1

Introduction

An antiemetic is a drug that is effective against vomiting and

nausea. Antiemetics are typically used to treat motion sickness and the

side effects of analgesics, general anaesthetics, and chemotherapy

directed against cancer. Anti-emetics are also used for morning

sickness, but there is little information about the is effect on foetus, and

doctors prefer not to use them unless it is strictly necessary.[1]

Antiemetics include:

5-HT3 receptor antagonists – these block serotonin receptors in

the central nervous system and gastrointestinal tract. As such,

they can be used to treat post-operative and cytotoxic drug

nausea & vomiting. However, they can also cause constipation,

diarrhea, drymouth, and fatigue. [2]

o Dolasetron (Anzemet) - can be administered in tablet form or in

an injection.

o Granisetron (Kytril, Sancuso) - can be administered in tablet

(Kytril), oral solution (Kytril), injection (Kytril), or in a single

transdermal patch to the upper arm (SANCUSO).

o Ondansetron (Zofran) - administered in an oral tablet form, oral

dissolving tablet form, or in an injection.

o Tropisetron (Navoban) - can be administered in oral capsules or

in injection form.

o Palonosetron (Aloxi) - can be administered in an injection or in

oral capsules.

2

o Mirtazapine (Remeron), an antidepressant that also has

antiemetic effects.

Dopamine antagonists act in the brain and are used to treat

nausea and vomiting associated with neoplastic disease, radiation

sickness, opioids, cytotoxic drugs and general anaesthetics. Side

effects include Muscle Spasms and Restlessness. [2]

o Domperidone

o Olanzapine

o Droperidol, haloperidol, chlorpromazine, promethazine,

prochlorperazine. Some of these drugs are limited in their

usefulness by their extra-pyramidal and sedative side-effects.

o Metoclopramide (Reglan) also acts on the GI tract as a pro-

kinetic, and is thus useful in gastrointestinal disease; however, it

is poor in cytotoxic or post-oprative vomiting.

o Alizapride

o Prochlorperazine (Compazine, Stemzine, Buccastem, Stemetil,

Phenotil)

NK1 receptor antagonist

o Aprepitant (Emend) Commercially available NK1 Receptor

antagonist

o Casopitant Investigational NK1 receptor antagonist

Antihistamines (H1 histamine receptor antagonists), effective in

many conditions, including motion sickness, morning sickness in

pregnancy, and to combat opioid nausea.

3

o Cyclizine

o Diphenhydramine (Benadryl)

o Dimenhydrinate (Gravol, Dramamine)

o Meclozine (Bonine, Antivert)

o Promethazine (Pentazine, Phenergan, Promacot) Promethazine

can be administered via a rectal suppository for adults and

children over 2 years of age.

o Hydroxyzine

Cannabinoids are used in patients with cachexia, cytotoxic

nausea, and vomiting, or who are unresponsive to other agents.

These may cause changes in perception, dizziness, and loss of

coordination. [2]

o Cannabis - Medical marijuana, in the U.S., it is a Schedule I

drug.]

o Dronabinol (Marinol) - a Schedule III drug in the U.S

o Some synthetic cannabinoids such as Nabilone (Cesamet) or the

JWH series.

o Sativex is an oral spray containing THC and CBD. It is

currently legal in Canada and a few countries in Europe but not

legal in the United States.

Benzodiazepines

o Midazolam given at the onset of anesthesia has been shown in

recent trials to be as effective as ondansetron Lorazepam said to

4

be very good as an adjunct treatment for nausea along with first

line medications such as Compazine or Zofran]

Anticholinergics

o Hyoscine (also known as scopolamine)

Steroids

o Dexamethasone given in low dose at the onset of a general

anaesthetic is an effective anti-emetic. The specific mechanism

of action is not fully understood.

o Trimethobenzamide; thought to work on the CTZ

o Ginger - contains 5HTantagonists gingerols and shogaols. [3]

o Emetrol also claimed to be an effective antiemetic.

o Propofol given intravenously. It has been used in an acute care

setting in hospital as a rescue therapy for emesis.

o Peppermint claimed to help nausea or stomach pain when added

into tea or peppermint candies.

o Muscimol purported as such. [4]

o Ajwain purported to be antiemetic. It is a popular spice in India,

Ethiopia and Eritrea.

Non-pharmaceutical therapies with some evidence of efficacy

include acupuncture and hypnosis.

Granisetron is a serotonin 5-HT3 receptor antagonist used as an

antiemetic to treat nausea and vomiting following chemotherapy. Its

main effect is to reduce the activity of the vagus nerve, which is a nerve

that activates the vomiting center in the medulla oblongata. It does not

5

have much effect on vomiting due to motion sickness. This drug does

not have any effect on dopamine receptors or muscarinic receptors.

Granisetron was developed by chemists working at the British Drug

Company Beecham around 1988 and is available as a generic. It is

produced by Roche Laboratories under the trade name Kytril. The drug

was approved in the United Kingdom in 1991 and in United States in

1994 by the FDA.

A granisetron transdermal patch with the trade name Sancuso

was approved by the US FDA on September 12, 2008.[5] Sancuso is

manufactured by ProStrakan, Inc., a pharmaceutical company

headquartered in Bedminster, NJ, with global headquarters in Scotland.

Granisetron breaks down slowly, staying in the body for a long time.

One dose usually lasts 4 to 9 hours and is usually administered once or

twice daily. This drug is removed from the body by the liver and

kidneys.

IInnddiiccaattiioonnss[[66]]

Chemotherapy-induced nausea and vomiting

o 5-HT3 receptor antagonists are the primary drugs used to treat

and prevent chemotherapy-induced nausea and vomiting. Many

times they are given intravenously about 30 minutes before

beginning therapy.

Post-operative and post-radiation nausea and vomiting

It is therapy for nausea and vomiting due to acute or chronic

medical illness or acute gastroenteritis

6

Treatment of Cyclic vomiting syndrome although there are no

formal trials to confirm efficacy.

AAddvveerrssee eeffffeeccttss

Granisetron is a well-tolerated drug with few side effects.

Headache, dizziness, and constipation are the most commonly reported

side effects associated with its use. There have been no significant drug

interactions reported with this drug's use. It is broken down by the

liver's cytochrome P450 system and it has little effect on the

metabolism of other drugs broken down by this system.

There are certain other drug substance also used as antiemtic or

example Ondansetron (INN) developed and first marketed by

GlaxoSmithKline as Zofran) is a serotonin 5-HT3 receptor antagonist

used mainly as an antiemetic (to treat nausea and vomiting), often

following chemotherapy. Its effects are thought to be on both peripheral

and central nerves. Ondansetron reduces the activity of the vagus nerve,

which deactivates the vomiting center in the medulla oblongata, and

also blocks serotonin receptors in the chemoreceptor trigger zone. It has

little effect on vomiting caused by motion sickness, and does not have

any effect on dopamine receptors or muscarinic receptors.

A 2006 double-blind, randomized controlled trial indicated that

ondansetron may have value in the treatment of schizophrenia, as an

adjunct to haloperidol. The study found the combination to

significantly improve negative schizophrenia symptoms, and people

taking both drugs experienced fewer of the adverse effects commonly

associated with haloperidol.[7] An earlier, smaller, open-label trial had

7

found ondansetron to be useful in treating antipsychotic-induced

tardive dyskinesia in people with schizophrenia, and the study patients

also showed significant improvement in the symptoms.[8][9]

Early studies have also examined ondansetron as a possible treatment

for psychosis resulting from advanced Parkinson's disease.[10] Its

apparent benefits despite a lack of any significant antagonistic

properties at dopamine receptors or the 5-HT2A receptor raises

interesting questions about psychosis.

Hewlett and others found that the treatment of obsessive

compulsive disorder with Ondansetron 1 mg three times daily was

associated with a significant decrease in the Yale Brown Obsessive

Compulsive scores in a small (n=8), 8-week, open-label study.[11]

Ondansetron lowers the craving for alcohol, especially in early-

onset alcoholics. In one cognitive-behavioral therapy study,

ondansetron patients with early-onset alcoholism had fewer drinks per

day and reported more days without drinking at all, as compared to the

other groups in the study. Also of note, individuals with the LL

genotype show significant improvements in alcohol misuse when

treated with ondansetron, compared with individuals with the other

genotypes of the 5HTTLPR polymorphism, who showed no

improvement over placebo.[12][13][14]

Researchers at the Stanford University School of Medicine have

demonstrated that ondansetron might be useful and effective for

treating withdrawal symptoms of opioid addictions.[15] Unlike the

existing treatments methadone and buprenorphine, it is not itself an

8

opioid.[15] Additionally, it does not require continued supervision like

treatment with clonidine.[15]

The original experiment used mice who were injected with

increasing doses of morphine, assayed with naloxone and then

underwent haplotypic analysis to isolate a gene candidate.[16] HTR3A

which codes for the 5-HT3 receptor emerged as the primary candidate,

which suggested 5-HT3 antagonist ondansetron as a possible

treatment.[16] The researchers were then able to show using an acute

morphine administration model the efficacy in withdrawal symptom

control in humans.[16]

Ondansetron blocks the 5-HT3 receptor in the enteric nervous

system, and thereby reduces colonic contractions, sensory perception,

and motility. A large number of drugs in this category, 5-HT3

antagonist, have been shown to have this effect, which positively

impacts irritable bowel syndrome with diarrhea (IBS-D). Thus,

ondansetron has been effective in treating diarrhea-predominant IBS in

initial studies, and is being used off label for this exact effect.[17]

Two small, placebo-controlled trials have been conducted to

assess the efficacy of ondansetron for postanesthetic shivering, a

common occurrence after surgery. Ondansetron was found to be as

effective as pethidine (meperidine, Demerol) when given as a single IV

dose before anesthesia.[18]

AAddvveerrssee eeffffeeccttss

Ondansetron is a well-tolerated drug with few side effects.

Constipation, dizziness and headache are the most commonly reported

9

side effects associated with its use. There have been no significant drug

interactions reported with this drug use. It is broken down by the

hepatic cytochrome P450 system and it has little effect on the

metabolism of other drugs broken down by this system.

On September 15, 2011, the FDA issued a Medwatch Safety

Alert for Zofran (ondansetron) in patients with congenital Long QT

syndrome, a heart arrhythmia. The FDA further required

GlaxoSmithKline to conduct a thorough QT study to determine the

degree to which Zofran may cause QT interval prolongation.

A vial of Zofran for intravenous injection

Ondansetron was developed around 1984 by scientists working

at Glaxo's laboratories in London. It is in both the imidazole and

carbazole families of heterocyclic compounds. After several attempts

the company successfully filed for U.S. patent protection for the drug in

1986. U.S. Patent 4,695,578 was granted in September 1987 while U.S.

Patent 4,753,789 was granted in June 1988. U.S. Patent 5,578,628, a

divisional patent of U.S. Patent 4,753,789, was granted on November

26, 1996. Ondansetron was granted FDA approval as Zofran in January

1991. Glaxo did pediatric research on Zofran's uses, and gained a

patent extension as a result, extending U.S. exclusivity until December

24, 2006. The FDA subsequently approved the first generic versions in

December 2006, with marketing approval granted to Teva

Pharmaceuticals USA and SICOR Pharmaceuticals.

