Pharmaceutical necessity

Pharmaceutical necessity a substance having slight or no value therapeutically, but

used in the preparation of various pharmaceuticals, including preservatives,
solvents, ointment bases, and flavoring, coloring, diluting, emulsifying, and
suspending agents.

Solvents for pharmaceutical manufacturing

What is solvent?
Solvents are chemical substances that can dissolve, suspend or extract other
materials usually without chemically changing either the solvents or the other
materials. Solvents can be organic, meaning the solvent contains carbon as part of
its makeup, or inorganic, meaning the solvent does not contain carbon. For
example, “rubbing” alcohol is an organic solvent and water is an inorganic solvent.
Hydrocarbon and oxygenated solvents are examples of types of organic solvents
that can effectively dissolve many materials.

A well-equipped medicine cabinet starts with solvents:

Solvents are used in hundreds of pharmaceutical products, many of which are found
in our homes. In fact, some of the products found in our medicine cabinets are
solvents, such as rubbing alcohol. Solvents can play a key role in our well-being,
and they also frequently play a role at the start of the pharmaceutical
manufacturing process.

Isopropyl alcohol, or rubbing alcohol, is an example of a solvent that plays a dual

role. A versatile solvent, it is often used in our homes as a disinfectant, and is also
used as an industrial solvent to dissolve products such as oils and resins in
manufacturing processes. Additionally, it can be used as a building block to make
other products.

Ointments and other topical products, such as antibacterial creams and

corticosteroids, often use solvents in the beginning of the process to manufacture
the active ingredients. As the drug is being transformed into its final form, whether
cream, lotion or liquid, solvents are used as a medium for blending materials.
Solvents also are used to help the final product achieve the proper consistency.

Other pharmaceutical items in our households that use solvents include pet care
products. Solvents are often found in pet shampoos, ointments, and oral
medications and topical. Pet shampoos use solvents to dissolve a drug for topical
treatment, or to provide moisture and softeners for our pets’ skin and hair.

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How do solvents work in pharmaceuticals?
Solvents can serve one or more functions in pharmaceutical manufacture. They
provide molecules to build some drugs. For other drugs, solvents are used for
extraction and purification. Solvents also can provide a reaction medium.

Solvents work in a variety of ways to contribute too many of the medicines people
use today. As helpers in the formulation of many health care products such as
penicillin, aspirin, cough syrup, and topical ointments, solvents play an important
role in the medicine cabinet.

Coloring agents used for pharmaceutical

manufacturing:

Numerous dyes are used in pharmaceutical manufacturing. These dyes give

products a distinctive, identifiable appearance, and they impart a uniform and
attractive color to products that might otherwise be drab and unappealing or exhibit
color variation among batches.

Several groups of dyes have been associated with serious adverse effects. The azo
dye tartrazine (FD&C Yellow No. 5) is known to be potentially dangerous in aspirin-
intolerant individuals. Approximately 2% to 20% of asthmatics are sensitive to
aspirin. The incidence of cross-reaction to tartrazine was previously believed to be
as high as 10%, but more recent carefully blinded studies have shown the incidence
to be less than 2.4%. Unlike aspirin, tartrazine does not alter prostaglandin
synthesis and does not, therefore, exert anti-inflammatory actions. Nonetheless,
reactions to tartrazine are similar to those produced by aspirin, occur in patients
both with and without a history of aspirin intolerance, and include acute
bronchospasm, nonimmunologic urticaria, eosinophilia, and angioedema. Rarely,
nonimmunologic anaphylactoid reactions occur. The most likely mechanism for
these reactions is dose-related histamine release from mast cells. Patients with
recurrent allergic vascular purpura may experience exacerbations after exposure to
azo dyes, such as tartrazine, sunset yellow and new coccine. Because of both the
seriousness of these reactions and the widespread use of tartrazine in foods and

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over-the-counter and prescription drugs, since 1980 the FDA has required that all
products containing tartrazine be labeled so that these substances can be avoided.

Patients with the classic aspirin triad reaction (asthma, urticaria, and rhinitis) or
anaphylactoid reactions may also develop similar reactions from dyes other than
tartrazine, including amaranth, erythrosine, indigo carmine (FD&C Blue No. 2),
ponceau, new coccine, sunset yellow, Brilliant Blue (FD&C Blue No. 1), methyl blue,
quinolone yellow, and FD&C Red No. 40.

