Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5441_Библиотеки_им_академика_М_И_Перельмана.pdf
88
methylcellulose or hydroxypropyl cellulose) and polyvinylpyrrolidone (PVP) are
used to hold the active ingredients and other additives together, forming a cohe-
sive mass.
4.3.1.3 Disintegrants
Disintegrants are mixed into the formulation to help break down the dosage form in
the gastrointestinal tract, which increases the surface area of particles, aiding in
drug dissolution and absorption. Examples include cross-linked sodium carboxy-
methylcellulose, cellulose, alginates, polyvinylpyrrolidone, starch, starch deriva-
tives, clay, etc. Substances like croscarmellose sodium, crospovidone, sodium
starch glycolate and modied cellulose act as superdisintegrants which are used to
prepare the fast dispersible oral formulations (Indurkhya etal. 2023).
4.3.1.4 Glidants andLubricants
Glidants (like colloidal silicon dioxide, Syloid
®
244, talc and starch) improve pow-
der owability (Parekh etal. 2023), while lubricants (such as magnesium stearate or
stearic acid) prevent tablet adhesion to the manufacturing equipment and aid in
tablet ejection.
4.3.1.5 Coating Agents
Coating agents like cellulose derivatives (cellulose acetate phthalate and ethyl cel-
lulose), shellac or polymethacrylates are used for lm coating or enteric coating to
modify drug release, protect the drug from degradation or mask taste.
Fig. 4.3 Types of additives used in solid dosage forms
M. Patel etal.
89
4.3.1.6 Sweeteners, Flavourings andColouring Agents
These additives improve the palatability and appearance of the dosage form, enhanc-
ing patient compliance. Titanium dioxide which is white in colour is employed as
an opacier to create an opaque shell which can prevent photodegradation of light-
sensitive components present in the formulation (Blundell etal. 2022).
4.3.1.7 Preservatives andAntioxidants
Preservatives like parabens and antioxidants such as ascorbic acid or tocopherols
are used to prolong the shelf life and stability of the dosage form by preventing
microbial growth or drug degradation. These additives are essential for transform-
ing an unstable medicine or formulation into one that is well tolerated. For instance,
saccharides help to maintain the formulation of lyophilised proteins.
4.3.1.8 Solubilisers
They are not commonly used in solid dosage forms, but certain solubilising agents
are incorporated to improve drug solubility and bioavailability, especially for poorly
water-soluble drugs. Surfactants like polysorbates (such as polysorbate 80) or
sodium lauryl sulphate can aid in improving the solubility of hydrophobic drugs.
Cyclodextrins (e.g. hydroxypropyl beta-cyclodextrin) are cyclic oligosaccharides
that can form inclusion complexes with poorly soluble drugs, thereby improving
their solubility and dissolution rates (Mandadapu etal. 2022).
4.3.2 Additives forOral Liquid Dosage Forms
The pharmaceutical industry has made extensive use of oral liquid formulations
because of their rapid onset of action, high degree of dosage exibility and ease of
swallowing. They are usually divided into two broad categories: monophasic and
biphasic formulations, which include a variety of dosage forms. In monophasic liq-
uids, the drug dissolves entirely in the vehicle; in biphasic liquids, the API is sus-
pended or dispersed in the vehicle, creating two phases instead of a complete
dissolve. The type of API and the intended therapeutic effect are thought to be the
two main determining factors when selecting a liquid dosage form. Various types of
additives used in the formulation of liquid dosage forms are given in Fig. 4.4.
Additives incorporated into liquid dosage forms play important role in enhancing
stability, palatability and overall formulation characteristics. Here are some com-
mon additives used in oral liquid formulations:
4.3.2.1 Vehicles
Vehicles acts as primary base that disperses or dissolves drug along with other addi-
tives, enabling them to achieve a liquid state. Vehicles are further classied into
aqueous and oily vehicles. Aqueous vehicles like glycerine, ethyl alcohol, propyl-
ene glycol, and water, as well as oily vehicles such as emulsied bases, organic oily
bases, mineral oils, and vegetable oils are commonlyused.
