Instrument, Chemicals, Excipients & API - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/9995/8/08_chapter 3.pdf · 15 Ethanol Loba chemicals 16 Eosin Y reagent Loba chenie Pvt.Ltd,Mumbai

Instrument, Chemicals,

Excipients & API

Chapter 3: Instrument, Chemicals, Excipients and API

Direct tabletting and BA improvements of MA by spherical crystallization tech. 41

3. Instruments and Materials: 3.1. List of instruments and softwares used

S. No Instrument Model Company

1 UV- Visible

spectrophotometer

Pharmaspec 1700 Shimadzu, Japan

2 HPLC PU-2080; UV-2075 Jasco, Japan

3 Incubator shaker Digital Shaker Samruth, India

4 pH meter LI 613 Elico, India

5 Sonicator 3.5 l 100 PCI, India

6 Tablet punching machine 8st,multi tooling CIP instruments, India

7 Tablet dissolution tester Disso 2000 Labindia, India

8 Tablet disintegration tester -- Lab Hosp, India

9 Hardness tester -- Rajesh chemicals, India

10 Friability tester -- Electro Lab, india

11 Stability chamber EC 2054 HMG India

12 FTIR IR 8400 Shimadzu, Japan

13 Differential scanning

calorimetry

TA 60 Shimadzu, Japan

14 Powder X ray Diffraction PW 1729 Philips, Holoand

15 Scanning electron

microscopy

JSM 5200 Jeol, Japan

16 Microscope VJ2 BIK Labo, India

17 Deep freezer 5001 Local made

18 Freeze drier A65TM Khera Instruments, Delhi

19 Photo Microscope Play Q X 3 Intel, UK,

20 Refrigeration Centrifuge RC4100 D Eitek, India

21 Micro-centrifuge Spinwin 1.5 ml Bio Era, India

22 Electronic balance HR 200 AND, India

23 Stirrer Remi stirrer Remi ,Mumbai

24 Water bath Dolphin Instrument Dolphin

25 Hot air oven Dolphin Model 1033 Dolphin

26 Vacuum filtration assembly Jet-Vac(water jet

vacuum pump) Aspirator

Prashant Industries Pune

27 Sieve shaker Dolphin

28 Tap density apparatus Dolphin

29 Peristaltic pump Electrolab Mumbai

30 Magnus Live Projection

microscope

IMPS Olympus.

Software used

1 Sigma plot 10 (Cranes software Industrial Ltd, Bangalore, India)

2 Sigma stat 3.5 (Cranes software Industrial Ltd, Bangalore, India)

3 GraphPad InStat.

4 Drug release kinetic model and Similarity factor (F2) calculation in dissolution study

5 Heckel plot and Excel Sheet-2003 and 2007.



3.2. List of API, chemicals and reagents:

S. No Chemicals Source/ Company name

Active Pharmaceutical Ingredients (API)

1 Azithromycin (ATM) Alembic Research Center(ARC)

2 Clarithromycin (CTM) Alembic Research Center(ARC)

3 Erythromycin (ETM) Alembic Research Center(ARC)

4 Roxithromycin (RTM) Alembic Research Center(ARC)

Chemicals/Reagents:

5 Disodium hydrogen phosphate Loba chemicals

6 Potassium dihydrogen phosphate Loba chemicals

7 Glacial Acetic acid Loba chemicals

8 Hydrochloric acid Loba chemicals

9 Sodium hydroxide Loba chemicals

10 Sodium chloride Loba chemicals

11 Methanol Loba chemicals

12 Dichloromethane Loba chemicals

13 Acetonitrile Loba chemicals

14 Water Loba chemicals

15 Ethanol Loba chemicals

16 Eosin Y reagent Loba chenie Pvt.Ltd,Mumbai

17 HPLC grade water Merck Specialties Private Ltd,

Mumbai.

18 Chloroform Merck Specialties Private Ltd,

Mumbai.

19 Sodium acetate Loba chemicals

20 Methylene blue crystals BDH Laboratory chemical

division Glaxo Lb(India) Ltd,

Mumbai



3.3. List of Polymers and Excipients:

S. No Chemicals Source/ Company name

1 HPMC Colorcon

2 HEC Lupin Research Park

3 HPC Alembic Research center

4 Chitosan Panacea Biotech

5 Beta Cyclodextrin Wockhdart

6 Eudragit S100 Degussa,Roehm Pharma polymers

7 Eudragit L100 Degussa,Roehm Pharma polymers

8 Eudragit RS100 Degussa,Roehm Pharma polymers

9 Eudragit E100 Degussa,Roehm Pharma polymers

10 Eudragit RLPO Degussa,Roehm Pharma polymers

11 Eudragit RSPO Degussa,Roehm Pharma polymers

12 Eudragit L100.55 Degussa,Roehm Pharma polymers

13 Glyceryl monostearate Loba chem.

14 Xanthan gum C Pkelco

15 Polyvinyl pyrrolidone(PVP) ISP Techno

16 Polyethylene glycol (PEG) Alembic Research center

17 Polyvinyl alcohol(PVA) Loba chem.

18 Carbopol-934 Research Lab fine chem. Industries Mumbai.

19 Carbomar-986 Research Lab fine chem. Industries Mumbai.

20 Poloxamer Alembic Research Center

21 Sodium starch glycolate Roquette

22 Croscarmellose sodium FMC Biopolymer

23 Cros povidone Alembic Research Center

24 Lactose monohydrate Loba chem.

25 Microcrystalline cellulose FMC Biopolymer

26 Dibasic calcium phosphate Rhodia

27 Colloidal silicon dioxide Degussa

28 Magnesium stearate Ferro

29 Talc Loba chemicals



3.4. Drug Profile 3.4.1. Azithromycin (1-9):

Azithromycin is an azalide, a subclass of macrolide antibiotics. It was approved by the

Food and Drug Administration for clinical use in 1992. It is a member of a new

generation of macrolide antibiotics and has several advantages over erythromycin. These

include improved oral bioavailability, higher tissue concentrations, and fewer side

effects. It also has enhanced antimicrobial activity and a longer half life, which allows for

once daily dosing.

Chemistry:

Azithromycin is a semisynthetic macrolide antibiotic of the erythromycin group with a

15-membered azalactone ring.Azithromycin is derived from erythromycin; however, it

differs chemically from erythromycin in that a methyl-substituted nitrogen atom is

incorporated into the lactone ring.

Chemical name:

(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-

methyl-α-L-ribo-hexopyranosyl) oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-

heptamethyl-11-[[3,4,6-trideoxy-3- (dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-

oxa-6-azacyclopentadecan-15-one.

