IMPACT OF FORMULATION INGREDIENTS ON QUALITY OF THE ...

www.wjpps.com Vol 4, Issue 03, 2015.

468

Shah et al. World Journal of Pharmacy and Pharmaceutical Sciences

IMPACT OF FORMULATION INGREDIENTS ON QUALITY OF THE

PARENTERAL PRODUCTS

Shah Neel Virendrakumar*, Solanki Himanshu, Prajapati Vipul, Jani Girish,

Solanki Sarvangi

SSR College of Pharmacy, Sayli, Silvassa, U.T of Dadra and Nagar Haveli-396230,

India.

ABSTRACT

Excipients are the integral part of pharmaceutical products

development to achieve desired product profile. This review discusses

the role of such excipients as well as the impact of formulation

ingredient on quality of the parenteral product. The role of excipients

such as bulking agents, buffering agents, tonicity modifiers,

antimicrobial agents, surfactants and co-solvents as well as their

impact on the quality of the products has also been discussed.

Development of parenteral preparations typically requires specific

consideration on the type and quality of excipients used. Excipients

play a critical role in the creation of medicines, helping to preserve the

efficacy, safety and stability of active pharmaceutical ingredients and

ensuring that they delivered their promised benefits to patients. A careful choice of

excipients is crucial for the development of effective and innovative pharmaceuticals. In spite

of proper excipients selection, judicious use during formulation manufacturing process based

on their critical properties is also important to avoid negative effects such as loss of drug

solubility, activity and stability. To deliver parenteral drugs to the final consumer, with intact

product quality has remained a prime concern for every parenteral drug manufacturer.

KEYWORDS: Parenterals, Excipients, Formulation development, Quality.

INTRODUCTION

The term comes from the Latin word excipiens, present participle of the verb excipere which

means to receive, to gather, to take out. This refers to one of the properties of an excipient,

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Article Received on

30 Dec 2014,

Revised on 25 Jan 2015,

Accepted on 18 Feb 2015

*Correspondence for

Author

Shah Neel

Virendrakumar

SSR College of Pharmacy,

Sayli, Silvassa, U.T of

Dadra and Nagar Haveli-

396230, INDIA.


469


which is to ensure that a medicinal product has the weight, consistency and volume necessary

for the correct administration of the active principle to the patient. In 1957, excipients were

defined as „the substance used as a medium for giving a medicament‟, that is to say with

simply the functions of an inert support of the active principle or principles.[1]

Again, in 1974

they are described as „any more or less inert substance added to a prescription in order to

confer a suitable consistency or form to the drug: a vehicle.

The International Pharmaceutical Excipients Council defines excipients as "substances, other

than the active drug substance of finished dosage form, which have been appropriately

evaluated for safety and are included in a drug delivery system to either aid the processing of

the drug delivery system during its manufacture; protect; support; enhance stability;

bioavaibility; andor patient acceptability; assist in product identification.

Parenteral preparations are sterile preparations intended for administration by injection,

infusion or implantation into the human or animal body, Types of sterile products are listed in

Table 1.

Table 1: Types of Sterile Products

Parenterals

Packaged in a manner for administration via hypodermic

injection either inthe form prepared or after addition of a

suitable solvent or suspending agent

Ophthalmics Intended for instillation in the eye

Irrigating solutions Contact with blood vessels of wounds or abraded

mucous membranes

Topicals for exposed

tissue

Ointments, gels or creams for burns, would healing and

other skin damage

IV Systems Administration devices

Implants A matrix for insertion into a defect site

Pulmonary dosage forms Inhalation delivery systems

Parenteral preparations may require the use of excipients, for example to make the

preparation isotonic with blood, to adjust the pH, to increase solubility, to prevent

deterioration of the active substances or to provide adequate antimicrobial properties but not

to adversely affect the intended medicinal action of the preparation or, at the concentrations

used, to cause toxicity or undue local irritation.[1,2]

Parenteral medications are products which are introduced in a manner which circumvents

the body‟s most protective barriers, the skin and mucous membranes, and, therefore, must be