4 Pharmaceutical Product Development: Formulation Additives
90
4.3.2.2 Solubilisers
Hydrogen bond between the particles is broken down by the solubilisers causing
them to dissolve in water. Modication in solubility can be done by the use of sur-
face active agents, pH change, co-solvent addition or forming the complex.
Ingredients like ethanol, propylene glycol or polyethylene glycol are used to solu-
bilise poorly soluble drugs or aid in the formulation process.
4.3.2.3 Sweeteners
Sweeteners like sucrose and sorbitol or articial sweeteners such as saccharin are
utilised to improve the taste prole, effectively masking bitter or unpleasant tastes
and enhancing overall palatability of oral liquid formulations. They are typically
added to the formulations at concentrations ranging from 30% to 50%, with the
exception of cold syrups, which have 80% sweetener content.
4.3.2.4 pH Adjusters
Substances such as citric acid or sodium citrate are used to regulate and maintain the
pH of the liquid formulation within a suitable range for stability and optimal solu-
bility of the API.
4.3.2.5 Preservatives
Preservatives are chemical substances that are added to prevent microbial growth
and ensure the stability and safety of the liquid formulation during its shelf life.
Fig. 4.4 Types of additives used in liquid dosage forms
M. Patel etal.
91
Some examples of preservatives are benzyl alcohol (2%), parabens (0.015%to0.2%
w/v), chlorocresol phenol, etc. (Al-Rubaye 2022).
4.3.2.6 Surfactant
They are added in liquid formulations for aiding the solubilisation, emulsication
and stabilisation of the formulation. Water-insoluble drugs can be dispersed as a
colloidal dispersion using surfactants, which are surface active agents that tend to
reduce the surface of interfacial tension between two liquids. Cationic surfactants
like cetylpyridinium chloride and anion surfactants like polysorbate, poloxamer,
etc., are used in liquid formulations (Gonçalves etal. 2023).
4.3.2.7 Suspending Agent
Suspending agents lower the rate at which suspensions settle by raising the viscosity
of the continuous phase. Some of the suspending agents utilised in liquid dosage
forms include carbopol, gelatin, kaolin, methylcellulose and hydroxypropyl methyl
cellulose (Kumar and Verma 2023).
4.3.2.8 Emulsifying Agent
The role of an emulsifying agent is to reduce the interfacial tension or form a lm
surrounding the globules that are dispersed in an emulsion emulsifying agents.
Sodium lauryl sulphate, sodium dioctyl sulfosuccinate, polymers (Spans and
Tweens) and tragacanth are examples of commonly used emulsifying agents
(Kamba etal. 2013).
4.3.2.9 Colorants
These additives, both natural and synthetic (e.g. FD&C dyes), serve to provide
visual identication, enhance appearance and distinguish between various
formulations.
4.3.2.10 Viscosity Modifiers
Substances such as carboxymethylcellulose (CMC), xanthan gum or glycerin are
employed to adjust the viscosity of the liquid, improving pourability, suspension
stability and ease of administration.
4.3.3 Additives forTransdermal Dosage Forms
Transdermal drug delivery system (TDDS) is a system which is used to deliver the
drug into the systemic system through skin. An appropriate selection of additives
and procedures is critical in TDDS to regulate the release of the drug. Each additive
in TDDS serves a specic purpose, contributing to the effectiveness of formulation,
its stability and patient compliance. The selection and combination of these addi-
tives are carefully considered to optimise drug delivery through the skin while
ensuring safety and efcacy. The classication of TDDS is dependent upon the type
of additive utilised, particularly the polymers incorporated during preparation. For
4 Pharmaceutical Product Development: Formulation Additives
92
instance, to create matrix-based TDDS, where the drug is dispersed within the poly-
mer matrix, polyvinylpyrrolidone, ethyl cellulose or polyethylene glycol is used as
polymer, and for formulating reservoir-type TDDS (Rajabalaya etal. 2012), where
drug is surrounded by polymeric membrane, ethylene-vinyl acetate, polyethylene or
isotactic polypropylene is used as the rate-controlling polymer (Kim etal. 2001).