10

BBrraanndd nnaammeess

Ondansetron is currently marketed by GlaxoSmithKline (GSK)

under the trade name Zofran. Other manufacturers include Opsonin

Pharma Bngladesh (Anset), Strativa Pharmaceuticals (Zuplenz), Cipla

Ltd. (Emeset), Gedeon Richter Ltd. (Emetron), Korea United

Pharmaceuticals (Emodan), Zentiva a.s. (Ondemet), Strides Arcolab

(Setronax), Glenmark Generics Ltd. (India) (Ondansetron) and

Novell Pharmaceutical Laboratories (Ondavell). On May 29, 2006,

Baxter Healthcare received tentative approval[19] to market its own

label of Ondansetron Injection, USP, 8 mg/50 mL and 32 mg/50 mL

iso-osmotic sodium chloride solution, beginning upon expiration of

GSK's patent later that year.[20]

Domperidone (trade names Motilium, Motillium, Motinorm

and Costi) is an antidopaminergic drug, developed by Janssen

Pharmaceutica, and used orally, rectally or intravenously, generally to

suppress nausea and vomiting, or as a prokinetic agent. It has also been

used to stimulate lactation in women, and could be used for the purpose

of breast enlargement.

UUsseess

Gastrointestinal problems

There is some evidence that domperidone has antiemetic

activity.[21] Domperidone is used, together with metoclopramide,

cyclizine, and 5HT3 receptor antagonists (such as granisetron) in the

treatment of nausea and vomiting. Domperidone is a first choice

antiemetic in some countries. However, it is not approved for

11

prescription in the US. Although it has never been officially approved

for use in the United States, domperidone is sometimes purchased from

pharmacies in other countries for this purpose.

It can be used in patients with Parkinson's disease[22] because,

unlike metoclopramide,[23] domperidone does not cross the blood-brain

barrier.

Domperidone has also been found effective in the treatment of

gastroparesis,[24] a stomach motility condition, and for paediatric

gastroesophageal reflux (infant vomiting).

In Canada, the drug is indicated "for the symptomatic

management of upper gastrointestinal motility disorders associated with

chronic and subacute gastritis and diabetic gastroparesis." The drug

may also be used "to prevent gastrointestinal symptoms associated with

the use of dopamine agonist antiparkinsonian agents". [25]

Lactation

The hormone prolactin stimulates lactation in humans and its

release is inhibited by the dopamine secreted by the hypothalamus.

Domperidone, by acting as an anti-dopaminergic, results in increased

prolactin secretion, and thus promotes lactation.

Since, according to the U.S. Food and Drug Administration

(FDA), domperidone is not approved for enhanced lactation in any

country,[26] it is sometimes self-prescribed from original research or

prescribed "off-label" for this use in countries around the world.[27]

12

CCoonnttrroovveerrssiieess

Janssen Pharmaceutical has brought domperidone before the

FDA several times in the last two decades, with the most recent effort

in the 1990s. Numerous U.S. clinical drug trials have demonstrated its

safety and efficacy in dealing with gastroparesis symptoms, but the

FDA turned down Janssen's application for domperidone, even though

the FDA's division of gastrointestinal drugs had approved

domperidone.[28]

In June 2004, the FDA issued a letter warning women not to take

domperidone, citing unknown risks to parents and infants, and warned

pharmacies that domestic sale was illegal, and that import shipments

from other countries would be searched and seized. Domperidone is

excreted in breast milk, and no studies on its effects on breastfeeding

infants have been reported in the literature.

Individual incidents of problems in patients receiving an

intravenous form of domperidone include cardiac arrest and

arrhythmia, complications with other medications, as well as

complications with improper intravenous use. This intravenous form

has since been withdrawn from marketing in several countries.[29] A

recent paper suggests there may be increased risk of seizures to

neonates of mothers taking oral domperidone.[30]

Some doctors and pharmacists do not fully accept the FDA's

reasoning and still favor domperidone's use in increasing milk supply.

Such doctors and pharmacists claim the drug is safe in the doses given

for this purpose[31] since the morbidity in question was limited to

13

intravenous use.[32] The American Academy of Pediatrics considers

domperidone "usually compatible with breastfeeding".[33]

There is a new controversy in Britain regarding lethal levels of

sodium found in children who are administered this drug. It is now

subject to a medical review following a number of criminal trials where

parents were charged with child abuse by salt poisoning based on

hypernatremia in the affected children.[34] Recent studies also cite

increased QT intervals in neonates taking Domperidone.[35]

PPhhaarrmmaaccoollooggyy

Domperidone blocks the action of dopamine. It has strong

affinities for the D2 and D3 dopamine receptors,[36] which are found in

the chemoreceptor trigger zone, located just outside the blood brain

barrier, which, among others, nausea and vomiting (area postrema on

the floor of the fourth ventricle and rhomboid fossa).

BBrraanndd

Brand-name Motilium was available in Canada from 1985-2002,

but generic versions of the drug are still available. [37]

Drug used for the study is from flouroquinolone antibiotic category.

Details of Granisetron Hydrochloride given are as follows.

Molecular Structure

14

Chemical name: endo - N-(9-methyl-9-azabicyclo [3.3.1] non-3-

yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride

Chemistry

Molecular weight : 348.9 (312.4 free base)

Molecular formula : C18 H24 N4 O•HCl

Description : Granisetron hydrochloride is a

white to off-white solid.

Solubility : Freely soluble in water;

sparingly soluble in

dichloromethane; slightly

soluble in methyl alcohol.

Category : Chemotherapy-Induced Nausea

and Vomiting

Storage :

CLINICAL PARTICULARS

! Therapeutic indications

Prevention or treatment of acute nausea and vomiting induced by

cytostatic therapy (cytotoxic chemotherapy and radiotherapy) in

children and adolescents aged 2 to 16 years. Prevention and treatment

of post-operative nausea and vomiting in adults.

! Posology and method of administration

For intravenous administration only.

Prevention and treatment of nausea and vomiting caused by cytostatic

therapy

15

Maximum dose and duration of treatment

Children and adolescents aged 2-16 years 40µg/kg (40µl/kg)

body weight (up to 3mg) should be given as an intravenous infusion,

diluted in 10 to 30ml infusion fluid and administered over five minutes.

The (first) dose should be administered immediately prior to the start of

cytostatic therapy. One additional dose of 40µg/kg body weight (up to

3mg) may be administered within a 24-hour period if required. This

additional dose should be administered at least 10 minutes apart from

the initial infusion.

Prevention and treatment of post-operative nausea and vomiting

Adults

1mg (1ml) should be diluted to 5ml and given as a slow

intravenous injection over 30 seconds. For prevention, administration

should be completed prior to induction of anaesthesia.

Maximum dose and duration of treatment

The usual maximum dose is 2mg in one day, although there is

clinical experience of patients being given a total dose of 3mg in 24

hours. There is no experience in the use of granisetron in the prevention

and treatment of postoperative nausea and vomiting in children. It is

not therefore recommended for this indication in this age group.

Special patient groups

Elderly

The same dose as for adults Renally and/or hepatically impaired

patients. The same dose as for adults.

16

! Contraindications

Hypersensitivity to granisetron, to related substances (e.g.

ondansetron) or to any of the excipients.

! Special warnings and precautions for use

As granisetron may reduce bowel motility, patients with signs of

(sub-) acute intestinal obstruction should be monitored following

administration of granisetron. No special precautions are required for

the elderly or renally or hepatically impaired patient. Although to date

no signs of an increased incidence of adverse events have been

observed in hepatically impaired patients, owing to the kinetics a

degree of caution should be exercised in using granisetron within this

category. 5-HT3 antagonists such as granisetron may be associated with

arrhythmias or ECG abnormalities. This potentially may have clinical

significance in patients with preexisting arrhythmias or cardiac

conduction disorders or patients who are being treated with

antiarrhythmic agents or beta-blockers.

! Interaction with other medicinal products and other forms of

interaction

Animal studies indicate that granisetron neither stimulates nor

inhibits the cytochrome P450 enzyme system. Because granisetron is

metabolized by hepatic cytochrome P450 enzymes, inducers or

inhibitors of these enzymes may change clearance and, hence, the half-

life of granisetron. In human subjects, hepatic enzyme induction by

phenobarbital has led to an increase in total plasma clearance (approx.

25%) following intravenous administration of granisetron. In vitro

17

studies have shown that ketoconazole may inhibit the metabolism of

granisetron via the cytochrome P450 3A isoenzyme family. The

clinical significance of this is unknown. To date no signs of interaction

have been observed between granisetron and medicinal products that

are often prescribed in anti-emetic therapy, such as benzodiazepines,

neuroleptics and agents for peptic indications. Furthermore, no

interaction has been observed between granisetron and emetogenic

cytostatic therapies.

! Pregnancy and lactation

Pregnancy

There are no data from the use of granisetron in pregnant

women. Animal studies do not indicate direct or indirect harmful

effects with respect to pregnancy, embryonal/fetal development,

parturition or postnatal development. Granisetron should not be used in

pregnant women unless strictly indicated. Caution should be exercised

when prescribing granisetron to pregnant women.

Lactation

There are no data concerning granisetron excretion in breast

milk. Therefore, breastfeeding should be discontinued during therapy.

! Effects on ability to drive and use machines

There are no known data on the effect of granisetron on the

ability to drive. In clinical studies occasional cases of drowsiness have

been reported, but no causal.

18

! Undesirable effects

The adverse events are classified according to the following

frequency categories: very common ( 1/10), common ( 1/100 to

<1/10), uncommon ( 1/1000 to <1/100), rare ( 1/10 000 to < 1/1000),

very rare (!1/10 000), not known (cannot be estimated from the

available data).

Cardiac disorders

Rare: Arrhythmia, chest pain

Nervous system disorders

Very common: Headache

Rare: Dystonias, dyskinesias*

Very rare: Coma

Gastrointestinal disorders

Very common: Nausea, constipation

Common: Reduced appetite, diarrhoea, vomiting, abdominal pain

Skin and subcutaneous tissue disorders

Very rare: Rash

Vascular disorders

Not known: Hypotension

General disorders

Common: Asthenia, pain, fever

Very rare: Anaphylaxis, fainting fits, dizziness, insomnia, agitation

19

Hepatobiliary disorders

Rare: Abnormal hepatic function, raised transaminase levels

Psychiatric disorders

Very rare: Anorexia

Dystonias and dyskinesias have been reported with medicines in the 5-

HT3 antagonist class. Such events have been reported rarely with

granisetron.