“essentially” free of biological contamination. Most are injected or placed into the body


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tissues and do not pass through the liver before entering the bloodstream. This can include

injections, topical and inhalation routes. Drugs given by parenteral route are quickly absorbed

by the body. The major routes of parenteral administration of drugs are subcutaneous,

intramuscular, and intravenous. Other more specialized routes are intrathecal, intracisternal,

intra-arterial, intraspinal, intraepidural and intradermal.[3,4]

They must be exceptionally pure and free from physical, chemical, and biological

contaminants. These requirements place a heavy responsibility on the pharmaceutical

industry to practice current good manufacturing practices (cGMPs) in the manufacture of

parenteral dosage forms and on pharmacists and other health care professionals to practice

good aseptic practices (GAPs) in dispensing parenteral dosage forms for administration to

patients.[5]

Development of injectable preparations or formulations typically requires specific

considerations on the type and quality of excipients used. The criteria for excipients selection

depend on a number of factors, including the type of drugs and route of injection. A number

of devices can be used to inject drugs, from conventional needle and syringe to needle-free

injectors. All these factors play a vital role in the selection of the excipients for injectable

formulations. The container-closure system may vary from a lyophilized vial to a prefilled

syringe or a flexible plastic bag.[6]

Excipients are vital of drug formulations which mean that the selection, concentration and the

quality of the excipients may directly influence the outcome of pharamacotherapy. Any

change in one of the components, including changes in excipients quantity or quality, may

affect the finished product's quality, safety or efficacy. In order to discuss the impact of an

excipient change, first the specific function of that excipient in the formulation and

manufacturing process has to be understood. These functions are different for each excipient,

but may depend on the formulation.[7]

Excipients used in injectable formulations have to meet

several stringent requirements. It is important that manufacturers identify and set appropriate

limits for impurities. These limits should be based upon appropriate toxicological data, or the

limits described in national compendial requirements. Solvents or catalysts used in the

excipient production process should be removed to appropriate levels. If naturally derived,

excipients should meet endotoxin levels and may require further testing for bovine

spongiform encephalopathy (BSE) / transmissible spongiform encephalopathy (TSE)

considerations.[8]


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Certain pharmaceutical agents, particularly peptides, proteins, and many chemotherapeutic

agents, can only be given parenterally, because they are inactivated in the gastrointestinal

tract when given by mouth. Parenterally-administered drugs are relatively unstable and

generally highly potent drugs that require strict control of administration to the patient. Due

to the advent of biotechnology, parenteral products have grown in number and usage around

the world.[9-12]

2. Criteria for the selection of excipient

The following key points should be considered in selecting an excipient for parenteral

products:

Influence of excipient on the overall quality, stability, and effectiveness of drug product.

Compatibility of excipient with drug and the packaging system.

Compatibility of excipient with the manufacturing process, for example, preservatives

may be absorbed by rubber tubes or filters, acetate buffers will be lost during

lyophilization process, etc.

The amount or percentage of excipients that can be added to the drug product.

Route of administration. The USP, Ph. Eur BP do not allow preservatives to be present in

injections intended to come in contact with brain tissues or CSF. Thus intracisternal,

epidural, and intradural injections should be preservative free. Also, it is preferred that a

drug product to be administered via intravenous (iv) route be free of particulate matter.

However, if the size of the particle is well controlled, like in fat emulsion or colloidal

albumin or amphotericin B dispersion, it can be administered by iv infusion.

Dose volume. All LVPs and those SVPs where the single dose injection volume can be

greater than 15 ml are required by the EP/BP to be preservative free (unless justified).

Whether the product is intended for single or multiple dose use. According to USP, single

dose injections should be free of preservative. The FDA takes the position that even

though a single dose injection may have to be aseptically processed, the manufacturer

should not use a preservative to prevent microbial growth. European agencies have taken

a more lenient attitude on this subject.