Some other important additives found in transdermal formulations include:
4.3.3.1 Penetration Enhancers
Penetration enhancers are important additive of TDDS used to overcome the barrier
property of stratum corneum (uppermost layer of skin) and enhance drug perme-
ation. These additives improve drug permeation through the skin by altering the
skin barrier properties. Examples include fatty acids (oleic acid), alcohols (ethanol),
surfactants (Tween, Span) or terpenes (limonene). Although several surface active
chemicals and lipophilic solvents have been shown to be useful penetration enhanc-
ers, their use is constrained by their sensitivity and irritation. Novel additives like
N-methyl-2-pyrrolidone, Labrasol
®
and Transcutol
®
have proved to be better pene-
tration enhancer than the conventional ones (Bácskay etal. 2023; Nakmode etal.
2022). Recent studies revealed that the type and concentration of the penetration
enhancers play an important role in penetrability and characteristics of the formula-
tion (Sakdiset etal. 2023).
4.3.3.2 Solvents/Solubilisers
Substances like propylene glycol, dimethyl sulphoxide (DMSO) or ethanol are used
to solubilise the drug and enhance its permeation across the skin. They prevent drug
precipitation and aid in maintaining a homogenous and stable pharmaceutical prep-
aration. The careful selection and combination of solvents and solubilisers are criti-
cal in designing transdermal drug delivery systems to ensure optimal drug delivery.
4.3.3.3 Adhesives
Acrylic adhesives or silicone adhesives are used to adhere the patch to the skin and
maintain its integrity during application (Banerjee etal. 2014). These adhesives
must strike a balance between secure attachment and skin compatibility to ensure
both effective drug delivery and patient comfort. Typically, they consist of pressure-
sensitive materials that adhere to the skin upon application of light pressure.
Silicone-based adhesives are commonly used due to their biocompatibility and
hypoallergenic properties.
4.3.3.4 Backings andRelease Liners
Backing materials provide structural support to the patch and restrict the release of
the drug leaking from the membrane on top of the skin patch. Release liners on the
other hand protect the adhesive surface of TDDS and are removed before applica-
tion of the formulation on skin. The material used for both the purposes should be
compatible with skin and should not cause any irritation to the skin. Backing layer
should have a low modulus, a high rate of moisture-vapour transfer, and high
M. Patel etal.
93
exibility. Polyethylene terephthalate, ethylene-vinyl acetate, polyethylene, poly-
urethane, etc., are few examples of polymers used as backing layers.
4.3.3.5 Plasticisers
Plasticisers like glycerin, dibutyl phthalate, polyethylene glycol, propylene glycol
and triacetin maintain the exibility of the patch. Additionally, plasticisers aid in
modulating the drug release kinetics by inuencing the diffusion characteristics of
the active pharmaceutical ingredient through the skin (Pichayakorn etal. 2012).
4.3.3.6 Stabilisers andAntioxidants
To prevent degradation, stabilisers and antioxidants (ascorbic acid, tocopherols) are
added to maintain the stability of the formulation. These additives inhibit the forma-
tion of free radicals that could potentially compromise the therapeutic properties of
the drugs.
4.3.4 Additives forParenteral Dosage Forms
In order to obtain the required product prole (stability and effectiveness), additives
are a crucial component of the creation of parenteral dosage forms. The physico-
chemical characteristics of the additives utilised in the parenteral formulations are
either lyophilised, suspended or are in a solution form. Even with appropriate addi-
tive selection, it is essential to employ them carefully during the formulation and
manufacturing process in order to prevent unfavourable outcomes including
decreased drug solubility, stability and activity. There are varieties of additives used
for preparing the desired formulation for parenteral use. For instance, buffers like
citrate or phosphate salts help to maintain the desired pH, ensuring the compatibility
of the formulation inside the body. Preservatives such as benzyl alcohol or phenol
prevent microbial growth in multi-dose vials, extending their shelf life and reducing
the risk of contamination. Additionally, tonicity-adjusting agents like sodium chlo-
ride or mannitol ensure isotonicity, preventing adverse reactions and uneasiness at
the injection site. Co-solvents like propylene glycol or ethanol aid in solubilising
poorly water-soluble drugs, facilitating their administration.
