Chapter 3
Drug and Excipients Profile
CHAPTER-III
DRUG AND EXCIPIENTS PROFILE
3.1.
PROFILE
OF
ACTIVE
DRUG
PANTOPRAZOLE
SODIUM
SESQUIHYDRATE
3.1.1.
Chemical Name of the Active Constituent
Pantoprazole sodium sesquihydrate
Sodium
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]
sulfinyl]1H-benzimidazole sesquihydrate (Delayed-Release Tablets Monograph.
Marketed by: Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101 under license
from
Nycomed,
GmbH
D78467
Konstanz,
Germany.
Available
at
http://www.rxlist.com/protonix-drug.htm.).
3.1.2. Description
Pantoprazole is a proton pump inhibitor that exerts its actions by binding
to the proton pump (H+,K+-adenosine triphosphatase) in the parietal cells of
stomach.
Pantoprazole
sodium
sesquihydrate
empirical
formula
is
C16H14F2N3NaO4S x 1.5 H2O. Its molecular weight is 432.4, and it has the
following structural formula:
Figure 3.1. Structural formula of Pantoprazole sodium
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
56
Chapter 3
Drug and Excipients Profile
Pantoprazole sodium sesquihydrate
Pantoprazole sodium sesquihydrate is a white to off-white crystalline
powder and is racemic. It is freely soluble in water, very slightly soluble in
phosphate buffer at pH 7.4, and practically insoluble in n-hexane.
3.1.3. Classification
Proton pump inhibitor
3.1.4. Pharmacokinetics
After oral and IV administration of Pantoprazole at single doses ranging
from 10 to 120 mg, a good linear correlation was seen between the dose
administered and the Cmax, as well as the area under the concentration time curve.
The
major
pharmacokinetic
parameters
of
Pantoprazole
after
administration of a single dose orally to healthy participants are summarized in the
below table:
Table 3.1. Pharmacokinetic parameters of Pantoprazole
Dose
Pantoprazole Parameters
Cmax (μg/mL)
tmax (h)
AUC
t1/2 (h)
(μg.h/mL)
40 mg
2.84
2.27
6.90
1.45
40 mg
2.97**
6.29**
5.70**
1.23**
40 mg
2.33**
7.50**
3.94**
1.10**
** under fed condition
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
57
Chapter 3
Drug and Excipients Profile
3.1.4.1. Absorption
Pantoprazole peak plasma concentrations (Cmax) occur in approximately
2.50 hours. Pantoprazole undergoes little first-pass metabolism with an estimated
absolute oral bioavailability of 77%.
Administration of Pantoprazole with food may delay its absorption up to
2 hours or longer; however, the Cmax and the extent of pantoprazole absorption
(AUC) are not altered. Thus, Pantoprazole Tablets may be taken without regard to
timing of meals.
3.1.4.2. Distribution
Pantoprazole is highly bound to plasma proteins (98%), primarily albumin.
Pantoprazole volume of distribution ranges from 0.15 to 0.17 L/Kg, suggesting
localization of a major fraction of it within the extracellular water.
3.1.4.3. Metabolism
Pantoprazole is extensively metabolized in the liver through the
cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the
route of administration (intravenous or oral). The main metabolic pathway is
demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways
include oxidation by CYP3A4.
There is no evidence that any of the Pantoprazole metabolites have
significant pharmacologic activity.
3.1.4.4. Excretion
After a single oral or intravenous dose of 14C-labeled Pantoprazole to
healthy, normal metabolizer volunteers, approximately 71% of the dose was
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
58
Chapter 3
Drug and Excipients Profile
excreted in the urine, with 18% excreted in the feaces through biliary excretion.
There was no renal excretion of unchanged Pantoprazole.
In various studies, mean or median clearance of Pantoprazole has ranged
from 0.7 to 1.3 L/Kg per hour, and the elimination half-life has ranged from 0.9 to
1.9 hours. Elimination half life and plasma clearance of Pantoprazole have been
shown to be independent of dose. In individuals who lack adequate CYP2C19
function, metabolism of Pantoprazole tends to be poor, with reported elimination
half-lives ranging from 6 to 9 hours.
3.1.5.
Indication
• Duodenal ulcers.
• Gastric ulcers.
• Moderate and severe forms of reflux esophagitis.
• Long-term treatment of Zollinger-Ellison syndrome and other disorders
accompanied by pathological gastric acid hypersecretion.
• In combination with two antibiotics for eradication of Helicobacter
pylori.
3.1.6. Dosage
3.1.6.1. Usual adult dose:
Moderate and sever reflux esophagitis:
The dose is one Pantoprazole 40 mg tablet daily. In individual cases,
particularly in patients, who have so far failed to respond to other forms of
medication, the dose can be doubled (i.e. increased to two Pantoprazole 40 mg
tablets daily).
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
59
Chapter 3
Drug and Excipients Profile
In most cases, a four-week course of therapy is required for the treatment
of reflux esophagitis. If this is not sufficient, healing will normally be achieved
within 4 weeks of further treatment.
Gastric ulcer
The dose is one Pantoprazole 40 mg tablet daily. In individual cases,
particularly in patients, who have so far failed to respond to other forms of
medication, the dose can be doubled (i.e. increased to two Pantoprazole 40 mg
tablets daily).
In most cases, a four-week course of therapy is required for the treatment
of gastric ulcer. If this is not sufficient, healing will normally be achieved within 4
weeks of further treatment.
Duodenal ulcer
The dose is one Pantoprazole 40 mg tablet daily. In individual cases,
particularly in patients who have so far failed to respond to other forms of
medication, the dose can be doubled (i.e. increased to two Pantoprazole 40 mg
tablets daily).
In most cases, duodenal ulcers generally heal within 2 weeks. If a twoweek course of treatment is not sufficient, healing will be achieved in almost all
cases within 2 weeks of further treatment.
Zollinger-Ellison syndrome:
For the long-term treatment of Zollinger-Ellison syndrome and other
disorders accompanied by pathological gastric acid hypersecretion, the
recommended initial dose is 80 mg (two Pantoprazole 40 mg gastro-resistant
tablets) daily. Thereafter, the dose can be individually titrated, depending on
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
60
Chapter 3
Drug and Excipients Profile
gastric acid secretion values. At dosages above 80 mg per day, the daily dosage
should be divided into two separate doses per day. Temporary dose increases
above 160 mg Pantoprazole are possible, but should not be applied for longer than
required to achieve adequate management of acid secretion. There are no
restrictions on the length of treatment for Zollinger-Ellison syndrome or other
disorders accompanied by pathological gastric acid hypersecretion; treatment
should be maintained for as long as it is clinically required.
Eradication of Helicobacter pylori:
Pantoprazole at dosages ranging from 40 to 80 mg/day has been combined
with 2 antibacterial agents in 7 to 14-day regimens for the eradication of H pylori.
In clinical studies, better eradication rates tended to be seen with longer durations
of treatment and when Pantoprazole was administered at 80 mg/day.
3.1.7. Adverse Drug Reactions
In the table below, Pantoprazole adverse events are classified by body
system and frequency (common ≥1/100 to <1/10, uncommon ≥1/1000 to <1/100,
rare ≥1/10,000 to <1/1000, and very rare <1/10,000 or not known (cannot be
estimated from the available data)) as follows:
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
61
Chapter 3
Drug and Excipients Profile
Table 3.2. Adverse Drug Reactions of Pantoprazole
Body System
Blood and the lymphatic
system disorders
Very rare
Immune system disorders
Very rare
Psychiatric disorders
Rare
Nervous system disorders
Common
Uncommon
Vascular disorders
Not known
Gastrointestinal disorders
Common
Uncommon
Rare
Hepatobiliary disorders
Rare
Skin and subcutaneous tissue
disorders
Uncommon
Very rare
Musculoskeletal, connective
tissue and bone disorders
Rare
Very rare
Renal and urinary disorders
Very rare
Reproductive system and
breast disorders
Very rare
General disorders
Very rare
Investigations
Very rare
Adverse Drug Reactions
Leukopenia, thrombocytopenia
Anaphylactic reactions including anaphylactic shock
Depression, hallucination, disorientation and
confusion, especially in predisposed patients as well as
the aggravation of these symptoms in case of preexistence
Headache
Dizziness, visual disturbances (blurred vision)
Peripheral edema
Upper abdominal complaints, diarrhea,
constipation, flatulence
Nausea , vomiting
Dry mouth
Severe hepatocellular damage leading to
jaundice with or without hepatic failure
Allergic reactions such as pruritis and skin
rash
Urticaria, angioedema, sever skin reactions
e.g. Stevens Johnson syndrome, erythema
multiforme, Lyell's syndrome, photosensitivity
reaction.
Arthralgia
Myalgia
Interstitial nephritis
Gynecomastia
Peripheral edema
Increased liver enzymes (gamma transaminases, GT),
elevated triglycerides, increased body temperature,
hypernatremia in the elderly.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
62
Chapter 3
Drug and Excipients Profile
3.1.8. Contraindication/Precautions
• Pantoprazole is contraindicated in patients with known hypersensitivity to the
active ingredient, or to any of the excipients.
• In patients with Zollinger-Ellison syndrome or other disorders accompanied by
pathological gastric acid hypersecretion that require long-term treatment,
Pantoprazole may, as with all other acid-blocking medicinal products, cause
vitamin B12 (cyanocobalamin) malabsorption as a result of hypo- or
achlorhydria. This should be taken into consideration if associated clinical
symptoms become manifest.
• In the presence of any alarm symptom (e.g. significant unintentional weight loss,
recurrent vomiting, dysphagia, hematemesis, anemia or melena) and when
gastric ulcer is suspected or present, malignancy should be excluded, as
treatment with Pantoprazole may alleviate symptoms and delay diagnosis.
• In patients with severe liver impairment, the dose should be adjusted and the
liver enzymes should be checked regularly during treatment, especially during
long-term treatment. In case of an increase of these enzymes, the treatment
should be stopped.
• Decreased gastric acidity due to any means – including proton pump inhibitors –
increases gastric count of bacteria normally present in the gastrointestinal tract.
Treatment with acid-reducing drugs leads to a slightly increased risk of
gastrointestinal infections, such as Salmonella and Campylobacter.
3.2. PROFILE OF ALKALIZING AGENTS OR BUFFERS (Pharmaceutical
excipients, 2009)
3.2.1. Magnesium Oxide
1. Nonproprietary Names
BP:
Heavy Magnesium Oxide
Light Magnesium Oxide
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
63
Chapter 3
Drug and Excipients Profile
JP:
Magnesium Oxide
Ph Eur:
Magnesium Oxide, Heavy
Magnesium Oxide, Light
USP:
Magnesium Oxide
2. Synonyms
Calcined magnesia; calcinated magnesite; Descote; E530; Magcal; Magchem 100;
Maglite; magnesia; magnesia monoxide; magnesia usta; magnesii oxidum leve;
magnesii oxidum ponderosum; Magnyox; Marmag; Oxymag; periclase.