The length or duration of time that the drug product will be used once the multidose

injection is opened.[13-15]


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3. Formulation ingredients used in parenteral formulation

Excipients are the integral part of pharmaceutical products development to achieve desired

product profile (stability and efficacy). Excipients are typically the major components in a

drug product. Many formulations contain only a small percentage of the active drug

molecules. Pharmaceutical excipients or additives are compounds added to the finished drug

products to serve a specific function. They are added to increase bulk, aid manufacturing,

improve stability, enhance drug delivery and targeting, and modify drug safety or

pharmacokinetic profile. Ingredients that are used during drug product manufacturing but

may not be present in the finished drug product are also considered excipients.

Excipients are traditionally referred to as inactive or inert ingredients to distinguish them

from active pharmaceutical ingredients. Excipients may not be as inert as the term inactive

suggests. Due to safety issues, several countries have restrictions on the type or amount of

excipient that can be included in the formulation of parenteral drug product. For example, in

Japan, the U.S., and the E.U., amino mercuric chloride or thiomersal use is prohibited, despite

the presence of these excipients in products in other regions.[16,17]

Injectable products require a unique formulation strategy. The formulated product must be

sterile, pyrogen-free, and, in the case of solution, free of particulate matter. No coloring agent

may be added solely for the purpose of coloring the parenteral preparation. The formulation

should preferably be isotonic, and depending on the route of administration, certain

excipients are not allowed. The injected drug by-passes natural defense barriers; hence, for

any given drug, the risk of an adverse event may be greater or the effects difficult to reverse

if administered as an injection rather than a non-parenteral route. For this reason ultra high

purity grades of excipients are available for parenteral administration. Sterility requirements

demand that an excipient is able to withstand terminal sterilization or aseptic processing.

These factors limit the choice of excipients available.[18,19]

Excipients which are already present in marketed formulations and accepted by the Food and

Drug Administration (FDA) as safe, increases the assurance to a formulator that these

excipients will probably be safe for a new drug product. But, this does not give complete

assurance when combined with other excipients or drug molecules as this may lead to

unwanted potentiation or synergistic toxic effects. However, regulatory bodies may favorably

view an excipient previously approved in an injectable dosage form, and will require less

safety data. A new additive in a formulated product always requires additional studies, adding


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to the cost and timeline of product development. Importantly, inclusion of an excipient in the

GRAS (Generally Recognized as Safe) list or pharmacopoeia does not mean that the

excipient has been deemed safe by the FDA for use in parenteral products.

Sterile formulations must meet a number of special criteria such as.

a. Sterility

b. Particulate material

c. Pyrogen free

d. Stability

e. pH

f. Osmotic pressure

During the formulation of parenteral products, the following factors are critical:

(a) The vehicle in which the drug is dissolved or dispersed

(b) Volume (dose) of the injection

(c) Adjustment to isotonicity

(d) Adjustment of pH

(e) Stabilisers

(f) Preservatives

(g) Adjustment of specific gravity (for spinal anaesthesia)

(h) Concentration units

3.1. Excipient used in formulation of Parenteral Preparation:

3.1.1. Vehicles

a. Water

b. Water miscible vehicles

c. Non- aqueous vehicles

3.1.2. Added substances (Additives)

a. Antimicrobials

b. Antioxidants

c. Buffers

d. Bulking agents

e. Chelating agents

f. Protectants


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g. Solubilizing agents

h. Surfactants

i. Tonicity- adjusting agents

3.1.1. Vehicle/solvents

The Selected Vehicles Should be

1. Non-irritating

2. Non toxic

3. Non-sensitizing

4. Must no exert pharmacological activity

5. It must not affect the activity of medicinal agents

6. Physically and chemically stable at various pH levels.

7. Its viscosity must be such as to allow ease of injection (syringeability)

8. Its fluidity must be maintained over a wide temperature

9. Its boiling point must be sufficiently enough to permit heat sterilization

a). Aqueous solvents

Water is used as vehicle for majority of injections because;

o It is tolerated well by the body and

o It is safest to administer.

