21

Chapter-V: Study the Impurity Profile and Polymorphism of Omeprazole

(121-143)

CHAPTER-I

INTRODUCTION TO DRUGS

Omeprazole

5.1 Synthetic scheme for preparation of N-alkylated

benzimidazole derivatives

129

5.2 Synthetic scheme for preparation of S-alkylated

benzimidazole derivatives

130

5.3 Synthetic scheme for preparation of N and S-

alkylated benzimidazole derivatives

131

22

1.1 Introduction

For therapeutic purposes, a drug substance with well-known chemical

structure is used. Man uses the drug from several millennia before the

development of study on therapeutics or pharmacology. Man digests various

plants found in the environment due to the inquisitive nature of homosapiens.

The term drug is also used to describe substances taken for recreational

rather than therapeutic purposes. However, these substances can also be used

as drugs. For example, Heroin1 (diamorphine) 1, is a very effective pain-killer

and is used to alleviate pain in terminal cancer cases.

OH3C

H

O

OH3C

NCH3O

O

1

3D-diagram of heroin

No drug is safe completely, due to the interference with the biological

processes. Some drugs are available commonly over the counter, such as

aspirin 2 and paracetamol 3 acts as poison if taken in excess. Paracetamol can

23

cause coma and death. Most of the drugs have beneficial and simultaneously

non-beneficial to biological system. Aspirin, which is commonly used to

alleviate headaches, can also cause gastric irritation and bleeding in some

people. When antibiotics are used in excess their

will be development of resistance to that drug in the patients. Drug resistance

or tolerance as it is known in humans, arises in people for a variety of reasons.

Man uses the drugs in two ways, one those which are helpful were

incorporated into his culture and the other those which are toxic are used in

hunting or warfare. Thus various parts of the world have seen the use of such

plant products as opium,2 hashish,3 cocaine4 alcohols as part of ritual of life.

1.2 Development of Science

The 19th century consign to growth of the science to investigate the

various plant products. The attempts were made to extract, isolate and

determine the structure from active principles. Initially, the work begins with

the attempts for the preparation of synthetic version of the compound which

embodied various known features of the natural products. The stripping down

to the molecule had the advantage to develop biological activity for that part of

the molecule and also to provide the synthesis for those molecules in

commercial.

COOH

OCOCH3

NHCOCH3

OH

2 3

24

Organic chemistry and medicinal chemistry share a venerable common

history. Many of the founders of the organic chemistry had an intense interest

not only to extract the molecules from nature but also in the effects of

synthetic compounds on living systems.

Organic molecules owe their biological activity to a variety of structural

features. Sometimes a set of activities is associated with the structural

backbone of a molecule (Table 1.1).

Table 1.1: Organic molecules having different pharmacological activity

S.

No

Drug Name Pharmacolog

ical activity

Structure Ref.

4

Famotidine

H2

antagonist

S

N

S

NH2

N SO2NH2

NH2N

H2N

5

5

Tenatoprazole

Anti ulcerative

6

6

Nefazodone

Anti

depressant

7

7

Enalapril

Anti

hypertensive

OH3C

NH O

N

HOOC

CH3

8

NS

NH

N

N

OCH3

OCH3

H3C CH3

O

ON

N

NN

N

Cl

O

H3C

25

8

Moxifloxacin

Antibacterial

F

N N

O

OH

OO

HN

H3C

9

9

Nelfinavir

Antiviral CH3

HONH

O

N

S

OH

HNO CH3

CH3

CH3

10

10

Pioglitazone

Antidiabetic N

H3C

OS

NH

O

O

11

In the field of gastroenterology and the management of acid-related

diseases including peptic ulcer disease led to the scientific advances in the 20th

century which include systematization of medical education, increased

research, improved diagnostics, effective medicines and the growth of medical

specialization.

Beginning of the 20th century, assessment on digestive tract was limited;

the diagnostic and therapeutic resources were insufficient. The tests like blood

counts, urine analysis and a few chemical tests are only available. Today,

comprehensive advancements have helped considerably in the overall and

successful management of patients with gastrointestinal disorders. Some of

these favorable advancements include:12

Diagnostic capabilities, including fiber-optic gastroscopy,

knowledge of risk factors,

26

tests of hepatic and pancreatic functions,

ultrasonography,

breath tests,

quality x-rays,

ability to perform biopsies,

x-ray guided biopsy of the liver and colon,

computerized abdominal tomography,

magnetic resonance imaging,

assessment of gastrointestinal motility and vascular status,

increased understanding of the inflammatory cascade and gastric

protective mechanisms.