3. Chemical Name and CAS Registry Number
Chemical Name: Magnesium oxide; CAS Registry Number: [1309-48-4]
4. Empirical Formula and Molecular Weight
Empirical Formula: MgO; Molecular Weight: 40.30
5. Functional Category
Anticaking agent; emulsifying agent; glidant; tablet and capsule diluent.
6. Applications in Pharmaceutical Formulation or Technology
Magnesium oxide is used as an alkaline diluent in solid-dosage forms to
modify the pH of tablets. It can be added to solid-dosage forms to bind excess
water and keep the granulation dry. In combination with silica, magnesium oxide
can be used as an auxiliary glidant. It is also used as a food additive and as an
antacid, either alone or in conjunction with aluminum hydroxide. Magnesium
oxide is additionally used as an osmotic laxative and a magnesium supplement to
treat deficiency states.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
64
Chapter 3
Drug and Excipients Profile
7. Description
Two forms of magnesium oxide exist: a bulky form termed light
magnesium oxide and a dense form termed heavy magnesium oxide. Both forms
of magnesium oxide occur as fine, white, odorless powders. Magnesium oxide
possesses a cubic crystal structure, though the BP 2009 and Ph Eur 6.4 describe
the appearance of light magnesium oxide as an amorphous powder.
8. Typical Properties
Acidity/alkalinity pH:
10.3 (saturated aqueous solution)
Boiling point:
3600°C
Melting point:
2800°C
Particle size distribution:
99.98% less than 45μm in size (light magnesium
oxide).
Refractive index:
1.735
Solubility: Soluble in dilute acids and ammonium salt solutions; very slightly
soluble in pure water (≈0.0086 g/100 mL at 30°C; solubility is increased by
carbon dioxide); practically insoluble in ethanol (95%).
Specific gravity:
3.58 g/cm3 at 25°C (heavy magnesium oxide).
9. Stability and Storage Conditions
Magnesium oxide is stable at normal temperatures and pressures.
However, it forms magnesium hydroxide in the presence of water. Magnesium
oxide is hygroscopic and rapidly absorbs water and carbon dioxide on exposure to
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
65
Chapter 3
Drug and Excipients Profile
the air, the light form more readily than the heavy form. The bulk material should
be stored in an airtight container in a cool, dry place.
10. Incompatibilities
Magnesium oxide is a basic compound and as such can react with acidic
compounds in the solid state to form salts or degrade alkaline-labile drugs.
Adsorption of various drugs onto magnesium oxide has been reported, such as
antihistamines, antibiotics (especially tetracyclines), salicylates, atropine sulfate,
hyoscyamine hydrobromide, paracetamol, chloroquine; and anthranilic acid
derivatives have been reported to adsorb onto the surface of magnesium oxide.
Magnesium oxide can also complex with polymers, e.g. Eudragit RS, to retard
drug release and can interact in the solid state with phenobarbitone sodium.
Magnesium
oxide
can
also
reduce
the
bioavailability
of
phenytoin,
trichlormethiazide, and anti-arrhythmics. The presence of magnesium oxide can
also have a negative impact on the solid-state chemical stability of drugs, such as
diazepam. Magnesium oxide has been used as a stabilizer for omeprazole due to
its strong waterproofing effect.
11. Safety
Magnesium oxide is widely used in oral formulations as an excipient and
as a therapeutic agent. Therapeutically, 250–500 mg is administered orally as an
antacid and 2–5 g as an osmotic laxative. Magnesium oxide is generally regarded
as a nontoxic material when employed as an excipient, although adverse effects,
due to its laxative action, may occur if high doses are ingested orally.
12. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Magnesium oxide may be harmful if inhaled, ingested, or
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
66
Chapter 3
Drug and Excipients Profile
absorbed through the skin in quantity, and is irritating to the eyes and respiratory
system. Gloves, eye protection, and a dust mask or respirator are recommended. In
the USA and UK, the long-term (8-hour TWA) workplace exposure limits for
magnesium oxide, calculated as magnesium, 10 mg/m3 for total dust and 4 mg/m3
for respirable dust. The short-term (15-minute) limit for respirable dust is 10
mg/m3.
13. Regulatory Status
Magnesium oxide is GRAS (Generally Recognized As Safe) listed.
Accepted for use as a food additive in Europe. Included in the FDA Inactive
Ingredients Database (oral capsules, tablets, and buccal). Included in
nonparenteral medicines licensed in the UK. Included in the Canadian List of
Acceptable Non-medicinal Ingredients.
3.2.2.
Magnesium hydroxide
Magnesium hydroxide is an inorganic compound with the chemical
formula Mg(OH)2. As a suspension in water, it is often called milk of magnesia
because of its milk-like appearance. The solid mineral form of magnesium
hydroxide is known as brucite.
Magnesium hydroxide is a common component of antacids and laxatives,
it interferes with the absorption of folic acid and iron. Magnesium hydroxide has
low solubility in water, with a Ksp of 1.5×10−11; all of magnesium hydroxide that
does dissolve dissociate. Since the dissociation of this small amount of dissolved
magnesium hydroxide is complete, magnesium hydroxide is considered a strong
electrolyte. Its low solubility makes it a weak base.
Uses: Suspensions of magnesium hydroxide in water (milk of magnesia) are used
as an antacid to neutralize stomach acid, and a laxative. The diarrhoea caused by
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
67
Chapter 3
Drug and Excipients Profile
magnesium hydroxide carries away much of the body's supply of potassium, and
failure to take extra potassium may lead to muscle cramps. Magnesium hydroxide
is also used as an antiperspirant armpit deodorant. Milk of magnesia is useful
against canker sores (aphthous ulcer) when used topically.
Milk of magnesia is sold for medical use as chewable tablets, capsules, and
as liquids having various added flavors. It is primarily used to alleviate
constipation, but also to relieve indigestion and heartburn. When taken orally as a
laxative, the osmotic force of the magnesia suspension acts to draw fluids from the
body and to retain those already within the lumen of the intestine, serving to
distend the bowel, thus stimulating nerves within the colon wall, inducing
peristalsis and resulting in evacuation of colonic contents. It is also used as an
antacid, though more modern formulations combine the antimotility effects of
equal concentrations of aluminum hydroxide to avoid unwanted laxative effects.
Milk of magnesia is also used as a folk remedy, applied and massaged into
the scalp a few minutes before washing, to relieve symptoms of seborrhea and
dandruff. The mechanism for its effectiveness in this application, like the causes
of seborrhea itself, are unknown. An additional folk use is for the treatment of
acne or oily skin by applying topically, allowing to dry and then washing it off the
face (or other body part). It is also said to be used for seborrheic dermatitis, which
is a drying and flaking of the skin similar to dandruff but often occurring on the
face.
Magnesium hydroxide powder is used industrially as a non-hazardous
alkali to neutralise acidic wastewaters. It also takes part in the Biorock method of
building artificial reefs.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
68
Chapter 3
Drug and Excipients Profile
Solid magnesium hydroxide also has smoke suppressing and fire retarding
properties. This is due to the endothermic decomposition it undergoes at 332°C
(630°F):
Mg(OH)2 → MgO + H2O
The heat absorbed by the reaction acts as a retardant by delaying ignition
of the associated substance. The water released dilutes any combustible gases and
inhibits oxygen from aiding the combustion. Common uses of magnesium
hydroxide as a fire retardant include plastics, roofing, and coatings. Another
mineral that is used in similar fire retardant applications is hydromagnesite.
Biological metabolism: When the patient drinks the milk of magnesia, the
suspension enters the stomach. Depending on how much was taken, one of two
possible outcomes will occur. As an antacid, milk of magnesia is dosed at
approximately 0.5–1.5g in adults and works by simple neutralization, where the
hydroxide ions from the Mg (OH)2 combine with acidic H+ ions produced in the
form of hydrochloric acid by parietal cells in the stomach to produce water.
As a laxative, milk of magnesia is dosed at 2–5 g, and works in a number
of ways. First, Mg2+ is poorly absorbed from the intestinal tract, so it draws water
from the surrounding tissue by osmosis. Not only does this increase in water
content soften the feces, it also increases the volume of feces in the intestine
(intraluminal volume) which naturally stimulates intestinal motility. Furthermore,
Mg2+ ions cause the release of cholecystokinin (CCK), which results in
intraluminal accumulation of water, electrolytes, and increased intestinal motility.
Although it has been stated in some sources, the hydroxide ions themselves do not
play a significant role in the laxative effects of milk of magnesia, as basic
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
69
Chapter 3
Drug and Excipients Profile
solutions (i.e. solutions of hydroxide ions) are not strongly laxative, and non-basic
Mg2+ solutions, like MgSO4, are equally strong laxatives mole for mole.
Only a small amount of the magnesium from milk of magnesia is usually
absorbed from a person's intestine (unless the person is deficient in magnesium).
However, magnesium is mainly excreted by the kidneys so long term, daily
consumption of milk of magnesia by someone suffering from renal failure could
lead in theory to hypermagnesemia.
As with any other medication, some people may have adverse reactions to
milk of magnesia. These can include weakness, nausea, vomiting, and diarrhea.
High doses increase the likelihood of these reactions. Patients with severe chronic
kidney disease are advised to avoid overconsumption of milk of magnesia.
Because the kidney functions to excrete magnesium, taking too much would wear
out the kidney and lead to toxic levels of magnesium in the blood. Healthy
individuals should not use this type of medication continuously for longer than
one week, or an excessively harsh laxative effect may result.
3.2.3.
Tribasic sodium phosphate
1. Empirical formula
Na3PO4 x H2O
2. Structural formula
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
70
Chapter 3
Drug and Excipients Profile
3. Molecular weight & CAS number
Molecular weight: 163.94 for the anhydrous material and 380.06 for the
dodecahydrate (12H2O)
CAS number: [7601-54-9] for the anhydrous material.
4. Synonyms E339; trisodium orthophosphate; trisodium phosphate; TSP.
5. Typical Properties
Acidity/alkalinity pH = 12.1 for a 1% w/v aqueous solution of the anhydrous
material at 25°C. A 1% w/v aqueous solution of the dodecahydrate at 25°C has a
pH of 12.0–12.2.
Density:
1.3 g/cm3 for the anhydrous material;
0.9 g/cm3 for the dodecahydrate.
Solubility: The anhydrous material is soluble 1 in 8 parts of water, while the
dodecahydrate is soluble 1 in 5 parts of water at 20°C.
3.2.4.
Sodium bicarbonate
1. Nonproprietary Names
BP:
Sodium Bicarbonate
JP:
Sodium Bicarbonate
PhEur:
Sodium Hydrogen Carbonate
USP:
Sodium Bicarbonate
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
71
Chapter 3
Drug and Excipients Profile
2. Synonyms
Baking
soda;
E500;
Effer-Soda;
monosodium
carbonate;
natrii
hydrogenocarbonas; Sal de Vichy; sodium acid carbonate; sodium hydrogen
carbonate.
