Formulation of Doxycline

CONTENTS

S.No. TITLE PAGE No.

1.0 INTRODUCTION 04

1.1 FORMULATION OF TABLETS 04

1.2 FILM COATING 11

1.3 ICH GUIDELINES ON STABILITY STUDY 18

2.0 OBJECTIVE OF WORK 22

2.1 PLAN OF WORK 24

3.0 DRUG SPECIFIC REVIEW 25

3.1 LITERATURE REVIEW 26

3.2 EXCIPIENTS PROFILE 32

4.0 MATERIALS & METHODS 63

4.1 LIST OF EQUIPMENTS 63

4.2 LIST OF INGREDIENTS 64

4.3 SELECTION OF EXCIPIENTS 65

4.4 EVALUATION OF MARKET SAMPLE 66

4.5OUTLINE OF MANUFACTURING PROCEDURE & OUTLINE OF COATING PROCEDURE

67

4.6 PRE COMPRESSION PARAMETER 69

4.6.1 LOSS ON DRYING 69

4.6.2 BULK DENSITY 69

4.6.3 TAPPED DENSITY 69

4.6.4 COMPRESSIBILITY INDEX 70

4.6.5 SIEVE ANALYSIS 70

S.No. TITLE PAGE No.

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4.7 POST COMPRESSION PARAMETER 71

4.7.1 DESCRIPTION 72

4.7.2 WEIGHT VARIATION TEST 72

4.7.3 HARDNESS 73

4.7.4 FRIABILITY 73

4.7.5 DISINTEGRATION TEST 75

4.7.6 IN-VITRO DISSOLUTION STUDY 75

4.7.7 ASSAY 77

5.0 RESULTS AND DISCUSSION 78

5.1 MANUFACTURING OF TRIALS 78

5.2 EVALUATION OF MARKET SAMPLE 80

5.3 INCOMPATIBILITY STUDIES 82

5.4 FORMULATION OF DOXYCYCLINE HYCLATE

TABLETS

84

5.5 EVALUATION OF DOXYCYCLINE HYCLATE

TABLETS & GRANULES

87

5.6 COMPARATIVE DISSOLUTION STUDY FOR

DOXYCYCLINE HYCLATE TABLET

89

5.7 STABILITY STUDY 90

6.0 SUMMARY AND CONCLUSION 91

7.0 BIBLIOGRAPHY 92

LIST OF ABBREVATIONS USED

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API - Active Pharmaceutical Ingredient

CTD - Common Technical Document

BCS - Biopharmaceutics Classification System

NDA - New Drug Application

USP - United States Pharmacopoeia

HPLC - High Performance Liquid Chromatography

UV - UltraViolet

No - Number

g - Gram

ml - milliliter

IPA - Isopropyl Alcohol

JP - Japan Pharmacopoeia

Ph Euro - European Pharmacopoeia

oC - Degree Celsius

mm - millimeter

FDA - Food & Drug Administration

UK - United Kingdom

# - Mesh Number (Size)

DT - Disintegration

RT - Room Temperature

RH - Relative Humidity

e.g. - Example

1.0 INTRODUCTION:

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Doxycycline Hydrochloride is (4S, 4aR, 5S, 5aR, 6R, 12aS) -4-dimethylamino-1,

4, 4a, 5, 5a, 6, 11, 12a – octahydro – 3, 5, 10, 12, 12a – pentahydroxy – 6 - methyl -1, 11

– dioxonaphthacene – 2 - carboxamide hydrochloride hemiethanolate hemihydrate,

antimicrobial substance obtained from oxytetracycline or methacycline or by any other

means .

Doxycycline Hyclate tablets contains equivalent of not less than 90% and not more

than 120% of the labeled amount of Doxycycline .

Monograph of Doxycycline is official in IP, BP & USP, where as tablet dosage

form is official in USP only. It is available in 100 & 200 mg tablet dosage form. Apart

from tablets it is available in capsules, dispersible tablets and modified release capsules.

1.1 FORMULATION OF TABLETS:

Tablets are solid unit dosage form of medicaments with or without suitable

diluents and prepared either by molding or compression. They are solid, flat or biconvex

disc in shape. They vary greatly in shape, size and weight which depend upon amount of

medicament used and mode of administration. They also vary in hardness, thickness,

disintegration and dissolution characteristics and in other aspects depending upon their

intended use and method of manufacture. Tablets are the most widely used solid dosage

form of medicament. Because of their advantages their popularity is continuously

increasing day by day.

Tablets are solid unit dosage form of medicaments with or without suitable

diluents and prepared either by molding or compression. They are solid, flat or biconvex

disc in shape. They vary greatly in shape, size and weight which depend upon amount of

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medicament used and mode of administration. They also vary in hardness, thickness,

disintegration and dissolution characteristics and in other aspects depending upon their

intended use and method of manufacture. Tablets are the most widely used solid dosage

form of medicament. Because of their advantages their popularity is continuously

increasing day by day.

TYPES AND CLASSES OF TABLETS

(A) Oral tablet for ingestion

1. Compressed tablets

2. Multiple compressed tablets

3. Delayed action tablets

4. Sugar coated

5. Film coated tablets

6. Chewable tablets

(B) Tablet used in oral cavity

1. Buccal tablets

2. Sublingual tablets

3. Troches and Lozenges

4. Dental cones

(C) Tablet administered by other routes

1. Implantation tablets

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2. Vaginal tablets

(D) Tablets used to prepare solution

1. Effervescent tablets

2. Dispensing tablets

3. Hypodermic tablets

4. Tablet triturates

PROPERTIES OF AN IDEAL TABLET

The objective of formulation and fabrication of tablet is to deliver the correct amount of

drug in proper form at or over proper time.

1. Tablet should be elegant having its own identity and free from defects such as

cracks, chips, contamination, discoloration etc.

2. It should have chemical and physical stability to maintain its physical integrity

over time.

3. It should be capable to prevent any alteration in the chemical and physical

properties of medicinal agent(s).

4. It should be capable of withstanding the rigors of mechanical shocks encountered

in its production, packaging, shipping and dispensing.