4.3.4.1 Additive Used inLyophilisation
Lyophilisation, a widely used process in the development of parenteral formula-
tions, holds a signicantly important role in preserving the stability and efcacy of
injectable medications (Pramanick etal. 2013). This process initiates with freezing
of the solution followed by the removal of water by sublimation technique, termed
as primary drying, and nally water removal by desorption process, referred to as
secondary drying. The extensive reduction in moisture content is helpful in prevent-
ing microbial growth and chemical reactions in the parenteral formulations.
Therefore, it is important to choose an appropriate additive used for this process.
Here are the additives used for the lyophilisation process.
4 Pharmaceutical Product Development: Formulation Additives
94
4.3.4.1.1 Bulking Agents
These are typically employed for high-potency, low-dose medications that lack the
bulk to sustain their own structure. These agents become even more important when
the total solid content is less than 2% (Rayaprolu etal. 2018). The bulking agents
help in the formation of proper lyophilised cake which ensures the better porosity
and subsequent sublimation process. Bulking agents also have the capability to
behave as stabilisers and tonicity-adjusting agents. Mannitol is the additive that is
most frequently and extensively utilised in lyophilised products. After crystallisa-
tion, mannitol has an extremely high eutectic melting point (−1.4°C) and is well
processed during lyophilisation. However, in some situations, the bulking agent’s
crystallisation could negatively impact the product’s physical stability; in these
cases, an amorphous bulking agent is recommended. Other substance like lactose,
sucrose, polyethylene glycol, glycine, etc., can also be used as bulking agents.
Combination of these bulking agents with mannitol is commonly practised to
address their individual limitations across various conditions. For instance,
Nutropin
®
lyophilised injection incorporates mannitol along with glycine, while
Enbrel
®
uses sucrose and mannitol as bulking agents.
4.3.4.1.2 Lyoprotectants
Lyoprotection involves stabilising and protecting the molecules from degradation
during freeze-drying and subsequent storage. Sucrose and trehalose are frequently
utilised for this purpose because they are not prone to crystallisation during lyophi-
lisation, and therefore they do not phase separate from the protein. Trehalose appears
to be a more advantageous lyoprotectant compared to sucrose due to its lower
hygroscopicity, minimal chemical reactivity and notably higher glass transition
temperature (Bjelošević etal. 2020).
4.3.4.1.3 Antioxidants
They are added to prevent the oxidation. Examples of marketed lyophilised inject-
able biopharmaceuticals containing antioxidants are Vivotif Berna
®
(live typhoid
vaccine) with ascorbic acid and ACTHREL
®
(corticorelin ovine) containing cyste-
ine hydrochloride and ascorbic acid (Mehmood and Farooq 2015).
4.3.4.1.4 Buffering Agents
In order to prevent drug deterioration during processing, storage and reconstitution,
pH control is essential. As a result, a buffering agent must be added to the lyophi-
lised formulation. Since the medication must be reconstituted and kept for a while
before it can be given to the patient, the pH stability prole of the active ingredient
determines which buffer is best. The drug’s optimal stability pH needs to be deter-
mined and maintained for this reason. For sensitive compounds, choosing an appro-
priate buffer and its concentration is crucial.
M. Patel etal.
95
4.3.4.2 Additives Used inLiquid Injection
Additives used in liquid injections serve various purposes, such as stabilising the
API, adjusting the pH, enhancing solubility or ensuring the injection’s safety and
efcacy. Common additives found in liquid injections include the following:
4.3.4.2.1 Buffers
These maintain the injection’s pH within a suitable range to prevent degradation of
the API.Common buffers include sodium phosphate, citrate, acetate or glycine.