3. Chemical Name and CAS Registry Number
Chemical Name: Carbonic acid monosodium salt
CAS Registry Number: [144-55-8]
4. Empirical Formula and Molecular Weight
Empirical Formula: NaHCO3; Molecular Weight: 84.01
5. Functional Category: Alkalizing agent; therapeutic agent.
6. Applications in Pharmaceutical Formulation or Technology
Sodium bicarbonate is generally used in pharmaceutical formulations as a
source of carbon dioxide in effervescent tablets and granules. It is also widely
used to produce or maintain an alkaline pH in a preparation.
In effervescent tablets and granules, sodium bicarbonate is usually
formulated with citric and/or tartaric acid; combinations of citric and tartaric acid
are often preferred in formulations as citric acid alone produces a sticky mixture
that is difficult to granulate, while if tartaric acid is used alone, granules lose
firmness. When the tablets or granules come into contact with water, a chemical
reaction occurs, carbon dioxide is evolved and the product disintegrates. Melt
granulation in a fluidized bed dryer has been suggested as a one-step method for
the manufacture of effervescent granules composed of anhydrous citric acid and
sodium bicarbonate, for subsequent compression into tablets.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
72
Chapter 3
Drug and Excipients Profile
Tablets may also be prepared with sodium bicarbonate alone since the acid
of gastric fluid is sufficient to cause effervescence and disintegration. Sodium
bicarbonate is also used in tablet formulations to buffer drug molecules that are
weak acids, thereby increasing the rate of tablet dissolution and reducing gastric
irritation.
Additionally, sodium bicarbonate is used in solutions as a buffering agent
for erythromycin, lidocaine, local anesthetic solutions, and total parenteral
nutrition (TPN) solutions. In some parenteral formulations, e.g. niacin, sodium
bicarbonate is used to produce a sodium salt of the active ingredient that has
enhanced solubility. Sodium bicarbonate has also been used as a freeze-drying
stabilizer and in toothpastes.
Recently, sodium bicarbonate has been used as a gas-forming agent in
alginate raft systems and in floating, controlled-release oral dosage forms for a
range of drugs. Tablet formulations containing sodium bicarbonate have been
shown to increase the absorption of paracetamol, and improve the stability of
levothyroxine. Sodium bicarbonate has also been included in formulations of
vaginal bioadhesive tablets and in carbon dioxide releasing suppositories.
Therapeutically, sodium bicarbonate may be used as an antacid, and as a
source of the bicarbonate anion in the treatment of metabolic acidosis. Sodium
bicarbonate may also be used as a component of oral rehydration salts and as a
source of bicarbonate in dialysis fluids; it has also been suggested as a means of
preventing radiocontrast-induced nephrotoxicity.
Sodium bicarbonate is used in food products as an alkali or as a leavening
agent, e.g. baking soda.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
73
Chapter 3
Drug and Excipients Profile
7. Description
Sodium bicarbonate occurs as an odorless, white, crystalline powder with a
saline, slightly alkaline taste. The crystal structure is monoclinic prisms. Grades
with different particle sizes, from a fine powder to free-flowing uniform granules,
are commercially available.
8. Typical Properties
Acidity/alkalinity pH = 8.3 for a freshly prepared 0.1 M aqueous solution at
25°C; alkalinity increases on standing, agitation, or heating.
Density (bulk):
0.869 g/cm3
Density (tapped):
1.369 g/cm3
Density(true):
2.173 g/cm3
Freezing point depression: 0.381°C (1% w/v solution)
Melting point:
270°C (with decomposition)
Moisture content: Below 80% relative humidity, the moisture content is less than
1% w/w. Above 85% relative humidity, sodium bicarbonate rapidly absorbs
excessive amounts of water and may start to decompose with loss of carbon
dioxide.
Osmolarity: A 1.39% w/v aqueous solution is iso osmotic with serum.
Refractive index n20D: 1.3344 (1% w/v aqueous solution)
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
74
Chapter 3
Drug and Excipients Profile
Solubility of sodium bicarbonate
Ethanol (95%)
Solubility at 20°C unless
otherwise stated
Practically insoluble
Ether
Practically insoluble
Water
1 in 11
Solvent
1 in 4 at 100°Ca
1 in 10 at 25°C
1 in 12 at 18°C
a. Note that in hot water, sodium bicarbonate is converted to the carbonate.
9. Stability and Storage Conditions
When heated to about 50°C, sodium bicarbonate begins to dissociate into
carbon dioxide, sodium carbonate, and water; on heating to 250–300°C, for a
short time, sodium bicarbonate is completely converted into anhydrous sodium
carbonate. However, the process is both time- and temperature-dependent, with
conversion 90% complete within 75 minutes at 93°C. The reaction proceeds via
surface-controlled kinetics; when sodium bicarbonate crystals are heated for a
short period of time, very fine needle-shaped crystals of anhydrous sodium
carbonate are formed on the sodium bicarbonate surface.
The effects of relative humidity and temperature on the moisture sorption
and stability of sodium bicarbonate powder have been investigated. Sodium
bicarbonate powder is stable below 76% relative humidity at 25°C and below 48%
relative humidity at 40°C. At 54% relative humidity, the degree of pyrolytic
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
75
Chapter 3
Drug and Excipients Profile
decarboxylation of sodium bicarbonate should not exceed 4.5% in order to avoid
detrimental effects on stability.
At ambient temperatures, aqueous solutions slowly decompose with partial
conversion into the carbonate; the decomposition is accelerated by agitation or
heat. Aqueous solutions begin to break up into carbon dioxide and sodium
carbonate at about 20°C, and completely on boiling.
Aqueous solutions of sodium bicarbonate may be sterilized by filtration or
autoclaving.
To
minimize
decomposition
of
sodium
bicarbonate
by
decarboxylation on autoclaving, carbon dioxide is passed through the solution in
its final container, which is then hermetically sealed and autoclaved. The sealed
container should not be opened for at least 2 hours after it has returned to ambient
temperature, to allow time for the complete reformation of the bicarbonate from
the carbonate produced during the heating process.
Aqueous solutions of sodium bicarbonate stored in glass containers may
develop deposits of small glass particles. Sediments of calcium carbonate with
traces of magnesium or other metal carbonates have been found in injections
sterilized by autoclaving; these are due to impurities in the bicarbonate or to
extraction of calcium and magnesium ions from the glass container.
Sedimentation may be retarded by the inclusion of 0.01–0.02% disodium edetate.
Sodium bicarbonate is stable in dry air but slowly decomposes in moist air and
should therefore be stored in a well-closed container in a cool, dry place.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
76
Chapter 3
Drug and Excipients Profile
10. Incompatibilities
Sodium bicarbonate reacts with acids, acidic salts, and many alkaloidal
salts, with the evolution of carbon dioxide. Sodium bicarbonate can also intensify
the darkening of salicylates.
In powder mixtures, atmospheric moisture or water of crystallization from
another ingredient is sufficient for sodium bicarbonate to react with compounds
such as boric acid or alum. In liquid mixtures containing bismuth subnitrate,
sodium bicarbonate reacts with the acid formed by hydrolysis of the bismuth salt.
In solution, sodium bicarbonate has been reported to be incompatible with
many drug substances such as ciprofloxacin, amiodarone, nicardipine, and
levofloxacin.
11. Method of Manufacture
Sodium bicarbonate is manufactured either by passing carbon dioxide into
a cold saturated solution of sodium carbonate, or by the ammonia–soda (Solvay)
process, in which first ammonia and then carbon dioxide is passed into a sodium
chloride solution to precipitate sodium bicarbonate while the more soluble
ammonium chloride remains in solution.
12. Safety
Sodium bicarbonate is used in a number of pharmaceutical formulations
including injections and ophthalmic, otic, topical, and oral preparations.
Sodium bicarbonate is metabolized to sodium cation, which is eliminated
from the body by renal excretion, and the bicarbonate anion, which becomes part
of the body's bicarbonate store. Any carbon dioxide formed is eliminated via the
lungs. Administration of excessive amounts of sodium bicarbonate may thus
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
77
Chapter 3
Drug and Excipients Profile
disturb the body's electrolyte balance, leading to metabolic alkalosis or possibly
sodium overload with potentially serious consequences. The amount of sodium
present in antacids and effervescent formulations has been sufficient to exacerbate
chronic heart failure, especially in elderly patients.
Orally ingested sodium bicarbonate neutralizes gastric acid with the
evolution of carbon dioxide and may cause stomach cramps and flatulence. When
used as an excipient, sodium bicarbonate is generally regarded as an essentially
nontoxic and nonirritant material.
LD50 (mouse, oral): 3.36 g/kg
LD50 (rat, oral): 4.22 g/kg
13. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Eye protection and gloves are recommended.
14. Regulatory Status
Sodium bicarbonate is GRAS listed. Accepted for use as a food additive in
Europe. Included in the FDA Inactive Ingredients Database (injections;
ophthalmic preparations; oral capsules, solutions, and tablets). Included in
parenteral (intravenous infusions and injections) and nonparenteral medicines
(chewing gums; ear drops; eye lotions; oral capsules, chewable tablets,
effervescent powders, effervescent tablets, granules, soluble tablets, orodispersible
tablets, and tablets; suppositories and suspensions) licensed in the UK.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
78
Chapter 3
Drug and Excipients Profile
15. Related Substances
Potassium bicarbonate
3.2.5. Calcium carbonate
1. Nonproprietary Names
BP:
Calcium Carbonate
JP:
Precipitated Calcium Carbonate
PhEur:
Calcium Carbonate
USP:
Calcium Carbonate
2. Synonyms
Calcii carbonas; calcium carbonate (1:1); carbonic acid calcium salt (1:1);
creta preparada; Destab; E170; MagGran CC; Micromite; Pharma-Carb;
precipitated carbonate of lime; precipitated chalk; Vitagran; Vivapress Ca;
Witcarb.
3. Chemical Name and CAS Registry Number
Chemical Name: Carbonic acid, calcium salt (1:1)
CAS Registry Number: [471-34-1]
4. Empirical Formula and Molecular Weight
Empirical Formula: CaCO3
Molecular Weight: 100.09
5. Functional Category
Buffering agent; coating agent; colorant; opacifier; tablet binder; tablet and
capsule diluent; therapeutic agent.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
79
Chapter 3
Drug and Excipients Profile
6. Applications in Pharmaceutical Formulation or Technology
Calcium carbonate, employed as a pharmaceutical excipient, is mainly
used in solid-dosage forms as a diluent. It is also used as a base for medicated
dental preparations, as a buffering agent, and as a dissolution aid in dispersible
tablets. Calcium carbonate is used as a bulking agent in tablet sugar-coating
processes and as an opacifier in tablet film-coating. Calcium carbonate is also
used as a food additive and therapeutically as an antacid and calcium supplement.
7. Description
Calcium carbonate occurs as an odorless and tasteless white powder or crystals.
8. Typical Properties
Acidity/alkalinity pH : 9.0 (10% w/v aqueous dispersion)
Density (bulk):
0.8 g/cm3
Density (tapped):
1.2 g/cm3
Flowability:
Cohesive.
Hardness (Mohs):
3.0 for Millicarb.
Melting point:
Decomposes at 825°C.
Refractive index:
1.59
Solubility: Practically insoluble in ethanol (95%) and water. Solubility in water is
increased by the presence of ammonium salts or carbon dioxide. The presence of
alkali hydroxides reduces solubility.