Now gastroenterology has qualified remarkable growth in the

understanding and use of therapeutic resources including blood transfusions,

nutritional support services, sulfonamides, antibiotics, adrenocorticosteroids,

immune modifiers, H2 blockers and proton pump inhibitors. These agents have

dramatically altered the management of gastroesophageal reflux disease

(GERD), management of peptic ulcer disease (PUD), the prevention and

treatment of non steroidal anti-inflammatory drug (NSAID)-related

gastrointestinal complications.13-14

1.3 Classification

A peptic ulcer may arise at various locations:

Stomach (called gastric ulcer)

Duodenum (called duodenal ulcer)

Esophagus (called esophageal ulcer)

27

Meckel‟s Diverticulum (called Meckel‟s Diverticulum ulcer)

1.4 Surgery to effective pharmacological therapies in gastroenterology

From the last 40 years there was an enormous development in the

treatment of acid-related diseases. Until then, there had been steady progress

in the surgical approach to this ailments.15 On the other hand; bland diet and

atropine were the only medical treatment options. Today, surgery reserved for

complications and failure of that therapy.

Research during the past 40 years into gastric acid related disorders

resulted the medical therapy is the first step in treating ulcer disease.

Impressive advances in gastroenterology along with the introduction of effective

treatments have changed this. The development of agents that effectively

suppress gastric acid represents a milestone in the management of these

diseases. Recent advances in medical therapy have further reduced the need

for operations with gastric surgery perhaps only being limited to emergent

(peptic ulcer disease) PUD and the treatment of gastric cancer.

This section reviews some of the significant growth that has occurred

over the past four decades in the management of acid-related disorders. The

understanding and new insights have contributed to the evolution of drug

therapy from antacids to histamine-2-receptor antagonists (H2RAs), discovery

of Helicobacter Pylori (H. Pylori) to the introduction of proton pump inhibitors

into the market. Impressive progresses that have been achieved in terms of

basic research and pharmaceutical developments which has totally changed

the management of PUD. In particular, the introduction of selective histamine

receptor antagonists and proton pump inhibitors has made the medical control

28

of acid secretion, including PUD, an effective means of therapy with less

reliance on costly and complicated surgical procedures. These impressive

advances highlight the successful intervention of effective pharmaceutical

therapies with closure of a therapeutic gap.16-17

1.5 History In the

beginning of 1958 John Lykoudis, a general practitioner in Greece, treated

patients with antibiotics for peptic ulcer disease, it was commonly recognized

that bacteria a dominant cause for the disease.18 It was recognized that acid

secretion is a regulated process based on the discovery of highly selective

vagotomy and reduced acid secretion. Dr. Black and his colleagues in 1963

discovered that pharmacological inhibition of gastric acid stimulation would

provide an alternative to surgery.16

Histamine had been discovered as a breakthrough to gastric acid

stimulation and although histamine antagonists were developed for treatment

of allergies, there were found to be too weak to provide any gastric acid

inhibition. In 1960‟s and

1970‟s, burimamide was developed as the first selective histamine antagonist.

In 1977 the breakthrough comes with the launching of cimetidine as a therapy

for peptic ulcer disease and was followed rapidly thereafter by other such

H2RAS with similar efficacy. The discovery of the pharmacological inhibition of

acid secretion by histamine 2 receptor antagonist (H2RAs) provided the first

possible alternative to surgery.

Two Australian scientists, J. Robin Warren and Barry J. Marshall

rediscovered H. pylori in 1982 as a causative factor for ulcers.19 Warren and

Marshall describe that most stomach ulcers and gastritis were caused by

29

colonization with this bacterium, not by stress or spicy food as had been

assumed before.20 In an act of self-

experimentation Marshall drank a Petri dish containing a culture of organisms

extracted from a patient and soon developed gastritis. He took antibiotics to kill

the bacteria at the advice of his wife. His symptoms disappeared after two

weeks, since halitosis is one of the symptoms of infection.21 He took antibiotics

to kill the remaining bacteria at the urging of his wife.

Furthermore, until recently GERD was considered a trivial problem with

very limited pharmaceutical interest. However, GERD has received significantly

more attention over the past 10 years, and it is now considered a major market

for antisecretory acid suppression agent despite effective medical therapy with

H2RAs, it was found that although ulcers healed approximately 70%

reoccurred after stopping therapy. The recurrence of peptic ulcer diseases was

thought to be responsible when infectious organism Camplobactor Pyloridis

(now called Helicobacter Pylori) was discovered in 1983.