Molecular formula: C38H72N2O12•2H2O

Molecular weight: 785.00

Description: It is white crystalline powder having better taste.

Physicochemical data: Solubility: Practically insolble in water, freely soluble in ethanol and in

methylene chloride, Soluble in chloroform

Solubility in water: 1.8mg/mL

BCS status: Class II

Polymorphism:

Azithromycin was found to exhibit pseudopolymorphism and can exist as

monohydrate and dihydrate. The anhydrous form of azithromycin seemed to be

unstable since it is converted to dihydrate on storage at room temperature. On the

other hand, monohydrate in the presence of moisture can convert to the more

stable dihydrate form. Therefore, the most stable form of azithromycin is

dihydrate.

Isoelectric Point (PKa):8.74



Partition coefficient (LogP): 3.03

Melting point: 113-115 oC

Pharmacodynamics:

Azithromycin binds to the 50S subunit of the 70S bacterial ribosomes, and therefore

inhibits RNA-dependent protein synthesis in bacterial cells.

Pharmacokinetics:

Azithromycin shows remarkable pharmacokinetic properties like acid stability, rapid oral

absorption, marked tissue distribution and intracellular penetration.

Bioavailability: ≈ 34%

Half life(T ½): 68 hours

Volume of distribution(Vd): 30 lit/Kg

Renal excretion: <10% largely excreted unchanged in bile and urine.

Spectrum of activity:

It is more active then other macrolide against H.Influnzae but less active against gram

positive cocci.High activity is exerted on respiratory pathogens like Chlamydia

pneumoniae, Mycoplasma pneumoniae or Streptococcus pneumoniae, Moraxella and

other camphylobactor and N.gonorrhoea.Good activity against MAC(Mycobact,Avium

complex)

Indications or use:

Acute bacterial exacerbations of chronic obstructive pulmonary disease due

to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis

or Streptococcus pneumoniae.

Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus

influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients

appropriate for oral therapy.

Pharyngitis/tonsillitis caused by Streptococcus pyogenes

Uncomplicated skin and skin structure infections due to Staphylococcus

aureus, Streptococcus pyogenes, or Streptococcus agalactiae

Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria

gonorrhoeae.

Genital ulcer disease in men due to Haemophilus ducreyi (chancroid).

Adverse drug reactions:

Mild gastric update, abdominal pain, headach and dizziness, anorexia, dyspepsia,

constipation, photosensistivity

Drug interaction: not administered with theophylline, Carbamazepine, Warefarin,

Terfenadine and cisapride.

Contraindications:

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin,

erythromycin, any macrolide or ketolide antibiotic.

Dose:

Upper and lower respiratory tract and skin and soft tissue infections: 500mg once daily

for 3 days or 500 mg once on day 1, followed by 250 mg once daily for the next 4 days.

Urogenital infection (Chlamydial): 1g as a single dose.

Dosage form:

Azithromycin is available for oral administration as a capsule, tablet, or oral suspension.

http://www.rxlist.com/script/main/art.asp?articlekey=2708









3.4.2. Clarithromycin (10-17):

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-

methylerythromycin. This antibiotic is chemically related to erythromycin and works by

fighting bacteria in your body.

Chemical name: (3R, 4S, 5S, 6R, 7R, 9R, 11R, 12R, 13S, 14R)-6-[(2S,3R,4S,6R)-4-dimethylamino-3-

hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-12,13-dihydroxy-4-[(2R,4R,5S,6S)-5-hydroxy-

4-methoxy-4,6-dimethyloxan-2-yl]oxy-7-methoxy-3,5,7,9,11,13-hexamethyl-1-

oxacyclotetradecane-2,10-dione

Molecular formula: C38H69NO13


Description: Clarithromycin is a white to off-white crystalline powder

Physicochemical data Solubility: It is soluble in acetone, slightly soluble in methanol, ethanol, and

acetonitrile, and practically insoluble in water.

Solubility in water: 0.342 µg/mL

BCS status: BCS Class-II

Polymorphism: Shows polymorphism

Isoelectric Point (pKa): 8.99


Melting point: 190-1930C

Pharmacodynamics:

Clarithromycin is first metabolized to 14-OH clarithromycin. Like other macrolides, it

then binds to the 50 S subunit of the 70 S ribosome of the bacteria, blocking RNA-

mediated bacterial protein synthesis. Clarithromycin also inhibits the hepatic microsomal

CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump.

Pharmacokinetics

Half Life: 3-4 hours

Metabolism: Hepatic(14-OH Clarithromycin)

Drug interaction:



Eletriptan, eplerenone, ergot alkaloids (e.g., ergotamine, dihydroergotamine), ivabradine,

quinupristin-dalfopristin, ranolazine, drugs which may affect the heart rhythm (cisapride,

pimozide) should not be used with the clarithromycin because very serious interactions

may occur.

Indications or uses:

It is used to treat the following:

Pharyngitis

Acute maxillary sinusitis

Acute bacterial exacerbation of chronic bronchitis

Tonsillitis

Pneumonia

Skin and skin structure infections

Used in HIV and AIDS patients to prevent, and treat, disseminated

mycobacterium avium complex or MAC.

It is used in combination with Prilosec in treating H. Pylori bacteria that leads to

stomach ulcers.

Spectrum of Activity:

It is effective against a wide variety of bacteria organisms, like Streptococcus

pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Staphylococcus aureus.

Side effect:

Abnormal taste, diarrhea, indigestion, headache, nausea, stomach discomfort/Severe

stomach pain, vomiting, severe allergic reactions, bloody stools, decreased urination,

depression, confusion Emotional or mood changes, trouble sleeping.

Contraindications/ Safety tips:

Do not use Clarithromycin if you are allergic to any ingredient in Clarithromycin

or any other medicine, foods or other substances.

Safe use in pregnancy has not been established. So do not take this medicine

when you are pregnant or breast feeding.

Tell your doctor if you have diarrhea, a blood disorder, a stomach infection,

severe kidney problems, or liver problems before taking this medicine.

Clarithromycin should not be used in children younger than 6 months old.

Dose: 250mg/500mg

Dosage form:

Film coated tablets, granules.



3.4.3. Roxithromycin (18-22):

Roxithromycin (RTM)—9-{O-[(2-methoxyethoxy)-methyl]-oxime}-erythromycin is a

semi-synthetic, 14-membered ring macrolide antibiotic, in which the erythronolide A

lactone ring has been altered to prevent inactivation in the gastric environment. It has

proven clinical efficacy against some Staphylococcus spp. and many Streptococcus spp.

RTM is a class IV drug has 50% absolute oral bioavailability due to poor aqueous

solubility.