! Overdose

There is no specific antidote for granisetron. In the event of

overdose, symptomatic treatment should be given. One patient has

received 30mg of granisetron intravenously. The patient reported a

slight headache but no other sequelae were observed.

PHARMACOLOGICAL PROPERTIES

! Pharmacodynamic properties

Pharmacotherapeutic group: Serotonin (5-HT3) antagonists

Anatomical Therapelitic Chemical Classfication (ATC code:)

A04A A02

Granisetron is a potent anti-emetic and highly selective

antagonist of 5-hydroxytryptamine (5-HT3) receptors. Pharmacological

studies have demonstrated that granisetron is effective against nausea

and vomiting as a result of cytotoxic chemotherapy and radiotherapy

and surgery. Radioligand binding studies have demonstrated that

granisetron has negligible affinity for other receptor types including 5-

HT1, 5-HT2, 5-HT4 and dopamine D2 binding sites.

20

! Pharmacokinetic properties

Absorption

Absorption pharmacokinetics are not relevant for this product as it is

administered intravenously.

Distribution

Granisetron is distributed with a mean volume of distribution of

approximately 3 L/kg; plasma protein binding is approximately 65%.

The mean plasma clearance in patients is approximately 27 L/h and the

mean plasma half-life is about 9 hours, with wide intersubject

variability. The plasma concentration of granisetron is not clearly

correlated with anti-emetic efficacy. Clinical benefit may be conferred

even when granisetron is not detectable in plasma.

Metabolism

Biotransformation pathways involve N-demethylation and aromatic

ring oxidation followed by conjugation.

Elimination

Granisetron clearance is primarily by metabolism. Urinary

excretion of unchanged granisetron averages 12% of dose. Urinary

excretion of metabolites amounts to about 47% of dose, with the

remainder being excreted in faeces as metabolites.

Pharmacokinetics in special populations

In elderly subjects after single intravenous doses,

pharmacokinetic parameters were within the range found for non-

elderly subjects. In patients with severe renal failure, studies have

21

shown that pharmacokinetic parameters after a single intravenous dose

are generally similar to those in healthy subjects. In patients with

hepatic impairment due to neoplastic liver involvement, total plasma

clearance of an intravenous dose was approximately halved compared

with patients without hepatic impairment. However, no dosage

adjustment is necessary. When volume of distribution and total

clearance are adjusted for body weight, the pharmacokinetics of

granisetron after single intravenous dose is similar in paediatric and

adult cancer patients.

! Preclinical safety data

Preclinical data revealed no special hazard for humans based on

conventional studies repeated dose toxicity, carcinogenicity,

reproductive toxicity and genotoxicity. A study in cloned human

cardiac ion channels has shown that granisetron has the potential to

affect cardiac repolarisation via blockade of HERG potassium

channels. Granisetron has been shown to block both sodium and

potassium channels, which potentially affects both depolarisation and

repolarisation through prolongation of PR, QRS, and QT intervals. This

data helps to clarify the molecular mechanisms by which some of the

ECG changes (particularly QT and QRS prolongation) associated with

this class of agents occur. However, there is no modification of the

cardiac frequency, blood pressure or the ECG trace.

General properties :

Description : White or almost white crystalline power.

Solubility : Freely soluble in water and slightly soluble in methanol.

Description of manufacturing process and process control.

22

Process flow

23

Chemical pathway

Parenteral preparations are sterile preparations intended for

administration by injection, infusion or implantation into the human or

animal body.

Parenteral preparations may require the use of excipients, for

example to make the preparation isotonic with respect to blood, to

24

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.

Containers for parenteral preparations are made as far as possible from

materials that are sufficiently transparent to permit the visual inspection

of the contents, except for implants and in other justified and

authorized cases.

Parenteral preparations are supplied in glass containers or in

other containers such as plastic containers and prefilled syringes. The

tightness of the container is ensured by suitable means. Closures ensure

a good seal, prevent the access of micro-organisms and other

contaminants and usually permit the withdrawal of a part or the whole

of the contents without removal of the closure. The plastic materials or

elastomers used to manufacture the closures are sufficiently firm and

elastic to allow the passage of a needle with the least possible shedding

of particles. Closures for multidose containers are sufficiently elastic to

ensure that the puncture is resealed when the needle is withdrawn.

Several categories of parenteral preparations may be distinguished:

—injections,

—infusions,

— concentrates for injections or infusions,

— powders for injections or infusions,

— gels for injections,

— implants.

25

The dictionary definition of parenteral is non enteral or non-oral

and, therefore, strictly speaking, the term parenteral includes all

products administered other than by the oral route. The parenteral

convention, however, is to use the term parenteral to describe

medicines administered by means of an injection. The most common

routes of parenteral administration are intravenous (IV), subcutaneous

and intramuscular, but there are a variety of lesser used routes, such as

intra-arterial. In addition, products such as subcutaneous implants are

usually classed as parenteral.

There are, arguably, a greater variety of formulations

administered by the parenteral route then by any other. These include

emulsions, suspensions, liposomes, particulate system and solid

implants as well as the ubiquitous simple solution. What sets parenteral

products apart from most other dosage forms (with the exception of

ocular products), is the absolute requirements for sterility, regardless of

the formulation type. This type of requirements must be upper most in

the pharmaceutical scientist’s mind from the first stages of formulation

conception, so that the formulation and manufacturing process can be

developed in tandem to produce an optimized sterile product.

Types of Injections

Pharmacopeias classify injectable into small-volume parenteral

(SVPs) and large –volume (LVPs).the U.S. pharmacopoeia (USP)

defines SVPs as containing less than 100 mL and LVPs as containing

more than 100 mL.many regulatory standards, for example, those for

subvisible particulate, have first been developed for LVPs prior to their

26

later application to all parenteral .SVPs can be given rapidly in a small

volume; this type of injection is known as a bolus. They may also add

to LVPs, such as 5 percent dextrose and 0.9 percent sodium chloride

infusion /injection, for administration by IV infusion. Some antibiotics

are sold as LVPs, which eliminates the need for the extemporaneous

addition of the drug to the infusion fluid prior to administration. The

selection of bolus or infusion will depends on the pharmacokinetics of

the drug and the distinction can be somewhat blurred. Infusions can be

as brief as 15 minutes or may continue for several days. Generally

speaking, if a medicament is to be administrated by infusion, the

simplest approach is to formulate it as a concentrate which will

subsequently diluted by the practitioner or pharmacist prior to

administration.

Intramuscular or subcutaneous injections are almost always

administered a bolus. Typically, the injection volume is less than 1-1.5

mL by the subcutaneous route and usually no more than 2 mL by the

intramuscular route, although higher volumes (up to 4 mL) can be

administered if essential have shown a correlation between pain and the

volume of a subcutaneous injection with volumes of 1=1.5 mL causing

significantly more pain than volumes of 0.5 mL or less. clearly, it is

preferable to minimize injection volume whenever possible,

particularly if chronic administration is anticipated. When the total

volume to be administrated cannot be reduced to an acceptable level,

two or more injections at multiple sites may be required.

One of the first steps in the formulation of a solution product is,

therefore, to select the administration volume and concentration. This

27

may be dictated primarily by physiological considerations, such as

maximum injections volumes as discussed above, or by

pharmaceutically considerations. For example, if solubility is low, a

larger volume/lower concentration formulation may be required, where

as if stability is improved at higher concentrations, then the converse

would be true.

pH and tonicity requirements

pH consideration

Clearly, a parenteral product should be formulated with a pH

close to physiological, unless stability or solubility considerations

preclude this. Often the pH selected for the product is a compromise

between the pH of maximum stability, solubility and physiological

acceptability.

The first step in selecting a suitable formulation pH will be the

generation of pH/stability and pH /solubility profiles. This type of

formulation is often available in the preformulation data package. The

target pH for maximum physiological acceptability is approximately

pH 7.4. In practice, however a reasonably wide pH range can be

tolerated, particularly when dosing is via the IV route, and dilution with

blood is rapid.

28

Table Buffer used in approved parenteral products.

Buffer pH Range

Acetate 3.8-5.8

Ammonium 8.25-10.25

Ascorbate 3.0-5.0

Benzoate 6.0-7.0

Bicarbonate 4.0-11.0

Citrate 2.1-6.2

Diethanolamine 8.0-10.0

Glycine 8.8-10.8

Lactate 2.1-4.1

Phosphate 3.0-8.0

Succinate 3.2-6.6

Tartrate 2.0-5.3

Tonicity considerations

Wherever possible, parenteral products should be isotonic,

typically, osmolarities between 280-290 mOsm/L are targeted during

formulation.

29

Choice of excipients

As with all pharmaceutical products, the most important “rule” to

bear in mind when formulating parenteral is the “keep it simple”

principle. whenever possible, formulation should be developed using

excipients which have an established use in parenteral administrated

by the same route as the product under development .both the

excipients concentration ,rate of administration and total daily dose

should fall within the boundaries established by precedent in existing

marketed products. The (U.S.food and drug administration) FDA

Inactive Ingredients Guide is a good place to start a search for

information about a potential excipients,as it consists of an alphabetical

list of all excipients in approved or conditionally approved drug

products, and includes the route of administration of the products

containing them. The Physician’s Desk Reference (PDR) provides an

essential source of detailed information on products available on the

U.S.market and includes the quantitative formulation of each product.

This enables both the rate of administration and total daily dose

of excipients in existing products to be calculated. The PDR can be

obtained in a CD-ROM format which has a word search facility, thus

providing a convenient means of searching for products containing a

specific excipients .The PDR is also available in a web-based format,

but unfortunately, this version doesn’t have the word search capability.

Sterility Considerations

The requirement for sterility in parenteral products is absolute

and must be borne in mind at all stages of formulation and process

30

development. The regulatory environment now requires that parenteral

products be terminally sterilized unless this is precluded, usually by

reason of instability (see the section “manufacturing of parenteral

products”).

For a solution product, one of the earliest investigations carried

out during formulation development will be a study of the stability to

moist heat sterilization. The results of this study may impact the

formulation selection; for example the stability to autoclaving may be

affected by solution pH. Where stability is marginal, attempts should be

made through the formulation process to stabilize the product such that

it can withstand the stresses of moist heat sterilization. The regulatory

authorities will expect to see good justification for new products that

are not terminally sterilized.

In many cases, however, the product will simply not withstand

the stress associated with autoclaving, and in this case, the usual

alternative is filtration through sterilizing grade filter followed by

aseptic processing. For the formulation scientist, it is important to

select a suitable filter early on in development and ensure that the

product is compatible with it.

Whilst the vast majority of parenteral products are rendered sterile

either by moist heat sterilization or by filtrations through sterilizing

grade filters, other methods of sterilization should be considered,

particularly in the development of non aqueous formulations or novel

drug delivery systems. For implants for example gamma irradiation is an

option that should be explored early on in development.