Gastrointestinal intolerance, with abdominal pain, vomiting, and indigestion, has

been associated with sunset yellow; in one case, eosinophilia and hives were also
present. Other dermatologic reactions, including photosensitivity, erythroderma, and
desquamation, have been attributed to erythrosine, an iodine-containing dye. By
mandate, erythrosine has been removed from topical products and is being
voluntarily removed from many oral drug products because of concerns about
carcinogenicity.

Contact dermatitis has been associated with neutral red, D&C Yellow No. 11, indigo
carmine (FD&C Blue No. 2), quinoline yellow, and gentian violet (CI Basic Violet No.
3).

Dyes and other food additives have also been suggested as a cause or aggravating
factor in some cases of hyperactivity in children; carefully controlled trials and
current opinion generally refute a possible association.

Because carefully controlled double-blind challenges often fail to confirm suspected

reactions in children with atopic eczema, a controlled challenge is recommended
before dyes are eliminated from the diet. Hypersensitive individuals should avoid
dyes; liquid medications and nutritional supplements that do not contain dyes are
listed in Table. These listings were originally compiled from voluntary responses to
personal communications received from 56 US drug manufacturers and updated
with a repeat mailing in December 1992. Until complete ingredient labeling is
mandated, these lists will provide a tool to prevent reactions through avoidance in
sensitive children using liquid dosage forms. Because inactive ingredients may
change without changes in labeling, information in these tables should be verified

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Sources Of Coloring Agents:
Most pharmaceutical colorants are synthetic origin, few are naturally occurring
principles obtained from mineral, plants and animal source

Example: red ferric oxide is mixed in small portions with ZnO powder to prepare
calamine giving the latter a characteristic pink color intended to match
the skin done upon application.

Chlorophyll in green plants imparts its color to many products.

The synthetic coloring agent come mostly from coal tar (pix carbonis) black, viscid
liquid which is a by product in the destructive distillation of coal.

Many coloring agents:

Colors are obtained from natural or synthetic

sources. Natural colors are obtained from mineral, plant and animal sources.
Mineral colors (also called as pigments) are used to color lotions, cosmetics,
and other external preparations. Plant colors are most widely used for oral
suspension. The synthetic dyes should be used within range of 0.0005 % to 0.001
% depending upon the depth of color required and thickness of column of the
container to be viewed in it.

Most widely used colors are as follows:

· Titanium dioxide (white)

· Brilliant blue (blue)

· Indigo carmine (blue)

· Amaranth (red)

·Tartarazine (yellow)

· Sunset yellow (yellow)

· Carmine (red)

·Caramel (brown)

·Chlorophyll (green)

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· Annatto seeds (yellow to orange)

· Carrots (yellow)

· Madder plant (reddish yellow)

· Indigo (blue)

· Saffron (yellow)

Flavoring agents used for pharmaceutical

manufacturing:

They are added to increase patient acceptance. There

are many flavoring and coloring agents are available in market. The choice of
color should be associated with flavor used to improve the attractiveness by
the patient. Only sweetening agent is not capable of complete taste masking of
unpleasant drugs therefore, flavoring agents are incorporated. Color aids in
identification of the product. The color used should be acceptable by the
particular country.

Most widely used Flavoring agents are as follows:

Acacia Ginger Sarsaparilla syrup

Anise oil Glucose Spearmint oil
Benzaldehyde Glycerin Thyme oil
Caraway oil Glycerrhiza Tolu balsam
Cardamom (oil, tincture, spirit) Honey Vanilla
Cherry syrup Lavender oil Vanilla tincture
Cinnamon (oil, water) Lemon oil Tolu balsam syrup
Citric acid syrup Mannitol Wild cherry syrup
Citric acid Nutmeg oil

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 Clove oil Methyl salicylate

Cocoa Orange oil

Cocoa syrup Orange flower water

Coriander oil Peppermint (oil, spirit, water)

Dextrose Raspberry

Ethyl acetate Rose (oil, water)

Ethyl vanillin Rosemary oil

Fennel oil Saccharin sodium

Table : Flavouring agents

 Certain flavoring materials have been found through

experience :>

1. Cocoa - flavored vehicles effective for masking bitter taste

2. Fruits or Citrus flavors for masking sour or acid tasting drugs

3. Orange, Cinnamon, Strawberry for improving taste of salty drugs

Different Types of Flavors:

1. Natural Flavor: Essential oil, oleoresin, essence or extractive, protein

hydrolysate, distillate, or nay product of roasting, heating or enzymolysis, which
contains the flavoring constituents derived from a spice, fruit, or fruit juice,
vegetables, edible yeast, herb, bark, bud, root, leaf or similar plant material, meat,

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seafood, poultry, eggs, dairy products or fermentation products thereof whose
significant function in food is flavoring rather than nutritional

2. Artificial Flavor: Any substance used to impart flavor that is not derived from a
spice, fruit, vegetables or anything mentioned above.