Chemical name:

(3R, 4S, 5S, 6R, 7R, 9R, 11S, 12R, 13S, 14R)-4-[(2,6-Dideoxy-3-Cmethyl-3-O-methyl-α-

L-ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13-trihydroxy-10-[(E)-[(2-

methoxyethoxy)methoxy]imino]-3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-

(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]oxacyclotetradecan-2-one (erythromycin

9-(E)-[O-[(2-methoxyethoxy)methyl]oxime]).

Molecular formula: C41H76N2O15

Molecular weight: 837

Description: White crystalline powder which exhibit polymorphism.

Physicochemical data Solubility: Very slightly soluble in water, freely soluble in alcohol, acetone and

dichloromethane

Solubility in water: 283.23 µg/ml

BCS status: class IV drug

Polymorphism: It shows polymorphism.

Isoelectric point (pKa): 7.0

Melting point: 115- 1200C

Partition coefficient (LogP):2.74

Water content: maximum 3.0 %

Pharmacodynamics:

Roxithromycin prevents bacteria from growing, by interfering with their protein

synthesis. Roxithromycin binds to the subunit 50S of the bacterial ribosome, and thus

inhibits the translocation of peptides. Roxithromycin has similar antimicrobial spectrum



as erythromycin, but is more effective against certain gram-negative bacteria, particularly

Legionella pneumophila.

Pharmacokinetics:

When taken before a meal, roxithromycin is very rapidly absorbed, and diffused into

most tissues and phagocytes. Due to the high concentration in phagocytes, roxithromycin

is actively transported to the site of infection. During active phagocytosis, large

concentrations of roxithromycin are released.

Absorption:

Roxithromycin is rapidly absorbed. The peak serum level is reached within 2.2 hours

after oral administration of 150 mg in the fasting subject. Administration of one tablet 15

minutes before a meal has no effect on the pharmacokinetics in a healthy subject.

Distribution and elimination:

Following administration of a single oral dose of roxithromycin 150 mg to healthy

subjects, mean plasma concentrations ranging from 6.6-7.9 mg/L are reached within 2

hours. The mean concentration (12 hours after administration) is 1.8 mg/L.

The elimination half-life of roxithromycin following administration of 150 mg and 300

mg doses ranges from 8.4 to 15.5 hours.

The half life of roxithromycin is prolonged in the elderly (27 hours); in patients with

impairment of hepatic function (25 hours) and in patients with impairment of renal

function (18 hours).

Tissue distribution:

Roxithromycin is extensively distributed throughout tissues and body fluids.

Maximum concentrations of roxithromycin in pulmonary tissue is 5.6 mg/L

6 hours after administration of 150 mg. Roxithromycin concentrations in bronchoalveolar

lavage cells were 2 and 10 times higher than corresponding levels in plasma and

epithelial fluid, respectively.

Plasma protein binding:

It is reported to be about 96% bound to plasma protein (mainly alpha1-acid glycoprotein)

at trough concentrations, but binding is saturable and only 86% is bound at usual peak

concentrations.

Metabolism:

Roxithromycin is only partially metabolised, more than half the parent compound being

excreted unchanged. Three metabolites have been identified in urine and faeces: the

major metabolite is descladinose roxithromycin, with N-mono and N-di-demethyl

roxithromycin as minor metabolites. The respective percentage of roxithromycin and

these three metabolites is similar in urine and faeces.

Excretion:

It is mainly excreted in faeces 72 hours after oral administration of 14C labelled

roxithromycin, urinary radioactivity is only 12% of total excreted radioactivity (urine and

faeces).Most of roxithromycin is secreted unchanged into the bile and some in expired

air. Under 10% is excreted into the urine. Roxithromycin's half-life is 12 hours.

Indications or Uses:

Roxithromycin is indicated for use in the treatment of mild to moderate infections of the

ear, nose and throat, respiratory tract, in the skin and skin structure and genito-urinary

tract caused by susceptible strains of organisms listed below:



Pharyngitis, tonsillitis, sinusitis and otitis media, due to Group A beta-haemolytic

Streptococci and Streptococcus pneumoniae.

Pneumonia and acute bronchitis due to Streptococcus pneumoniae.

Atypical pneumonia due to Mycoplasma pneumoniae.

Pyoderma and erysipelas due to Staphylococcus aureus and Group A beta-

haemolytic Streptococci.

Non-gonococcal urethritis in men, due to Chlamydia trachomatis and Ureaplasma

urealyticum.

Side effects:

Most common side effects are gastrointestinal; diarrhoea, nausea, abdominal pain and

vomiting. Less common side effects include central or peripheral nervous system events

such as headaches, dizziness, vertigo, and also the rarely seen rashes, abnormal liver

function values and alteration in senses of smell and taste.

Drug interaction:

Roxithromycin has less interaction than erythromycin as it has a lower affinity for

cytochrome P450.Roxithromycin does not interact with hormonal contraceptives,

prednisolone, carbamazepine, ranitidine or antacids. When roxithromycin is administered

with theophylline, some studies have shown an increase in the plasma concentration of

theophylline.

Dose:

150 mg one tablet by mouth 12 hourly, before meals

Dosage form available:

Roxithromycin is commonly available as tablets or oral suspension.



3.4.4. Erythromycin Base (23-28):

Erythromycin is a macrolide antibiotic produced from a strain of Saccharopolyspora

erythraea (formerly Streptomyces erythreus). It is a base and readily forms salts with

acids. Erythromycin is a polyhydroxylactone that contains two sugars. The aglycone

portion of the molecule, erythranolide, is a 14-membered lactone ring. An amino sugar,

D-desosamine, is attached through a β-glycosidic linkage to the C-5 position of the

lactone ring. The tertiary amine of desosamine confers a basic character to erythromycin

(pK 8.8). Through this group, a number of acid salts of the antibiotic have been prepared.

A second sugar, L- cladinose, which is unique to erythromycin, is attached via a β-

glycosidic linkage to the C-3 position of the lactone ring.

Chemical structure:

[(3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-[(2,6- dideoxy-3-C-methyl-

3-O-methyl-a- L-ribo-hexopyranosyl)-oxy]-14- ethyl-7,12,13-trihydroxy- 3,5,7,9,11,13-

hexa-methyl-6-[ [3,4,6-trideoxy-3-(dimethylamino)-b-D- xylo-hexopyranosyl]

oxy]oxacyclotetradecane-2,10- dione].