5. An ideal tablet should be able to release the medicament(s) in body in predictable

and reproducible manner.

COMMONLY USED EXCIPIENTS IN TABLET MANUFACTURING

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Substances other than active ingredients are commonly referred as excipients. The

commonly used exipients are diluents, binders and adhesives, disintegrants, lubricants,

anti adherents, glidants, fillers, colors and sweeteners etc. Tablet excipients must meet

certain criteria in the formulation such as;

• They must be non toxic and acceptable to the regulatory agencies in all countries

where the product is to be marketed

• They must be commercially available in an acceptable grade in all countries where

the product is to be manufactured.

• Their cost must be acceptably low

• They must be physiologically inert.

• They must be physically and chemically stable by themselves and in combination

with the drug (s) and other tablet components.

• They must be free of any unacceptable microbiologic load.

• They must be color compatible ( not producing any off-color appearance)

• If the drug product is also classified as a food (e.g. certain vitamins products), the

diluents and other exipient must be approved direct to food additives.

• They must have no any deleterious effect on the bioavailability of the drug(s) in

the product.

DILUENTS

These are the inert substances which are added to increase the bulk to make the

tablet of a practical size for compression. Diluents like mannitol, lactose, sorbitol,

sucrose, and inositol when present in sufficient quantity can impart properties to some

compressed tablet that permit disintegration in the mouth by chewing ( Chewable tablet ).

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In the formulation, the incompatibility of diluents must be considered (Calcium salts used

as diluents for the broad spectrum antibiotics like Tetracycline have been shown to

interfere with the drug absorption from GIT. Microcrystalline cellulose (Avicel®) usually

is used as an excipient in direct compression formula. Hydroxyl propyl methyl cellulose

is used to prolong the release from tablet and as a film former in tablet coating.

BINDERS

Binders are the agents generally used to impart cohesive qualities to the powdered

material. In tablet formulation the diluents ensures that the tablet remains intact after

compression. It improves free flow qualities by formulation of granules of desired

hardness and size. Starch, gelatin, sucrose, glucose, dextrose and lactose are frequently

used as binders. Natural and synthetic gums that have been used include acacia, sodium

alginate, panwar gum, ghatti gum, CMC, veegum etc. Starch paste in varying

concentration from 10-20% are used as a binder. HPMC which is more soluble in cold

water as compared to hot water is also used in special cases. Excessive use of binder in

the tablet may lead to prolong disintegration time which is not desired. Therefore they are

used in prescribed concentration to overcome the same.

LUBRICANTS

Lubricants are the substance which prevent adhesion of the tablet material to the

surface of the dies and punches, reduce interparticle friction, facilitate an easy ejection of

tablets from the die cavity and improves rate of flow of tablet granulation. Commonly

used lubricants are talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated

8

vegetable oil and PEG. The method of adding lubricant is an important factor for

satisfactory results. The quantity of lubricant significantly varies from 0.1 to 5%. The

additions of lubricant to granules in the form of emulsion or suspension are used to

reduce the processing time. The primary problem in the preparation of water soluble

tablet is the selection of satisfactory lubricant. Soluble lubricants include Sodium

benzoate, sodium acetate, sodium chloride and carbowax 4000.

GLIDANTS

A glidant is a substance that improves the flow characteristics of a powder mixture.

These materials are always added in the dry state just prior to compression. The most

commonly used glidants are colloidal silicon dioxide (Cabosil®, Cabot®) and asbestos

free talc. They are used in concentration less than 1%. Talc is also used and may serve

the dual purpose of lubricant/glidant.

DISINTEGRANTS

Disintegrants are the substance or a mixture of substances added to a tablet to

facilitate its break up or disintegration after administration. Starches, clays, cellulose and

cross linked polymers are most commonly used disintegrants. The oldest and still the

most popular disintegrants are corn and potato starch. Other ingredients like veegum,

methyl cellulose, agar, bentonite, cellulose, citrus pulp and CMC are also used. They are

mostly added into two portions, one part is added prior to granulation and the remainder

is mixed with the lubricant and finally both are mixed just before the compression.

COLOURING AGENTS

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Colors in compressed tablet are used to impart aesthetic appearance to the dosage

form. Colour helps the manufacturer to control the product during its preparation as well

as serves as a means of identification to the user. One of the basic requirements

concerning the use of colorant in pharmaceuticals is it must be approved and certified by

the FDA. Colourants can be used in solution form or in suspension form. Pproper

distribution of suspended colourants in the coating solution requires the use of the

powdered colourants (<10 microns). Most commonly used colourants in use are certified

FD & C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for

sugar or film coating as they give reproducible results. Concentration of colourants in the

coating solutions depends on the colour shade desired, the type of dye, and the

concentration of opaquant-extenders. If very light shade is desired, concentration of less

than 0.01 % may be adequate on the other hand, if a dark colour is desired a

concentration of more than 2.0 % may be required. The inorganic materials (e.g. iron

oxide) and the natural colouring materials (e.g. anthrocyanins, carotenoids, etc) are also

used to prepare coating solution. Magenta red dye is non absorbable in biologic system

and resistant to degradation in the gastro intestinal tract. Flavouring agents Flavours are

usually limited to chewable tablets or other tablets intended to dissolve in the mouth. In

general flavours that are water soluble have been found little acceptance in manufacturing

of tablets because of there poor stability. Flavouring agents do not affect any physical

characteristics of the tablet granulation.

METHOD OF TABLET PREPARATION

There are three general methods of tablet preparation.

1. Direct compression method

2. Dry granulation method

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3. Wet granulation method

1.2 FILM COATING

Film coating is deposition of a thin film of polymer surrounding the tablet core.

Conventional pan equipments may be used but now a day’s more sophisticated

equipments are employed to have a high degree of automation and coating time. The

polymer is solubilized into solvent. Other additives like plasticizers and pigments are

added. Resulting solution is sprayed onto a rotated tablet bed. The drying conditions

cause removal of the solvent, giving thin deposition of coating material around each

tablet core.