Specific gravity:
2.7
Specific surface area: 6.21–6.47 m2/g
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
80
Chapter 3
Drug and Excipients Profile
9. Stability and Storage Conditions
Calcium carbonate is stable and should be stored in a well-closed container
in a cool, dry place.
10. Incompatibilities
Incompatible with acids and ammonium salts
11. Method of Manufacture
Calcium carbonate is prepared by double decomposition of calcium
chloride and sodium bicarbonate in aqueous solution. Density and fineness are
governed by the concentrations of the solutions. Calcium carbonate is also
obtained from the naturally occurring minerals aragonite, calcite, and vaterite.
12. Safety
Calcium carbonate is mainly used in oral pharmaceutical formulations and
is generally regarded as a nontoxic material. However, calcium carbonate
administered orally may cause constipation and flatulence. Consumption of large
quantities (4–60 g daily) may also result in hypercalcemia or renal impairment.
Therapeutically, oral doses of up to about 1.5 g are employed as an antacid. In the
treatment of hyperphosphatemia in patients with chronic renal failure, oral daily
doses of 2.5–17 g have been used. Calcium carbonate may interfere with the
absorption of other drugs from the gastrointestinal tract if administered
concomitantly.
LD50 (rat, oral): 6.45 g/kg
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
81
Chapter 3
Drug and Excipients Profile
13. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Calcium carbonate may be irritant to the eyes and on
inhalation. Eye protection, gloves, and a dust mask are recommended. Calcium
carbonate should be handled in a well-ventilated environment. In the UK, the
long-term (8-hour TWA) workplace exposure limit for calcium carbonate is 10
mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust.
14. Regulatory Status
Calcium carbonate is GRAS listed. Accepted for use as a food additive in
Europe. Included in the FDA Inactive Ingredients Database (buccal chewing gum,
oral capsules and tablets; otic solutions; respiratory inhalation solutions). Included
in nonparenteral medicines licensed in the UK. Included in the Canadian List of
Acceptable Non-medicinal Ingredients.
3.2.6. Tromethamine (TRIS Buffer)
1. CAS No.: 77-86-1
2. Formula: (HOCH2)3CNH2
3. Mol. Wt.: 121.14
4. Toxicity: LD50 (rat, oral): 5900 mg/kg
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
82
Chapter 3
Drug and Excipients Profile
5. Synonyms:THAM; Tris(hydroxymethyl)aminomethane; Trisamine; Trimethylol
aminomethane; Trisaminol; TRIS; Tris buffers; Tris amine buffer; 2-Amino-2(hydroxymethyl)-1,3-propanediol;
1,1,1-Tris(hydroxyl
methyl)
Methylamine;
Tromethamol;
6. Physical and Chemical Properties
Physical State: white crystalline powder
Melting Point: 168 - 172°C
Boiling Point: 219 - 220°C
Solubility in Water: 550 mg/ml
pH: 10.5 (0.1 molar solution)
NFPA Ratings: Health: 1; Flammability: 0; Reactivity: 0
Stability Stable under ordinary conditions. Hygroscopic.
7. General Description & Applications
Buffer is a substance, generally a solution that can keep its pH constant,
despite the addition of strong acids or strong bases and external influences of
temperature, pressure, volume, redox potential. Buffer prevents change in the
concentration of another chemical substance, e.g., proton donor and acceptor
systems that prevent marked changes in hydrogen ion concentration (pH). Many
acid-base reactions take place in living organisms. However, for organisms to
perform certain vital functions, the body fluids associated with these functions
must maintain a constant pH. For example, blood must maintain a pH of close to
7.4 in order to carry oxygen from the lungs to cells; blood is therefore a powerful
buffer. The commonest buffer in chemical solution systems is the acid-base
buffer.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
83
Chapter 3
Drug and Excipients Profile
TRIS buffer (tromethamine): an amine base used intravenously as an
alkalizer for the correction of metabolic acidosis. The pH values of all buffers are
temperature- and concentration-dependent. For Tris buffers, pH increases about
0.03 unit per Centigrade temperature decrease, and decreases 0.03-0.05 unit per
ten-fold dilution.
Tromethamine is used as an intermediate for the preparation of surface
active agents, vulcanization accelerators, and pharmaceuticals, and used as a
titrimetric standard.
3.3. PROFILE OF OTHER FORMULATION ADDITIVES (Pharmaceutical
excipients, 2009)
3.3.1. Crospovidone
1. Nonproprietary Names
BP:
Crospovidone
PhEur:
Crospovidone
USP-NF:
Crospovidone
2. Synonyms
Crospovidonum; Crospopharm; crosslinked povidone; E1202; Kollidon CL;
Kollidon
CL-M;
Polyplasdone
XL;
Polyplasdone
XL-10;
polyvinylpolypyrrolidone; PVPP; 1-vinyl-2-pyrrolidinone homopolymer.
3. Chemical Name and CAS Registry Number
Chemical Name: 1-Ethenyl-2-pyrrolidinone homopolymer
CAS Registry Number: [9003-39-8]
4. Empirical Formula and Molecular Weight
Empirical Formula: (C6H9NO)n
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
84
Chapter 3
Drug and Excipients Profile
Molecular Weight: >1 000 000
The USP32–NF27 describes crospovidone as a water-insoluble synthetic
crosslinked homopolymer of N-vinyl-2-pyrrolidinone. An exact determination of
the molecular weight has not been established because of the insolubility of the
material.
5. Structural Formula
6. Functional Category
Tablet disintegrant.
7. Applications in Pharmaceutical Formulation or Technology
Crospovidone is a water-insoluble tablet disintegrant and dissolution agent
used at 2–5% concentration in tablets prepared by direct-compression or wet- and
dry-granulation methods. It rapidly exhibits high capillary activity and
pronounced hydration capacity, with little tendency to form gels. Studies suggest
that the particle size of crospovidone strongly influences disintegration of
analgesic tablets. Larger particles provide a faster disintegration than smaller
particles. Crospovidone can also be used as a solubility enhancer. With the
technique of co-evaporation, crospovidone can be used to enhance the solubility
of poorly soluble drugs. The drug is adsorbed on to crospovidone in the presence
of a suitable solvent and the solvent is then evaporated. This technique results in
faster dissolution rate.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
85
Chapter 3
Drug and Excipients Profile
8. Description
Crospovidone is a white to creamy-white, finely divided, free-flowing,
practically tasteless, odorless or nearly odorless, hygroscopic powder.
9. Typical Properties
Acidity/alkalinity pH = 5.0–8.0 (1% w/v aqueous slurry)
Density: 1.22 g/cm3
Moisture content: Maximum moisture sorption is approximately 60%.
Particle size distribution: Less than 400 μm for Polyplasdone XL; less than
74μm for Polyplasdone XL-10. Approximately 50% greater than 50 μm and
maximum of 3% greater than 250 μm in size for Kollidon CL. Minimum of 90%
of particles are below 15 μm for Kollidon CL-M. The average particle size for
Crospopharm type A is 100 μm and for Crospopharm type B it is 30 μm.
Solubility: Practically insoluble in water and most common organic solvents.
10. Stability and Storage Conditions
Since crospovidone is hygroscopic, it should be stored in an airtight
container in a cool, dry place.
11. Incompatibilities
Crospovidone
is
compatible
with
most
organic
and
inorganic
pharmaceutical ingredients. When exposed to a high water level, crospovidone
may form molecular adducts with some materials.
12. Method of Manufacture
Acetylene and formaldehyde are reacted in the presence of a highly active
catalyst to form butynediol, which is hydrogenated to butanediol and then
cyclodehydrogenated to form butyrolactone. Pyrrolidone is produced by reacting
butyrolactone with ammonia. This is followed by a vinylation reaction in which
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
86
Chapter 3
Drug and Excipients Profile
pyrrolidone and acetylene are reacted under pressure. The monomer
vinylpyrrolidone is then polymerized in solution, using a catalyst. Crospovidone is
prepared by a 'popcorn polymerization' process.
13. Safety
Crospovidone is used in oral pharmaceutical formulations and is generally
regarded as a nontoxic and nonirritant material. Short-term animal toxicity studies
have shown no adverse effects associated with crospovidone. However, owing to
the lack of available data, an acceptable daily intake in humans has not been
specified by the WHO.
LD50 (mouse, IP): 12 g/kg
14. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Eye protection, gloves, and a dust mask are recommended.
15. Regulatory Status
Accepted for use as a food additive in Europe. Included in the FDA
Inactive Ingredients Database (IM injections, oral capsules and tablets; topical,
transdermal, and vaginal preparations). Included in nonparenteral medicines
licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal
Ingredients.
16. Related Substances
Copovidone; povidone.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
87
Chapter 3
Drug and Excipients Profile
3.3.2. Sodium carbonate
1. Nonproprietary Names
BP: Anhydrous Sodium Carbonate
JP: Dried Sodium Carbonate
PhEur: Sodium Carbonate, Anhydrous
USP-NF: Sodium Carbonate
2. Synonyms
Bisodium carbonate; calcined soda; carbonic acid disodium salt; cenzias
de soda; crystol carbonate; disodium carbonate; E500; natrii carbonas anhydricus;
soda ash; soda calcined.
3. Chemical Name and CAS Registry Number
Chemical Name: Sodium carbonate anhydrous and CAS Registry Number:
[497-19-8]
Chemical Name: Sodium carbonate monohydrate and CAS Registry Number:
[5968-11-6]
Chemical Name: Sodium carbonate decahydrate and CAS Registry Number:
[6132-02-1]
4. Empirical Formula and Molecular Weight
Empirical Formula: Na2CO3 and Molecular Weight: 105.99
Empirical Formula: Na2CO3·H2O and Molecular Weight: 124.0
Empirical Formula: Na2CO3·10H2O and Molecular Weight: 286.1
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
88
Chapter 3
Drug and Excipients Profile
5. Functional Category
Alkalizing agent; buffering agent.
6. Applications in Pharmaceutical Formulation or Technology
Sodium carbonate is used as an alkalizing agent in injectable, ophthalmic,
oral, and rectal formulations.
In effervescent tablets or granules, sodium carbonate is used in
combination with an acid, typically citric acid or tartaric acid. When the tablets or
granules come into contact with water, an acid–base reaction occurs in which
carbon dioxide gas is produced and the product disintegrates. Raw materials with
low moisture contents are required to prevent the early triggering of the
effervescent reaction.
As an alkalizing agent, concentrations of sodium carbonate between 2%
and 5% w/w are used in compressed tablet formulations. As an effervescent agent,
concentrations of sodium carbonate up to 10% w/w can be used. Therapeutically,
sodium carbonate is also used as an oral antacid.
7. Description
Sodium carbonate is a white, almost white, or colorless inorganic salt,
produced as crystalline powder or granules. It is hygroscopic and odorless with an
alkaline taste.
8. Typical Properties
Acidity/alkalinity Strongly alkaline; pH = 11.4 (1% w/v aqueous solution at
25°C).