Molecular formula: C37H67NO13


Description: It is a white crystalline powder Physicochemical data

Solubility: slightly soluble in water, soluble in alcohol, chloroform, and in ether

Solubility in water: 1.44 mg/L

BCS status: BCS Class-II

Polymorphism: Erythromycin exist in several solid forms, including solvates,

anhydrate, and amorphous solid, but in commerce erythromycin is usually

available as the dihydrate

The transformation of erythromycin dehydrate to either erythromycin anhydrate

or amorphous erythromycin requires a high activation energy, whereas

transformation to its isomorphic dehydrate requires a much smaller activation

energy and can occur at low relative humidity. Conversion of erythromycin

dehydrate to these forms may influence the manufacturing process, dissolution

rate, storage stability and bioavailability of the achieved product – e.g. the






formation to erythromycin dehydrate in a tablet containing also magnesium

hydroxide leads to a slower dissolution rate.

PKa/Isoelectric point: 8.88

Melting point: 190-1930C


Pharmacodynamics:

Erythromycin acts by penetrating the bacterial cell membrane and reversibly binding to

the 50 S subunit of bacterial ribosomes or near the ―P‖ or donor site so that binding of

tRNA (transfer RNA) to the donor site is blocked. Translocation of peptides from the ―A‖

or acceptor site to the ―P‖ or donor site is prevented, and subsequent protein synthesis is

inhibited.

Pharmacokinetics:

Orally administered erythromycin base and its salts are readily absorbed in the

microbiologically active form. After absorption, erythromycin diffuses readily into most

body fluids. In the absence of meningeal inflammation, low concentrations are normally

achieved in the spinal fluid, but the passage of the drug across the blood-brain barrier

increases in meningitis. Erythromycin is excreted in breast milk. The drug crosses the

placental barrier, but fetal plasma levels are low. Erythromycin is not removed by

peritoneal dialysis or hemodialysis. Erythromycin is largely bound to plasma proteins,

and the freely dissociating bound fraction after administration of erythromycin base

represents 90% of the total erythromycin absorbed. Extensively metabolized in liver after

oral administration, less than 5% of the administered dose can be recovered in the active

form in the urine.

Half Life: 1.5 hours

Spectrum of Activity:

Respiratory tract infections (upper and lower) of mild to moderate degree,

pertussis (whooping cough),

As adjunct to antitoxin in infections due to Corynebacterium diphtheriae,

In the treatment of infections due to Corynebacterium minutissimum,

Intestinal amebiasis caused by Entamoeba histolytica,

Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae,

Skin and soft tissue infections of mild to moderate severity caused by

Streptococcus pyogenes and Staphylococcus aureus,

Primary syphilis caused by Treponema pallidum,

Infections caused by Chlamydia trachomatis,

Nongonococcal urethritis caused by Ureaplasma urealyticum,

Legionnaires' disease caused by Legionella pneumophila.

Indications/Uses: It is used to treat the following:

Bronchitis

Legionnaires' disease (streptococcal pneumoniae, mycoplasma pneumoniae, and

legionella pneumophila)

Diphtheria

Whooping cough (pertussis)

Pneumonia

Venereal disease (VD)



Rheumatic fever

Lung infection (pneumonias)

Ear, urinary tract, intestine, and skin infections.

It is also used before some surgery or dental work to prevent infection.

Dose:

250mg, 500mg

Dosage form:

Available as capsule, tablet, long-acting capsule/tablet, chewable tablet, liquid, and

pediatric drops

Side effects:

Diarrhea

Vomiting

Wheezing

Skin rash

Itching

Hives

Pale stools

Upset stomach

Difficulty

swallowing

Stomach cramps

Dark urine

Unusual

tiredness

Vaginal infection



3.5. Excipients and polymers profile:

3.5.1. Polymers: a) Polymethacrylates (29):

Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl

methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several

different types are commercially available and may be obtained as the dry powder, as an

aqueous dispersion, or as an organic solution.

Table: 3.4. Solubility, permeability profile of used Eudragit and their application.

Type Solubility /permeability Application

Eudragit E 100 Soluble in gastric fluid to pH 5 Film coating

Eudragit L 100 Soluble in intestinal fluid from pH 6 Enteric coatings

Eudragit S 100 Soluble in intestinal fluid from pH 7 Enteric coatings

Eudragit RS 100 Low permeability Sustained release

Eudragit RL PO Low permeability Sustained release

Eudragit RS PO Low permeability Sustained release

Eudragit L100-55 Soluble in intestinal fluid from pH 7 Enteric coatings

1) Eudragit S100 and Eudragit L100:

Eudragit L-100 and Eudragit S-100 are white free-flowing powders with at least 95% of

dry polymers. Eudragit L 100 and Eudragit S 100 are anionic copolymers based on

methacrylic acid and methyl methacrylate. The ratio of the free carboxyl groups to the

ester groups is ≈ 1:1 in Eudragit L 100 and 1:2 in Eudragit S 100. They are white

powders with a faint characteristic odour. 1 g of Eudragit L 100 or Eudragit S 100

dissolves in 7 g methanol, ethanol, in aqueous isopropyl alcohol and acetone (containing

≈ 3 % water), as well as in 1 N sodium hydroxide to give clear to slightly cloudy

solutions. Eudragit L 100 and Eudragit S 100 are practically insoluble in ethyl acetate,

methylene chloride, petroleum ether and water.

2) Eudragit-RLPO and Eudragit-RSPO:

Eudragit RL PO and Eudragit RS PO are fine, white powders with a slight amine-like

odor.They are characteristically the same polymers as Eudragit RL and RS. They contain

≥97% of dry polymer.

3) Eudragit E100:

Eudragit E is used as a plain or insulating film former; it is soluble in gastric fluid below

PH 5.0. Eudragit E 100 is a cationic copolymer based on dimethylaminoethyl

methacrylate and neutral methacrylic esters. It is colourless to yellow tinged granules

with a characteristic amine-like odour. One gram of Eudragit E 100 dissolves in 7 g

methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, methylene chloride or 1 N

hydrochloric acid to give clear to slightly cloudy solutions. The solid substance is

practically insoluble in petroleum ether and water.

4) Eudragit RL and Eudragit RS:

Eudragit RL and Eudragit RS, also referred to as ammoniomethacrylate copolymers in

the USPNF 23 monograph, are copolymers synthesized from acrylic acid and methacrylic

acid esters, with Eudragit RL (Type A) having 10% of functional quaternary ammonium

groups and Eudragit RS (Type B) having 5% of functional quaternary ammonium groups.

The ammonium groups are present as salts and give rise to pH-independent permeability

of the polymers. Both polymers are water-insoluble, and films prepared from Eudragit



RL are freely permeable to water, whereas, films prepared from Eudragit RS are only

slightly permeable to water. They are available as 12.5% ready-to-use solutions in

propan-2-ol–acetone (60: 40). Solutions are colorless or slightly yellow in color, and may

be clear or slightly turbid; they have an odor characteristic of the solvents. Solvent-free

granules (Eudragit RL 100 and Eudragit RS 100) contain ≥97% of the dried weight

content of the polymer.