BASIC PROCESS REQUIREMENTS FOR FILM COATING

The fundamental requirements are independent of the actual type of equipments

being used and include adequate means of atomizing the spray liquid for application to

the tablet core, adequate mixing and agitation of tablet bed, sufficient heat input in the

form of drying air to provide the latent heat of evaporation of the solvent. This is

particularly important with aqueous-based spraying and good exhaust facilities to remove

dust and solvent laden air.

DEVELOPMENT OF FILM COATING FORMULATIONS

If the following questions are answered concomitantly then one can go for film coating:

Colour, shape and size of final coated tablet are important for marketing and these

properties have a significant influence on the marketing strategies. An experienced

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formulator usually takes the pragmatic approach and develops a coating formulations

modification of one that has performed well in the past. Spraying or casting films can

preliminarily screen film formulations. Cast films cab is prepared by spreading the

coating composition on teflon, glass or aluminum foil surface using a spreading bar to get

a uniform film thickness. Sprayed films can be obtained by mounting a plastic-coated

surface in a spray hood or coating pan.

COATING FORMULA OPTIMIZATION

Basic formula is obtained from past experience or from various sources in the

literature. Modifications are required to improve adhesion of the coating to the core, to

decrease bridging of installations, to increase coating hardness, etc. Usually concentration

of colorant and opaquant are fixed to get predetermined shade. Common modification is

to alter polymer-to-plasticizer ratio or addition of different plasticizer/ polymer.

Experimentation of this type can be best achieved by fractional factorial study.

MATERIALS USED IN FILM COATING

I.Film formers, which may be enteric or nonenteric

II.Solvents

III.Plasticizers

IV.Colourants

V.Opaquant-Extenders

VI. Miscellaneous coating solution components

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I.FILM FORMERS

Ideal requirements of film coating materials are summarized below:

i) Solubility in solvent of choice for coating preparation

ii) Solubility requirement for the intended use e.g. free water-solubility, slow water-

solubility or pH -dependent solubility

iii) Capacity to produce an elegant looking product

iv) High stability against heat, light, moisture, air and the substrate being coated

v) No inherent colour, taste or odor

vi) High compatibility with other coating solution additives

vii) Nontoxic with no pharmacological activity

viii) High resistance to cracking

ix) Film former should not give bridging or filling of the debossed tablet

x) Compatible to printing procedure

Commonly used film formers are as follow

i.HYDROXY PROPYL METHYL CELLULOSE (HPMC)

It is available in different viscosity grades. It is a polymer of choice for air suspension

and pan spray coating systems because of solubility characteristic in gastric fluid, organic

and aqueous solvent system. Advantages include: it does not affect tablet disintegration

and drug availability, it is cheap, flexible, highly resistant to heat, light and moisture, it

has no taste and odor, colour and other additives can be easily incorporated.

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Disadvantage includes: when it is used alone, the polymer has tendency to bridge or fill

the debossed tablet surfaces. So mixture of HPMC and other polymers/ plasticizers is

used.

ii.METHYL HYDROXY ETHYL CELLULOSE (MHEC)

It is available in wide variety of viscosity grades. It is not frequently used as HPMC

because soluble in fewer organic solvents.

iii. ETHYL CELLULOSE (EC)

Depending on the degree of ethoxy substitution, different viscosity grades are available.

It is completely insoluble in water and gastric fluids. Hence it is used in combination with

water-soluble additives like HPMC and not alone. Unplasticized ethyl cellulose films are

brittle and require film modifiers to obtain an acceptable film formulation. Aqua coat is

aqueous polymeric dispersion utilizing ethyl cellulose. These pseudolatex systems

contain high solids, low viscosity compositions that have coating properties quite

different from regular ethyl cellulose solution.

iv.HYDROXY PROPYL CELLULOSE (HPC)

It is soluble in water below 40oc (insoluble above 45 oC), gastric fluid and many polar

organic solvents. HPC is extremely tacky as it dries from solution system. It is used for

sub coat and not for colour or glass coat. It gives very flexible film.

v. POVIDONE

Degree of polymerization decides molecular weight of material. It is available in four

viscosity grades i.e. K-15, K-30, K-60 and K-90. Average molecular weight of these

grades is 10000, 40000, 160000 and 360000 respectively. K-30 is widely used as tablet

binder and in tablet coating. It has excellent solubility in wide variety of organic solvents,

water, gastric and intestinal fluids. Povidone can be cross-linked with other materials to

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produce films with enteric properties. It is used to improve dispersion of colourants in

coating solution.

vi. SODIUM CARBOXY METHYL CELLULOSE

It is available in medium, high and extra high viscosity grades. It is easily dispersed in

water to form colloidal solutions but it is insoluble in most organic solvents and hence

not a material of choice for coating solution based on organic solvents. Films prepared by

it are brittle but adhere well to tablets. Partially dried films of are tacky. So coating

compositions must be modified with additives.

viii. POLYETHYLENE GLYCOLS (PEG)

Lower molecular weights PEG (200-600) are liquid at room temperature and are used as

plasticizers. High molecular weights PEG (900-8000series) are white, waxy solids at

room temperature. Combination of PEG waxes with CAP gives films that are soluble in

gastric fluids.

ix. ACRYLATE POLYMERS

E is cationic. EudragitIt is marketed under the name of Eudragit E is freely soluble in

gastric fluid up to pH 5 andco-polymer. Only Eudragit expandable and permeable

above pH 5. This material is available as organic solution (12.5% in

isopropanol/acetone), solid material or 30% aqueous RLdispersion. Eudragit & RS are

co-polymers with low content of quaternary ammonium groups. These are available only

as organic solutions and solid materials. They produce films for delayed action (pH

dependent).

II. SOLVENTS

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Solvents are used to dissolve or disperse the polymers and other additives and convey

them to substrate surface.

Ideal requirement are summarized below:

i) Should be either dissolve/disperse polymer system

ii) Should easily disperse other additives into solvent system

iii) Small concentration of polymers (2-10%) should not in an extremely viscous solution

system creating processing problems

iv) Should be colourless, tasteless, odorless, inexpensive, inert, nontoxic and

nonflammable

v) Rapid drying rate

vi) No environmental pollution

Mostly solvents are used either alone or in combination with water, ethanol, methanol,

isopropanol, chloroform, acetone, methylene chloride, etc. Water is more used because

no environmental and economic considerations. For drugs that readily hydrolyze in

presence of water, non aqueous solvents are used.