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
89
Chapter 3
Drug and Excipients Profile
Hygroscopicity: One mole of sodium carbonate will gradually absorb 1 mole of
water (approximately 15%) on exposure to air.
Melting point: 851°C
Refractive index n20D: 1.3352 at 1.0% w/w solution; 1.3440 at 5.0% w/w
solution; 1.3547 for 10.0% w/w solution.
Solubility:
Freely soluble in water, with solubility initially increasing with
temperature and then settling at 30.8% w/w above 80°C. Soluble in glycerin;
practically insoluble in ethanol (95%).
Specific gravity: 2.53
9. Stability and Storage Conditions
Sodium carbonate converts to the monohydrate form when in contact with
water and produces heat. It begins to lose carbon dioxide at temperatures above
400°C and decomposes before boiling. Store in airtight containers.
10. Incompatibilities
Sodium carbonate decomposes when in contact with acids in the presence
of water to produce carbon dioxide and effervescence. It may react violently with
aluminum, phosphorous pentoxide, sulfuric acid, fluorine, and lithium.
11. Method of Manufacture
Sodium carbonate is produced by the ammonia-soda process, also known
as the Solvay process.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
90
Chapter 3
Drug and Excipients Profile
12. Safety
Sodium carbonate is used in injectable, oral, and rectal pharmaceutical
formulations. The pure form of sodium carbonate is mildly toxic by ingestion,
moderately toxic by inhalation and SC routes, and very toxic by the IP route. It is
irritating to the skin and eyes. Dust and vapors of sodium carbonate may irritate
mucous membranes, causing coughing and shortness of breath. It also has
experimental reproductive effects.
Sodium carbonate can migrate to food from packaging materials. When
used as an excipient or antacid, sodium carbonate is generally regarded as a
nontoxic and nonirritating material.
LD50 (mouse, IP): 0.12 g/kg
LD50 (mouse, SC): 2.21 g/kg
LD50 (rat, oral): 4.09 g/kg
13. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of the material handled. When heated to decomposition it emits toxic fumes of
sodium oxide. Eye protection and gloves are recommended. Respiratory
protection is also recommended if inhalable dust is present.
14. Regulatory Status
Sodium carbonate is GRAS listed. Accepted for use as a food additive in
Europe. Included in the FDA Inactive Ingredients Database (injections;
ophthalmic solution; oral capsules and tablets; rectal suspensions). Included in the
Canadian List of Acceptable Non-medicinal Ingredients. Included in parenteral
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
91
Chapter 3
Drug and Excipients Profile
(powder for solution for injection) and nonparenteral medicines (oral effervescent
tablets, soluble tablets, granules, lozenges, chewing gums) licensed in the UK.
15. Related Substances
Sodium bicarbonate; sodium carbonate decahydrate; sodium carbonate
monohydrate.
3.3.3. Mannitol
1. Nonproprietary Names
BP: Mannitol
JP: d-Mannitol
PhEur: Mannitol
USP: Mannitol
2. Synonyms
Cordycepic acid; C*PharmMannidex; E421; Emprove; manna sugar; dmannite; mannite; mannitolum; Mannogem; Pearlitol.
3. Chemical Name and CAS Registry Number
Chemical Name: d-Mannitol and CAS Registry Number: [69-65-8]
4. Empirical Formula and Molecular Weight
Empirical Formula: C6H14O6 and Molecular Weight: 182.17
5. Structural Formula
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
92
Chapter 3
Drug and Excipients Profile
6. Functional Category
Diluent; plasticizer; sweetening agent; tablet and capsule diluent;
therapeutic agent; tonicity agent.
7. Applications in Pharmaceutical Formulation or Technology
Mannitol is widely used in pharmaceutical formulations and food products.
In pharmaceutical preparations it is primarily used as a diluent (10–90% w/w) in
tablet formulations, where it is of particular value since it is not hygroscopic and
may thus be used with moisture-sensitive active ingredients.
Mannitol may be used in direct-compression tablet applications, for which
the granular and spray-dried forms are available, or in wet granulations.
Granulations containing mannitol have the advantage of being dried easily.
Specific tablet applications include antacid preparations, glyceryl trinitrate tablets,
and vitamin preparations. Mannitol is commonly used as an excipient in the
manufacture of chewable tablet formulations because of its negative heat of
solution, sweetness, and 'mouth feel'.
In lyophilized preparations, mannitol (20–90% w/w) has been included as
a carrier to produce a stiff, homogeneous cake that improves the appearance of the
lyophilized plug in a vial. A pyrogen-free form is available specifically for this
use.
Mannitol has also been used to prevent thickening in aqueous antacid
suspensions of aluminum hydroxide (<7% w/v). It has been suggested as a
plasticizer in soft-gelatin capsules, as a component of sustained-release tablet
formulations, and as a carrier in dry powder inhalers. It is also used as a diluent in
rapidly dispersing oral dosage forms. It is used in food applications as a bulking
agent.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
93
Chapter 3
Drug and Excipients Profile
Therapeutically, mannitol administered parenterally is used as an osmotic
diuretic, as a diagnostic agent for kidney function, as an adjunct in the treatment
of acute renal failure, and as an agent to reduce intracranial pressure, treat cerebral
edema, and reduce intraocular pressure. Given orally, mannitol is not absorbed
significantly from the gastrointestinal tract, but in large doses it can cause osmotic
diarrhea.
8. Description
Mannitol is d-mannitol. It is a hexahydric alcohol related to mannose and
is isomeric with sorbitol.
Mannitol occurs as a white, odorless, crystalline powder, or free-flowing
granules. It has a sweet taste, approximately as sweet as glucose and half as sweet
as sucrose, and imparts a cooling sensation in the mouth. Microscopically, it
appears as orthorhombic needles when crystallized from alcohol. Mannitol shows
polymorphism.
9. Typical Properties
Density (bulk):
0.430 g/cm3 for powder; 0.7 g/cm3 for granules.
Density (tapped):
0.734 g/cm3 for powder; 0.8 g/cm3 for granules.
Density (true):
1.514 g/cm3
Dissociation constant pKa: 13.5 at 18°C
Flash point:
<150°C
Flowability:
Powder is cohesive, granules are free flowing.
Heat of combustion:
16.57 kJ/g (3.96 kcal/g)
Heat of solution:
−120.9 J/g (−28.9 cal/g) at 25°C
Melting point:
166–168°C
Osmolarity:
A 5.07% w/v aqueous solution is isoosmotic with
serum.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
94
Chapter 3
Drug and Excipients Profile
Particle size distribution:
Pearlitol 300 DC: maximum of 0.1% greater than 500 μm and minimum of 90%
greater than 200 μm in size;
Pearlitol 400 DC: maximum of 20% greater than 500 μm and minimum of 85%
greater than 100 μm in size;
Pearlitol 500 DC: maximum of 0.5% greater than 841 μm and minimum of 90%
greater than 150 μm in size.
Average particle diameter is 250 μm for Pearlitol 300 DC, 360 μm for Pearlitol
400 DC and 520 μm for Pearlitol 500 DC.
Refractive index n 20D: 1.333
Solubility of mannitol
Solvent
Solubility at 20°C
Alkalis
Soluble
Ethanol (95%) 1 in 83
Ether
Practically insoluble
Glycerin
1 in 18
Propan-2-ol
1 in 100
Water
1 in 5.5
Specific surface area: 0.37–0.39 m2/g
10. Stability and Storage Conditions
Mannitol is stable in the dry state and in aqueous solutions. Solutions may
be sterilized by filtration or by autoclaving and if necessary may be autoclaved
repeatedly with no adverse physical or chemical effects. In solution, mannitol is
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
95
Chapter 3
Drug and Excipients Profile
not attacked by cold, dilute acids or alkalis, nor by atmospheric oxygen in the
absence of catalysts. Mannitol does not undergo Maillard reactions.
The bulk material should be stored in a well-closed container in a cool, dry place.
11. Incompatibilities
Mannitol solutions, 20% w/v or stronger, may be salted out by potassium
chloride or sodium chloride. Precipitation has been reported to occur when a 25%
w/v mannitol solution was allowed to contact plastic. Sodium cephapirin at 2
mg/mL and 30 mg/mL concentration is incompatible with 20% w/v aqueous
mannitol solution. Mannitol is incompatible with xylitol infusion and may form
complexes with some metals such as aluminum, copper, and iron. Reducing sugar
impurities in mannitol have been implicated in the oxidative degradation of a
peptide in a lyophilized formation. Mannitol was found to reduce the oral
bioavailability of cimetidine compared to sucrose.
12. Method of Manufacture
Mannitol may be extracted from the dried sap of manna and other natural
sources by means of hot alcohol or other selective solvents. It is commercially
produced by the catalytic or electrolytic reduction of monosaccharides such as
mannose and glucose.
13. Safety
Mannitol is a naturally occurring sugar alcohol found in animals and
plants; it is present in small quantities in almost all vegetables. Laxative effects
may occur if mannitol is consumed orally in large quantities. If it is used in foods
as a bodying agent and daily ingestion of over 20 g is foreseeable, the product
label should bear the statement 'excessive consumption may have a laxative
effect'. After intravenous injection, mannitol is not metabolized to any appreciable
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
96
Chapter 3
Drug and Excipients Profile
extent and is minimally reabsorbed by the renal tubule, about 80% of a dose being
excreted in the urine in 3 hours.
A number of adverse reactions to mannitol have been reported, primarily
following the therapeutic use of 20% w/v aqueous intravenous infusions. The
quantity of mannitol used as an excipient is considerably less than that used
therapeutically and is consequently associated with a lower incidence of adverse
reactions. However, allergic, hypersensitive-type reactions may occur when
mannitol is used as an excipient.
An acceptable daily intake of mannitol has not been specified by the WHO
since the amount consumed as a sweetening agent was not considered to represent
a hazard to health.
LD50 (mouse, IP):
14 g/kg
LD50 (mouse, IV):
7.47 g/kg
LD50 (mouse, oral):
22 g/kg
LD50 (rat, IV):
9.69 g/kg
LD50 (rat, oral):
13.5 g/kg
14. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Mannitol may be irritant to the eyes; eye protection is
recommended.
15. Regulatory Status
Mannitol is GRAS listed. Accepted for use as a food additive in Europe.
Included in the FDA Inactive Ingredients Database (IP, IM, IV, and SC injections;
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
97
Chapter 3
Drug and Excipients Profile
infusions; buccal, oral and sublingual tablets, powders and capsules; ophthalmic
preparations; topical solutions).
16. Related Substances
Sorbitol
3.3.4 Colloidal Silicon Dioxide
1. Nonproprietary Names
BP:
Colloidal Anhydrous Silica
JP:
Light Anhydrous Silicic Acid
PhEur:
Silica, Colloidal Anhydrous
USP-NF:
Colloidal Silicon Dioxide
2. Synonyms
Aerosil; Cab-O-Sil; Cab-O-Sil M-5P; colloidal silica; fumed silica; fumed
silicon dioxide; hochdisperses silicum dioxid; SAS; silica colloidalis anhydrica;
silica sol; silicic anhydride; silicon dioxide colloidal; silicon dioxide fumed;
synthetic amorphous silica; Wacker HDK.