5) Eudragit L 100-55:

It is prepared by spray-drying Eudragit L 30 D-55.It is white, free-flowing powder that is

redispersible in water to form a latex that has properties similar to those of Eudragit L 30

D-55.It is soluble in acetone, alcohol and 1N NaOH and insoluble in dichloromethane,

ethyl acetate,perolium ether and water.

b) Glyceryl monostearate (30):

It is a white to cream-colored, waxlike solid in the form of beads, flakes, or powder. It is

waxy to the touch and has a slight fatty odor and taste. It is soluble in hot ethanol, ether,

chloroform, hot acetone, mineral oil, and fixed oils. Practically insoluble in water, but

may be dispersed in water with the aid of a small amount of soap or other surfactant. The

many varieties of glyceryl monostearate are used as nonionic emulsifiers, stabilizers,

emollients, and plasticizers in a variety of food, pharmaceutical, and cosmetic

applications. It acts as an effective stabilizer, that is, as a mutual solvent for polar and

nonpolar compounds that may form water-in-oil or oil-in-water emulsions. These

properties also make it useful as a dispersing agent for pigments in oils or solids in fats,

or as a solvent for phospholipids, such as lecithin. It has also been used in a novel

fluidized hot-melt granulation technique for the production of granules and tablets. It is a

lubricant for tablet manufacturing and may be used to form sustained-release matrices for

solid dosage forms.

c) Hydroxypropylmethyl cellulose (31):

It is odorless and tasteless, white or creamy-white fibrous or granular powder. It is

soluble in cold water, forming a viscous colloidal solution; practically insoluble in

chloroform, ethanol (95%), and ether, but soluble in mixtures of ethanol and

dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and

alcohol. It is used as Emulsifying agent, suspending agent and stabilizer.

In oral products, it is primarily used as a tablet binder, in film-coating, and as a matrix for

use in extended-release tablet formulations. Concentrations between 2% and

5% w/w may be used as a binder in either wet- or dry-granulation processes. High-

viscosity grades may be used to retard the release of drugs from a matrix at levels of 10–

80% w/w in tablets and capsules. Depending upon the viscosity grade, concentrations of

2–20% w/w are used for film-forming solutions to film-coat tablets. Lower-viscosity

grades are used in aqueous film-coating solutions, while higher-viscosity grades are used

with organic solvents. Examples of film coating materials that are commercially available

include AnyCoat C, Spectracel, and Pharmacoat.

It is also used as a suspending and thickening agent in topical formulations. Compared

with methylcellulose, HPMC produces aqueous solutions of greater clarity, with fewer

undispersed fibers present, and is therefore preferred in formulations for ophthalmic use.

HPMC at concentrations between 0.45–1.0% w/w may be added as a thickening agent to

vehicles for eye drops and artificial tear solutions.HPMC is also used as an emulsifier,

suspending agent, and stabilizing agent in topical gels and ointments. As a protective



colloid, it can prevent droplets and particles from coalescing or agglomerating, thus

inhibiting the formation of sediments. In addition, hypromellose is used in the

manufacture of capsules, as an adhesive in plastic bandages, and as a wetting agent for

hard contact lenses. It is also widely used in cosmetics and food products.

d) Hydroxypropyl cellulose (32):

Hydroxypropyl cellulose is a white to slightly yellow-colored, odorless and tasteless

powder. Hydroxypropyl cellulose as partially substituted poly (hydroxypropyl) ether of

cellulose. It may contain not more than 0.6% of silica or another suitable anticaking

agent. Hydroxypropyl cellulose is commercially available in a number of different grades

that have various solution viscosities. Molecular weight has a range of 50 000–1 250 000.

In oral products, HPC is primarily used in tableting as a binder, filmcoating, and

extended-release-matrix former. Concentrations of HPC of 2–6% w/w may be used as a

binder in either wet-granulation or dry, direct-compression tableting processes.

Concentrations of 15–35% w/w of HPC may be used to produce tablets with an extended

drug release. The release rate of a drug increases with decreasing viscosity of HPC.

The addition of an anionic surfactant similarly increases the viscosity of hydroxypropyl

cellulose and hence decreases the release rate of a drug. Typically, a 5% w/w solution of

HPC may be used to filmcoat tablets. Aqueous solutions containing HPC along with an

amount of methyl cellulose or ethanolic solutions have been used. Low-substituted HPC

is used as a tablet disintegrants and also used in microencapsulation processes and as a

thickening agent. In topical formulations, HPC is used in transdermal patches and

ophthalmic preparations. HPC is also used in cosmetics and in food products as an

emulsifier and stabilizer.

e) Chitosan (33):

Chitosan occurs as odorless, white or creamy-white powder or flakes. Fiber formation is

quite common during precipitation and the chitosan may look 'cottonlike'.

Chitosan produces by Partial deacetylation of chitin, which is a polysaccharide

comprising copolymers of glucosamine and N-acetylglucosamine. Chitosan is the term

applied to deacetylated chitins in various stages of deacetylation and depolymerization

and it is therefore not easily defined in terms of its exact chemical composition. A clear

nomenclature with respect to the different degrees of N-deacetylation between chitin and

chitosan has not been defined, and as such chitosan is not one chemical entity but varies

in composition depending on the manufacturer. In essence, chitosan is chitin sufficiently

deacetylated to form soluble amine salts. The degree of deacetylation necessary to obtain

a soluble product must be greater than 80–85%. Chitosan is commercially available in

several types and grades that vary in molecular weight by 10000–1000000, and vary in

degree of deacetylation and viscosity.

Chitosan is used in cosmetics and is under investigation for use in a number of

pharmaceutical formulations. These include controlled drug delivery applications, use as

a component of mucoadhesive dosage forms, rapid release dosage forms, improved

peptide delivery, colonic drug delivery systems, and use for gene delivery. Chitosan has

been processed into several pharmaceutical forms including gels, films, beads,

microspheres, tablets, and coatings for liposomes. Furthermore, chitosan may be

processed into drug delivery systems using several techniques including spraydrying,

coacervation, direct compression, and conventional granulation processes.



3.5.2. Stabilizers: The introduction of proper amount of stabilizers probably polymers into the distilled

water to prevent the coalescence of the droplets.

a) Polyvinyl Pyrrolidone (Povidone-K30)(34):

Povidone occurs as a fine, white to creamy-white colored, odorless or almost odorless,

hygroscopic powder. Povidones with K-values equal to or lower than 30 are

manufactured by spray-drying and occur as spheres. Povidone K-90 and higher K-value

povidones are manufactured by drum drying and occur as plates. It is synthetic polymer

consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of

polymerization of which results in polymers of various molecular weights. It is

characterized by its viscosity in aqueous solution, relative to that of water, expressed as a

K-value, in the range 10–120.