But aqueous vehicles – Water used for making of parenteral preparations must comply

with all specifications available in Pharmacopoeia (USP);

o Free from dissolved gases (CO2 (g))

o Free from volatile and non-volatile impurities

o Free from Pyrogens (Meet the requirement of the pyrogen test <151> OR the bacterial

endotoxin test <85> of USP)

The preferred vehicle is water as it is well tolerated by the body and easy to administer.

Water-miscible vehicles

A number of solvents that are miscible with water have been used as a portion of the vehicle

in the formulation of parenterals. These solvents are used to solubilize certain drugs in an

aqueous vehicle and to reduce hydrolysis. The most important solvents in this group are ethyl

alcohol, liquid polyethylene glycol, and propylene glycol. Ethyl alcohol is used in the

preparation of solutions of cardiac glycosides and the glycols in solutions of barbiturates,


475


certain alkaloids, and certain antibiotics. Such preparations are given intramuscularly. There

are limitations with the amount of these co-solvents that can be administered, due to toxicity

concerns, greater potential for hemolysis, and potential for drug precipitation at the site of

injection.

Nonaqueous vehicle

Ideal properties

1. Nonirritating, nontoxic, no pharmacological effect, stable

2. Allow ease of injection

3. Its boiling point should be sufficiently high to permit heat sterilization

4. Should have low vapour pressure to avoid problems during sterilization

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Additives are essential for almost every product to enhance its stability.

They must exhibit the following characteristics.

1. Perform its function throughout the useful life of the product

2. Must be non-toxic and non-irritating

3. Must not exert any adverse effect on the product

4. Must be compatible in all components of the formulation

5. Must not interfere with

a. Therapeutic efficacy

b. Assay of the active therapeutic compound(20)

Antimicrobial Agents

The USP states that antimicrobial agents in bacteriostatic or fungistatic concentrations must

be added to preparations contained in multiple-dose containers. The European Pharmacopeia


476


requires multiple-dose products to be bacteriocidal and fungicidal. They must be present in

adequate concentration at the time of use to prevent the multiplication of microorganisms

inadvertently introduced into the preparation, while withdrawing a portion of the contents

with a hypodermic needle and syringe. The USP provides a test for Antimicrobial

Preservative Effectiveness to determine that an antimicrobial substance or combination

adequately inhibits the growth of microorganisms in a parenteral product. Because

antimicrobials may have inherent toxicity for the patient, the USP prescribes maximum

volume and concentration limits for those commonly used in parenteral products. (e.g.,

phenylmercuric nitrate and thimerosal 0.01%, benzethonium chloride and benzalkonium

chloride 0.01%, phenol or cresol 0.5%, and chlorobutanol 0.5%).[21]

The above limit is rarely used for phenylmercuric nitrate, most frequently employed in a

concentration of 0.002%. Methyl p-hydroxybenzoate 0.18% and propyl p-hydroxybenzoate

0.02%, in combination, and benzyl alcohol 2% are also used frequently. Benzyl alcohol,

phenol, and the parabens are the most widely used antimicrobial preservative agents used in

injectable products. Although the mercurials are still allowed to be used in older products,

they are not used for new products, due to concerns regarding mercury toxicity.

Buffers are used to stabilize a solution against chemical degradation or, especially for

proteins, physical degradation (i.e., aggregation and precipitation) which might occur if the

pH changes appreciably. Buffer systems should have as low a buffering capacity as feasible,

so as not to significantly disturb the body‟s buffering systems when injected. In addition, the

buffer type and concentration on the activity of the active ingredient must be evaluated

carefully. Buffer components are known to catalyze degradation of drugs. The acid salts most

frequently employed as buffers are citrates, acetates, and phosphates. Amino acid buffers,

especially histidine, have become buffer systems of choice for controlling solution pH of

monoclonal antibody solutions.

Anitoxidants are frequently required to preserve products, due to the ease with which many

drugs, including proteins with methionine or cysteine amino acids conformationally exposed,

are oxidized. Sodium bisulfite and other sulfurous acid salts are used most frequently.