3. Chemical Name and CAS Registry Number
Chemical Name: Silica and CAS Registry Number: [7631-86-9]
4. Empirical Formula and Molecular Weight
Empirical Formula: SiO2 and Molecular Weight: 60.08
5. Functional Category
Adsorbent; anticaking agent; emulsion stabilizer; glidant; suspending
agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
98
Chapter 3
Drug and Excipients Profile
6. Applications in Pharmaceutical Formulation or Technology
Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and
food products; Its small particle size and large specific surface area give it
desirable flow characteristics that are exploited to improve the flow properties of
dry powders in a number of processes such as tableting and capsule filling.
Colloidal silicon dioxide is also used to stabilize emulsions and as a
thixotropic thickening and suspending agent in gels and semisolid preparations.
With other ingredients of similar refractive index, transparent gels may be formed.
The degree of viscosity increase depends on the polarity of the liquid (polar
liquids generally require a greater concentration of colloidal silicon dioxide than
nonpolar liquids). Viscosity is largely independent of temperature. However,
changes to the pH of a system may affect the viscosity. In aerosols, other than
those for inhalation, colloidal silicon dioxide is used to promote particulate
suspension, eliminate hard settling, and minimize the clogging of spray nozzles.
Colloidal silicon dioxide is also used as a tablet disintegrant and as an adsorbent
dispersing agent for liquids in powders. Colloidal silicon dioxide is frequently
added to suppository formulations containing lipophilic excipients to increase
viscosity, prevent sedimentation during molding, and decrease the release rate.
Colloidal silicon dioxide is also used as an adsorbent during the preparation of
wax microspheres; as a thickening agent for topical preparations; and has been
used to aid the freeze-drying of nanocapsules and nanosphere suspensions.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole
99
Chapter 3
Drug and Excipients Profile
Table I. Uses of colloidal silicon dioxide
Use
Concentration (%)
Aerosols
0.5–2.0
Emulsion stabilizer
1.0–5.0
Glidant
0.1–1.0
Suspending and thickening agent 2.0–10.0
7. Description
Colloidal silicon dioxide is a submicroscopic fumed silica with a particle
size of about 15 nm. It is a light, loose, bluish-white-colored, odorless, tasteless,
amorphous powder.
8. Typical Properties
Acidity/alkalinity pH = 3.8–4.2 (4% w/v aqueous dispersion) and 3.5–4.0 (10%
w/v aqueous dispersion) for Cab-O-Sil M-5P
Density (bulk):
0.029–0.042 g/cm3
Melting point:
1600°C
Particle size distribution:
Primary particle size is 7–16 nm. Aerosil forms
loose agglomerates of 10–200 µm.
Refractive index:
Solubility:
1.46
Practically insoluble in organic solvents, water, and acids, except
hydrofluoric acid; soluble in hot solutions of alkali hydroxide. Forms a colloidal
dispersion with water. For Aerosil, solubility in water is 150 mg/L at 25°C (pH 7).
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 100
Chapter 3
Drug and Excipients Profile
Specific gravity:
2.2
Specific surface area:
100–400 m2/g depending on grade.
Several grades of colloidal silicon dioxide are commercially available,
which are produced by modifying the manufacturing process. The modifications
do not affect the silica content, specific gravity, refractive index, color, or
amorphous form. However, particle size, surface areas, and densities are affected.
9. Stability and Storage Conditions
Colloidal silicon dioxide is hygroscopic but adsorbs large quantities of
water without liquefying. When used in aqueous systems at a pH 0–7.5, colloidal
silicon dioxide is effective in increasing the viscosity of a system. However, at a
pH greater than 7.5 the viscosity-increasing properties of colloidal silicon dioxide
are reduced; and at a pH greater than 10.7 this ability is lost entirely since the
silicon dioxide dissolves to form silicates. Colloidal silicon dioxide powder should
be stored in a well-closed container.
10. Incompatibilities
Incompatible with diethylstilbestrol preparations.
11. Method of Manufacture
Colloidal silicon dioxide is prepared by the flame hydrolysis of
chlorosilanes, such as silicon tetrachloride, at 1800°C using a hydrogen–oxygen
flame. Rapid cooling from the molten state during manufacture causes the product
to remain amorphous.
12. Safety
Colloidal silicon dioxide is widely used in oral and topical pharmaceutical
products and is generally regarded as an essentially nontoxic and nonirritant
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 101
Chapter 3
Drug and Excipients Profile
excipient. However, intraperitoneal and subcutaneous injection may produce local
tissue reactions and/or granulomas. Colloidal silicon dioxide should therefore not
be administered parenterally.
LD50 (rat, IV):
0.015 g/kg
LD50 (rat, oral):
3.16 g/kg
13. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Eye protection and gloves are recommended. Considered a
nuisance dust, precautions should be taken to avoid inhalation of colloidal silicon
dioxide. In the absence of suitable containment facilities, a dust mask should be
worn when handling small quantities of material. For larger quantities, a dust
respirator is recommended.
Inhalation of colloidal silicon dioxide dust may cause irritation to the
respiratory tract but it is not associated with fibrosis of the lungs (silicosis), which
can occur upon exposure to crystalline silica.
14. Regulatory Acceptance
Colloidal silicon dioxide is GRAS listed. Included in the FDA Inactive
Ingredients Database (oral capsules, suspensions, and tablets; transdermal, rectal,
and vaginal preparations). Also approved by the FDA as a food additive and for
food contact. Included in nonparenteral medicines licensed in the UK. Included in
the Canadian List of Acceptable Non-medicinal Ingredients.
15. Related Substances
Hydrophobic colloidal silica
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 102
Chapter 3
Drug and Excipients Profile
3.3.5 Magnesium Stearate
1. Nonproprietary Names
BP:
Magnesium Stearate
JP:
Magnesium Stearate
PhEur:
Magnesium Stearate
USP-NF:
Magnesium Stearate
2. Synonyms
Dibasic magnesium stearate; magnesium distearate; magnesii stearas;
magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid,
magnesium salt; Synpro 90.
3. Chemical Name and CAS Registry Number
Chemical Name: Octadecanoic acid magnesium salt and CAS Registry
Number: [557-04-0]
4. Empirical Formula and Molecular Weight
Empirical Formula: C36H70MgO4 and Molecular Weight: 591.24
The USP32–NF27 describes magnesium stearate as a compound of
magnesium with a mixture of solid organic acids that consists chiefly of variable
proportions of magnesium stearate and magnesium palmitate (C32H62MgO4). The
PhEur 6.5 describes magnesium stearate as a mixture of solid organic acids
consisting mainly of variable proportions of magnesium stearate and magnesium
palmitate obtained from sources of vegetable or animal origin.
5. Structural Formula
[CH3(CH2)16COO]2Mg
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 103
Chapter 3
Drug and Excipients Profile
6. Functional Category
Tablet and capsule lubricant.
7. Applications in Pharmaceutical Formulation or Technology
Magnesium
stearate
is
widely
used
in
cosmetics,
foods,
and
pharmaceutical formulations. It is primarily used as a lubricant in capsule and
tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used
in barrier creams.
8. Description
Magnesium stearate is a very fine, light white, precipitated or milled,
impalpable powder of low bulk density, having a faint odor of stearic acid and a
characteristic taste. The powder is greasy to the touch and readily adheres to the
skin.
9. Typical Properties
Crystalline forms High-purity magnesium stearate has been isolated as a
trihydrate, a dihydrate, and an anhydrate.
Density (bulk):
0.159 g/cm3
Density (tapped):
0.286 g/cm3
Density (true):
1.092 g/cm3
Flash point:
250°C
Flowability:
Poorly flowing, cohesive powder.
Melting range: 117–150°C (commercial samples); 126–130°C (high purity
magnesium stearate).
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 104
Chapter 3
Drug and Excipients Profile
Solubility: Practically insoluble in ethanol, ethanol (95%), ether and water;
slightly soluble in warm benzene and warm ethanol (95%).
Specific surface area: 1.6–14.8 m2/g
10. Stability and Storage Conditions
Magnesium stearate is stable and should be stored in a well-closed
container in a cool, dry place.
11. Incompatibilities
Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with
strong oxidizing materials. Magnesium stearate cannot be used in products
containing aspirin, some vitamins, and most alkaloidal salts.
12. Method of Manufacture
Magnesium stearate is prepared either by the interaction of aqueous
solutions of magnesium chloride with sodium stearate or by the interaction of
magnesium oxide, hydroxide, or carbonate with stearic acid at elevated
temperatures.
13. Safety
Magnesium stearate is widely used as a pharmaceutical excipient and is
generally regarded as being nontoxic following oral administration. However, oral
consumption of large quantities may produce a laxative effect or mucosal
irritation.
No toxicity information is available relating to normal routes of
occupational exposure. Limits for heavy metals in magnesium stearate have been
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 105
Chapter 3
Drug and Excipients Profile
evaluated in terms of magnesium stearate worst-case daily intake and heavy metal
composition.
Toxicity assessments of magnesium stearate in rats have indicated that it is
not irritating to the skin, and is nontoxic when administered orally or inhaled.
Magnesium stearate has not been shown to be carcinogenic when implanted into
the bladder of mice.
LD50 (rat, inhalation):
>2 mg/L
LD50 (rat, oral):
>10 g/kg
14. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Eye protection and gloves are recommended. Excessive
inhalation of magnesium stearate dust may cause upper respiratory tract
discomfort, coughing, and choking. Magnesium stearate should be handled in a
well-ventilated environment; a respirator is recommended. In the USA, the OSHA
limit is 10 mg/m3 TWA for magnesium stearate.
15. Regulatory Acceptance
Magnesium stearate is GRAS listed. Accepted as a food additive in the
USA and UK. Included in the FDA Inactive Ingredients Database (oral capsules,
powders, and tablets; buccal and vaginal tablets; topical preparations; intravitreal
implants and injections). Included in nonparenteral medicines licensed in the UK.
Included in the Canadian List of Acceptable Non-medicinal Ingredients. Listed on
the US TSCA inventory.
16. Related Substances
Calcium stearate; magnesium aluminum silicate; stearic acid; zinc stearate.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 106
Chapter 3
Drug and Excipients Profile
3.3.6 Polyethylene glycol 8000
1. Nonproprietary Names
BP:
Macrogols
JP:
Macrogol 400; Macrogol 1500; Macrogol 4000; Macrogol 6000; Macrogol
20000
PhEur: Macrogols
USP-NF: Polyethylene Glycol
2. Synonyms
Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; macrogola; PEG; Pluriol E;
polyoxyethylene glycol.
3. Chemical Name and CAS Registry Number
Chemical Name: α-Hydro-ω-hydroxypoly(oxy-1,2-ethanediyl)
CAS Registry Number: [25322-68-3]
4. Empirical Formula
Empirical Formula: HOCH2(CH2OCH2)mCH2OH where m represents the
average number of oxyethylene groups.