4.3.4.2.2 Preservatives
Preservatives in the form of antioxidants, antimicrobial and chelating agents are
added in the liquid injections to prevent microbial growth in multi-dose vials. The
antioxidants are utilised to reduce or inhibit the oxidation reaction of the drug or
additives throughout the product’s shelf life, while antimicrobial agents are utilised
to inhibit the growth of microbes in the dosage form. Monothioglycerol, butylated
hydroxytoluene, ascorbic acid, acetylcysteine and sulfurous acid salts (bisulphite,
metabisulte) are the most often utilised antioxidants in formulations that are sterile.
In the category of chelating agents, substances like disodium edetate, edetate calcium
disodium and diethylenetriamine pentaacetate are used (Rayaprolu etal. 2018).
4.3.4.2.3 Tonicity Adjusters
There are certain substances used to adjust the tonicity of the solution, making it
isotonic with body uids to prevent tissue injury. Dextrose is most preferred tonicity
adjuster than glycerol and sodium chloride. Glycerine and mannitol are two more
tonicity-adjusting substances that are frequently employed.
4.3.4.2.4 Solvent System
Aqueous and nonaqueous vehicles are the two types of solvent systems utilised in
parenteral suspension. Both water-miscible and water-immiscible vehicles fall
under the category of nonaqueous vehicles. Usually, the best solvent system for
injection is water. However, to increase the solubility and stability in parenteral
preparation, nonaqueous water-miscible substances are utilised as co-solvents with
water for injection. Propylene glycol, glycerine, N-lactamide and ethanol are a few
examples of nonaqueous water-miscible vehicles.
4.3.4.2.5 Solubilisers
Surfactants and co-solvents are two main categories into which the solubilising
agents can be divided. Surfactants work by lowering the drug components’ surface
tension, increasing dissolution, while co-solvents are dened as solvents that, when
combined with another solvent, can dissolve a solute. Ethanol, glycerol, various
grades of polyethylene glycol, etc., can be used as co-solvents (Nema and Brendel
2011). Sorbitan monooleate (Span 80), polyoxyethylene sorbitan monolau-
rate(Tween 20), polyoxyethylene sorbitan monooleate(Tween 80) are some exam-
ples of surfactants, which are used in liquid injections. -α-Tocopherol polyethylene
glycol 1000 succinate is a novel nonionic surfactant which is considered potential
4 Pharmaceutical Product Development: Formulation Additives
96
emulsifying agent or surfactant for injectables and to inhibit the multi-drug resis-
tance (Rayaprolu and Strom 2013).
4.3.4.2.6 Complexing andDispersing Agents
Sometimes, complexation is used to increase a drug’s solubility in a solvent, par-
ticularly water. Cyclodextrins have shown to be incredibly successful additives for
solubilising medications that are hydrophobic. Modied cyclodextrins, like
hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin, have been found
to solubilise and stabilise a variety of injectable medications, such as interleukin-2,
oestradiol, dexamethasone and other proteins and peptides, in the parenteral dosage
form without seeming to cause any compatibility issues.
4.3.4.2.7 Flocculating/Suspending Agents (For Pharmaceutical Injectable
Suspension)
The controlled occulation method uses one or more occulating agents to create
ocs, or loosely bonded aggregate, that settle quickly but readily redisperse when
agitated. A suitable quantity of occulating agent is used to achieve the maximum
volume of sedimentation and inhibit the development of cakes. Traditionally, oc-
culating agents have included hydrophilic colloids, surfactants and electrolytes. The
formation of ocs is dependent on the surface charge of the particles and is facili-
tated by surfactants and electrolytes, which minimise the electrical forces of repul-
sion between the particles. Examples of some of the electrolytes utilised in parenteral
suspensions are salt/potassium citrate, salt/potassium chloride and sodium/potas-
sium acetate.