It is primarily used in solid-dosage forms. In tableting, povidone solutions are used as

binders in wet-granulation processes. Povidone is also added to powder blends in the dry

form and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions.

Povidone is used as a solubilizer in oral and parenteral formulations and has been shown

to enhance dissolution of poorly soluble drugs from solid-dosage forms.Povidone

solutions may also be used as coating agents.Povidone is additionally used as a

suspending, stabilizing, or viscosity-increasing agent in a number of topical and oral

suspensions and solutions. The solubility of a number of poorly soluble active drugs may

be increased by mixing with povidone.

b) Polyethylene Glycol-6000(35):

It is 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. Polyethylene glycols are now days used to enhance the aqueous

solubility or dissolution characteristics of poorly soluble compounds by making solid

dispersions with an appropriate polyethylene glycol. It has also been used in

microparticles and nanoparticles for the oral delivery of drugs to improve the oral

bioavailability.

Polyethylene glycols have the following disadvantages:

They are chemically more reactive than fats;

The rate of release of water-soluble medications decreases with the increasing

molecular weight of the polyethylene glycol;

Plyethylene glycols tend to be more irritating to mucous membranes than fats.

c) Polyvinyl Alcohol (PVA) (36):

It is odourless and tasteless, translucent, white or cream colored granular powder. It is

soluble in water, slightly soluble in ethanol, but insoluble in other organic solvents. It is

completely water soluble and thus used as a thickener in some suspensions and

emulsions. Typically a 5% solution of polyvinyl alcohol exhibits a pH in the range of 5.0

to 6.5. Polyvinyl alcohol has a melting point of 180 to 190°C. It has a molecular weight

of between 26,300 and 30,000, and a degree of hydrolysis of 86.5 to 89%. However, the

melting point of the crystallites is above the thermal degradation temperature.

As a component of tablet coating formulations intended for products including food

supplement tablets, Polyvinyl alcohol protects the active ingredients from moisture,

oxygen and other environmental components, while simultaneously masking their taste

and odor. It allows for easy handling of finished product and facilitates ingestion and



swallowing. The viscosity of Polyvinyl alcohol allows for the application of the

Polyvinyl alcohol coating agents to tablets, capsules and other forms to which film

coatings are typically applied at relatively high solids contents.

It is used as a stabilizing agent for emulsions (0.25–3.0% w/v). Polyvinyl alcohol is also

used as a viscosity-increasing agent for viscous formulations such as ophthalmic

products. It is used in artificial tears and contact lens solutions for lubrication purposes, in

sustained release formulations for oral administration, and in transdermal patches.

Polyvinyl alcohol may be made into microspheres when mixed with a glutaraldehyde

solution.

D) Poloxamers (37):

Poloxamers generally occur as white, waxy, free-flowing prilled granules, or as cast

solids. They are practically odorless and tasteless.Poloxamers are nonionic triblock

copolymers composed of a central hydrophobic chain of polyoxypropylene (poly

(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene

oxide)).Poloxamers are nonionic polyoxyethylene–polyoxypropylene copolymers used

primarily in pharmaceutical formulations as emulsifying or solubilizing agents. The

polyoxyethylene segment is hydrophilic while the polyoxypropylene segment is

hydrophobic. All of the poloxamers are chemically similar in composition, differing only

in the relative amounts of propylene and ethylene oxides added during manufacture.

Their physical and surface-active properties vary over a wide range and a number of

different types are commercially available.Poloxamers are used as emulsifying agents in

intravenous fat emulsions, and as solubilizing and stabilizing agents to maintain the

clarity of elixirs and syrups. Poloxamers may also be used as wetting agents; in

ointments, suppository bases, and gels; and as tablet binders and coatings.

Poloxamer 188 has also been used as an emulsifying agent for fluorocarbons used as

artificial blood substitutes and in the preparation of solid-dispersion systems. More

recently, poloxamers have found use in drug-delivery systems. Therapeutically,

poloxamer 188 is administered orally as a wetting agent and stool lubricant in the

treatment of constipation; it is usually used in combination with a laxative such as

danthron. Poloxamers may also be used therapeutically as wetting agents in eye-drop

formulations, in the treatment of kidney stones, and as skin-wound cleansers.

Poloxamer 407 is a hydrophilic non-ionic surfactant of the more general class of

copolymers known as poloxamers. Poloxamer 407 is a triblock copolymer consisting of a

central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of

polyethylene glycol. Most of the common uses of poloxamer 407 are related to its

surfactant properties. For example, it is widely used in cosmetics for dissolving oily

ingredients in water. It can also be found in multi-purpose contact lens cleaning solutions,

where its purpose there is to help remove lipid films from the lens. It can also be found in

some mouthwashes.

e) Beta Cyclodextrin (38):

A non-reducing cyclic saccharide consisting of seven alpha-1, 4-linked D-glucopyranosyl

units manufactured by the action of cyclodextrin transglycolase on hydrolysed starch

followed by purification of the ß-cyclodextrin; purification is by preparation of a ß-

cyclodextrin/solvent inclusion compound followed by steam-stripping of the solvent

before final purification. It is sparingly soluble in water; freely soluble in hot water;

slightly soluble in ethanol. The molecular structure of Cyclodextrins approximates a



truncated cone with a hydrophilic exterior surface and a non-polar interior cavity.

Because of this feature, Cyclodextrins can form inclusion complexes with drug molecules

resulting in some changes in the physicochemical properties of guest molecules such as

solubility and stability. One of the most important applications of Cyclodextrins is

enhancing the solubility of poorly water-soluble drugs by complex formation.

Cyclodextrins were successfully employed as protective stabilizers of the prepared

dispersions. This stabilizing effect is possibly attributed to the formation of Cyclodextrins

network by intermolecular interaction of Cyclodextrins molecules that could prevent

aggregation of formed droplents in dispersion medium.

Beta-cyclodextrin is most widely used complexing agent for inclusion type complexes. It

is sweet, nontoxic, cyclic oligosacchride obtained from starch. In inclusion complex

formation, the drug molecule fits into the cavity of a complexing agent i.e., the host

molecule forming a stable complex. The complexing agent is capable of masking the

bitter taste of the drug by either decreasing its oral solubility on ingestion or decreasing

the amount of drug particles exposed to taste buds thereby reducing the perception of

bitter taste.

