membrane permeability
32. Microbiological stability
3.1 Introduction—Importance ofPreformulation Studies inDosage Form Design
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33. Noyes-Whitney equation
34. Oxidation
35. Partition coefcient
36. Phase transitions
37. Photolysis
38. Physical stability
39. Physicochemical properties
40. pK
a
41. Polymer
42. Polymorph
43. Preformulation studies
44. Prodrug
45. Relative humidity
46. Saturated solution
47. Solubility
48. Solvate/pseudopolymorph
49. Stereoisomer
50. Supersaturated solution
51. Tapped density
52. Thermogravimetric analysis
53. Volume-weighted distribution
54. X-ray diffraction
55. Zwitterion
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3.1 Introduction—Importance ofPreformulation Studies
inDosage Form Design
The study of pharmaceutics is centered on the development and manufacturing of
dosage forms for the acceptable delivery of therapeutic agents. Dosage form design
is based upon many factors including but not limited to:
(a) Therapeutic indication and the target tissue for the drug.
(b) Physiology and pathophysiology of the intended patient populations.
(c) Bioavailability and pharmacokinetics of the drug.
(d) Stability and physicochemical properties of the drug.
(e) Anticipated adverse drug effects.
The decisions made about the design of a particular dosage form are guided by
the information obtained about the drug through preformulation studies, which refer
to characterization studies on and determination of the physical and chemical properties (i.e., physicochemical properties) of a drug (i.e., drug substance, active pharmaceutical ingredient). Preformulation studies are performed prior to designing a
dosage form and help guide the pharmaceutical scientist with their scientic basis
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for formulation development. The physicochemical properties of the drug substance
include properties such as:
(a) Solubility.
(b) Dissociation constant.
(c) Partition coefcient.
(d) Crystalline state.
(e) Melting point.
(f) Stability.
These physicochemical properties can affect the therapeutic efcacy of the drug.
Therefore, to achieve the desired therapeutic effect, it can be necessary to overcome
the limitations of a drug through various formulation and processing techniques
and/or inclusion of specic functional excipients. Excipients are dened by the
FDA as any ingredient other than the drug substance contained in the dosage form
and are typically presumed to exert no therapeutic effect. Characterization of the
drug in combination with excipients is often performed as a part of preformulation
studies.
By determining the physicochemical characteristics of a drug, the pharmacist/
formulation scientist can better understand the most suitable approaches to develop
the drug into a pharmaceutical dosage form, such as: which excipients are needed,
which excipients will be compatible with the drug, and which dosage form is best
utilized. Physicochemical characterization of the drug can also allow for the approximation of drug absorption.
3 Preformulation inDrug Product Design
3.2 Preformulation Studies—Factors Affecting
Drug Bioavailability
Bioavailability is dened by the FDA as the rate and extent to which the active drug
ingredient is absorbed from a drug product and becomes available at the site of drug
action. Bioavailability can be affected by drug properties such as solubility, ionization, dissolution rate, and lipophilicity, but this is inuenced by the specic properties of the drug.
3.2.1 Solubility
Solubility is dened as the concentration of solute (e.g., drug in this context) that
will dissolve to form a saturated solution at a given temperature and pressure. A
saturated solution is dened as a solution in which a thermodynamic equilibrium
exists between the dissolved solute and the solid solute phase. Under certain conditions, it is also possible to form a supersaturated solution, in which the solution
contains a greater amount of solute than it contains at its equilibrium solubility.
3.2 Preformulation Studies—Factors Affecting Drug Bioavailability
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Solubility is an intrinsic property, meaning that its value is inherent to the drug and
is dependent on the chemical composition and crystalline structure of the drug. The
solubility of a drug in a given solvent depends on the chemical and physical properties of both the drug and the solvent. In general, the rules of solubility follow “like
dissolves like.” For aqueous solvents, the polarity of a solute as well as its ability to
form hydrogen bonds can be key factors affecting the drug’s extent of solubility.
Solubility can be enhanced in a number of ways, for example, by modifying the
drug into a salt or ester form, complexing the drug with an excipient (e.g., a cyclodextrin), or utilizing a co-solvent (e.g., ethanol, propylene glycol) in the
formulation.
Solubility is typically determined by adding an excess amount of solid drug to a
liquid and shaking at a constant temperature until the suspension system reaches
equilibrium and no more drug effectively dissolves. The solution is then analyzed to
determine the drug content in the solution by separating the dissolved drug from the
suspended drug. The United States Pharmacopeia (USP) denes the extent of solubility for drugs in terms of parts of solvent required to dissolve one part of solute,
and the USP uses descriptive categories (Table 3.1) based upon parts of solvent
required. These descriptors of drug solubility are often included in the prescribing
information for pharmaceutical products.
The solubility of a drug is critically important for its therapeutic action. Generally
for a drug to exert its pharmacological effect, it must be dissolved in its molecular
form so that it can permeate a membrane, interact with a biological pathway, and/or
bind to receptors. For example, to permeate the membrane of the gastrointestinal
(GI) tract and reach systemic circulation, an orally delivered drug must rst dissolve
in the gastric or intestinal uids. A drug that is insoluble in aqueous uids can have
erratic or incomplete absorption. Similarly, drug solubility affects decisions regarding dosage form design and administration route. For example, considering delivery
via an intravenous injection, a physiologically safe liquid solvent must be utilized
and the volume of the injection can be limited. Overall, determining drug solubility
is an important component of preformulation studies, and the formulation and delivery of poorly water-soluble drugs is a major challenge in the pharmaceutical
industry.
Table 3.1 USP descriptive solubility terms
Parts of solvent required to dissolve one part of solute
USP term
Very soluble Less than 1 >1000
Freely soluble 1–10 100–1000
Soluble 10–30 30–100
Sparingly soluble 30–100 10–30
Slightly soluble 100–1000 1–10
Very slightly
soluble
Practically
insoluble
(e.g., drug)
1000–10,000 0.1–1
Greater than 10,000 < 0.01
Solubility (mg/
mL)
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