III. PLASTICIZERS

As solvent is removed, most polymeric materials tend to pack together in 3-D honey

comb arrangement. “Internal” or “External” plasticizing technique is used to modify

quality of film. Combination of plasticizer may be used to get desired effect.

Concentration of plasticizer is expressed in relation to the polymer being plasticized.

Recommended levels of plasticizers range from 1-50 % by weight of the film former.

Commonly used plasticizers are castor oil, PG, glycerin, lower molecular weight (200-

400 series), PEG, surfactants, etc. For aqueous coating PEG and PG are more used while

castor oil and spans are primarily used for organic-solvent based coating solution.

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External plasticizer should be soluble in the solvent system used for dissolving the film

former and plasticizer. The plasticizer and the film former must be at least partially

soluble or miscible in each other.

IV. COLOURANTS

Colourants can be used in solution form or in suspension form. To achieve proper

distribution of suspended colourants in the coating solution requires the use of the

powdered colourants (<10 microns). Most common colourants in use are certified FD &

C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for sugar or

film coating as they give reproducible results. Concentration of colourants in the coating

solutions depends on the colour shade desired, the type of dye, and the concentration of

opaquant-extenders. If very light shade is desired, concentration of less than 0.01 % may

be adequate on the other hand, if a dark colour is desired a concentration of more than 2.0

% may be required. The inorganic materials (e.g. iron oxide) and the natural colouring

materials (e.g. anthrocyanins, carotenoids, etc) are also used to prepare coating solution.

Magenta red dye is non absorbable in biologic system and resistant to degradation in the

gastro (opaque colour concentrate for film coating) andintestinal track. Opasray

(complete film coating concentrate) are promoted as achieving lessOpadry lot-to-lot

colour variation.

V. OPAQUANT-EXTENDERS

These are very fine inorganic powder used to provide more pastel colours and increase

film coverage. These inorganic materials provide white coat or mask colour of the tablet

core. Colourants are very expensive and higher concentration is required. These inorganic

materials are cheap. In presence of these inorganic materials, amount of colourants

required decreases. Most commonly used materials are titanium dioxide, silicate (talc

&aluminum silicates), carbonates (magnesium carbonates), oxides (magnesium oxide) &

hydroxides (aluminum hydroxides). Pigments were investigated in the production of

17

opaque films and it was found that they have good hiding power and film-coated tablets

have highlighted intagliations.

1.3 ICH GUIDELINES ON STABILITY STUDY

The following guideline is a revised version of the ICH Q1A guideline and

defines the stability data package for a new drug substance or drug product that is

sufficient for a registration application within the three regions of the EC, Japan,

and the United States. It does not seek necessarily to cover the testing for

registration in or export to other areas of the world.

The guideline seeks to exemplify the core stability data package for new

drug substances and products, but leaves sufficient flexibility to encompass the

variety of different practical situations that may be encountered due to specific

scientific considerations and characteristics of the materials being evaluated.

Alternative approaches can be used when there are scientifically justifiable

reasons.

SCOPE OF THE GUIDELINE

The guideline addresses the information to be submitted in registration

applications for new molecular entities and associated drug products. This

guideline does not currently seek to cover the information to be submitted for

abbreviated or abridged applications, variations, clinical trial applications, etc.

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Specific details of the sampling and testing for particular dosage forms in their

proposed container closures are not covered in this guideline.

Further guidance on new dosage forms and on biotechnological/biological

products can be found in ICH guidelines Q1C and Q5C, respectively.

GENERAL PRINCIPLES

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

a drug substance or drug product varies with time under the influence of a variety

of environmental factors such as temperature, humidity, and light, and to establish

a re-test period for the drug substance or a shelf life for the drug product and

recommended storage conditions.

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

analysis of the effects of climatic conditions in the three regions of the EC, Japan

and the United States. The mean kinetic temperature in any part of the world can

be derived from climatic data, and the world can be divided into four climatic

zones, I-IV. This guideline addresses climatic zones I and II.

The principle has been established that stability information generated in any

one of the three regions of the EC, Japan and the United States would be mutually

acceptable to the other two regions, provided the information is consistent with this

guideline and the labeling is in accord with national/regional requirements.

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STRESS TESTING

Stress testing of the drug substance can help identify the likely degradation

products, which can in turn help establish the degradation pathways and the

intrinsic stability of the molecule and validate the stability indicating power of the

analytical procedures used. The nature of the stress testing will depend on the

individual drug substance and the type of drug product involved.

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

substance. It should include the effect of temperatures (in 10°C increments (e.g.,

50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or

greater) where appropriate, oxidation, and photolysis on the drug substance. The

testing should also evaluate the susceptibility of the drug substance to hydrolysis

across a wide range of pH values when in solution or suspension. Photostability

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

photostability testing are described in ICH Q1B.

Examining degradation products under stress conditions is useful in

establishing degradation pathways and developing and validating suitable

analytical procedures. However, it may not be necessary to examine specifically

for certain degradation products if it has been demonstrated that they are not

formed under accelerated or long term storage conditions.

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

provided to regulatory authorities.

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SELECTION OF BATCHES

Data from formal stability studies should be provided on at least three

primary batches of the drug substance. The batches should be manufactured to a

minimum of pilot scale by the same synthetic route as, and using a method of

manufacture and procedure that simulates the final process to be used for,

production batches. The overall quality of the batches of drug substance placed on

formal stability studies should be representative of the quality of the material to be

made on a production scale.

TESTING FREQUENCY

For long-term studies, frequency of testing should be sufficient to establish

the stability profile of the drug substance. For drug substances with a proposed re-

test period of at least 12 months, the frequency of testing at the long term storage

condition should normally be every 3 months over the first year, every 6 months

over the second year, and annually thereafter through the proposed re-test period.

At the accelerated storage condition, a minimum of three time points,

including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month

study is recommended. Where an expectation (based on development experience)

exists that results from accelerated studies are likely to approach significant change

criteria, increased testing should be conducted either by adding samples at the final

time point or by including a fourth time point in the study design.