3. Spice: Any aromatic vegetable substance in whole, broken, or ground from,

except substances traditionally regarded as foods, such as onions, garlic,
celery; whose significant function in food is seasoning rather than nutritional; that is
true of any volatile oil or other flavoring principle has been removed.

Commercial Flavor Designation:

Natural ABCD flavor: All components derived from ABCD

ABCD flavor, natural and artificial: At least one component derived from ABCD.
NO definition of natural to artificial ratio

ABCD flavor, WONF: All components natural. At least one component derived
from ABCD

Natural flavor, ABCD Type: All components are natural. No components derived
from ABCD

ABCD flavor, artificial: All components are artificial

Conceptual flavors: May contain artificial flavors. No reference point. May

only have to declare in ingredient declaration

Water soluble flavors: Generally start at 0.2% for artificial and 1-2% for natural
flavors.

Oil-soluble flavors: Generally start at 0.1% in finished product for artificial flavors
and 0.2% for natural flavors

Powdered flavors: Generally start at 0.1% in finished product for artificial flavors
and o.75% for natural flavors.

Sweetening agents used for pharmaceutical

manufacturing:

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They are used for taste masking of bitter drug
particles. Following is the list of sweetening agents:-

Sweeteners:

Bulk sweeteners:

 Sugars such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose,

sucrose,maltose

 Hydrogenated glucose syrup

 Sugar alcohols such as sorbitol, xylitol, mannitol and glycerin

 Partially hydrolysed starch

 Corn syrup solids

Artificial sweetening agents:

 Sodium cyclamate

 Na saccharin

 Aspartame

 Ammonium glycyrrhizinate

 Mixture of thereof

A bulk sweeter is used at concentration of 15-70 %

w/w of the total weight of the suspension. This concentration is dependent on
presence of other ingredient such as alginate, which have thickening effect.
For example, in presence of alginate, sorbitol is used at concentration of 35-55 %
particularly at 45 % w/w of the total suspension composition.

Hydrogenated glucose syrup can be used at

concentration of 55-70 % w/w, when alginate is absent.

Combination of bulk sweeteners can also be used. E.g. Combination of sorbitol and
hydrogenated glucose syrup or sucrose and sorbitol. Generally the taste-masking
composition consists of at least one sweetening agent and at least one flavoring
agent. The type and amount of flavoring and coloring agent is dependent on
intended consumer of such suspension e.g. pediatric or adult.

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Sugar sweetener concentration is dependent on the
degree of sweetening effect required by particular suspension. The preferred
amount of sugar sweetener should be between 40 to 100 gm per 100 mL of the
suspension. Water soluble artificial sweeteners can also be added in place of
sugar sweetener or in addition to them.

The amount of artificial sweetening agents should be between 0 to 5 gms per 100
mL of suspension. Optimum taste-masking of API in the suspension can be obtained
by limiting the amount of water in the suspension, but the amount of water must
not be too low to hydrate MCC, Na CMC or other suitable suspending agent. The low
amount of water should provide a sufficient aqueous base to impart desired degree
of viscosity. The preferred total amount of water contained in the suspension should
be between 30 to 55 grams per 100 mL of suspension.

Antioxidants used for pharmaceutical

manufacturing:

An antioxidant is a molecule capable of inhibiting the oxidation of other molecules.

Oxidation is a chemical reaction that transfers electrons from a substance to an
oxidizing agent. Oxidation reactions can produce free radicals. In turn, these
radicals can start chain reactions that damage cells. Antioxidants terminate these
chain reactions by removing free radical intermediates, and inhibit other oxidation
reactions. They do this by being oxidized themselves, so antioxidants are often
reducing agents such as thiols, ascorbic acid or polyphenols.

Although oxidation reactions are crucial for life, they can also be damaging; hence,
plants and animals maintain complex systems of multiple types of antioxidants,
such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase,
superoxide dismutase and various peroxidases. Low levels of antioxidants, or
inhibition of the antioxidant enzymes, cause oxidative stress and may damage or
kill cells.