4.4 Drug-Additive Interaction Studies inDevelopment
ofPharmaceutical Formulations
Pharmaceutical additives are generally considered pharmacologically inert sub-
stances, but studies have revealed that they can actively interact physically, chemi-
cally and physiologically with drugs to compromise the stability of the nished
product and the therapeutic function of the drug component (Gorain etal. 2018).
The interaction depends on the amount of the drug, its chemical makeup and the
characteristics of the additives used. While drug-additive interactions may have
some advantageous effects on occasions, in the majority of cases, they tend to delay
drug release and diminish bioavailability. For instance, during a study on the com-
patibility of superdisintegrants with various model drugs of differing aqueous solu-
bility, it was found that ionic interactions between cationic drugs and anionic
superdisintegrants lead to delayed drug release and poor dissolution
(Balasubramaniam etal. 2008). A study revealed the positive impact of a drug-
additive complex, wherein the presence of cyclodextrin exhibited improved solubil-
ity, bioavailability and stability (Liu etal. 2023). Predicting the precise mechanism
of such an interaction remains challenging, despite the records of several probable
reasons in the literature. These interactions can be categorised as the following:
M. Patel etal.
97
4.4.1 Physical Incompatibilities
Physical interactions such as van der Waals forces, hydrogen bonding or electro-
static forces between drugs and additives have the potential to inuence the proper-
ties of drug. Such interactions can have either positive or negative effect on the
performance of formulation including its dissolution rate and solid-state character-
istics. The undesirable insoluble complex formation between drug and additive
causes a slower rate of drug dissolution and absorption like tetracycline and calcium
carbonate complex. On the other hand, drug cyclodextrin complex enhances the
solubility of poorly water-soluble drugs (Saokham etal. 2018). A capsule formula-
tion prepared using stearic acid with povidone showed decreased dissolution stabil-
ity and hence indicated that this combination of additives should not be used for the
formulation of immediate release formulations (Desai etal. 2008). In another study,
the bioavailability of ganciclovir, a BCS class III, drug was enhanced when its solid
dispersion was prepared using cyclodextrin and shellac polymers (Gaber et al.
2022). Furthermore, in the course of the study, it was observed that the incorpora-
tion of polyvinylpyrrolidone K30 into the binary solid dispersion (comprising indo-
methacin and kaolin) not only enhanced the physical stabilisation of amorphous
indomethacin but also addressed the solubility challenges arising from the presence
of kaolin (Bejaoui etal. 2021). There are many such examples showing the signi-
cance of physical interaction of additives with the drug molecule.
4.4.2 Chemical Incompatibilities
Another type of interaction that can arise between drug and additives is chemical
interaction, and it is imperative to study this for complete pharmaceutical research
and avoid incompatibility. These interactions can give rise to covalent or noncova-
lent bonds, profoundly inuencing the drug’s stability, solubility and bioavailability.
As compared to physical interaction, chemical interactions may lead to adverse
impacts on the product, resulting in the formation of a different compound. The
studies have proved the complexity of chemical interactions which emphasises their
signicance in formulation development. One of the examples is the chemical
incompatibility observed between magnesium stearate and aspirin which gives rise
to several potentially undesirable products, including salicyl salicylic acid, salicylic
acid and acetyl salicyl salicylic acid (Mitrevej and Hollenbeck 1983). Whether
facilitating or impeding the drug’s performance, these interactions necessitate care-
ful consideration during the design and optimisation of pharmaceutical formula-
tions. Among the different types of chemical reactions, leading to incompatibility,
hydrolysis stands out as the most common in pharmaceutical formulations (Gabrič
etal. 2022). Hydrolysis is a common degradation process, particularly in the pres-
ence of water, affecting esters, amides, lactones or lactams. Oxidation, the second-
most likely degradation process, involves alcohols, aldehydes, alkaloids, phenols
and unsaturated fatty substances. Although less common, other potential reactions
include isomerisation, photolysis and polymerisation. These reactions have the
4 Pharmaceutical Product Development: Formulation Additives