When testing at the intermediate storage condition is called for as a result of

significant change at the accelerated storage condition, a minimum of four time

points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a

12-month study is recommended.

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STORAGE CONDITIONS

In general, a drug substance should be evaluated under storage conditions

(with appropriate tolerances) that test its thermal stability and, if applicable, its

sensitivity to moisture. The storage conditions and the lengths of studies chosen

should be sufficient to cover storage, shipment, and subsequent use.

The long term testing should cover a minimum of 12 months’ duration on at

least three primary batches at the time of submission and should be continued for a

period of time sufficient to cover the proposed re-test period. Additional data

accumulated during the assessment period of the registration application should be

submitted to the authorities if requested. Data from the accelerated storage

condition and, if appropriate, from the intermediate storage condition can be used

to evaluate the effect of short term excursions outside the label storage conditions

(such as might occur during shipping).

Long term, accelerated, and, where appropriate, intermediate storage

conditions for drug substances are detailed in the sections below. The general case

applies if the drug substance is not specifically covered by a subsequent section.

Alternative storage conditions can be used if justified.

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2.0 OBJECTIVE OF WORK

The objective of this work is formulation and evaluation of Doxycycline Hyclate

Tablets, which comprises of

* Literature Survey

* Innovator Product Characteristics

* Preformulation Studies

* Formulation development of core tablets

* Analysis of Trials

* Coating of final formula

* Comparative Study

* Stability study of final formula

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2.1 PLAN OF WORK

Literature Collection

Evaluation of Market Sample

Selection of Excipients

Formulation of Doxycycline Hyclate tablets

Evaluation of Doxycycline Hyclate tablets

Pre-compression Characteristics Post-compression Characteristics

% Water Content Thickness

Bulk Density Hardness

Tapped Density Friability

Compressibility Index Weight variation

Sieve analysis In-vitro dissolution study

Assay

Stability study

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3.0 DRUG PROFILE

DOXYCYCLINE HYCLATE

Category: Anti bacterial

Dosage forms available Tablets, Capsules, Modified release capsules

Physico – chemical properties

Dose

Description A yellow crystalline powder, hygroscopic.

Solubility Freely soluble in water and methyl alcohol. Practically insoluble in chloroform and ether.

Standard

pH 2.0 to 3.0 in solution contains 10mg of Doxycycline per ml

Water 1.4% to 2.8%

Molecular Weight 512.94

Molecular Formula & Chemical Name

C22H24HClN2O8½ C2H6O.½ H2ODoxycycline hydrochloride hemi ethanolate hemi hydrate

Melting Point 110CLoss On Drying NMT 0.5%

Pharmacokinetics

Route of administration Oral

Absorption Completely absorbed

T max 2.6g / ml

t½ 12 to 24 Hours

Effect of food Food does not affected the extent and absorption

Plasma protein binding 80 to 95%

Metabolism at Liver

Excretion Through facieses

US Innovator Product Observations

Vibramycin

Storage Store in air tight containers

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3.1 LITERATURE REVIEW

Edward B. Breitschwerdt, et.al, experimented Doxycycline Hyclate in the

treatment of Canine Ehrlichiosis Followed by Challenge Inoculation with two

Ehrlichia canis Strains dogs were experimentally inoculated with Ehrlichia canis

Florida to assess the efficacy of doxycycline hyclate for the treatment of acute

ehrlichiosis. Treatment with doxycycline eliminated infection in eight of eight dogs.

Untreated infected control dogs appeared to eliminate the infection or, alternatively,

suppress the degree of ehrlichiemia to a level not detectable by tissue culture

isolation or PCR or by transfusion of blood into recipient dogs. Prior infection did

not infer protection against homologous (strain Florida) or heterologous (strain

NCSU Jake) strains of E. canis. We conclude that doxycycline hyclate is an

effective treatment for acute E. canis infection; however, these results may not be

applicable to chronic infections in nature. Spontaneous resolution of infection,

induced by the dog's innate immune response, provides evidence that an E. canis

vaccine, once developed, might potentially confer protective immunity against the

organism.

Meijer LA, et.al. performed Pharmacokinetics and bioavailability of

doxycycline hyclate after oral administration in calves in which the bioavailability

and pharmacokinetics of doxycycline hyclate were determined in calves with

immature rumen function. The bioavailability of doxycycline after oral

administration in a milk replacer was approximately 70%. The elimination half-life

of doxycycline was found to be 9.5 +/- 3.0 h. after intravenous administration, and

12.6 +/- 5.0 h. after single oral administration. Plasma concentrations were

determined after repeated oral administration of doxycycline dissolved in a milk

replacer, at a dose of 5 mg per kg body weight, twice daily. During the period of

26

administration, the plasma concentrations varied between Cmin of 1.0 +/- 0.19

mg/L and Cmax of 2.3 +/- 0.19 mg/L.

Stoller NH, et. al, experimented the pharmacokinetic profile of a

biodegradable controlled-release delivery system containing doxycycline hyclate

compared to systemically delivered doxycycline in gingival crevicular fluid, saliva,

and serum.

The primary goal of this study was to characterize the release profile of doxycycline

hyclate (8.5% w/w) from a biodegradable controlled-release delivery system (DH)

placed in periodontal pockets. Pharmacokinetic data were obtained from gingival

crevicular fluid (GCF), saliva, and serum of adult periodontitis patients. These

results were compared to those obtained from individuals who received standard

oral doses of doxycycline hyclate (200 mg on day 0, then 100 mg/day for 7 days).