As oxidative stress might be an important part of many human diseases, the use of
antioxidants in pharmacology is intensively studied, particularly as treatments for
stroke and neurodegenerative diseases. However, it is unknown whether oxidative
stress is the cause or the consequence of disease.

Antioxidants are widely used as ingredients in dietary supplements in the hope of

maintaining health and preventing diseases such as cancer, coronary heart disease
and even altitude sickness. Although initial studies suggested that antioxidant
supplements might promote health, later large clinical trials did not detect any
benefit and suggested instead that excess supplementation may be harmful. In
addition to these uses of natural antioxidants in medicine, these compounds have

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many industrial uses, such as preservatives in food and cosmetics and preventing
the degradation of rubber and gasoline.

Classification:

Antioxidants are classified into two broad divisions, depending on whether they are
soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble
antioxidants react with oxidants in the cell cytosol and the blood plasma, while lipid-
soluble antioxidants protect cell membranes from lipid peroxidation. These
compounds may be synthesized in the body or obtained from the diet. The different
antioxidants are present at a wide range of concentrations in body fluids and
tissues, with some such as glutathione or ubiquinone mostly present within cells,
while others such as uric acid are more evenly distributed (see table below). Some
antioxidants are only found in a few organisms and these compounds can be
important in pathogens and can be virulence factors.

The relative importance and interactions between these different antioxidants is a

very complex question, with the various metabolites and enzyme systems having
synergistic and interdependent effects on one another. The action of one
antioxidant may therefore depend on the proper function of other members of the
antioxidant system. The amount of protection provided by any one antioxidant will
also depend on its concentration, its reactivity towards the particular reactive
oxygen species being considered, and the status of the antioxidants with which it
interacts.

Some compounds contribute to antioxidant defense by chelating transition metals

and preventing them from catalyzing the production of free radicals in the cell.
Particularly important is the ability to sequester iron, which is the function of iron-
binding proteins such as transferrin and ferritin. Selenium and zinc are commonly
referred to as antioxidant nutrients, but these chemical elements have no
antioxidant action themselves and are instead required for the activity of some
antioxidant enzymes, as is discussed below.

Diluents used for pharmaceutical manufacturing:

A diluents (also referred to as filler, dilutant or thinner) is a diluting agent.

Certain fluids are too viscous to be pumped easily or too dense to flow from one
particular point to the other. This can be problematic, because it might not be
economically feasible to transport such fluids in this state.

To ease this restricted movement, diluents are added. This decreases the viscosity
of the fluids, thereby also decreasing the pumping/transportation costs.

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One industrial application is the transport of crude oil via pipelines. Heavy crude
oil/bitumen are fluids with high viscosity, especially at low temperatures. The
addition of a diluent enables the diluted fluid (dilbit in the case of bitumen) to meet
pipeline specifications in order for it to be efficiently transported. Typical diluents in
this case is naphtha or condensate.

Types of diluents more familiar to the general public include paint thinner and nail
polish thinner, both of which improve the consistency and applicability of the
products to which they are added.

Diluents are also used as a term in solvent extraction for an inert solvent in which a
metal extraction agent (extractant) is dissolved in. In solvent extraction the diluents
has potentially several uses. It can be used as a solvent (in the purely chemical
sense rather than the solvent extraction sense) to dissolve an extractant which is a
solid and so render it suitable for use in a liquid-liquid extraction process. In other
cases such as PUREX nuclear reprocessing the diluent (kerosene) is used to reduce
the maximum metal loading which the organic layer can reach. If the organic layer
was to acquire too much metal then a solid metal complex might form, or more
worryingly in a nuclear process the potential for a criticality accident if the fissile
metal concentration in the organic phase becomes too high.

Uses of diluents in Pharmaceuticals

Diluents are also very important in the pharmaceutical industry. They are inactive
ingredients that are added to tablets and capsules in addition to the active drug. For
example, a Tylenol 325 mg tablet does not weigh 325 mg. This is the weight of the
active acetaminophen, while the tablet weighs more due to other additives known
as diluents. These additives may be used as binders, disintegrants (help the tablet
break apart in the digestive system), or flavor enhancers. Some very common
diluents in tablets include starch, cellulose derivatives, and magnesium stearate (a
lubricant). (See also Excipient.)

