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Pharmaceutical Dosage Forms and Drug Delivery
phthalate [CAP], ethylcellulose [EC], methylcellulose [MC]], and synthetic materials (e.g., polylactic
acid [PLA], poly(lactide- co- glycolide) [PLGA]).
testicular testosterone production. To be effective, the recommended dose was 1 mg/ daily via subcuta-
every 4 months. The latest approved microsphere- based product Zilretta (triamcinolone), is administered
Therapeutic effects from IA corticosteroids are typically short- lived. However, these PLGA microspheres
slowly release triamcinolone acetonide in the synovium for over three months. Further, the microspheres
related systemic adverse reactions, such as blood glucose elevations.
velocity, aggregation in blood, and immunogenicity, affecting their circulation time. Larger particles are
other hand, smaller particles <5 nm are readily cleared by the kidney. Therefore, the balance between
particles may evade immune system recognition, offering an advantage over spherical particles. Other
minutes, but not non- spherical particles, even after 32 minutes. The reason is the shape of the particles
in vivo circulation time. Positively
effects on normal cells. Conversely, whereas negatively charged particles have a lengthy circulation, they
diminish the negatively charged cell membrane interaction required for cellular uptake. The adsorption
and increase the chances of phagocytosis. Hence, to extend the duration of particle circulation in vivo,
it is imperative to enhance the hydrophilic nature of their surface. Common “stealth” molecules with
increased hydrophilicity include PEG.
22.5.2 Multivesicular Liposomes
Different packing lipid compositions of liposomes can be applied to control drug release. Most liposome formulations have concentric bilayer packing, which allows drug aggregation and rapid release.
icity but cannot control drug release needed for long- term effects. To address this issue, multivesicular
FDA- approved products Depocyt, DepoDur, and Exparel. Multivesicular liposomes, with an average
diameter of 3– 30 nm, consist of hundreds of non- concentric and polyhedral aqueous compartments
separated by lipid membranes. They achieve sustained drug release through the gradual degradation of
outermost vesicles while maintaining their structure during internal vesicle rearrangement. For a hydro-
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a viable strategy to control the rate of drug release from liposomes.
22.5.3 Oil- Based Formulation
Oil- based long- acting parenteral formations are prepared by covalently attaching a fatty acid chain and
therapeutics, forming prodrugs in the oil phase. Ester bonds between drugs and lipids like decanoate,
enanthate, and caproate can increase drug solubility and partitioning in fatty tissues. Two common oilbased parenteral formulations, Lyogen Depot and Haldol Depot, are approved as antipsychotic therapy.
the bloodstream. The drug release rate depends on the rate of prodrug release from fatty tissues and the
hydrolysis of ester bonds to release the parent drug. Furthermore, factors like drug concentration in the
are crucial for controlling drug release.
22.5.4 Nano- Crystallization
improve the solubility of poorly soluble drugs and to provide long- acting effects. The solubility of a
these nanocrystals. These nanocrystals can be formulated as suspension formulations. In 2009, the FDA
insoluble prodrug into soluble paliperidone results in a long- acting pharmacological action. These LAFs
have shown a lower rate of medication non- compliance- related disease relapse than conventional antipsychotic therapies.
22.5.5 Biomineralization
In vivo, macromolecule
biomineral complexes can load and release bioactive molecules. Studies reported the formation of
ions and acidic amino acid residues in a supersaturated environment. This biomimetic system responded
to physiological supersaturation and formed tiny crystals from calcium phosphate nucleation around
exendin- 4 can be dissociated and sustainably released after spontaneous absorption by a living body.
22.5.6 Injectable Hydrogels
Hydrogels are crosslinked hydrophilic 3D polymer networks with high water absorption capacity.
Hydrogels can be used for long- acting drug preparations and can be either implanted or inserted into
living bodies with minimal invasion. Hydrogels can transition from solution (liquid) to gel (solid) to
generate solid- like gel states to administer and help in the encapsulation and release of medications,
genes, DNA, proteins, and cells in a sustained and regulated fashion. The sol- gel transition necessitates
a kind of spontaneous chemical or physical crosslinking between the polymer branches. Chemical
reaction, or thiol- based Michael reaction. In physical crosslinking, the solution to the gel state is achieved
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Pharmaceutical Dosage Forms and Drug Delivery
by changing its intermolecular forces, such as hydrogen bonding, hydrophobic interactions, and electrostatic ionic forces. Physical crosslinking can be induced by changes in temperature, pH, ionic strength,
22.6 Quality Attributes and Evaluation
In addition to meeting the physical and chemical stability attributes of the dosage form being formulated,
all parenteral products must be sterile, nonpyrogenic, and free from extraneous insoluble materials.