31

Preservatives should not usually be included in parenteral

formulations except where a multidose product is being developed. The

Committee for Proprietary Medicinal Products (CPMP)” Notes for

Guidance on Inclusion of Antioxidant and Antimicrobial Preservatives

in Medicinal Products” states that the physical and chemical

compatibility of the preservative (or antioxidant) with the other

constituents of the formulations, the container and closure must be

demonstrated during the development process. The minimum

concentration of preservative should be used, which gives the required

level of efficacy, as tested using pharmacopoeial methods. Certain

preservatives should be avoided under certain circumstances, and

preservative should be avoided entirely for some specialized routes.

The guidelines also require that both the concentration and efficacy of

the preservative are monitored over the shelf life of the product. in

multiple dose injectable products, the efficacy of the preservative must

be established under simulated in-use conditions.

Co-solvent

Co-solvent are reportedly used in 10 percent of FDA approved

parenteral products although the range is limited to glycerin, ethanol,

propylene glycol and N, N-dimethylacetamide (Sweetana and Akers

1996). Quite often, mixtures of co-solvent are used so that the dose or

concentration of individual solvents can be minimized, and any

synergistic effects can be maximized. The concentration of co-solvent

which is acceptable will vary depending on the route, rate of

administration and whether the product is to be given chronically.

again, the formulator will do well to be guided by the established

32

precedent in marketed products and is once again referred to the

publication of powel etal (1998) and strickley (1999).

Non aqueous vehicle: Poorly soluble drugs for IM administration

can be formulated in non aq vehicle this can have the additional benefit

of providing a slow release of the active moiety. Oily vehicle have been

used historically, the most commonly encountered is sesame oil and 6

products containing it are listed in the PDR (name of nema et al 1997).

Federal regulation however now require the specific oil to be included

in the product labeling, because of the risk of allergic reaction to certain

vegetable oils . This and the irritancy of the oily vehicles has led to

their decreased use.

Formulation consistent entirely, or almost entirely, of organic

solvents have also been developed . Eg. Propulene glycol , PEG 300.

Surfactants : Surfactants generally the polysarbates are firequently

encountered in parentral products but generally at very low level and most

commenly to prevent aggregation in formulation of micro molecules few

IV prodiuts containt significant level of surfactants to notable exception

are cardarone IV Etoposide IV which contains 10 and 8 % respectively, of

polysorbate 80 ( Tween 80 ) both products required dilution before

administration, such that the maximum concentration of polysorbate 80 in

the infusion solution is 1.2 and 0.16 %, respectively. It is worth noting,

however, that the polysorbate componants of cardarone IV has been

implicated in a few cases of acute hepatitis which have developed with in

hours of the start of administration some what higher level of surfactants

can be tolerated in products intended for the SC route of administration.

33

Complexing agents : Complexing agent, in this context , are

molecules that have the ability to form soluble complex with insoluble

drugs. The most well known examples are the cyclodextranes which

have been widely studied as agents for solubalization and stabilization ,

they are able to increase the aqueous solubility of some poorly soluble

drug molecule by orders of magnitude, as a result of their ability to

form inclusion complex. Cyclodextrins are oligosaccharides obtained

from the enzymatic conversion of starch. Depending on the numbers of

Glucopyranase units , they are named as alpha “(6 units) Beta (7 Units)

or Gamma (8 Units). These parent molecules can then be further

substituted at the Hydroxyl groups to alter the proertose of the molecule

the nature of the subtituents and the degree of subtotution will influence

the aqueous solubility, complexing capacity and safety of the molecule.

Method of sterilization :

Sterility is the absence of viable micro-organisms. The sterility

of a product cannot be guaranteed by testing; it has to be assured by

the application of a suitably validated production process. It is essential

that the effect of the chosen sterilisation procedure on the product

(including its final container or package) is investigated to ensure

effectiveness and the integrity of the product and that the procedure is

validated before being applied in practice. It is recommended that the

choice of the container is such as to allow the optimum sterilisation to

be applied. Failure to follow meticulously a validated process involves

the risk of a non-sterile product or of a deteriorated product.

34

Wherever possible, a process in which the product is sterilised in its

final container (terminal sterilisation) is chosen. When a fully validated

terminal sterilisation method by steam, dry heat or ionising radiation is

used, parametric release, that is the release of a batch of sterilised

items based on process data rather than on the basis of submitting a

sample of the items to sterility testing, may be carried out, subject to

the approval of the competent authority.

If terminal sterilisation is not possible, filtration through a

bacteria-retentative filter or aseptic processing is used; wherever

possible, appropriate additional treatment of the product (for example,

heating of the product) in its final container is applied. In all cases, the

container and closure are required to maintain the sterility of the

product throughout its shelf-life.

Steam sterilisation (Heating in an autoclave)

Sterilisation by saturated steam under pressure is preferred,

wherever applicable, especially for aqueous preparations. For this

method of terminal sterilisation the reference conditions for aqueous

preparations are heating at a minimum of 121 °C for 15 min. Other

combinations of time and temperature may be used provided that it has

been satisfactorily demonstrated that the process chosen delivers an

adequate and reproducible level of lethality when operating routinely

within the established tolerances. The procedures and precautions

employed are such, as to give an SAL of 10-6 or better. Guidance

concerning validation by means of the F0 concept is provided below.

35

Knowledge of the physical conditions (temperature and pressure)

within the autoclave chamber during the sterilisation procedure is

obtained. The temperature is usually measured by means of

temperature-sensing elements inserted into representative containers

together with additional elements at the previously established coolest

part of the loaded chamber. The conditions throughout each cycle are

suitably recorded, for example, as a temperature-time chart, or by any

other suitable means.

Dry heat sterilisation

For this method of terminal sterilisation the reference conditions

are a minimum of 160 °C for at least 2 h. Other combinations of time

and temperature may be used provided that it has been satisfactorily

demonstrated that the process chosen delivers an adequate and

reproducible level of lethality when operated routinely within the

established tolerances. The procedures and precautions employed are

such as to give an SAL of 10-6 or better.

Dry heat sterilisation is carried out in an oven equipped with

forced air circulation or other equipment specially designed for the

purpose. The steriliser is loaded in such a way that a uniform

temperature is achieved throughout the load. Knowledge of the

temperature within the steriliser during the sterilisation procedure is

usually obtained by means of temperature-sensing elements inserted

into representative containers together with additional elements at the

previously established coolest part of the loaded steriliser. The

temperature throughout each cycle is suitably recorded.

36

Where a biological assessment is carried out, this is obtained using a

suitable biological indicator.

Dry heat at temperatures greater than 220 °C is frequently used

for sterilisation and depyrogenation of glassware. In this case

demonstration of a 3-log reduction in heat resistant endotoxin can be

used as a replacement for biological indicators.

Ionising radiation sterilisation

Sterilisation by this method is achieved by exposure of the

product to ionising radiation in the form of gamma radiation from a

suitable radioisotopic source (such as cobalt 60) or of a beam of

electrons energised by a suitable electron accelerator.

In some countries there are regulations that lay down rules for

the use of ionising radiation for sterilisation purposes, for example, in

the appropriate European Community Notes for Guidance.

For this method of terminal sterilisation the reference absorbed

dose is 25 kGy. Other doses may be used provided that it has

satisfactorily been demonstrated that the dose chosen delivers an

adequate and reproducible level of lethality when the process is

operated routinely within the established tolerances. The procedures

and precautions employed are such as to give an SAL of 10-6 or better.

During the sterilisation procedure the radiation absorbed by the product

is monitored regularly by means of established dosimetry procedures

that are independent of dose rate. Dosimeters are calibrated against a

standard source at a reference radiation plant on receipt from the

supplier and at suitable intervals of not longer than one year thereafter.

37

Where a biological assessment is carried out, this is obtained

using a suitable biological indicator.

Gas sterilisation

This method of sterilisation is only to be used where there is no

suitable alternative. It is essential that penetration by gas and moisture

into the material to be sterilised is ensured and that it is followed by a

process of elimination of the gas under conditions that have been

previously established to ensure that any residue of gas or its

transformation products in the sterilised product is below the

concentration that could give rise to toxic effects during use of the

product. Guidance on this aspect with respect to the use of ethylene

oxide is provided, for example, in the appropriate European

Community Notes for Guidance.

Wherever possible, the gas concentration, relative humidity,

temperature and duration of the process are measured and recorded.

Measurements are made where sterilisation conditions are least likely

to be achieved, as determined at validation.

The effectiveness of the process applied to each sterilisation

load is checked using a suitable biological indicator.

A suitable sample of each batch is tested for sterility before the batch

is released.

Filtration

Certain active ingredients and products that cannot be terminally

sterilised may be subjected to a filtration procedure using a filter of a

type that has been demonstrated to be satisfactory by means of a

38

microbial challenge test using a suitable test micro-organism. A

suspension of Pseudomonas diminuta (ATCC 19146, NCIMB 11091

or CIP 103020) may be suitable. It is recommended that a challenge of

at least 107 CFU per cm2 of active filter surface is used and that the

suspension is prepared in tryptone soya broth which, after passage

throug the filter, is collected aseptically and incubated aerobically at

32 °C. Such products need special precautions. The production process

and environment are designed to minimise microbial contamination

and are regularly subjected to appropriate monitoring procedures. The

equipment, containers and closures and, wherever possible, the

ingredients are subjected to an appropriate sterilisation process. It is

recommended that the filtration process is carried out as close as

possible to the filling point. The operations following filtration are

carried out under aseptic conditions.

Solutions are passed through a bacteria-retentive membrane with

a nominal pore size of 0.22 µm or less or any other type of filter

known to have equivalent properties of bacteria retention. Appropriate

measures are taken to avoid loss of solute by adsorption on to the filter

and to avoid the release of contaminants from the filter. Attention is

given to the bioburden prior to filtration, filter capacity, batch size and

duration of filtration. The filter is not used for a longer period than has

been approved by validation of the combination of the filter and the

product in question.

The integrity of an assembled sterilising filter is verified before

use and confirmed after use by carrying out tests appropriate to the

39

type of filter used and the stage of testing, for example bubble-point,

pressure hold or diffusion rate tests.

Due to the potential additional risks of the filtration method as

compared with other sterilisation processes, a prefiltration through a

bacteria-retentative filter may be advisable in cases where a low

bioburden cannot be ensured by other means.

Aseptic preparation

The objective of aseptic processing is to maintain the sterility of

a product that is assembled from components, each of which has been

sterilised by one of the above methods. This is achieved by using

conditions and facilities designed to prevent microbial contamination.

Aseptic processing may include aseptic filling of products into

container/closure systems, aseptic blending of formulations followed

by aseptic filling and aseptic packaging.

In order to maintain the sterility of the components and the

product during processing, careful attention needs to be given to:

— environment,

— personnel,

— critical surfaces,

— container/closure sterilisation and transfer procedures,

— maximum holding period of the product before filling into the

final container.