All participants presented with multiple pockets > or = 5 mm that bled upon

probing. At the baseline visit patients receiving local drug delivery had all pockets >

or = 5 mm that bled upon probing on one side of the mouth filled with DH. Drug

retention was enhanced with 1 of 2 periodontal dressings (non-eugenol [NE] or 2-

octyl cyanoacrylate [2-octyl]). Doxycycline concentrations were analyzed with the

aid of reverse phase high performance liquid chromatography. GCF saliva, and

serum samples were obtained just prior to drug delivery and then at hours 2, 4, 6, 8,

18, 24 and days 2, 3, 5, 7, and 8. GCF and saliva samples were also obtained at days

10, 14, 21, and 28. Thirty two subjects participated in the study; 13 in the NE group,

13 in the 2-octyl group, and 6 in the group taking oral doxycycline. The release of

doxycycline in the GCF peaked at 2 hours (1473 microg/ml in the NE group, and

1986 microg/ml in the 2-octyl group). The mean concentration at day 7 was 309

microg/ml for the NE group and 148 microg/ml for the 2-octyl group. Minimal

levels of drug were detected in the GCF of the oral doxycycline group with a peak

27

concentration of 2.53 microg/ml at 12 hours. Salivary concentrations for both local

delivery groups peaked at hour 2 (4.05 microg/ml for the NE group and 8.78

microg/ml for the 2-octyl group); by the end of day 1 levels were < or = 2

microg/ml. For subjects who took the oral doxycycline, salivary concentrations

never exceeded 0.11 microg/ml. Serum concentrations of doxycycline for

individuals receiving the local drug delivery never exceeded 0.1 microg/ml. For the

oral doxycycline group serum concentrations ranged from 0.91 to 2.26 microg/ml

over the 8 days data were collected. The high concentration of drug available at the

treated sites coupled with the relatively low levels in the saliva and almost non-

existent levels in the serum indicate that this biodegradable controlled-release

delivery system displays an appropriate pharmacokinetic profile for the delivery of

doxycycline into periodontal pockets

Monica L. Dumont et. al., investigated about probability of passing

dissolution criteria for immediate release tablets. During development of solid

dosage products, a pharmaceutical manufacturer is typically required to propose

dissolution criteria unless the product false into Biopharmaceutics Classification

System (BCS) Class1, in which case disintegration test may be used. At the time of

filing the new drug application (NDA) or common technical document (CTD), the

manufacture has already met with regulatory agencies to discuss and refine

dissolution strategy. The dissolution acceptance criteria are based on stability and

batch history data and are often arrived at by considering the percentage of batches

that pass United States Pharmacopeias (USP) criteria at Stage 1(S1), when in fact,

the product is deemed unacceptable only when a batch fails USP criteria at Stage 3

(S3).Calculating the probability of passing (or failing) dissolution criteria at S1, S2,

or S3 can assist a manufacturer in determining appropriate acceptance criteria. The

article discusses a general statistical method that was developed to assess the

28

probability of passing the multistage USP test for dissolution and how it was

applied to an immediate release tablet formulation. In this case, acceptance criteria

were set and the analysis was conducted to assess the probabilities of passing or

failing based on this acceptance criterion. Whether the acceptance criteria were

relevant to the product was also considered. This mathematical approach uses a

Monte Carlo simulation and considers a range of values for standard deviation and

mean of historical data

Riond JL., et.al, investigated Comparative pharmacokinetics of doxycycline

hyclate in cats and dogs.in which disposition of doxycycline hyclate was studied in

six adult mixed-breed female cats and six adult mid-sized female dogs following a

single intravenous administration of 5 mg/kg body weight. Doxycycline volume of

the central compartment, area volume of distribution, volume of distribution at

steady state, and total body clearance were significantly smaller in cats. The

differences were attributed to more extensive binding of doxycycline to plasma

protein including albumin in cats. The significant differences in the volume of

distribution and total body clearance were not reflected in elimination half-lives

under the conditions of this study (sample size, inhomogeneous population).

Doxycycline elimination half-life was 4.56 +/- 0.68 (SEM) h for cats and 6.99 +/-

1.09 h for dogs. Dosage regimens recommended in the veterinary literature were

evaluated by the computer program PETDR.

Zeidner NS, et. al, performed the formulation of doxycycline hyclate for

prophylaxis of tick bite infection in a murine model of Lyme borreliosis.The

prophylactic potential of a single injection of doxycycline hyclate (Atridox) was

compared to that of a single oral dose of doxycycline hyclate in a murine model of

Lyme borreliosis. Prophylaxis, as measured by the lack of cultivable spirochetes and

demonstrable pathology, was noted for 43% of orally treated mice; in contrast, the

29

release characteristics of doxycycline hyclate completely protected mice from

infection and resultant pathology.

Alsarra IA, et, al, Comparared the bioavailability study of doxycycline

hyclate (equivalent to 100 mg doxycycline) capsules (doxycin vs vibramycin) for

bioequivalence evaluation in healthy adult volunteers which was carried out to

evaluate the bioavailability of a new capsule formulation of doxycycline (100 mg),

doxycin, relative to the reference product, vibramycin (100 mg) capsules. The

bioavailability was carried out in 24 healthy male volunteers who received a single

dose (100 mg) of the test (A) and the reference (B) products after an overnight fast

of at least 10 hours on 2 treatment days. The treatment periods were separated by a

2-week washout period. A randomized, balanced 2-way cross-over design was used.

After dosing, serial blood samples were collected for a period of 48 hours. Plasma

concentrations of doxycycline were analyzed by a sensitive and validated high-

performance liquid chromatography assay. The pharmacokinetic parameters for

doxycycline were determined using standard noncompartmental methods. The

parameters AUC(0-t), AUC(0-infinity), Cmax, K(el), t(1/2) and Cmax/AUC(0-

infinity) were analyzed statistically using log-transformed data. The time to

maximum concentration (tmax) was analyzed using raw data. The parametric 90%

confidence intervals of the mean values of the pharmacokinetic parameters: AUC(0-

t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were within the range 80-

125% which is acceptable for bioequivalence (using log-transformed data). The

calculated 90% confidence intervals based on the ANOVA analysis of the mean

test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-

infinity) were 95.98-109.56%, 92.21 to 107.66%, 93.90-112.56%, and 96.0 to

106.91% respectively. The test formulation was found bioequivalent to the

reference formulation with regard to AUC(0-t), AUC(0-infinity), Cmax and

30

Cmax/AUC(0-infinity) by the Schuirmann's two 1-sided t-tests. Therefore, the 2

formulations were considered to be bioequivalent.