22.6.1 Sterility
Sterility testing is carried out by incubating the drug product in a conducive environment for microbial
growth. Such a conducive environment includes appropriate temperature, humidity, and nutrient media.
Microbial growth is monitored after a given period of time, determined by standard protocols for each
type of microbes.
There are two methods of sterility testing:
• Direct inoculation: The drug product is added to the nutrient media and incubated, followed by
observation for microbial growth.
• Membrane ltration: Whenever the nature of the drug product is likely to hinder the detectability
nutrient media for observation of microbial growth.
medium is used.
22.6.2 Pyrogens
22.6.2.1 Endotoxins, Exotoxins, and Pyrogens
Bacterial toxins could be endotoxins or exotoxins. Endotoxins are the structural molecules of certain
reactions. Exotoxins, on the other hand, are the toxins secreted by microorganisms, such as bacteria,
substances are termed as pyrogens. Some of the effects caused by pyrogens in the body are an increase
in body temperature, chills, cutaneous vasoconstriction, a decrease in respiration, an increase in arterial
from nonsterile components, there is always a concern about endotoxin contamination.
22.6.2.2 Endotoxin Components and Tolerance Limits
saccharide (LPS) portion of the cell wall that gets released during cell lysis is the principal constituent of
the endogens that cause the pyrogenic response. The LPS can be sloughed off the bacteria, which do not
have to be living for the LPS to be pyrogenic. Gram- negative bacteria produce more potent endotoxins
than gram- positive bacteria and fungi.
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pg (picogram, i.e., 10
22.6.2.3 Sources
g) of Escherichia coli LPS, present in approximately 105 bacteria.
Water is the main source of pyrogens. This is because Pseudomonas, a gram- negative bacterium, grows
readily in water. Other sources of endotoxins or pyrogens are raw materials, processing equipment, and
human contamination.
22.6.2.4 Depyrogenation
by dry heat. Thus, compounding a sterile product from nonsterile starting material that can withstand the
22.6.2.5 Detection
A preferred method for the detection of pyrogens is the Limulus amebocyte lysate (LAL) test. A test
sample is incubated with amebocyte lysate from the blood of the horseshoe crab, Limulus polyphemus.
A pyrogenic substance causes gelling.
22.6.3 Particulate Matters
container, and environmental contamination. Any parenteral product samples found containing particulate matter are discarded. If the quantity and the type of discard exceed a predetermined quality threshold,
an investigation is initiated to determine and remediate the cause of the particulate.
22.7 Formulation Components
are excipients added to vaccines to help boost the body’s immune response. The excipients include
vehicles, cosolvents, buffers, preservatives, antioxidants, inert gases, surfactants, complexing, and chelating agents.
• Vehicle is the larger continuous phase or the medium in which the formulation is prepared. Water
corn oil, sesame oil, and cottonseed oil or peanut oil.
•
•
manner to ensure that it is pure and free from pyrogens.
• -
tion. It is often used as a vehicle to prepare parenteral solutions and suspensions.
• Cosolvents, such as ethyl alcohol, glycerin, propylene glycol, or PEG, may be used to increase
drug solubility in the medium. When cosolvents are used as vehicles, the preparations should not
be diluted with water, or precipitation may occur.
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• Buffer systems are used to maintain a desired pH of optimum drug solubility and stability.
• Preservative(s) is used in drug products packaged in multiple- dose vials to prevent the growth
of microorganisms that may be introduced when the container is pierced for dosing. When
preservatives are used, their compatibility with drugs should be carefully examined. For example,
phenol preservatives are incompatible with nitrofurantoin, amphotericin B, and erythromycin.
• Antioxidants are used to prevent oxidative degradation of sensitive drugs. Salts of sulfur dioxide,
parenterals.
• -
•
to achieve isotonicity in a parenteral formulation.
• An isotonic solution has an equal amount of dissolved solute compared to the solution it is being
•
• A hypertonic solution contains a higher concentration of dissolved substances than the red blood
cells, which causes the red blood cells to shrink. In contrast, a hypotonic solution contains a lower
concentration of dissolved substances than the red blood cells, causing the red blood cells to swell
and possibly burst.