Endotoxin Test: There are various methods of endotoxin

determination test as follows:

40

Gel-clot method: semi-quantitative test

Turbidimetric kinetic method

Chromogenic kinetic method

Chromogenic end-point method

Turbidimetric end-point method

The test is carried out in a manner that avoids endotoxin

contamination.

Anti Microbial Preservations :

If a pharmaceutical preparation does not itself have adequate

antimicrobial activity, antimicrobial preservatives may be added,

particularly to aqueous preparations, to prevent proliferation or to limit

microbial contamination which, during normal conditions of storage

and use, particularly for multidose containers, could occur in a product

and present a hazard to the patient from infection and spoilage of the

preparation. Antimicrobial preservatives must not be used as a

substitute for good manufacturing practice.

The efficacy of an antimicrobial preservative may be enhanced

or diminished by the active constituent of the preparation or by the

formulation in which it is incorporated or by the container and

closure used. The antimicrobial activity of the preparation in its

final container is investigated over the period of validity to ensure

that such activity has not been impaired by storage. Such

investigations may be carried out on samples removed from the final

container immediately prior to testing.

41

During development of a pharmaceutical preparation, it shall be

demonstrated that the antimicrobial activity of the preparation as such

or, if necessary, with the addition of a suitable preservative or

preservatives provides adequate protection from adverse effects that

may arise from microbial contamination or proliferation during storage

and use of the preparation.

The efficacy of the antimicrobial activity may be demonstrated

by the test described below. The test is not intended to be used for

routine control purposes.

Test for efficacy of antimicrobial preservation

The test consists of challenging the preparation, wherever

possible in its final container, with a prescribed inoculum of suitable

micro-organisms, storing the inoculated preparation at a prescribed

temperature, withdrawing samples from the container at specified

intervals of time and counting the organisms in the samples so

removed.

The preservative properties of the preparation are adequate if, in

the conditions of the test, there is a significant fall or no increase, as

appropriate, in the number of micro-organisms in the inoculated

preparation after the times and at the temperatures prescribed. The

criteria of acceptance, in terms of decrease in the number of micro-

organisms with time, vary for different types of preparations according

to the degree of protection intended.

42

Test micro-organisms

Pseudomonas aeruginosa

ATCC 9027; NCIMB 8626; CIP 82.118.

Staphylococcus aureus

ATCC 6538; NCTC 10788; NCIMB 9518; CIP 4.83.

Candida albicans

ATCC 10231; NCPF 3179; IP 48.72.

Aspergillus niger

ATCC 16404; IMI 149007; IP 1431.83.

Single-strain challenges are used and the designated micro-organisms

are supplemented, where appropriate, by other strains or species that

may represent likely contaminants to the preparation. It is

recommended, for example, that Escherichia coli (ATCC 8739;

NCIMB 8545; CIP 53.126) is used for all oral preparations and

Zygosaccharomyces rouxii (NCYC 381; IP 2021.92) for oral

preparations containing a high concentration of sugar.

Partical Count Testing

Particulate contamination of injections and infusions consists of

extraneous, mobile undissolved particles, other than gas bubbles,

unintentionally present in the solutions.

For the determination of particulate contamination 2 procedures,

Method 1 (Light Obscuration Particle Count Test) and Method 2

(Microscopic Particle Count Test), are specified hereinafter. When

examining injections and infusions for sub-visible particles, Method 1

43

is preferably applied. However, it may be necessary to test some

preparations by the light obscuration particle count test followed by the

microscopic particle count test to reach a conclusion on conformance

to the requirements.

For large-volume parenterals, single units are tested. For small-

volume parenterals less than 25 ml in volume, the contents of 10 or

more units are combined in a cleaned container to obtain a volume of

not less than 25 ml; where justified and authorised, the test solution

may be prepared by mixing the contents of a suitable number of vials

and diluting to 25 ml with particle-free water R or with an appropriate

solvent without contamination of particles when particle-free water R

is not suitable. Small-volume parenterals having a volume of 25 ml or

more may be tested individually.

The preparation complies with the test if the average number of

particles present in the units tested does not exceed 6000 per container

equal to or greater than 10 µm and does not exceed 600 per container

equal to or greater than 25 µm.

Viscocity : -

Viscosity is a measure of the resistance of a fluid which is being

deformed by either shear or tensile stress. In everyday terms (and for

fluids only), viscosity is "thickness" or "internal friction". Thus, water

is "thin", having a lower viscosity, while honey is "thick", having a

higher viscosity. Put simply, the less viscous the fluid is, the greater its

ease of movement (fluidity).[38]

44

Viscosity describes a fluid's internal resistance to flow and may be

thought of as a measure of fluid friction. For example, high-viscosity

felsic magma will create a tall, steep stratovolcano, because it cannot

flow far before it cools, while low-viscosity mafic lava will create a

wide, shallow-sloped shield volcano. All real fluids (except

superfluids) have some resistance to stress and therefore are viscous,

but a fluid which has no resistance to shear stress is known as an ideal

fluid or inviscid fluid.

The study of flowing matter is known as rheology, which

includes viscosity and related concepts.

EEttyymmoollooggyy

The word "viscosity" is derived from the Latin "viscum alba",

meaning white mistletoe. A viscous glue called birdlime was made

from mistletoe berries and was used for lime-twigs to catch birds.[39]

Property and Behiviour

Overview

45

Laminar shear of fluid between two plates. Friction between the

fluid and the moving boundaries causes the fluid to shear. The force

required for this action is a measure of the fluid's viscosity. This type of

flow is known as a Couette flow.

Laminar shear, the non-constant gradient, is a result of the

geometry the fluid is flowing through (e.g. a pipe).

In general, in any flow, layers move at different velocities and

the fluid's viscosity arises from the shear stress between the layers that

ultimately opposes any applied force. The relationship between the

shear stress and the velocity gradient can be obtained by considering

two plates closely spaced at a distance y, and separated by a

homogeneous substance. Assuming that the plates are very large, with a

large area A, such that edge effects may be ignored, and that the lower

plate is fixed, let a force F be applied to the upper plate. If this force

causes the substance between the plates to undergo shear flow with a

velocity gradient u/y (as opposed to just shearing elastically until the

46

shear stress in the substance balances the applied force), the substance

is called a fluid.

The applied force is proportional to the area and velocity

gradient in the fluid:

,

where µ is the proportionality factor called dynamic viscosity.

This equation can be expressed in terms of shear stress .

Thus as expressed in differential form by Isaac Newton for straight,

parallel and uniform flow, the shear stress between layers is

proportional to the velocity gradient in the direction perpendicular to

the layers:

Hence, through this method, the relation between the shear stress

and the velocity gradient can be obtained.

Note that the rate of shear deformation is which can be also

written as a shear velocity, .

James Clerk Maxwell called viscosity fugitive elasticity because

of the analogy that elastic deformation opposes shear stress in solids,

while in viscous fluids, shear stress is opposed by rate of deformation.

47

Types of viscosity

Viscosity, the slope of each line, varies among materials

Newton's law of viscosity, given above, is a constitutive equation

(like Hooke's law, Fick's law, Ohm's law). It is not a fundamental law

of nature but an approximation that holds in some materials and fails in

others. Non-Newtonian fluids exhibit a more complicated relationship

between shear stress and velocity gradient than simple linearity. Thus

there exist a number of forms of viscosity:

Newtonian: fluids, such as water and most gases which have a

constant viscosity.

Non-Newtonian flids :

Shear thickening: viscosity increases with the rate of shear.

48

Shear thinning: viscosity decreases with the rate of shear. Shear

thinning liquids are very commonly, but misleadingly, described

as thixotropic.

Thixotropic: materials which become less viscous over time

when shaken, agitated, or otherwise stressed.

Rheopectic: materials which become more viscous over time

when shaken, agitated, or otherwise stressed.

A Bingham plastic is a material that behaves as a solid at low

stresses but flows as a viscous fluid at high stresses.

A magnetorheological fluid is a type of "smart fluid" which,

when subjected to a magnetic field, greatly increases its apparent

viscosity, to the point of becoming a viscoelastic solid.

VViissccoossiittyy ccooeeffffiicciieennttss

Viscosity coefficients can be defined in two ways:

Dynamic viscosity, also absolute viscosity, the more usual one

(typical units Pa·s, Poise, P);

Kinematic viscosity is the dynamic viscosity divided by the

density (typical units cm2/s, Stokes, St).

Viscosity is a tensorial quantity that can be decomposed in different

ways into two independent components. The most usual decomposition

yields the following viscosity coefficients:

Shear viscosity, the most important one, often referred to as

simply viscosity, describing the reaction to applied shear stress;

simply put, it is the ratio between the pressure exerted on the

49

surface of a fluid, in the lateral or horizontal direction, to the

change in velocity of the fluid as you move down in the fluid

(this is what is referred to as a velocity gradient).

Volume viscosity (also called bulk viscosity or second viscosity)

becomes important only for such effects where fluid compressibility is

essential. Examples would include shock waves and sound propagation.

It appears in the Stokes' law (sound attenuation) that describes

propagation of sound in Newtonian liquid.

Extensional viscosity, a linear combination of shear and bulk

viscosity, describes the reaction to elongation, widely used for

characterizing polymers. For example, at room temperature, water has a

dynamic shear viscosity of about 1.0×10"3 Pa·s and motor oil of about

250×10"3 Pa·s.[40]

VViissccoossiittyy mmeeaassuurreemmeenntt

Viscometer

Viscosity is measured with various types of viscometers and

rheometers. A rheometer is used for those fluids which cannot be

defined by a single value of viscosity and therefore require more

parameters to be set and measured than is the case for a viscometer.

Close temperature control of the fluid is essential to accurate

measurements, particularly in materials like lubricants, whose viscosity

can double with a change of only 5 °C.

For some fluids, viscosity is a constant over a wide range of

shear rates (Newtonian fluids). The fluids without a constant viscosity

(non-Newtonian fluids) cannot be described by a single number. Non-

50

Newtonian fluids exhibit a variety of different correlations between

shear stress and shear rate. One of the most common instruments for

measuring kinematic viscosity is the glass capillary viscometer.In paint

industries, viscosity is commonly measured with a Zahn cup, in which

the efflux time is determined and given to customers. The efflux time

can also be converted to kinematic viscosities (centistokes, cSt) through

the conversion equations. Also used in paint, a Stormer viscometer uses

load-based rotation in order to determine viscosity. The viscosity is

reported in Krebs units (KU), which are unique to Stormer viscometers.

A Ford viscosity cup measures the rate of flow of a liquid. This, under

ideal conditions, is proportional to the kinematic viscosity. Vibrating

viscometers can also be used to measure viscosity. These models such

as the Dynatrol use vibration rather than rotation to measure viscosity.

Extensional viscosity can be measured with various rheometers that

apply extensional stress. Volume viscosity can be measured with an

acoustic rheometer.

Apparent viscosity is a calculation derived from tests performed

on drilling fluid used in oil or gas well development. These calculations

and tests help engineers develop and maintain the properties of the

drilling fluid to the specifications required.