The causative agents for most peptic ulcers are H. Pylori, which was

established after thorough research into this area, with the exception of PUD

caused by non-steroidal anti-inflammatory drugs (NSAIDs). Eradication of H.

pylori resulted in a cure for PUD and a sharp reduction in morbidity.12, 22

The more efficient a new group of drugs

proton pump inhibitors (PPIs) were launched into the market on inhibiting acid

secretion and targeting acid secretion, the H+/K+ Atpase or acid pump.

The revolutionized ability to inhibit acid secretion and control

intragastric pH take place with the discovery of omeprazole and its unique

30

mechanism of action on the proton pump inhibitors (PPIs). All the current PPIs

have the same core structure and are pro-drugs.

The maximal acid secretion was effectively reduced, to approximately

70% with the addition of PPIs and its addition to the H. Pylori treatment further

assisted in the rapid eradication of the infectious organism.16

1.6 Peptic ulcer disease (PUD)

H. pylori are the main causative factor for the chronic gastritis, peptic

ulcer disease, gastric adenocarcinoma and gastric mucosa-associated with

lymphoid tissue (MALT lymphoma).

The term PUD in general refers to spectrum of disorders that includes

gastric ulcer (GU), pyloric channel ulcer, duodenal ulcer (DU) and postoperative

ulcers at or near the site of surgical anastomosis.12

Although H. Pylori is an established cause of several gastric diseases

mentioned above debate continues over whether it has any role in the etiology

of disease outside the stomach.22-24

1.7 Epidemiology

In developing countries H. pylori infection is about 80% compared to

prevalence of 20-50% in developed countries.22 H. pylori infection is greater for

older persons in the United States, about 50% in individuals older than 50

years. A higher prevalence of 40 to 50%, in minorities of varying age groups

and prevalence rates greater than 60% from immigrating developed countries

such as Latinos. H. pylori infection is very less in more wealthy caucasians at

20% for individuals less than 40 years of age.25 Even though H. pylori

infections are caused in most of the gastric ulcer, reports from the US show

that 30% of gastric ulcers can be related to aspirin and other non-steroidal

31

anti-inflammatory drugs (NSAIDs). In developing countries, the ulcer groups

are smaller and the gastric cancer group may be larger. For example, in

northern Brazil, gastric cancer is the most common malignancy in men.25

1.8 Western countries

To report the prevalence of H. Pylori in Western countries the following

statements are made:25 H. Pylori affects about 20% of persons below the age of

40 years and 50% of those above the age of 60 years. Young children are

mostly not infected with H. pylori. H. Pylori infection is more common in low

socio-economic status.

In some Western countries, immigration is responsible for isolated areas of

high prevalence of H. Pylori.

1.9 Developing Countries

Most adults are infected, with H. Pylori in developing countries which

occur in about 10% of children annually between the ages of 2 and 8 years so

that most are infected by their teens. It is noticed from careful survey that the

majority of persons in the world are infected with H. Pylori.

H. pylori can be noticed from the stools in most infected persons. This is

evidence that spread by fecal oral contact with infected persons is likely. H.

Pylori are detected through polymerase chain reaction (PCR) in dental plaque

from 30% of persons with the gastric infection. However, this may be a less

common source of transmission.20

1.10 Transmission

In developing countries the transmission is through oral ingestion,

vomits, saliva or feces and possible through water sources. The exact mode of

32

transmission of H. pylori still remains mysterious. Although H. pylori may be

destroyed with antibiotics, infection may be carried if specific combination of

antibiotics and acid suppressing agents are not used.

1.11 Diagnostic Tests

Infection with H. pylori can be diagnosed by endoscopic biopsy (rapid

urease testing, histological examination, culture or polymerase reaction) or by

non-invasive methods (serology, urea breath test, or the detection of H. pylori

antigens in the stool). The choice of appropriate test is based on clinical

situation.

1.12 Therapy

Significantly the management of PUD and treatment has changed.

Treatment of PUD has changed from dietary modifications and surgery to acid

suppression with antacids, H2RAs, proton pump inhibitors and eradication of

H. Pylori infection. Patients were frequently admitted as inpatients and surgery

was common before the development of H2RAs, but now the use of H2RAs and

later PPIs have dramatically changed the management of PUD from In-hospital

to a largely outpatient setting with decline in the number of surgical

procedures.26 In 1970 Histamine-2 (H2) blockers are introduced. Proton pump

inhibitors (PPIs) are the new class of drugs that profoundly inhibit acid

secretion and have been shown to be very effective in ulcer healing.