F) Carbopol (39):

Carbopols are white-colored, ‗fluffy‘, acidic, hygroscopic powders with a slight

characteristic odor. These are acrylic acid polymers crosslinked with polyalkenyl

polyethers or divinyl glycol. Although these polymers are very mild acids - weaker than

acetic acid - they readily react with alkali to form salts. Aqueous dispersions of Carbopol

polymers have an approximate pH range of 2.8 to 3.2 depending on polymer

concentration. The greater the concentration, the higher the carboxyl concentration and,

therefore, the lower the pH.

A molecule of these polymers in the dry powder state is tightly coiled, thus limiting its

thickening capability. When dispersed in water, the molecule begins to hydrate and

uncoil slightly, generating an increase in viscosity. However, to achieve the highest

possible performance with the polymer, the molecule must be completely uncoiled. There

are two mechanisms by which the molecule can become completely uncoiled, providing

maximum thickening, emulsion formation and stabilization, or bioadhesion performance.

The most commonly used mechanism is accomplished by neutralizing the polymer with a

suitable base. Neutralization ionizes the Carbopol polymer, generating negative charges

along the polymer backbone. Repulsions of the like negative charges cause the molecule

to completely uncoil into an extended structure. This reaction is rapid and results in

efficient performance. This is readily done with sodium or potassium hydroxide or amine

bases such as Tris(r) (tris (hydroxymethyl) aminomethane). Less polar or non polar

solvent systems should be neutralized only with amines.

A second thickening mechanism involves the use of a hydroxyl donor. The combination

of a carboxyl group and one or more hydroxyl donors will result in thickening because of

the formation of hydrogen bonds. This mechanism is time dependent and can take from

five minutes to several hours to attain maximum thickening. The pH of such systems will

tend to be acidic. Some commonly used hydroxyl donors are polyols (glycerine,

propylene glycol, PEGs etc.), sugar alcohols (mannitol, sorbitol etc.), non-ionic

surfactants with 5 or more ethoxy groups and others.

Carbomers are mainly used in liquid or semisolid pharmaceutical formulations as

suspending or viscosity-increasing agents. Formulations include creams, gels, and



ointments for use in ophthalmic, rectal, and topical preparations.Carbomers are also

employed as emulsifying agents in the preparation of oil-in-water emulsions for external

use. For this purpose, the carbomer is neutralized partly with sodium hydroxide and

partly with a long-chain amine such as stearylamine. Carbomer 951 has been investigated

as a viscosity-increasing aid in the preparation of multiple emulsion microspheres.

g) Xanthan gum (40):

Xanthan gum occurs as a cream- or white-colored, odorless, freeflowing; fine powder.

Xanthan gum is widely used in oral and topical pharmaceutical formulations, cosmetics,

and foods as a suspending and stabilizing agent. It is also used as a thickening and

emulsifying agent. It is nontoxic, compatible with most other pharmaceutical ingredients,

and has good stability and viscosity properties over a wide pH and temperature range.

Xanthan gum gels show pseudoplastic behavior, the shear thinning being directly

proportional to the shear rate. The viscosity returns to normal immediately on release of

shear stress. Xanthan gum has been used as a suspending agent for conventional, dry and

sustained-release suspensions.

It is a high molecular weight polysaccharide gum. It contains D-glucose and D-mannose

as the dominant hexose units, along with D-glucuronic acid, and is prepared as the

sodium, potassium, or calcium salt. Each xanthan gum repeat unit contains five sugar

residues: two glucose, two mannose, and one glucuronic acid. The polymer backbone

consists of four b-D-glucose units linked at the 1 and 4 positions, and is therefore

identical in structure to cellulose.

h) Hydroxy Ethyl cellulose (41):

HEC occurs as a light tan or cream to white-colored, odorless and tasteless, hygroscopic

powder. Soluble in water, forming clear, smooth, uniform solutions. Practically insoluble

in acetone, ethanol (95%), ether, toluene, and most other organic solvents. It is used as

Coating agent; suspending agent; tablet binder; thickening agent; viscosity-increasing

agent. HEC is a nonionic, water-soluble polymer widely used in pharmaceutical

formulations. It is primarily used as a thickening agent in ophthalmic1 and topical

formulations, although it is also used as a binder3 and film-coating agent for tablets. It is

present in lubricant preparations for dry eye, contact lens care, and dry mouth. The

concentration of HEC used in a formulation is dependent upon the solvent and the

molecular weight of the grade.

i) Colloidal silicon dioxide (Aerosil) (42):

Colloidal silicon dioxide is submicroscopic fumed silica with a particle size of about 15

nm. It is a light, loose, bluish-white-colored, odorless, tasteless, nongritty amorphous

powder. It is mostly used as Adsorbent; anticaking agent; emulsion stabilizer; glidant;

suspending agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent in

Pharmaceutical Formulation. 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.

These are having particles with high porosity and specific surface area. When introduced

in the formulation of agglomerates they avoid the coalescence of the droplets and act as

drug dispersion agent closely packed in the agglomerates.



3.5.3. Super disintegrants: a) Sodium starch glycolate (43): Sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch. The

molecular weight is typically 500 000-11 000 000.It is very fine, white or off white, free

flowing powder; odourless or almost odourless. Practically insoluble in water, insoluble

in most organic solvents.

Sodium starch glycolate is widely used in oral pharmaceuticals as a disintegrant in

capsule and tablet formulations. It is recommended to use in tablets prepared by either

direct-compression or wet-granulation processes. The recommended concentration in a

formulation is 2-8%, with the optimum concentration about 4% although in many cases

2% is sufficient. Disintegration occurs by rapid uptake of water followed by rapid and

enormous swelling. The disintegrant efficiency of sodium starch glycolate is unimpaired

in the presence of hydrophobic excipients, such as lubricants unlike many other

disintegrants.Sodium starch glycolate has also been investigated for use as a suspending

vehicle.

b) Croscarmellose Sodium (44):

It is odorless, white or grayish-white powder.Croscarmellose sodium is a crosslinked

polymer of carboxymethylcellulose sodium.Croscarmellose sodium is used in oral

pharmaceutical formulations as a disintegrant for Capsules, tablets and granules. In tablet

formulations, croscarmellose sodium may be used in both direct-compression and wet-

granulation processes. When used in wet granulations, the croscarmellose sodium should

be added in both the wet and dry stages of the process (intra- and extragranularly) so that

the wicking and swelling ability of the disintegrant is best utilized. In a concentrations up

to 5% w/w may be used as a tablet disintegrant, although normally 2% w/w is used in

tablets prepared by direct compression and 3% w/w in tablets prepared by a wet-

granulation process.

c) Crospovidone (Polyplsdone XL-10) (45):

Crospovidone is a white to creamy-white, finely divided, free-flowing, practically

tasteless, odorless or nearly odorless, hygroscopic powder. It is compressible powder,

synthetic homopolymer of cross-linked N-vinyl-2-pyrrolidone. Completely insoluble in

water, acids, alkalis, and all organic solvents. It is Hygroscopic. Swells rapidly in water.