Ascorbic acid and its salts are also good antioxidants. The sodium salt of

ethylenediaminetetraacetic acid (EDTA) has been found to enhance the activity of

antioxidants.


477


Displacing the air (oxygen) in and above the solution, by purging with an inert gas, such as

nitrogen, can also be used as a means to control oxidation of a sensitive drug. Process control

is required for assurance that every container is deaerated adequately and uniformly.

However, conventional processes for removing oxygen from liquids and containers do not

absolutely remove all oxygen. The only approach for completely removing oxygen is to

employ isolator technology, where the entire atmosphere can be recirculating nitrogen or

another non-oxygen gas [22]

.

Tonicity Agents are used in many parenteral products to adjust the tonicity of the solution.

Although it is the goal for every injectable product to be isotonic with physiologic fluids, this

is not an essential requirement for small volume injectables administered intravenously.

However, products administered by all other routes, especially into the eye or spinal fluid,

must be isotonic. Injections into the subcutaneous tissue and muscles should also be isotonic

to minimize pain and tissue irritation. The agents most commonly used are electrolytes and

mono or disaccharides [23]

.

Bulking Agents and Lyoprotectants

Bulking agents forms the bulk of the lyophilized product and provide an adequate structure to

the cake. These are generally used for low dose (high potency) drugs that do not have the

necessary bulk to support their own structure. These are particularly more important when the

total solid content is less than 2%.[24]

In such cases, a bulking agent is added to the

formulation matrix. The structure of the lyophilized cake is important, since proper cake

formation leads to proper pore formation that provides the means for vapor to escape from

the product during the drying cycle. Lyoprotection is defined as the stabilization and

prevention of the degradation of a molecule both during freeze-drying and afterwards, during

storage. Among disaccharides, sucrose and trehalose appear to be the most commonly used.

In comparison to sucrose, trehalose seems to be a preferable lyoprotectant, because it has a

less hygroscopicity, very low chemical reactivity and finally, higher glass transition

temperature (Tg′).[25]

Critical temperature is the temperature above which the freeze-dried

product loses macroscopic structure and collapses during freeze drying. Therefore, the

excipients which provide higher critical temperature are preferred for lyophilization.

Mannitol: it is the most commonly and widely used excipient in the lyophilized products.

Mannitol has a very high eutectic melting temperature (-1.4°C) after crystallization and is

processed well in lyophilization. Crystallization of the bulking agent, however, might


478


adversely affect the physical stability of the product in certain instances, for which, an

amorphous bulking agent is preferred.[21]

Lactose: It is a good bulking agent but is a reducing sugar and may undergo Maillard

reaction with proteins leading to instability of the formulation. The critical temperature of 1%

lactose is -32°C.[22]

Sucrose: It is having similar collapse temperature i.e -31°C (2%) as of lactose but it is not a

reducing sugar and does not undergo Maillard reaction.[23]

Sucrose has a higher density as

compared to lactose which can cause slight collapse during drying.

Polyethylene glycol (PEG): It provides good cake structure and increases viscosity of

water.[24]

The 2% solution of PEG has a critical temperature of -22°C. Apart from

lyophilization it is also used as a co-solvent and viscosity modifier in parenteral including

ophthalmics.

Polyvinyl pyrollidone (PVP): The low-molecular grades, Povidone K 12 and K 17 are used

as solubilizing agents, dispersants and crystallization inhibitors, particularly for injectables.

This application is used in particular for antibiotics in solution or in lyophilized form.

Povidones with higher K-values may not be administered parenterally as, due to their high

molecular weights, they cannot be excreted by the kidneys and hence accumulate within the

body. The povidone grades K12 and K 17 are used as solubilizers in parenteral applications.

In addition Polyvinyl pyrollidone also provides cryo-protection to the product.