In the black market in illegal drugs such as cocaine, drugs may be "cut" with
diluents or fillers to give the appearance of a larger quantity.

Diluents are also used in vaccines to reconstitute the vaccine after storage, such as
MMR.

Preservatives used for pharmaceutical

manufacturing:

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The naturally occurring suspending agents such as tragacanth, acacia,
xanthan gum are susceptible to microbial contamination. If suspension is not
preserved properly then the increase in microbial activity may cause stability
problem such as loss in suspending activity of suspending agents, loss of
color, flavor and odor, change in elegance etc. Antimicrobial activity is
potentiated at lower pH.

The preservatives used should not be

 Adsorbed on to the container

 It should be compatible with other formulation additives.

 Its efficacy should not be decreased by pH.

This occurs most is commonly in antacid suspensions because the pH of antacid

suspension is 6-7 at which parabens, benzoates and sorbates are less active.
Parabens are unstable at high pH value so parabens are used effectively when pH is
below 8.2. Most commonly observed
incompatibility of PABA (Para amino benzoic acid) esters is with non-ionic
surfactant, such as polysorbate 80, where PABA is adsorbed into the micelles of
surfactant. Preservative efficacy is expected to be maintained in glass container if
the closure is airtight, but now a days
plastic container are widely used where great care is taken in selection of
preservative. The common problem associated with plastic container is permeation
of preservatives through container or adsorption of preservatives to the internal
plastic surface. The use of cationic antimicrobial agents is limited because as they
contain positive charge they alter surface charge of drug particles. Secondly they
are incompatible with many adjuvants.

Most common incidents, which cause loss in preservative action, are,

 Solubility in oil

 Interaction with emulsifying agents, suspending agents

 Interaction with container

 Volatility

Active form of preservative may be ionized or unionized form.

For example active form of benzoic acid is undissociated

form. The pKa of benzoic acid is 4.2. Benzoic acid is active below pH 4.2 where
it remains in unionized form.

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The combination of two or more preservative has many
advantages in pharmaceutical system such as

 Wide spectrum of activity

 Less toxicity

 Less incidence of resistance

 Preservatives can be used in low concentration.

For example, older formulation of eye drops, contain combination of methyl and
propyl paraben, which provide antifungal and antibacterial property. Now a days,
combination of phenylethyl alcohol, phenoxetol and benzalkonium chloride are used
in eye drops. EDTA (ethylenediaminetetra-acetate) is also used in combination with
other preservative.

Propylene glycol is added to emulsions containg parabens to reduce loss to

micelles.

Probable Modes Of Action Of Some Preservatives

1. Benzoic acid, boric acid, p-hydroxybenzoates: Denaturation of proteins

2. Phenols, chlorinated phenolic compounds: lytic, denaturation action on

cytoplasmic membranes and for chlorinated preservatives, also by
oxidation of enzymes

3. Alcohols: lytic and denaturation action on membranes

Quaternary compounds: Lytic action on membranes

5. Mercurials: Denaturation of enzymes by combining with thiol (-SH) groups

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List Of Preservatives

Name of preservatives Concentration range

Propylene 5-10
glycol %
Disodium 0.1
edentate %
Benzalkonium 0.01-0.02
chloride %
Benzoic 0.1
acid %
Butyl 0.006-0.05
paraben % oral suspension

0.02-0.4
% topical formulation
Cetrimide 0.005
%
Chlorobutanol 0.5
%
Phenyl 0.001-0.002
mercuric acetate %

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 Potassium 0.1-0.2
sorbate %
Sodium 0.02-0.5
benzoate %
Sorbic 0.05-0.2
acid %
Methyl 0.015-0.2
paraben %

Table: Preservatives and their optimal concentration.

References:

 en.wekipedia.org

 Encyclopedia of pharmaceutical manufacturing. Third edition,A-H

 American Academy of Pediatrics, Committee on Drugs "Inactive" ingredients

in pharmaceutical products. Pediatrics 1985; 76:635-643

 Brown JL Incomplete labeling of pharmaceuticals: a list of "inactive"

ingredients. N Engl J Med. 1983; 309:439-441

 Food and Drug Administration Sulfite update. FDA Drug Bull. 1984; 14:24

 Subramanyam C.V.S., Second edition, “Suspensions” Text Book of Physical

Pharamaceutics, Page

 No. 374-387.

 www.google.com

 Introduction to pharmaceutics third edition.

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