Rapidly disperses in water, but does not gel even after prolonged exposure.

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.



3.6. References:

1. Turner S, Ravishankar J, Fassihi R. Method for improving the bioavailability of

orally delivered therapeutics. USPTO patent Applicaton: 20060068010.

2. Gandhi R, Pillai O, Thilagavathi R, Gopalakrishnan B , Kaula CL Panchagnulaa

R(2002)Characterization of Azithromycin hydrates. Eur. J.Pharm. Sci. 16; 175–

184.

3. Kremer CJ (2002) Azithromycin—A New Macrolide.9 (5); 174-175.

4. Zhao M, You Y, Ren Y, Zhang Y, Tang X (2008) Formulation, characteristics

and aerosolization performance of azithromycin DPI prepared by spray-drying.

Powder Technology. 187; 214–221.

5. Niederman MS (2005) Introduction International Journal of Antimicrobial

Agents. 26 (3); S141 S142.

6. www.rxlist.com/cgi/generic/Azithromycin.htm.

7. www.medicinenet.com/Azithromycin/article.htm.

8. http://www.drugbank.ca/drugs/Azithromycin.

9. http://en.wikipedia.org/wiki/Azithromycin

10. Yonemochi E, Kitahara S, Maeda S, Yamamura S, Oguchi T, Yamamotoa

K(1999)Physicochemical properties of amorphous clarithromycin obtained by

grinding and spray drying. Eur.J.Pharm. Sci.7; 331–338.

11. Salem II, Duzgunes N (2003) Efficacies of cyclodextrin-complexed and liposome

encapsulated clarithromycin against Mycobacterium avium complex infection in

human macrophages Int.J. Pharm. 250; 403-414.

12. Inoue Y, Yoshimura S , Tozuka Y, Moribe K, Kumamoto T, Ishikawa T,

Yamamoto K (2007)Application of ascorbic acid 2-glucoside as a solubilizing

agent for clarithromycin: Solubilization and nanoparticle formation. Int. J.Pharm.

331; 38–45.

13. Turner S, Ravishankar J, Fassihi R Method for improving the bioavailability of

orally delivered therapeutics. USPTO Applicaton: 20060068010 - Class:

424469000 (USPTO).

14. www.rxlist.com/cgi/generic/Clarithromycin.htm.

15. www.medicinenet.com/c/Clarithromycin/article.htm.

16. http://www.drugbank.ca/drugs/Clarithromycin

17. http://en.wikipedia.org/wiki/Clarithromycin

18. Biradar SV, Patil AR, Sudarsan GV, Pokharkar VB (2006) A comparative study

of approaches used to improve solubility of roxithromycin. Powder Technology.

169; 22–32.

19. www.rxlist.com/cgi/generic/Roxithromycin.htm.

20. www.medicinenet.com/c/Roxithromycin/article.htm.

21. http://www.drugbank.ca/drugs/Roxithromycin

22. http://en.wikipedia.org/wiki/Roxithromycin

23. Kanfer I, Skinner MF, Walker RB (1998) Analysis of macrolide antibiotics.

Journal of Chromatography A. 812; 255–286.

24. Romer M, Heinamaki J, Miroshnyk I, Sandler N, Rantanen J, Yliruusi J(2007)

Phase transformations of erythromycin A dihydrate during pelletisation and

drying., Eur. J.Pharm. and Biopharm. 67; 246–252.

25. www.rxlist.com/cgi/generic/Roxithromycin.htm.

http://www.rxlist.com/cgi/generic/Azithromycin.htm

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http://www.drugbank.ca/drugs/Azithromycin.

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http://www.rxlist.com/cgi/generic/Clarithromycin.htm

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26. www.medicinenet.com/c/Roxithromycin/article.htm.

27. http://www.drugbank.ca/drugs/Erythromycin

28. http://en.wikipedia.org/wiki/Erythromycin.

29. Rowe RC, Sheskey PJ, Quinn ME. (2006) Polymethacrylates In: Handbook of

Pharmaceutical Excipients, 6th ed, Pharmaceutical Press, London, UK, p. 525.

30. Rowe RC, Sheskey PJ, Quinn ME. (2006) Glyceryl Monostearate In: Handbook

of Pharmaceutical Excipients, 6th ed, Pharmaceutical Press, London, UK, p. 290.

31. Rowe RC, Sheskey PJ, Quinn ME. (2006) Hypromellose In: Handbook of


32. Rowe RC, Sheskey PJ, Quinn ME. (2006) Hydroxypropyl Cellulose In:

Handbook of Pharmaceutical Excipients, 6th ed, Pharmaceutical Press, London,

UK, p. 317.

33. Rowe RC, Sheskey PJ, Quinn ME. (2006) Chitosan In: Handbook of


34. Rowe RC, Sheskey PJ, Quinn ME. (2006) Povidone In: Handbook of


35. Rowe RC, Sheskey PJ, Quinn ME. (2006) Polyethylene Glycol In: Handbook of


36. Rowe RC, Sheskey PJ, Quinn ME. (2006) Polyvinyl Alcohol In: Handbook of


37. Rowe RC, Sheskey PJ, Quinn ME. (2006) Poloxamer In: Handbook of


38. Rowe RC, Sheskey PJ, Quinn ME. (2006) Cyclodextrins In: Handbook of


39. Rowe RC, Sheskey PJ, Quinn ME. (2006) Carbomer In: Handbook of


40. Rowe RC, Sheskey PJ, Quinn ME. (2006) Xanthin gum In: Handbook of


41. Rowe RC, Sheskey PJ, Quinn ME. (2006) Hydroxyethyl Cellulose In: Handbook


42. Rowe RC, Sheskey PJ, Quinn ME. (2006) Colloidal Silicon Dioxide In:

Handbook of Pharmaceutical Excipients, 6th ed, Pharmaceutical Press, London,

UK, p. 185.

43. Rowe RC, Sheskey PJ, Quinn ME. (2006) Sodium Starch Glycolate In: Handbook


44. Rowe RC, Sheskey PJ, Quinn ME. (2006) Croscarmellose sodim In: Handbook of


45. Rowe RC, Sheskey PJ, Quinn ME. (2006) Crospovidone In: Handbook of


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http://en.wikipedia.org/wiki/

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Instrument, Chemicals, Excipients & API - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/9995/8/08_chapter 3.pdf · 15 Ethanol Loba chemicals 16 Eosin Y reagent Loba chenie Pvt.Ltd,Mumbai