UUnniittss

Dynamic viscosity

The usual symbol for dynamic viscosity used by mechanical and

chemical engineers — as well as fluid dynamicists — is the Greek

51

letter mu (µ).[41][42][43] The symbol is also used by chemists, physicists,

and the IUPAC.[44]

The SI physical unit of dynamic viscosity is the pascal-second

(Pa·s), (equivalent to N·s/m2, or kg/(m·s)). If a fluid with a viscosity of

one Pa·s is placed between two plates, and one plate is pushed sideways

with a shear stress of one pascal, it moves a distance equal to the

thickness of the layer between the plates in one second. Water at 20 °C

has a viscosity of 0.001002 Pa·s.

The cgs physical unit for dynamic viscosity is the poise[45] (P),

named after Jean Louis Marie Poiseuille. It is more commonly

expressed, particularly in ASTM standards, as centipoise (cP). Water at

20 °C has a viscosity of 1.0020 cP.

1 P = 0.1 Pa·s,

1 cP = 1 mPa·s = 0.001 Pa·s.

Kinematic viscosity

In many situations, we are concerned with the ratio of the inertial

force to the viscous force (i.e. the Reynolds number, Re = VD / #), the

former characterized by the fluid density $. This ratio is characterized

by the kinematic viscosity (Greek letter nu, !), defined as follows:

The SI unit of ! is m2/s. The SI unit of " is kg/m3.

The cgs physical unit for kinematic viscosity is the stokes (St),

named after George Gabriel Stokes. It is sometimes expressed in terms

52

of centiStokes (cSt). In U.S. usage, stoke is sometimes used as the

singular form.

1 St = 1 cm2·s"1 = 10"4 m2·s"1.

1 cSt = 1 mm2·s"1 = 10"6m2·s"1.

Water at 20 °C has a kinematic viscosity of about 1 cSt.

The kinematic viscosity is sometimes referred to as diffusivity of

momentum, because it is analogous to diffusivity of heat and

diffusivity of mass. It is therefore used in dimensionless numbers

which compare the ratio of the diffusivities.

Fluidity

The reciprocal of viscosity is fluidity, usually symbolized by

# = 1 / µ or F = 1 / µ, depending on the convention used, measured in

reciprocal poise (cm·s·g"1), sometimes called the rhe. Fluidity is

seldom used in engineering practice.

The concept of fluidity can be used to determine the viscosity of

an ideal solution. For two components a and b, the fluidity when a and

b are mixed is

which is only slightly simpler than the equivalent equation in terms of

viscosity:

where $a and $b is the mole fraction of component a and b respectively,

and µa and µb are the components pure viscosities.

53

Non-standard units

The Reyn is a British unit of dynamic viscosity.

Viscosity index is a measure for the change of kinematic

viscosity with temperature. It is used to characterise lubricating oil in

the automotive industry.

At one time the petroleum industry relied on measuring

kinematic viscosity by means of the Saybolt viscometer, and expressing

kinematic viscosity in units of Saybolt Universal Seconds (SUS).[46]

Other abbreviations such as SSU (Saybolt Seconds Universal) or SUV

(Saybolt Universal Viscosity) are sometimes used. Kinematic viscosity

in centistoke can be converted from SUS according to the arithmetic

and the reference table provided in ASTM D 2161.[47]

MMoolleeccuullaarr oorriiggiinnss

The viscosity[48] of a system is determined by how molecules

constituting the system interact. There are no simple but correct

expressions for the viscosity of a fluid. The simplest exact expressions

54

are the Green–Kubo relations for the linear shear viscosity or the

Transient Time Correlation Function expressions derived by Evans and

Morriss in 1985. Although these expressions are each exact in order to

calculate the viscosity of a dense fluid, using these relations requires

the use of molecular dynamics computer simulations.

Gases

Viscosity in gases arises principally from the molecular diffusion

that transports momentum between layers of flow. The kinetic theory of

gases allows accurate prediction of the behavior of gaseous viscosity.

Within the regime where the theory is applicable:

Viscosity is independent of pressure and

Viscosity increases as temperature increases.[49]

James Clerk Maxwell published a famous paper in 1866 using the

kinetic theory of gases to study gaseous viscosity.[50] To understand

why the viscosity is independent of pressure, consider two adjacent

boundary layers (A and B) moving with respect to each other. The

internal friction (the viscosity) of the gas is determined by the

probability a particle of layer A enters layer B with a corresponding

transfer of momentum. Maxwell's calculations showed him that the

viscosity coefficient is proportional to both the density, the mean free

path and the mean velocity of the atoms. On the other hand, the mean

free path is inversely proportional to the density. So an increase of

pressure doesn't result in any change of the viscosity.

In relation to diffusion, the kinematic viscosity provides a better

understanding of the behavior of mass transport of a dilute species.

55

Viscosity is related to shear stress and the rate of shear in a fluid, which

illustrates its dependence on the mean free path, %, of the diffusing

particles.

From fluid mechanics, for a Newtonian fluid, the shear stress, &, on a

unit area moving parallel to itself, is found to be proportional to the rate

of change of velocity with distance perpendicular to the unit area:

for a unit area parallel to the x-z plane, moving along the x axis.

We will derive this formula and show how µ is related to %.

Interpreting shear stress as the time rate of change of momentum, p, per

unit area A (rate of momentum flux) of an arbitrary control surface

gives.

where is the average velocity along x of fluid molecules hitting the

unit area, with respect to the unit area.

Further manipulation will show[51]

, assuming that molecules hitting the unit area

come from all distances between 0 and % (equally distributed),

and that their average velocities change linearly with distance

(always true for small enough %). From this follows:

56

where

is the rate of fluid mass hitting the surface,

" is the density of the fluid,

' is the average molecular speed ( ),

µ is the dynamic viscosity.

Sutherland's formula can be used to derive the dynamic viscosity of an

ideal gas as a function of the temperature:[52]

This in turn is equal to

where is a constant.

in Sutherland's formula:

µ = dynamic viscosity in (Pa·s) at input temperature T,

µ0 = reference viscosity in (Pa·s) at reference temperature T0,

T = input temperature in kelvins,

T0 = reference temperature in kelvins,

C = Sutherland's constant for the gaseous material in question.

Valid for temperatures between 0 < T < 555 K with an error due to

pressure less than 10% below 3.45 MPa.

Sutherland's constant and reference temperature for some gases

57

GasC

[K]

T0

[K]

µ0

[µPa s]

air 120 291.15 18.27

nitrogen 111 300.55 17.81

oxygen 127 292.25 20.18

carbon dioxide 240 293.15 14.8

carbon monoxide 118 288.15 17.2

hydrogen 72 293.85 8.76

ammonia 370 293.15 9.82

sulfur dioxide 416 293.65 12.54

helium 79.4 [53] 273 19 [54]

The Chapman-Enskog equation[55] may be used to estimate

viscosity for a dilute gas. This equation is based on a semi-theoretical

assumption by Chapman and Enskog. The equation requires three

empirically determined parameters: the collision diameter ((), the

maximum energy of attraction divided by the Boltzmann constant ()/*)

and the collision integral (+(T*)).

with

T* = ,T/- — reduced temperature (dimensionless),

µ0 = viscosity for dilute gas (µPa.s),

M = molecular mass (g/mol),

58

T = temperature (K),

( = the collision diameter (Å),

- / , = the maximum energy of attraction divided by the

Boltzmann constant (K),

+µ = the collision integral.

Liquids

In liquids, the additional forces between molecules become

important. This leads to an additional contribution to the shear stress

though the exact mechanics of this are still controversial. Thus, in

liquids:

Viscosity is independent of pressure (except at very high

pressure); and Viscosity tends to fall as temperature increases (for

example, water viscosity goes from 1.79 cP to 0.28 cP in the

temperature range from 0 °C to 100 °C); see temperature dependence

of liquid viscosity for more details.

The dynamic viscosities of liquids are typically several orders of

magnitude higher than dynamic viscosities of gases.

The viscosity of the blend of two or more liquids can be

estimated using the Refutas equation[56]. The calculation is carried out

in three steps.

The first step is to calculate the Viscosity Blending Number

(VBN) (also called the Viscosity Blending Index) of each component

of the blend:

- (1)

59

where v is the kinematic viscosity in centistokes (cSt). It is important

that the kinematic viscosity of each component of the blend be obtained

at the same temperature.

The next step is to calculate the VBN of the blend, using this equation:

- (3)

where xX is the mass fraction of each component of the blend.

Once the viscosity blending number of a blend has been calculated

using equation (2), the final step is to determine the kinematic viscosity

of the blend by solving equation (1) for v:

- (3)

where VBNBlend is the viscosity blending number of the blend.

VViissccoossiittyy ooff sseelleecctteedd ssuubbssttaanncceess

The viscosity of air and water are by far the two most important

materials for aviation aerodynamics and shipping fluid dynamics.

Temperature plays the main role in determining viscosity.

Viscosity of air

60

Pressure dependence of the dynamic viscosity of dry air at the

temperatures of 300, 400 and 500 K

The viscosity of air depends mostly on the temperature. At 15.0 °C, the

viscosity of air is 1.78×10 5 kg/(m·s), 17.8 µPa.s or 1.78×10 5 Pa.s..

One can get the viscosity of air as a function of temperature from the

Gas Viscosity Calculator

Viscosity of water

Dynamic Viscosity of Water

The dynamic viscosity of water is 8.90 × 10 4 Pa·s or 8.90 × 10 3

dyn·s/cm2 or 0.890 cP at about 25 °C.Water has a viscosity of 0.0091

poise at 25 °C, or 1 centipoise at 20 °C.As a function of temperature T

(K): (Pa·s) = A × 10B/(T C) where A=2.414 × 10 5 Pa·s ; B = 247.8 K ;

and C = 140 K.[57]

Viscosity of liquid water at different temperatures up to the

normal boiling point is listed below.