5. Structural Formula
6. Functional Category
Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 107
Chapter 3
Drug and Excipients Profile
7. Applications in Pharmaceutical Formulation or Technology
Polyethylene glycols (PEGs) are widely used in a variety of
pharmaceutical formulations, including parenteral, topical, ophthalmic, oral, and
rectal preparations. Polyethylene glycol has been used experimentally in
biodegradable polymeric matrices used in controlled-release systems.
Polyethylene glycols are stable, hydrophilic substances that are essentially
nonirritant to the skin. They do not readily penetrate the skin, although the
polyethylene glycols are water-soluble and are easily removed from the skin by
washing, making them useful as ointment bases. Solid grades are generally
employed in topical ointments, with the consistency of the base being adjusted by
the addition of liquid grades of polyethylene glycol.
Mixtures of polyethylene glycols can be used as suppository bases, for
which they have many advantages over fats. For example, the melting point of the
suppository can be made higher to withstand exposure to warmer climates; release
of the drug is not dependent upon melting point; the physical stability on storage
is better; and suppositories are readily miscible with rectal fluids. Polyethylene
glycols have the following disadvantages: they are chemically more reactive than
fats; greater care is needed in processing to avoid inelegant contraction holes in
the suppositories; the rate of release of water-soluble medications decreases with
the increasing molecular weight of the polyethylene glycol; and polyethylene
glycols tend to be more irritating to mucous membranes than fats.
Aqueous polyethylene glycol solutions can be used either as suspending agents or
to adjust the viscosity and consistency of other suspending vehicles. When used in
conjunction with other emulsifiers, polyethylene glycols can act as emulsion
stabilizers.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 108
Chapter 3
Drug and Excipients Profile
Liquid polyethylene glycols are used as water-miscible solvents for the
contents of soft gelatin capsules. However, they may cause hardening of the
capsule shell by preferential absorption of moisture from gelatin in the shell.
In concentrations up to approximately 30% v/v, PEG 300 and PEG 400 have been
used as the vehicle for parenteral dosage forms.
In solid-dosage formulations, higher-molecular-weight polyethylene
glycols can enhance the effectiveness of tablet binders and impart plasticity to
granules. However, they have only limited binding action when used alone, and
can prolong disintegration if present in concentrations greater than 5% w/w. When
used for thermoplastic granulations, a mixture of the powdered constituents with
10–15% w/w PEG 6000 is heated to 70–75°C. The mass becomes pastelike and
forms granules if stirred while cooling. This technique is useful for the preparation
of dosage forms such as lozenges when prolonged disintegration is required.
Polyethylene glycols can also be used to enhance the aqueous solubility or
dissolution characteristics of poorly soluble compounds by making solid
dispersions with an appropriate polyethylene glycol. Animal studies have also
been performed using polyethylene glycols as solvents for steroids in osmotic
pumps.
In film coatings, solid grades of polyethylene glycol can be used alone for
the film-coating of tablets or can be useful as hydrophilic polishing materials.
Solid grades are also widely used as plasticizers in conjunction with film-forming
polymers. The presence of polyethylene glycols in film coats, especially of liquid
grades, tends to increase their water permeability and may reduce protection
against low pH in enteric-coating films. Polyethylene glycols are useful as
plasticizers in microencapsulated products to avoid rupture of the coating film
when the microcapsules are compressed into tablets.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 109
Chapter 3
Drug and Excipients Profile
Polyethylene glycol grades with molecular weights of 6000 and above can
be used as lubricants, particularly for soluble tablets. The lubricant action is not as
good as that of magnesium stearate, and stickiness may develop if the material
becomes too warm during compression. An antiadherent effect is also exerted,
again subject to the avoidance of overheating.
Polyethylene glycols have been used in the preparation of urethane
hydrogels, which are used as controlled-release agents. Polyethylene glycol has
also been used in insulin-loaded microparticles for the oral delivery of insulin; it
has been used in inhalation preparations to improve aerosolization; polyethylene
glycol nanoparticles have been used to improve the oral bioavailability of
cyclosporine; it has been used in self-assembled polymeric nanoparticles as a drug
carrier; and copolymer networks of polyethylene glycol grafted with
poly(methacrylic acid) have been used as bioadhesive controlled drug delivery
formulations.
8. Description
The USP32–NF27 describes polyethylene glycol as being an addition
polymer of ethylene oxide and water. Polyethylene glycol grades 200–600 are
liquids; grades 1000 and above are solids at ambient temperatures.
Liquid grades (PEG 200–600) occur as clear, colorless or slightly yellow-colored,
viscous liquids. They have a slight but characteristic odor and a bitter, slightly
burning taste. PEG 600 can occur as a solid at ambient temperatures.
Solid grades (PEG>1000) are white or off-white in color, and range in
consistency from pastes to waxy flakes. They have a faint, sweet odor. Grades of
PEG 6000 and above are available as free-flowing milled powders.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 110
Chapter 3
Drug and Excipients Profile
9. Typical Properties
Density:
1.11–1.14 g/cm3 at 25°C for liquid PEGs;
1.15–1.21 g/cm3 at 25°C for solid PEGs.
Flash point: 182°C for PEG 200; 213°C for PEG 300; 238°C for PEG 400;
250°C for PEG 600.
Freezing point: <−65°C PEG 200 sets to a glass; −15 to −8°C for PEG 300;
4–8°C for PEG 400; 15–25°C for PEG 600.
Melting point: 37–40°C for PEG 1000; 44–48°C for PEG 1500; 40–48°C for
PEG 1540; 45–50°C for PEG 2000; 48–54°C for PEG 3000;
50–58°C for PEG 4000; 55–63°C for PEG 6000; 60–63°C for
PEG 8000; 60–63°C for PEG 20000.
Moisture content: Liquid polyethylene glycols are very hygroscopic, although
hygroscopicity decreases with increasing molecular weight. Solid grades, e.g.
PEG 4000 and above, are not hygroscopic.
Refractive index: n25D = 1.459 for PEG 200; n25D = 1.463 for PEG 300;
n25D = 1.465 for PEG 400; n25D = 1.467 for PEG 600.
Solubility All grades of polyethylene glycol are soluble in water and miscible in
all proportions with other polyethylene glycols (after melting, if necessary).
Aqueous solutions of higher-molecular-weight grades may form gels. Liquid
polyethylene glycols are soluble in acetone, alcohols, benzene, glycerin, and
glycols. Solid polyethylene glycols are soluble in acetone, dichloromethane,
ethanol (95%), and methanol; they are slightly soluble in aliphatic hydrocarbons
and ether, but insoluble in fats, fixed oils, and mineral oil.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 111
Chapter 3
Drug and Excipients Profile
Surface tension Approximately 44 mN/m (44 dynes/cm) for liquid polyethylene
glycols; approximately 55 mN/m (55 dynes/cm) for 10% w/v aqueous solution of
solid polyethylene glycol.
10. Stability and Storage Conditions
Polyethylene glycols are chemically stable in air and in solution, although
grades with a molecular weight less than 2000 are hygroscopic. Polyethylene
glycols do not support microbial growth, and they do not become rancid.
Polyethylene glycols and aqueous polyethylene glycol solutions can be sterilized
by autoclaving, filtration, or gamma irradiation. Sterilization of solid grades by
dry heat at 150°C for 1 hour may induce oxidation, darkening, and the formation
of acidic degradation products. Ideally, sterilization should be carried out in an
inert atmosphere. Oxidation of polyethylene glycols may also be inhibited by the
inclusion of a suitable antioxidant.
If heated tanks are used to maintain normally solid polyethylene glycols in
a molten state, care must be taken to avoid contamination with iron, which can
lead to discoloration. The temperature must be kept to the minimum necessary to
ensure fluidity; oxidation may occur if polyethylene glycols are exposed for long
periods to temperatures exceeding 50°C. However, storage under nitrogen reduces
the possibility of oxidation.
Polyethylene glycols should be stored in well-closed containers in a cool,
dry place. Stainless steel, aluminum, glass, or lined steel containers are preferred
for the storage of liquid grades.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 112
Chapter 3
Drug and Excipients Profile
11. Incompatibilities
The chemical reactivity of polyethylene glycols is mainly confined to the
two terminal hydroxyl groups, which can be either esterified or etherified.
However, all grades can exhibit some oxidizing activity owing to the presence of
peroxide impurities and secondary products formed by autoxidation.
Liquid and solid polyethylene glycol grades may be incompatible with
some coloring agents.
The antibacterial activity of certain antibiotics is reduced in polyethylene
glycol bases, particularly that of penicillin and bacitracin. The preservative
efficacy of the parabens may also be impaired owing to binding with polyethylene
glycols.
Physical effects caused by polyethylene glycol bases include softening and
liquefaction in mixtures with phenol, tannic acid, and salicylic acid. Discoloration
of sulfonamides and dithranol can also occur, and sorbitol may be precipitated
from mixtures. Plastics, such as polyethylene, phenolformaldehyde, polyvinyl
chloride, and cellulose-ester membranes (in filters) may be softened or dissolved
by polyethylene glycols. Migration of polyethylene glycol can occur from tablet
film coatings, leading to interaction with core components.
12. Method of Manufacture
Polyethylene glycol polymers are formed by the reaction of ethylene oxide
and water under pressure in the presence of a catalyst.
13. Safety
Polyethylene glycols are widely used in a variety of pharmaceutical
formulations. Generally, they are regarded as nontoxic and nonirritant materials.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 113
Chapter 3
Drug and Excipients Profile
Adverse reactions to polyethylene glycols have been reported, the greatest
toxicity being with glycols of low molecular weight. However, the toxicity of
glycols is relatively low.
Polyethylene glycols administered topically may cause stinging, especially
when applied to mucous membranes. Hypersensitivity reactions to polyethylene
glycols applied topically have also been reported, including urticaria and delayed
allergic reactions.
The most serious adverse effects associated with polyethylene glycols are
hyperosmolarity, metabolic acidosis, and renal failure following the topical use of
polyethylene glycols in burn patients. Topical preparations containing
polyethylene glycols should therefore be used cautiously in patients with renal
failure, extensive burns, or open wounds.
Oral administration of large quantities of polyethylene glycols can have a
laxative effect. Therapeutically, up to 4 L of an aqueous mixture of electrolytes
and high-molecular-weight polyethylene glycol is consumed by patients
undergoing bowel cleansing.
Liquid polyethylene glycols may be absorbed when taken orally, but the
higher-molecular-weight polyethylene glycols are not significantly absorbed from
the gastrointestinal tract. Absorbed polyethylene glycol is excreted largely
unchanged in the urine, although polyethylene glycols of low molecular weight
may be partially metabolized.
The WHO has set an estimated acceptable daily intake of polyethylene
glycols at up to 10 mg/kg body-weight.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 114
Chapter 3
Drug and Excipients Profile
In parenteral products, the maximum recommended concentration of PEG
300 is approximately 30% v/v as hemolytic effects have been observed at
concentrations greater than about 40% v/v.
14. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Eye protection is recommended.
15. Regulatory Status
Included in the FDA Inactive Ingredients Database (dental preparations;
IM and IV injections; ophthalmic preparations; oral capsules, solutions, syrups,
and tablets; rectal, topical, and vaginal preparations). Included in nonparenteral
medicines licensed in the UK. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.