Therapy for H. Pylori includes 1-2 weeks of a triple therapy of a proton

pump inhibitor plus clarithromicin and either amoxicillin or metronidazole.

Quadruple therapy of proton-pump inhibitor with bismuth subcitrate,

33

tetracycline and metronidazole for more than a week is equally efficient.22

A number of novel drugs are also under investigation for GERD which

may be promising for PUD. These include transient lower esophageal sphincter

relaxation-reducing agents, serotonergic agents, potassium-competitive acid

blockers, mucosal protectants, histamine H3 agonists and anti-gastrin agents.

If one or more of these groups prove to effective, additional options will become

available to clinicians to manage acid-related diseases.30-31

Table-1.2: Currently approved agents for the management of gastric acid

related diseases27-29

Therapeutic class Agents

Antacids Calcium carbonate

Magnesium hydroxide

Aluminum hydroxide

Prokinetic agents Bethanechol

Metoclopramide

Domperidone

Cisapride

Mucosal Protective agents Sucralfate

Alginic acid

Histamine-2 Receptor antagonists Cimetidine

34

Nizatidine

Ranitidine

Famotidine

Proton pump inhibitors Omeprazole

Lansoprazole

Pantoprazole

Rabeprazole

Esomeprazole

Antacids, which were once considered an old-fashioned acid suppression

therapy, may increase esophageal pH up to 90 minutes. There is new interest

now in developing combination over the counter therapies of H2RA‟s plus

antacids. The strategy is aimed at allowing for prompt treatment of „heartburn‟

with the prevention of subsequent episodes for several hours. At present a

combination product is not available but given over the counter market

potential for low dose H2RA‟s and the competition from PPI going over the

counter development and availability of these agents is not far off.32

1.13 Several substituted benzimidazoles are known such as proton

pump inhibitors (PPIs)

1 5-[Methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl]methyl]sulfinyl-1H-

benzimidazole] [Omeprazole]

2 2-[3-Methyl-4-[[[2,2,2-trifluoroethoxy]-2-pyridinyl]methyl]sulfinyl-1H-

benzimidazole] [Lansoprazole]

3 2-[[[4-[3-Methoxypropoxy]-3-methyl-2-pyridinyl]methyl]sulfinyl-1H-

benzimidazole] [Rabeprazole]

35

4 5-[Difluoromethoxy-2-[[3,4-dimethoxy-2-pyridinyl]methyl]sulfinyl-1H-

benzimidazole] [Pantoprazole]

a) Omeprazole

Omeprazole (PRILOSEC) is a substituted benzimidazole, 5-methoxy-2-

[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole 11,

well known pharmaceutical useful in proton pump inhibitor and inhibits the

action of H+-K+ ATPase in parietal cells. In general these classes of compounds

are used for the prevention and treatment of gastric acid related diseases.

Omeprazole is used in the treatment of gastro esophageal (GERD) of ulcers.33-35

b) Lansoprazole

Lansoprazole (PREVACID) is a substituted benzimidazole, 2-[[[3-methyl-

4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole 12, an

antiulcer agent and proton pump inhibitor. It is used to treat gastroesophageal

reflux disease (GERD), severe erosive esophagitis, poorly responsive systemic

GERD, and pathologic hypersecretory conditions (Zollinger-Ellison syndrome,

systemic mastocytosis, multiple endocrine adenomas). It is also a potentially

effective treatment for duodenal and gastric ulcers and for maintenance of

healed duodenal ulcers.36-37

36

c) Pantoprazole

Pantoprazole sodium (PROTONIX) is a substituted benzimidazole, 5-

[difluoromethoxy-2-[[[3,4-dimethoxy-2-pyridinyl]methyl]sulfinyl]-1H-

benzimidazole] sodium 13, Pantoprazole sodium is a proton pump inhibitor

drug used for short-term treatment of erosion and ulceration of the esophagus

caused by gastroesophageal reflux disease. Pantoprazole suppresses the final

step in gastric acid production by forming a covalent bond to two sites of the

(H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal

cell.38-39 This effect is dose-related and leads to inhibition of both basal and

stimulated gastric acid secretion irrespective of the stimulus.

d) Rabeprazole

Rabeprazole sodium is chemically known as 2-[[[4-(3-methoxy propoxy)-

3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium 14.