61

Temperature [°C] Viscosity[mPa·s]

10 1.308

20 1.002

30 0.7978

40 0.6531

50 0.5471

60 0.4668

70 0.4044

80 0.3550

Some dynamic viscosities of Newtonian fluids are listed below:

Viscosity of selected gases at

100 kPa, [µPa·s]

Gasat 0 °C

(273 K)

at 27 °C

(300

K)[58]

air 17.4 18.6

hydrogen 8.4 9.0

helium 20.0

argon 22.9

xenon 21.2 23.2

carbon

dioxide 15.0

Viscosity of liquids

(at 25 °C unless otherwise specified)

Liquid (): Viscosity

[Pa·s]

Viscosity

[cP=mPa·s

]

acetone[61] 3.06×10 4 0.306

benzene[61] 6.04×10 4 0.604

castor oil[61] 0.985 985

corn syrup[61] 1.3806 1380.6

ethanol[61] 1.074×10

3 1.074

ethylene

glycol 1.61×10 2 16.1

62

methane 11.2

ethane 9.5

Viscosity of fluids with

variable compositions

Fluid

Viscosit

y

[Pa·s]

Viscosit

y

[cP]

blood (37

°C)[59]

(3–

4)×10 3 3–4

honey 2–10 2,000–

10,000

molasses 5–10 5,000–

10,000

molten

glass

10–

1,000

10,000–

1,000,00

0

chocolate

syrup 10–25

10,000–

25,000

molten

chocolate*

45–130 [60]

45,000–

130,000

ketchup* 50–100 50,000–

glycerol (at 20

°C)[62] 1.2 1200

HFO-380 2.022 2022

mercury[61] 1.526×10

3 1.526

methanol[61] 5.44×10 4 0.544

motor oil SAE

10 (20 °C) 0.065 65

motor oil SAE

40 (20 °C) 0.319 319

nitrobenzene[6

1]

1.863×10

3 1.863

liquid nitrogen

@ 77K 1.58×10 4 0.158

propanol[61] 1.945×10

3 1.945

olive oil .081 81

pitch 2.3×108 2.3×1011

sulfuric

acid[61] 2.42×10 2 24.2

63

100,000

lard ! 100 !

100,000

peanut

butter* ! 250

!

250,000

shortening*

! 250 !

250,000

water 8.94×10 4 0.894

* These materials are highly non-Newtonian.

VViissccoossiittyy ooff sslluurrrryy

The term slurry designs mixtures of a liquid and solid particles that

retain some fluidity. The viscosity of slurry can be described as relative

to the viscosity of the liquid phase:

where µs and µl are respectively the dynamic viscosity of the slurry and

liquid (Pa·s), and µr is the relative viscosity (dimensionless).

Depending on the size and concentration of the solid particles, several

models exist that describe the relative viscosity as a function of volume

fraction of solid particles.

In the case of extremely low concentrations of fine particles, Einstein's

equation[63] may be used:

64

In the case of higher concentrations, a modified equation was proposed

by Guth and Simha[64] which takes into account interaction between the

solid particles:

Further modification of this equation was proposed by Thomas from

the fitting of empirical data:

where A = 0.00273 and B = 16.6.

In the case of very high concentrations, another empirical equation was

proposed by Kitano et al.[66]:

where A = 0.68 for smooth spherical particles.

VViissccoossiittyy ooff ssoolliiddssss

On the basis that all solids such as granite[67] flow in response to

small shear stress, some researchers[68] have contended that substances

known as amorphous solids, such as glass and many polymers, may be

considered to have viscosity. This has led some to the view that solids

are simply "liquids" with a very high viscosity, typically greater than

1012 Pa·s. This position is often adopted by supporters of the widely

held misconception that glass flow can be observed in old buildings.

This distortion is the result of the undeveloped glass making process of

earlier eras, and not due to the viscosity of glass.[69]

65

However, others argue that solids are, in general, elastic for

small stresses while fluids are not.[70] Even if solids flow at higher

stresses, they are characterized by their low-stress behavior. This

distinction is muddled if measurements are continued over long time

periods, such as the Pitch drop experiment. Viscosity may be an

appropriate characteristic for solids in a plastic regime. The situation

becomes somewhat confused as the term viscosity is sometimes used

for solid materials, for example Maxwell materials, to describe the

relationship between stress and the rate of change of strain, rather than

rate of shear.

These distinctions may be largely resolved by considering the

constitutive equations of the material in question, which take into

account both its viscous and elastic behaviors. Materials for which both

their viscosity and their elasticity are important in a particular range of

deformation and deformation rate are called viscoelastic. In geology,

earth materials that exhibit viscous deformation at least three times

greater than their elastic deformation are sometimes called rheids.

VViissccoossiittyy ooff aammoorrpphhoouuss mmaatteerriiaallss

Common glass viscosity curves.

66

Viscous flow in amorphous materials (e.g. in glasses and melts)[72][73][74]

is a thermally activated process:

where Q is activation energy, T is temperature, R is the molar gas

constant and A is approximately a constant.

The viscous flow in amorphous materials is characterized by a

deviation from the Arrhenius-type behavior: Q changes from a high

value QH at low temperatures (in the glassy state) to a low value QL at

high temperatures (in the liquid state). Depending on this change,

amorphous materials are classified as either

strong when: QH QL < QL or

fragile when: QH QL " QL.

The fragility of amorphous materials is numerically characterized by

the Doremus’ fragility ratio:

and strong material have RD < 2 whereas fragile materials have RD " 2.

The viscosity of amorphous materials is quite exactly described by a

two-exponential equation:

with constants A1, A2, B, C and D related to thermodynamic parameters

of joining bonds of an amorphous material.

Not very far from the glass transition temperature, Tg, this equation can

be approximated by a Vogel-Fulcher-Tammann (VFT) equation.

67

If the temperature is significantly lower than the glass transition

temperature, T < Tg, then the two-exponential equation simplifies to an

Arrhenius type equation:

with:

where Hd is the enthalpy of formation of broken bonds (termed

configuron s) and Hm is the enthalpy of their motion. When the

temperature is less than the glass transition temperature, T < Tg, the

activation energy of viscosity is high because the amorphous materials

are in the glassy state and most of their joining bonds are intact.

If the temperature is highly above the glass transition temperature,

T > Tg, the two-exponential equation also simplifies to an Arrhenius

type equation:

with:

When the temperature is higher than the glass transition

temperature, T > Tg, the activation energy of viscosity is low because

amorphous materials are melt and have most of their joining bonds

broken which facilitates flow.

EEddddyy vviissccoossiittyy

In the study of turbulence in fluids, a common practical strategy

for calculation is to ignore the small-scale vortices (or eddies) in the

68

motion and to calculate a large-scale motion with an eddy viscosity that

characterizes the transport and dissipation of energy in the smaller-

scale flow Values of eddy viscosity used in modeling ocean circulation

may be from 5x104 to 10

6 Pa·s depending upon the resolution of the

numerical grid.

TThhee lliinneeaarr vviissccoouuss ssttrreessss tteennssoorr

For more details on an analogous development for linearly

elastic materials, Hooke's law and strain tensor.

Viscous forces in a fluid are a function of the rate at which the

fluid velocity is changing over distance. The velocity at any point r is

specified by the velocity field v(r). The velocity at a small distance dr

from point r may be written as a Taylor series:

where dv / dr is shorthand for the dyadic product of the del operator

and the velocity:

This is just the Jacobian of the velocity field.

Viscous forces are the result of relative motion between elements

of the fluid, and so are expressible as a function of the velocity field. In

other words, the forces at r are a function of v(r) and all derivatives of

v(r) at that point. In the case of linear viscosity, the viscous force will

69

be a function of the Jacobian tensor alone. For almost all practical

situations, the linear approximation is sufficient.

If we represent x, y, and z by indices 1, 2, and 3 respectively, the

i,j component of the Jacobian may be written as i vj where i is

shorthand for / xi. Note that when the first and higher derivative terms

are zero, the velocity of all fluid elements is parallel, and there are no

viscous forces.

Any matrix may be written as the sum of an antisymmetric

matrix and a symmetric matrix, and this decomposition is independent

of coordinate system, and so has physical significance. The velocity

field may be approximated as:

where Einstein notation is now being used in which repeated indices in

a product are implicitly summed. The second term from the right is the

asymmetric part of the first derivative term, and it represents a rigid

rotation of the fluid about r with angular velocity ! where:

For such a rigid rotation, there is no change in the relative

positions of the fluid elements, and so there is no viscous force

associated with this term. The remaining symmetric term is responsible

for the viscous forces in the fluid. Assuming the fluid is isotropic (i.e.

its properties are the same in all directions), then the most general way

that the symmetric term (the rate-of-strain tensor) can be broken down

70

in a coordinate-independent (and therefore physically real) way is as

the sum of a constant tensor (the rate-of-expansion tensor) and a

traceless symmetric tensor (the rate-of-shear tensor):

where "ij is the unit tensor. The most general linear relationship

between the stress tensossr and the rate-of-strain tensor is then a

linear combination of these two tensors:[75]

where # is the coefficient of bulk viscosity (or "second viscosity") and µ

is the coefficient of (shear) viscosity.

The forces in the fluid are due to the velocities of the individual

molecules. The velocity of a molecule may be thought of as the sum of

the fluid velocity and the thermal velocity. The viscous stress tensor

described above gives the force due to the fluid velocity only. The force

on an area element in the fluid due to the thermal velocities of the

molecules is just the hydrostatic pressure. This pressure term ( p "ij)

must be added to the viscous stress tensor to obtain the total stress

tensor for the fluid.

The infinitesimal force dFi on an infinitesimal area dAi is then given by

the usual relationship:

71

Storage: :[76]

A container for pharmaceutical use is an article which contains

or is intended to contain a product and is, or may be, in direct contact

with it. The closure is a part of the container.

The container is so designed that the contents may be removed

in a manner appropriate to the intended use of the preparation. It

provides a varying degree of protection depending on the nature of the

product and the hazards of the environment, and minimises the loss of

constituents. The container does not interact physically or chemically

with the contents in a way that alters their quality beyond the limits

tolerated by official requirements.

Single-dose container A single-dose container holds a quantity of the

preparation intended for total or partial use as a single administration.

Multidose container A multidose container holds a quantity of the

preparation suitable for two or more doses.

Well-closed container A well-closed container protects the contents

from contamination with extraneous solids and liquids and from loss

of contents under ordinary conditions of handling, storage and

transport.

Airtight container An airtight container is impermeable to solids,

liquids and gases under ordinary conditions of handling, storage and

transport. If the container is intended to be opened on more than one

occasion, it must be so designed that it remains airtight after re-

closure.

72

Sealed container A sealed container is a container closed by fusion of

the material of the container.

Tamper-proof container A tamper-proof container is a closed

container fitted with a device that reveals irreversibly whether the

container has been opened.

Child-proof container A container that is fitted with a closure that

prevents opening by children

Glass containers for pharmaceutical use are glass articles intended to

come into direct contact with pharmaceutical preparations.

Colourless glass is highly transparent in the visible spectrum.

Coloured glass is obtained by the addition of small amounts of metal

oxides, chosen according to the desired spectral absorbance.

Neutral glass is a borosilicate glass containing significant amounts of

boric oxide, aluminium oxide alkali and/or alkaline earth oxides. Due

to its composition neutral glass has a high hydrolytic resistance and a

high thermal shock resistance.

Soda-lime-silica glass is a silica glass containing alkali metal oxides,

mainly sodium oxide and alkaline earth oxides, mainly calcium oxide.

Due to its composition soda-lime-silica glass has only a moderate

hydrolytic resistance.