22.8 Sterilization
All parenteral products must be sterile. Sterility is assured by a three- step process: (1) use of sterile
gas, and radiation.
22.8.1 Filtration
stress, leading to alteration in their three- dimensional structure. In certain cases, formulation might affect
22.8.2 Dry Heat Sterilization
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22.8.3 Steam Sterilization (Autoclaving)
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22.8.4 Radiation Sterilization
Review Questions
22.1 All parenteral products must be
A Sterile
B Pyrogen free
C Isotonic
D Sterile and pyrogen free
E All of the above
22.2
A A rapid action is required
B An oral administration is ineffective
C A prolonged action is required
D A and B
22.3
a Systemic drug absorption occurs more rapidly than from oral administration compared to
intravenous administration.
b All parenteral products must be isotonic.
c
d
e
f
g
h
FURTHER READINGS
Ansel’s Pharmaceutical Dosage Forms and Drug Delivery
Systems, 8th ed., Philadelphia, PA: Lippincott Williams & Wilkins.
drug discovery and development: An emerging therapeutic candidate. Biofactors 4
J Control Release
160: 117– 134.
ACS Omega 8:
35470– 35498.
review. J Parenter Sci Technol 40: 212– 241.
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Modern
Pharmaceutics
Pharmaceutical Dosage Forms and Drug Delivery
orders of magnitude. Nat Commun 9
Pharmaceutics: The Science of Dosage Form
Design
nanoparticles. Cancer Lett 579
Biomater Res 26: 22– 27.
Bioconjug Chem 19: 2144– 2155.
Adv Drug Deliv Rev 167
Theory and Practice of Contemporary Pharmaceutics, Boca Raton, FL: CRC Press, pp. 387– 419.
Thoma L.A. (2005) Sterile products. In Gourley D.R. (Ed.) APhA’s Complete Review for Pharmacy, 3rd ed.,
Sterile Dosage Forms: Their Preparation and Clinical Application, 4th ed., Philadelphia,
PA: Lippincott Williams & Wilkins.
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Semisolid Dosage Forms
LEARNING OBJECTIVES
On completion of this chapter, the students should be able to
1.
2. Describe different types of ointment bases.
3. Differentiate between hydrogels and organogels.
23.1 Introduction
Dosage forms in plastic (i.e., change shape upon application of force), malleable semisolid state at
preparations may contain dissolved and/ or suspended drugs. These preparations are designed to stay in
physical contact with the surface of the product for a reasonable duration of time before they are inadvertently or intentionally removed or washed off. Their semisolid state and plastic rheological behavior
semisolid.
Most of the semisolid formulations are used topically to deliver drugs to/ through the skin. They can
also be used for topical or systemic drug action in/ through the eye, nose, ear, vagina, rectum, buccal
tissue, or the urethral membrane. In addition, unmedicated semisolid formulations are frequently used as
protectants or lubricants. Topical applications can be designed for either local effects or systemic absorption. For example, a topical dermatological product is designed to deliver a drug into the skin for treating
dermal disorders. A transdermal product is designed to deliver drugs through the skin (percutaneous
absorption) to the underlying tissue or the systemic circulation.
The primary categories of agents applied topically encompass corticosteroids, antifungals, acne
medications, antibiotics, emollients, antiseptics, and local anesthetics. Topical agents are used as
protectives, adsorbents, emollients, and cleansing agents.
23.2 Ointments
Ointments are semisolid preparations that incorporate a lipid or hydrophobic excipient and are intended
Ointments are designed to soften or melt at body temperature, spread easily, and have a smooth, nongritty feel. Ointments are typically used as (1) emollients to make the skin more pliable, (2) protective
barriers to prevent harmful substances from coming in contact with the skin, and (3) vehicles for hydrophobic drugs.
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23.2.1 Types of Ointment Bases
Pharmaceutical Dosage Forms and Drug Delivery
groups: (1) hydrocarbon bases, (2) absorption bases, (3) emulsion or water- removable bases, and
(4) water- soluble bases (Table 23.1).
23.2.1.1 Hydrocarbon Bases
Oily or oleaginous bases include hydrocarbons derived from petroleum, which are called hydrocarbon
bases. These bases are anhydrous and insoluble in water. These bases are used for their emollient effect
(to hydrate the skin) and as an occlusive dressing. They cannot absorb or contain water. Thus, they can
be protective against water- labile drugs, such as bacitracin and tetracycline. However, they are greasy
and not water washable. Thus, they can stain clothing and are generally not preferred. Oily or fatty- base
render an ointment to be of suitable consistency.