Rabeprazole sodium, (ACHIPHEX) is a proton pump inhibitor, inhibits the

action of H+-K+ ATPase in parietal cells39-40 and is used for the prevention and

treatment of gastric acid related diseases. It has also demonstrated efficacy in

healing and symptom relief of gastric and duodenal ulcers and has shown a

high-eradication rate of the microorganism, Helicobacter pylori when associated

with antimicrobial therapy.40-42

37

N

OCH3

NH

NS

O

11

H3C CH3H3CO

N

OCH2CF3

NH

NS

O

12

H3C

N

O-(CH2)3-OCH3

NH

NS

O

14

H3C

N

OCH3

NH

NS

O

13

H3COF2HCO

In the prazoles the main moiety involved is a benzimidazole and pyridine

ring, most of the benzimidazoles share certain biological properties despite

some changes in functionality. The imidazole nucleus has proven to be an

unusually fertile source of medicinal activities nitroimidazoles are very often

associated with antimicrobial activity, where as substituted benzimidazoles act

as anti ulcer agents. These considerations suggest, as a working hypothesis,

that the particular imidazole derivatives are integral parts of the respective

pharmacophores.

The change in the substitution on the benzimidazole changes the

potency.

The major advances in the development of gastric acid related diseases,

gave us the boost to improve the process related necessaries in the peptic ulcer

N

R2

NH

NS

O

15

R1 R3R4

38

associated molecules like rabeprazole and omeprazole. The first chapter

presents the introduction of drugs and the development occurred in

antiulcerative drugs. The second chapter presents the synthesis of rabeprazole

sodium and polymorphic study. The third chapter presents the impurity profile

of rabeprazole sodium. The fourth chapter presents the impurity profile and

polymorphism of omeprazole. The fifth chapter presents the synthesis and

characterization of some novel benzimidazole derivatives.

1.14 References

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2. http://opiods.com/jh/index.html.

3. http://www.druglibrary.org/SCHAFFER/library/studies/canada

senate/voll/chapter5_from_plant_to_joing.htm#_ftnref1.

4. http://en.wikipedia.org/wiki/Cocaine#cite_note_mummies_5#cit

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32(7), 1982, 734.

b) Porro G. B,

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6. a) Burleydes J. G, Varannes S, Ducrotte P, Huvelin S. S, Vavasseur

F, Taccoen A, Fiorentini P, Homerin M,

39

liment Pharmacol Ter., 19(6), 2004, 655.

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b) Biollaz J, Brunner H. R, Gavras I, Waeber B, Gavras H, J.

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British J. of Psychiatry., 164, 1994, 802.

11. Ishizuka T, Itaya S, Wada H, Ishizawa M, Kimura M, Kajita K,

Kanoh Y, Miura A, Muto N, Yasuda K,

Diabetes., 47(9), 1998, 1494.

12. http://www.medscape.com/viewarticlce/407942. Kirsner J. B,

Review Article: 100 years of American Gastroenterology., 1990.

13. http://www.medscape.com/viewarticle/424446_1 Feb 2000.

14. http://www.medlina.com/gastroenterology_organizations.htm, List of

gastroenerology organizations.

15. Weil P, Buchberger M. D, World

J. Surg., 23, 1999, 736.

16. Sachs G, Shin J. M, Vaginl O, Best

Practice and Resercag Clinical Gastroenterology., 16(6), 2002, 835.

40

17. Earnest D. L, Robinson M, The

American J. of Gastroenterology., 94(11), 1999, 7.

18. Marshall B. J,

Helicobacter Pioneers., 2002.

19. Marshall B. J, Lancet.,

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20. Marshall B. J, Warren J. R,

Lancet., 1(8390), 1984, 1311.

21. Research Enterprise,

The 2005 Nobel Prize in Physiology or Medicine., 2007.

22. Moss S, Sood S. Helicobacter Pylori, Current

Opinion in Infectious Disease., 16, 2003, 445.

23. http://www.diagnosishealth.com/ulcer.htm. Diagnosis Health 2004.

24. http://www.cdc.gov/ulcer/md.htm. Center for Disease Control, 2004.

25. http://www.helico.com. The Helicobacter Foundation. 2004.

26. Smooth D. T, Go MF, Cryer B, Peptic

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27. Maton P,

Cleveland Clinic Journal of Medicine., 70(3), 2003, 51.

28. Brunner G, European J.

of Gastroenterology and Hepatology., 8(1), 1996, 9.

29. Webb D, The

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30. Vakil K, Aliment

Pharmacol Ther., 19, 2004, 1041.

41

31. Lanas L, Santolaria S, Current

Pharm Design., 7, 2001, 1.

32. Robinson M,

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42

Jpn. J. Physiol., 42, 1992, 75.

CHAPTER-II

SYNTHESIS AND POLYMOPHISM OF

RABEPRAZOLE SODIUM