Vargas-Estrada D, et. al, performed Pharmacokinetics of doxycycline and

tissue concentrations of an experimental long-acting parenteral formulation of

doxycycline in Wistar rats.which shows that antibacterial with time-dependent

action, was formulated as a non-irritating long-acting parenteral formulation based

on a beta-cyclodextrin: poloxamer-based matrix (doxycycline-h-LA). Tissue and

serum concentrations vs time profile were investigated after its subcutaneous

injection to Wistar rats. Serum concentration profiles and key pharmacokinetic (PK)

variables of doxycycline-h-LA were compared to the corresponding profiles and PK

values obtained with an aqueous formulation of doxycycline-h administered either

intramuscularly, orally or intravenously to Wistar rats. In all groups, the dose was

10 mg/kg. Doxycycline-h-LA showed outstanding bioavailability (951% or 477% if

a correction formula is considered), as compared to the one obtained with an

aqueous formulation (106-82%, respectively). Corresponding values for maximum

serum concentration were 3.19 microg/ml and 3.00 microg/ml, respectively, and

elimination half-lives were completely different: 42.49 h and 2.77 h for

doxycycline-h-LA and the aqueous formulation, respectively. Considering minimal

inhibitory concentrations of doxycycline for sensitive and resistant bacteria (from <

or = 0.5 to > or =1.5 microg/ml), doxycycline-h-LA could be injected every 2 or 3

days, while aqueous doxycycline-h would require a dosing interval from 7.5 to 11 h.

But if tissue concentrations are taken as braking points, the dosing interval will vary

from 48 to 94 h. For doxycycline-h-LA, mean tissue:serum ratios were 2:1 for

lungs, 9.8:1 for kidneys and 2.2:1 for intestine homogenates. These values are in

close agreement with those found for the distribution of doxycycline in other

species.

31

3.2 EXCIPIENTS PROFILE

MICROCRYSTALLINE CELLULOSE

Synonyms:

Avicel, Cellulose gel, crystalline cellulose, E460, Emocel, Fibrocel,

Tabulose, Vivacel.

Functional category:

Tablet and Capsule diluent, suspending agent, adsorbent and tablet

disintegrant.

Applications:

As a diluent in tablets (wet granulation and direct compression) and capsule

formulation. It also has some lubricant and disintegrant property.

Description:

White-colored, tasteless crystalline powder composed of porous particles. It

is commercially available in different particle sizes and moisture grades. That

have different properties and application.

Solubility:

Slightly soluble in 5 % w/v NaOH solution, practically insoluble in water,

dilute acids and most organic solvents.

Stability:

It is a stable, though hygroscopic material.

32

Storage conditions:

The bulk material should be stored in a well-closed container in a cool, dry,

place.

Incompatibilities:

Incompatible with strong oxidizing agents.

Safety:

It is generally regarded as a nontoxic and nonirritant material

pH:

Between 5.5 and 8.0

Loss on drying:

Not more than 10.0%, determined on 0.5 g by drying in an oven at 105o

MAGNESIUM STEARATE

Magnesium Stearate consists mainly of magnesium stearate (C17H35CO2)2Mg

with variable proportions of magnesium palmitate, (C15H31CO2)2Mg and

magnesium oleate, (C17H33CO2)2Mg.

Category:

Pharmaceutical aid (lubricant).

Description:

Very fine, light, white powder; odourless or with a very faint odour of

stearic acid; unctuous and free from grittiness.

33

Solubility:

Practically insoluble in water, ethanol and ether.

STANDARDS

Magnesium Stearate contains not less than 3.8 per cent and not more than

5.0 per cent of Mg, calculated with reference to the dried substance.

Loss on drying:

Not more than 6.0%, determined on 1 g by drying in an oven at 105o.

ISOPROPYL ALCOHOL

NONPROPRIETARY NAMES BP: ISOPROPYL ALCOHOL

JP: Isopropanol

PhEur: Alcohol isopropylicus

USP: Isopropyl alcohol

Synonyms

Dimethyl carbinol; IPA; isopropanol; petrohol; 2-propanol; sec-propyl

alcohol.

Chemical Name and CAS Registry Number

Propan-2-ol [67-63-0]

Empirical Formula and Molecular Weight

C3H8O 60.1

34

STRUCTURAL FORMULA

Functional Category

Disinfectant; solvent.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Isopropyl alcohol (propan-2-ol) is used in cosmetics and pharmaceutical

formulations primarily as a solvent in topical formulations. It is not recommended

for oral use owing to its toxicity.

Although it is used in lotions, the marked degreasing properties of isopropyl

alcohol may limit its usefulness in preparations used repeatedly. Isopropyl alcohol

is also used as a solvent both for tablet film-coating and for tablet granulation,

where the isopropyl alcohol is subsequently removed by evaporation. It has also

been shown to significantly increase the skin permeability of nimesulide from

carbomer 934.

Isopropyl alcohol has some antimicrobial activity and a 70% v/v aqueous

solution is used as a topical disinfectant. Therapeutically, isopropyl alcohol has

been investigated for the treatment of postoperative nausea or vomiting.

Description

Isopropyl alcohol is a clear, colorless, mobile, volatile, flammable liquid

with a characteristic, spirituous odor resembling that of a mixture of ethanol and

acetone; it has a slightly bitter taste.

35

TYPICAL PROPERTIES

Antimicrobial activity: 

Isopropyl alcohol is bactericidal; at concentrations greater than 70% v/v it is

a more effective antibacterial preservative than ethanol (95%). The bactericidal

effect of aqueous solutions increases steadily as the concentration approaches

100% v/v. Isopropyl alcohol is ineffective against bacterial spores.

Autoignition temperature: 425°C

Boiling point: 82.4°C

Explosive limits: 2.5–12.0% v/v in air.

Flammability: flammable.

Flash point: 

11.7°C (closed cup); 13°C (open cup). The water azeotrope has a flash point

of 16°C.

Freezing point: −89.5°C

Melting point: −88.5°C

Moisture content:

0.1–13% w/w for commercial grades (13% w/w corresponds to the water

azeotrope).

Refractive index:

n20D = 1.3776;

n25D = 1.3749.