16. Related Substances
Polyoxyethylene alkyl ethers; polyethylene oxide; polyoxyethylene
sorbitan fatty acid esters; polyoxyethylene stearates; suppository bases.
3.3.7 Hydroxypropylcellulose
1. Nonproprietary Names
JP:
Low Substituted Hydroxypropylcellulose
USP-NF: Low-Substituted Hydroxypropyl Cellulose
2. Synonyms
Cellulose, 2-hydroxypropyl ether; 2-hydroxypropyl ether (low-substituted)
cellulose; hyprolose, low-substituted; L-HPC; oxypropylated cellulose.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 115
Chapter 3
Drug and Excipients Profile
3. Chemical Name and CAS Registry Number
Chemical Name: Cellulose, 2-hydroxypropyl ether (low-substituted)
CAS Registry Number: [9004-64-2]
4. Empirical Formula and Molecular Weight
The USP32–NF27 describes low-substituted hydroxypropyl cellulose as a
low-substituted hydroxypropyl ether of cellulose. Compared to hydroxypropyl
cellulose, low-substituted hydroxypropyl cellulose has only a small proportion of
the three free hydroxyl groups per glucose subunit converted to a hydroxypropyl
ether. When dried at 105°C for 1 hour, it contains not less than 5.0% and not more
than 16.0% of hydroxypropoxy groups (—OCH2CHOHCH3).
5. Structural Formula
R is H or [CH2CH(CH3)O]m H
6. Functional Category
Tablet and capsule disintegrant; tablet binder.
7. Applications in Pharmaceutical Formulation or Technology
Low-substituted hydroxypropyl cellulose is widely used in oral soliddosage forms. It is primarily used as a disintegrant, and as a binder for tablets and
granules in wet or dry granulation. It has been used in the preparation of rapidly
disintegrating tablets produced by direct compression methods. In addition, lowsubstituted hydroxypropyl cellulose has been used as a binder/disintegrant
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 116
Chapter 3
Drug and Excipients Profile
included in the powder layering process on spherical cores and to prepare pellets
by extrusion/spheronization. A low particle size and high hydroxypropyl content
is recommended to produce round spheres and rapid dissolution.
There are a number of grades that have different particle sizes and
substitution levels. LH-11 has the longest fibrous particles, and is typically used as
an anticapping agent and disintegrant for direct compression. LH-21 is less fibrous
and is used as a binder and disintegrant for tablets through the wet-granulation
process. LH-31 is a small-particle grade used especially for extrusion to produce
granules, as it has a small particle size that is better for passing a screen. LH-B1 is
the nonfibrous, high-density grade designed for fluid-bed granulation, and can be
used for direct compression and/or formulations with a high low-substituted
hydroxypropyl cellulose loading. Lower substitution grades LH-22 and LH-32 can
be used for better disintegration capability, depending on the characteristics of the
active ingredients.
The typical content of low-substituted hydroxypropyl cellulose in a
formulation is approximately 5–50%.
8. Description
Low-substituted hydroxypropyl cellulose occurs as a white to yellowish
white powder or granules. It is odorless or has a slight, characteristic odor, and it
is tasteless.
9. Typical Properties
Acidity/alkalinity pH = 5.0–7.5 for 1% w/v aqueous suspension.
Ash: 0.5%
Density (true): 1.3 g/cm3
Melting point: Decomposition at 290°C.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 117
Chapter 3
Drug and Excipients Profile
Moisture content:
8% at 33% relative humidity; 38% at 95% relative humidity.
Particle size distribution:
LH-11: average size 50 μm; not more than 2% larger than 150 μm;
LH-21 and LH-22: average size 40 μm; not more than 10% larger than 75 μm;
LH-31 and LH-32: average size 25 μm; not more than 50% larger than 45 μm.
Solubility: Practically insoluble in ethanol (95%) and in ether. Dissolves in a
solution of sodium hydroxide (1 in 10) and produces a viscous solution. Insoluble,
but swells in water.
Specific surface area:
0.756 m2/g for LH-21; 0.469 m2/g for LH-B1.
10. Stability and Storage Conditions
Low-substituted hydroxypropyl cellulose is a stable, though hygroscopic,
material. The powder should be stored in a well-closed container.
11. Incompatibilities
Alkaline substances may interact. If a tablet formulation contains such a
material, the disintegration time may be extended after storage.
12. Method of Manufacture
Low-substituted hydroxypropyl cellulose is manufactured by reacting
alkaline cellulose with propylene oxide at elevated temperature. Following the
reaction, the product is recrystallized by neutralization, washed, and milled.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 118
Chapter 3
Drug and Excipients Profile
13. Safety
Low-substituted hydroxypropyl cellulose is generally regarded as a
nontoxic and nonirritant material.
Animal toxicity studies showed no adverse effects in rats fed orally 6
g/kg/day over 6 months. No teratogenic effects were noted in rabbits and rats fed
5 g/kg/day.
LD50 (rat, oral): >15 g/kg
14. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Excessive dust generation should be avoided to minimize the
risk of explosions.
15. Regulatory Status
Included in the FDA Inactive Ingredients Database (oral capsules, tablets,
pellets). Approved for use in pharmaceuticals in Europe, Japan, USA, and other
countries. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
16. Related Substances
Hydroxyethylmethyl cellulose; hydroxypropyl cellulose; methylcellulose.
3.3.8 Microcrystalline cellulose
1. Nonproprietary Names
BP: Microcrystalline Cellulose
JP: Microcrystalline Cellulose
PhEur: Cellulose, Microcrystalline
USP-NF: Microcrystalline Cellulose
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 119
Chapter 3
Drug and Excipients Profile
2. Synonyms
Avicel PH; Cellets; Celex; cellulose gel; hellulosum microcristallinum; Celphere;
Ceolus KG; crystalline cellulose; E460; Emcocel; Ethispheres; Fibrocel; MCC
Sanaq; Pharmacel; Tabulose; Vivapur.
3. Chemical Name and CAS Registry Number
Chemical Name: Cellulose and CAS Registry Number: [9004-34-6]
4. Empirical Formula and Molecular Weight
(C6H10O5) n ≈36 000; where n ≈ 220
5. Structural Formula
6. Functional Category
Adsorbent; suspending agent; tablet and capsule diluent; tablet
disintegrant.
7. Applications in Pharmaceutical Formulation or Technology
Microcrystalline cellulose is widely used in pharmaceuticals, primarily as
a binder/diluent in oral tablet and capsule formulations where it is used in both
wet-granulation and direct-compression processes. In addition to its use as a
binder/diluent, microcrystalline cellulose also has some lubricant and disintegrant
properties that make it useful in tableting.
Microcrystalline cellulose is also used in cosmetics and food products.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 120
Chapter 3
Drug and Excipients Profile
8. Description
Microcrystalline cellulose is a purified, partially depolymerized cellulose
that occurs as a white, odorless, tasteless, crystalline powder composed of porous
particles. It is commercially available in different particle sizes and moisture
grades that have different properties and applications.
9. Typical Properties
Angle of repose:
49° for Ceolus KG; 34.4° for Emcocel 90M.
Density (bulk):
0.337 g/cm3; 0.32 g/cm3 for Avicel PH-101; 0.80 ± 5 g/cm3
for Cellets 100, 200, 350, 500, 700, 1000; 0.29 g/cm3 for
Emcocel 90M;0.26–0.31 g/cm3 for MCC Sanaq 101;0.28–
0.33 g/cm3 for MCC Sanaq 102; 0.29–0.36 g/cm3 for MCC
Sanaq 200;0.34–0.45 g/cm3 for MCC Sanaq 301;0.35–0.46
g/cm3 for MCC Sanaq 302; 0.13–0.23 g/cm3 for MCC
Sanaq UL-002; 0.29 g/cm3 for Vivapur 101.
Density (tapped):
0.478 g/cm3; 0.45 g/cm3 for Avicel PH-101; 0.35 g/cm3 for
Emcocel 90M.
Density (true):
1.512–1.668 g/cm3; 1.420–1.460 g/cm3 for Avicel PH-102.
Flowability:
1.41 g/s for Emcocel 90M.
Melting point:
Chars at 260–270°C.
Moisture content: Typically less than 5% w/w. However, different grades may
contain varying amounts of water. Microcrystalline cellulose is hygroscopic.
Particle size distribution: Typical mean particle size is 20–200 μm. Different
grades may have a different nominal mean particle size.
Solubility: Slightly soluble in 5% w/v sodium hydroxide solution; practically
insoluble in water, dilute acids, and most organic solvents.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 121
Chapter 3
Drug and Excipients Profile
Specific surface area: 1.06–1.12 m2/g for Avicel PH-101; 1.21–1.30 m2/g for
Avicel PH-102; 0.78–1.18 m2/g for Avicel PH-200.
10. Stability and Storage Conditions
Microcrystalline cellulose is a stable though hygroscopic material. The
bulk material should be stored in a well-closed container in a cool, dry place.
11. Incompatibilities
Microcrystalline cellulose is incompatible with strong oxidizing agents.
12. Method of Manufacture
Microcrystalline cellulose is manufactured by controlled hydrolysis with
dilute mineral acid solutions of α-cellulose, obtained as a pulp from fibrous plant
materials. Following hydrolysis, the hydrocellulose is purified by filtration and the
aqueous slurry is spray-dried to form dry, porous particles of a broad size
distribution.
13. Safety
Microcrystalline cellulose is widely used in oral pharmaceutical
formulations and food products and is generally regarded as a relatively nontoxic
and nonirritant material.
Microcrystalline cellulose is not absorbed systemically following oral
administration and thus has little toxic potential. Consumption of large quantities
of cellulose may have a laxative effect, although this is unlikely to be a problem
when cellulose is used as an excipient in pharmaceutical formulations.
Deliberate abuse of formulations containing cellulose, either by inhalation
or by injection, has resulted in the formation of cellulose granulomas.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 122
Chapter 3
Drug and Excipients Profile
14. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Microcrystalline cellulose may be irritant to the eyes. Gloves,
eye protection, and a dust mask are recommended. In the UK, the workplace
exposure limits for cellulose have been set at 10 mg/m3 long-term (8-hour TWA)
for total inhalable dust and 4 mg/m3 for respirable dust; the short-term limit for
total inhalable dust has been set at 20 mg/m3.
15. Regulatory Status
Microcrystalline cellulose is GRAS listed. Accepted for use as a food
additive in Europe. Included in the FDA Inactive Ingredients Database
(inhalations; oral capsules, powders, suspensions, syrups, and tablets; topical and
vaginal preparations). Included in nonparenteral medicines licensed in the UK.
Included in the Canadian List of Acceptable Non-medicinal Ingredients.
16. Related Substances
Microcrystalline cellulose and carrageenan; microcrystalline cellulose and
carboxymethylcellulose sodium; microcrystalline cellulose and guar gum;
powdered cellulose; silicified microcrystalline cellulose.
Design And Development Of A Novel Concept For Immediate Release Of Pantoprazole 123