The hydrolytic stability of glass containers for pharmaceutical use is

expressed by the resistance to the release of soluble mineral substances

into water under the prescribed conditions of contact between the inner

surface of the container or glass grains and water. The hydrolytic

73

resistance is evaluated by titrating released alkali. According to their

hydrolytic resistance, glass containers are classified as follows:

— Type I glass containers: neutral glass, with a high hydrolytic

resistance due to the chemical composition of the glass itself,

— Type II glass containers: usually of soda-lime-silica glass with a

high hydrolytic resistance resulting from suitable treatment of

the surface,

— Type III glass containers: usually of soda-lime-silica glass with

only moderate hydrolytic resistance.

The following italicised statements constitute general

recommendations concerning the type of glass container that may be

used for different types of pharmaceutical preparations. The

manufacturer of a pharmaceutical product is responsible for ensuring

the suitability of the chosen container.

Type I glass containers are suitable for most preparations whether or

not for parenteral use.

Type II glass containers are suitable for most acidic and neutral,

aqueous preparations whether or not for parenteral use.

Type III glass containers are in general suitable for non-aqueous

preparations for parenteral use, for powders for parenteral use

(except for freeze-dried preparations) and for preparations not for

parenteral use.

Glass containers with a hydrolytic resistance higher than that

recommended above for a particular type of preparation may generally

also be used.

74

The container chosen for a given preparation shall be such that

the glass material does not release substances in quantities sufficient to

affect the stability of the preparation or to present a risk of toxicity. In

justified cases, it may be necessary to have detailed information on the

glass composition, so that the potential hazards can be assessed.

Preparations for parenteral use are normally presented in colourless

glass, but coloured glass may be used for substances known to be

light-sensitive. Colourless or coloured glass is used for the other

pharmaceutical preparations. It is recommended that all glass

containers for liquid preparations and for powders for parenteral use

permit the visual inspection of the contents.

The inner surface of glass containers may be specially treated to

improve hydrolytic resistance, to confer water-repellancy, etc. The

outer surface may also be treated, for example to reduce friction and to

improve resistance to abrasion. The outer treatment is such that it does

not contaminate the inner surface of the container.

Except for type I glass containers, glass containers for

pharmaceutical preparations are not to be re-used. Containers for

human blood and blood components must not be re-used.

Glass containers for pharmaceutical use comply with the relevant test

or tests for hydrolytic resistance. When glass containers have non-glass

components, the tests apply only to the glass part of the container.

To define the quality of glass containers according to the

intended use, one or more of the following tests are necessary.

75

Tests for hydrolytic resistance are carried out to define the type of

glass (I, II or III) and to control its hydrolytic resistance.

Determination of the filling volume

The filling volume is the volume of water to be filled in the

container for the purpose of the test. For vials and bottles the filling

volume is 90 per cent of the brimful capacity. For ampoules it is the

volume up to the height of the shoulder.

Vials and bottles Select, at random, 6 containers from the sample lot,

or 3 if their capacity exceeds 100 ml, and remove any dirt or debris.

Weigh the empty containers with an accuracy of 0.1 g. Place the

containers on a horizontal surface and fill them with distilled water R

until about the rim edge, avoiding overflow and introduction of air

bubbles. Adjust the liquid levels to the brimful line. Weigh the filled

containers to obtain the mass of the water expressed to 2 decimal places

for containers having a nominal volume less or equal to 30 ml, and

expressed to 1 decimal place for containers having a nominal volume

greater than 30 ml. Calculate the mean value of the brimful capacity in

millilitres and multiply it by 0.9. This volume, expressed to 1 decimal

place, is the filling volume for the particular container lot.

Ampoules Place at least 6 dry ampoules on a flat, horizontal surface

and fill them with distilled water R from a burette, until the water

reaches point A, where the body of the ampoule declines to the

shoulder (see Figure 3.2.1.-1). Read the capacities (expressed to 2

decimal places) and calculate the mean value. This volume, expressed

76

to 1 decimal place, is the filling volume for the particular ampoule lot.

The filling volume may also be determined by weighing.

Figure 3.2.1 Filling Volume of ampoules (up to point A)

Stability Studies :[77]

:

General Principles

The purpose of stability testing is to provide evidence on how the

quality of a drug substance or drug product varies with time under the

influence of a variety of environmental factors such as temperature,

humidity, and light, and to establish a re-test period for the drug

substance or a shelf life for the drug product and recommended storage

conditions.

The choice of test conditions defined in this guideline is based on

an analysis of the effects of climatic conditions in the three regions of

the EC, Japan and the United States. The mean kinetic temperature in

any part of the world can be derived from climatic data, and the world

77

can be divided into four climatic zones, I-IV. This guideline addresses

climatic zones I and II. The principle has been established that stability

information generated in any one of the three regions of the EC, Japan

and the United States would be mutually acceptable to the other two

regions, provided the information is consistent with this guideline and

the labeling is in accord with national/regional requirements.

GUIDELINES

Drug Substance

Information on the stability of the drug substance is an integral

part of the systematic approach to stability evaluation.

Stress Testing

Stress testing of the drug substance can help identify the likely

degradation products, which can in turn help establish the degradation

pathways and the intrinsic stability of the molecule and validate the

stability indicating power of the analytical procedures used. The nature

of the stress testing will depend on the individual drug substance and

the type of drug product involved.

Stress testing is likely to be carried out on a single batch of the

drug substance. It should include the effect of temperatures (in 10°C

increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing),

humidity (e.g., 75% RH or greater) where appropriate, oxidation, and

photolysis on the drug substance. The testing should also evaluate the

susceptibility of the drug substance to hydrolysis across a wide range of

pH values when in solution or suspension. Photostability [79]

testing

78

should be an integral part of stress testing. The standard conditions for

photostability testing are described in ICH Q1B.

Examining degradation products under stress conditions is useful

in establishing degradation pathways and developing and validating

suitable analytical procedures.

However, it may not be necessary to examine specifically for

certain degradation products if it has been demonstrated that they are

not formed under accelerated or long term storage conditions.

Results from these studies will form an integral part of the information

provided to regulatory authorities.

Selection of Batches

Data from formal stability studies should be provided on at least

three primary batches of the drug substance. The batches should be

manufactured to a minimum of pilot scale by the same synthetic route

as, and using a method of manufacture and procedure that simulates the

final process to be used for, production batches. The overall quality of

the batches of drug substance placed on formal stability studies should

be representative of the quality of the material to be made on a

production Scale.

Other supporting data can be provided.

Container Closure System

The stability studies should be conducted on the drug substance

packaged in a container closure system that is the same as or simulates

the packaging proposed for storage and distribution.

79

Specification

Specification, which is a list of tests, reference to analytical

procedures, and proposed acceptance criteria, is addressed in ICH Q6A

and Q6B. In addition, specification for degradation products in a drug

substance is discussed in Q3A.

Stability studies should include testing of those attributes of the

drug substance that are susceptible to change during storage and are

likely to influence quality, safety, and/or efficacy. The testing should

cover, as appropriate, the physical, chemical, biological, and

microbiological attributes. Validated stability-indicating analytical

procedures should be applied. Whether and to what extent replication

should be performed will depend on the results from validation studies.

Testing Frequency

If significant change occurs within the first 3 months’ testing at

the accelerated storage condition, a discussion should be provided to

address the effect of short term excursions outside the label storage

condition, e.g., during shipping or handling. This discussion can be

supported, if appropriate, by further testing on a single batch of the

drug substance for a period shorter than 3 months but with more

frequent testing than usual. It is considered unnecessary to continue to

test a drug substance through 6 months when a significant change has

occurred within the first 3 months. Drug substances intended for

storage below -20°C should be treated on a case-by-case basis.

The data may show so little degradation and so little variability

that it is apparent from looking at the data that the requested re-test

80

period will be granted. Under these circumstances, it is normally

unnecessary to go through the formal statistical analysis; providing a

justification for the omission should be sufficient.

Selection of Batches

Data from stability studies should be provided on at least three

primary batches of the drug product. The primary batches should be of

the same formulation and packaged in the same container closure

system as proposed for marketing. The manufacturing process used for

primary batches should simulate that to be applied to production

batches and should provide product of the same quality and meeting the

same specification as that intended for marketing. Two of the three

batches should be at least pilot scale batches and the third one can be

smaller, if justified. Where possible, batches of the drug product should

be manufactured by using different batches of the drug substance.

Stability studies should be performed on each individual strength and

container size of the drug product unless bracketing or matrixing is

applied. Other supporting data can be provided.

Container closure system

The sum of packaging components that together contain and

protect the dosage form. This includes primary packaging components

and secondary packaging components, if the latter are intended to

provide additional protection to the drug product. A packaging system

is equivalent to a container closure system.

81

Dosage form

A pharmaceutical product type (e.g., tablet, capsule, solution, cream)

that contains a drug substance generally, but not necessarily, in

association with excipients.

Drug product

The dosage form in the final immediate packaging intended for

marketing.

Drug substance

The unformulated drug substance that may subsequently be formulated

with excipients to produce the dosage form.

Excipient

Anything other than the drug substance in the dosage form.

Expiration date

The date placed on the container label of a drug product designating the

time prior to which a batch of the product is expected to remain within

the approved shelf life specification if stored under defined conditions,

and after which it must not be used.

Formal stability studies

Long term and accelerated (and intermediate) studies undertaken on

primary and/or commitment batches according to a prescribed stability

protocol to establish or confirm the re-test period of a drug substance or

the shelf life of a drug product.

82

Intermediate testing

Studies conducted at 30°C/65% RH and designed to moderately

increase the rate of chemical degradation or physical changes for a drug

substance or drug product intended to be stored long term at 25°C.

Long term testing

Stability studies under the recommended storage condition for

the re-test period or shelf life proposed (or approved) for labeling.

Mass balance

The process of adding together the assay value and levels of

degradation products to see how closely these add up to 100% of the

initial value, with due consideration of the margin of analytical error.

Matrixing

The design of a stability schedule such that a selected subset of

the total number of possible samples for all factor combinations is

tested at a specified time point. At a subsequent time point, another

subset of samples for all factor combinations is tested.

The design assumes that the stability of each subset of samples tested

represents the stability of all samples at a given time point. The

differences in the samples for the same drug product should be

identified as, for example, covering different batches, different

strengths, different sizes of the same container closure system, and,

possibly in some cases, different container closure systems.

83

Pilot scale batch

A batch of a drug substance or drug product manufactured by a

procedure fully representative of and simulating that to be applied to a

full production scale batch. For solid oral dosage forms, a pilot scale is

generally, at a minimum, one-tenth that of a full production scale or

100,000 tablets or capsules, whichever is the larger.

Primary batch

A batch of a drug substance or drug product used in a formal

stability study, from which stability data are submitted in a registration

application for the purpose of establishing a re-test period or shelf life,

respectively. A primary batch of a drug substance should be at least a

pilot scale batch. For a drug product, two of the three batches should be

at least pilot scale batch, and the third batch can be smaller if it is

representative with regard to the critical manufacturing steps. However,

a primary batch may be a production batch.

Production batch

A batch of a drug substance or drug product manufactured at

production scale by using production equipment in a production facility

as specified in the application.