Common hydrocarbon bases include the following:
• Petrolatum
®
• Liquid petrolatum
obtained from petroleum that are liquid at room temperature. It is used as a levigating agent to
incorporate lipophilic solids into ointments.
• Synthetic esters are used as constituents of oleaginous bases. These esters include glycerol
monostearate, isopropyl myristate, isopropyl palmitate, butyl stearate, and butyl palmitate.
TABLE 23.1
Various Types of Ointment Bases
Types of ointment Bases Characteristics Applications Examples
Hydrocarbon/ oleaginous • Anhydrous
• Water insoluble
• Not water washable
Absorption • w/ o emulsions or oleaginous
bases that allow incorporation
of aqueous solution to form w/
o emulsions
• Not easily water washable
Emulsion • o/ w emulsions
the surface of the skin when
water evaporates
Water soluble • Hydrophilic polymer (e.g.,
PEG) mixture
• Incorporation of
hydrophobic drugs
• Emollients • Anhydrous: hydrophilic
• Drug carriers
• Foundation for
makeup
• Drug carriers • PEG 400 + PEG 4,000 in
• Petrolatum
• Wax
• Synthetic esters, for
example, glycerol
monostearate
petrolatum and anhydrous
lanolin
• w/ o emulsion: lanolin and
cold cream
• Hydrophilic ointment
• Vanishing cream
• Propylene glycol + ethanol
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• Long- chain alcohols, such as cetyl alcohol and stearyl alcohol, are sometimes also incorporated
in oleaginous bases. In addition, lanolin derivatives, such as lanolin oil and hydrogenated lanolin,
are sometimes used.
• Plastibase®
mineral oil. It is useful for the extemporaneous preparation of ointments by cold incorporation of
drugs, thus being suitable for heat- labile compounds.
23.2.1.2 Absorption Bases
absorb water to form or expand w/ o emulsions. Absorption bases are useful as emollients, although they
do not provide the degree of occlusion afforded by the oleaginous bases. Emollients are preparations that
soften and soothe the skin. These preparations may be used to reduce the dryness and scaling of skin.
However, they are greasy because the external phase of the emulsion is oily. Absorption bases are not
easily removed from the skin with water.
Absorption bases are of two types:
1. Anhydrous bases that permit the incorporation of aqueous solutions, resulting in the formation
of w/ o emulsions. These absorption bases are anhydrous vehicles composed of a hydrocarbon
base and an additive. The hydrocarbon base could be, for example, hydrophilic petrolatum and
anhydrous lanolin. The additive is a miscible substance with polar groups (a surfactant), which
sterols, or the partial esters of polyhydric alcohols, such as monostearate or monooleate, can
serve as additives.
2. Bases that are already w/ o emulsions (emulsion bases) and permit the incorporation of small additional quantities of aqueous solutions. For example, lanolin and cold cream.
a. Lanolin-
lient, effectively preventing epidermal water loss. It retards but does not completely inhibit
Lanolin is a pale yellow substance obtained from sheep wool. It is chemically a wax consisting
of high molecular weight alcohols (e.g., sterols) and fatty acids. Lanolin can absorb twice its
own weight of water. It is self- emulsifying and produces stable w/ o emulsions. Lanolin is used
to help prevent drying and chapping of the skin.
b. Cold cream is a semisolid white w/ o emulsion prepared with cetyl ester wax, white wax, min-
is employed as an emollient and ointment base. For example, Eucerin cream is a w/ o emulsion
of petrolatum, mineral oil, mineral wax, wool wax, alcohol, and bronopol. It contains urea as
the active ingredient and is used to help rehydrate dry, scaly skin.
23.2.1.3 Emulsion or Water- Removable Bases and Creams
Emulsion or water- removable bases are oil- in- water (o/ w) emulsions. As these emulsion bases have
an aqueous external phase, they are water washable or water removable. They are non/ less greasy
and occlusive than oleaginous bases. They can be diluted with water and have a better cosmetic
appearance. Highly viscous emulsion bases are commonly referred to as creams. These represent the
most commonly used type of ointment base. Most dermatologic drug products are formulated in an
emulsion or cream base.
An emulsion base has three components: (a) an internal oil phase, which is typically made of petrol-
phase. Drugs can be included in one of these phases before forming the emulsion or can be added to the
formed emulsion.
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