Flocculating/suspending agents

The controlled flocculation approach uses a flocculating agents, to from loosely bound

aggregate or flocs in a controlled manner that settles rapidly but redisperses easily upon

agitation. An appropriate amount or flocculating agent is added that result in maximum

sedimentation volume & prevents cake formation. Electrolytes, surfactant and hydrophilic

colloids have been typically used as flocculating agents. Electrolytes & surfactants reduce the

electrical forces of repulsion between particles & allow the flocs to form, which in turn is

influenced by the surface charge on the particles. E.g. Electrolytes used in Parenteral

Suspensions. Potassium/sodium chloride, Potassium/sodium acetate.[26-28]

The surface charge of the system can be measured by the zeta potential. The zeta potential

must be controlled so as to lie within a range (generally less than 25 mV) to obtain a

flocculated, noncaking suspension with maximum sedimentation. Hydrophilic colloids


479


(generally negatively charged) not only affect the repulsive force but also provide mechanical

barrier to the particles. Some viscosity building agents used in formulation of injectable

suspension are.

• Sodium carboxymethyl cellulose

• Acacia

• Gelatin

• Methyl cellulose

• Polyvinyl pyrrolidone

Wetting Agents

Various nonionic surfactants and non-aqueous solvents like glycerin, alcohol & propylene

glycol are types of wetting agents commonly used in injectable suspensions. Wetting agents

reduce the contact angle between the surface of the particle & the wetting liquid to obtain

maximum wetting efficiency; surfactants with hydrophilic lipophilic balance (HLB) value in

the range of 7 to 9 should be selected. The usual concentration of surfactants varies from

0.05% to 0.5% depending on the solid contents of the suspension. excessive amounts may

cause foaming or caking or provide an undesirable taste/odor to the product.[29]

Surfactants (wetting agent)

Lecithin, Polysorbate 20, Polysorbate 80, Pluronic F-68, Sorbitan trioleate (span 85) are used,

as surfactants in injectable suspensions for e.g. in the preparation of a non-aqueous

suspension of Cefazolin sodium in peanut oil, addition of polysorbate 80 at concentration

greater than 0.17% resulted in deflocculated suspension which was difficult to redisperse.[30-

32]

CONCLUSION

The parenteral route of administration is the most effective route for the delivery of the active

pharmaceutical substances with narrow therapeutic index, poor bioavailability especially for

those drugs, prescribed to unconscious patients. Development of injectable preparations or

formulations typically requires specific considerations on the type and quality of excipients

used. The criteria for excipients selection depend on a number of factors, including the type

of drugs and route of injection.

Medicinal products can be considered a dosed combination of two types of constituents: the

active principles and the excipients. The latter are the more important as far as weight is


480


concerned, whether in solid forms, suspensions or solutions. The ideal excipient should be

able to fill numerous and important functions, first among which that of guaranteeing the

dose, stability and release of the active principle, and the patient‟s „compliance‟.

Furthermore, it should possess particular chemical, physical and mechanical characteristics,

so as to optimise the formulation‟s „performance‟ both during the manufacturing phase and

when used by the patient. This multiplicity of roles fits very ill with the traditional galenic

view, that saw these „non medicinal ingredients‟ as chemically and pharmaco-toxicologically

inert.

The present article describes the effect of formulation ingredients means ingredients other

than active pharmaceutical ingredient on the quality of the parenteral product. It is more

impartment to use good quality as well as appropriate grade of the excipients which is

compatible with drug for producing good quality of parenterals. Parenterals are the pyrogen

free liquids, these are manufactured and stored according to cGMP guidelines.

Antimicrobial preservatives are used in a significant number of parenteral products, including

peptide, protein, vaccine, and small molecule formulations. The overall dominated

concentration range of the preservatives used is between 0.002% and 1% although in a few

cases, the preservative concentration used is beyond 1%. It was also demonstrated that

various analytical and biophysical assays may be used to monitor the impact of a preservative

on the active ingredient, whether it be a protein or small molecule pharmaceutical.

Antimicrobial preservatives continue to play an important role in multi-dose pharmaceuticals.

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