36

Solubility:

  Miscible with benzene, chloroform, ethanol (95%), ether, glycerin, and

water. Soluble in acetone; insoluble in salt solutions. Forms an azeotrope with

water, containing 87.4% w/w isopropyl alcohol (boiling point 80.37°C).

Specific gravity:   0.786

Vapor density (relative): 2.07 (air = 1)

STABILITY AND STORAGE CONDITIONS

Isopropyl alcohol should be stored in an airtight container in a cool, dry

place.

Safety

Isopropyl alcohol is widely used in cosmetics and topical pharmaceutical

formulations. It is readily absorbed from the gastrointestinal tract and may be

slowly absorbed through intact skin. Prolonged direct exposure of isopropyl

alcohol to the skin may result in cardiac and neurological deficits. In neonates,

isopropyl alcohol has been reported to cause chemical burns following topical

application.

Isopropyl alcohol is metabolized more slowly than ethanol, primarily to

acetone. Metabolites and unchanged isopropyl alcohol are mainly excreted in the

urine.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules, tablets, and

topical preparations). Included in nonparenteral medicines licensed in the UK.

Included in the Canadian List of Acceptable Non-medicinal Ingredients.

37

TALC

Synonyms: Purified Talc; Talcum

Talc is a powdered, selected natural hydrated magnesium silicate. It may

contain varying amounts of aluminium and iron.

Category:

Anticaking agent, glidant, tablet and capsule diluant, tablet & capsule

lubricant.

Solubility:

Practically insoluble in water and in dilute solutions of acids and alkali

hydroxides.

Storage: Store in well-closed containers.

Loss on drying:

Not more than 1.0%, determined on 1 g by drying in an oven at 180o for 1

hour.

38

STARCH

NONPROPRIETARY NAMES

• BP: Maize starch

• Potato starch

• Rice starch

• Tapioca starch

• Wheat starch

• JP: Corn starch

• Potato starch

• Rice starch

• Wheat starch

Synonyms

Amido; amidon; amilo; amylum; Aytex P; C*PharmGel; Fluftex W; Instant

Pure-Cote; Melojel; Meritena; Paygel 55; Perfectamyl D6PH; Pure-Bind; Pure-

Cote; Pure-Dent; Pure-Gel; Pure-Set; Purity 21; Purity 826; Tablet White.

Chemical Name and CAS Registry Number

Starch [9005-25-8]

Empirical Formula and Molecular Weight

(C6H10O5)n 50 000–160 000

where n = 300–1000.

39

Functional Category

Glidant; tablet and capsule diluent; tablet and capsule disintegrant; tablet

binder.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Starch is used as an excipient primarily in oral solid-dosage formulations

where it is utilized as a binder, diluent, and disintegrant. As a diluent, starch is used

for the preparation of standardized triturates of colorants or potent drugs to

facilitate subsequent mixing or blending processes in manufacturing operations.

Starch is also used in dry-filled capsule formulations for volume adjustment of the

fill matrix.

In tablet formulations, freshly prepared starch paste is used at a

concentration of 5–25% w/w in tablet granulations as a binder. Selection of the

quantity required in a given system is determined by optimization studies, using

parameters such as granule friability, tablet friability, hardness, disintegration rate,

and drug dissolution rate.

Starch is one of the most commonly used tablet disintegrants at

concentrations of 3–15% w/w.2–9 However, unmodified starch does not compress

well and tends to increase tablet friability and capping if used in high

concentrations. In granulated formulations, about half the total starch content is

included in the granulation mixture and the balance as part of the final blend with

the dried granulation. Also, when used as a disintegrant, starch exhibits type II

isotherms and has a high specific surface for water sorption.

40

Description

Starch occurs as an odorless and tasteless, fine, white-colored powder

comprising very small spherical or ovoid granules whose size and shape are

characteristic for each botanical variety.

TYPICAL PROPERTIES

Acidity/alkalinity:

pH = 5.5–6.5 for a 2% w/v aqueous dispersion of corn starch, at 25°C.

Density (bulk):

0.462 g/cm3 for corn starch.

Density (tapped):

0.658 g/cm3 for corn starch.

Flowability:

10.8–11.7 g/s for corn starch; 30% for corn starch (Carr compressibility

index). Corn starch is cohesive and has poor flow characteristics.

Gelatinization temperature:

73°C for corn starch; 72°C for potato starch; 63°C for wheat starch.

Moisture content:

All starches are hygroscopic and rapidly absorb atmospheric moisture.21,22

Approximate equilibrium moisture content values at 50% relative humidity are

11% for corn starch; 18% for potato starch; 14% for rice starch; and 13% for wheat

starch. Between 30% and 80% relative humidity, corn starch is the least

41

hygroscopic starch and potato starch is the most hygroscopic. Commercially

available grades of corn starch usually contain 10–14% water.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (buccal

tablets, oral capsules, powders, suspensions and tablets; topical preparations; and

vaginal tablets). Included in nonparenteral medicines licensed in the UK. Included

in the Canadian List of Acceptable Non-medicinal Ingredients.

POVIDONE

NONPROPRIETARY NAMES

• BP: Povidone

• JP: Povidone

• PhEur: Povidonum

• USP: Povidone

Synonyms

E1201; Kollidon; Plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone;

polyvinylpyrrolidone; PVP; 1-vinyl-2-pyrrolidinone polymer.

Chemical Name and CAS Registry Number

1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]

42

Empirical Formula and Molecular Weight

(C6H9NO)n 2500–3 000 000

Functional Category

Disintegrant; dissolution aid; suspending agent and tablet binder.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Although povidone is used in a variety of pharmaceutical formulations, it is

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

binders in wet-granulation processes.2,3 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.4–6 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.

Description

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.

43

TYPICAL PROPERTIES

Acidity/alkalinity:

pH = 3.0–7.0 (5% w/v aqueous solution).

Density (bulk):

0.29–0.39 g/cm3 for Plasdone.

Density (tapped):

0.39–0.54 g/cm3 for Plasdone.

Flowability:

• 20 g/s for povidone K-15;

• 16 g/s for povidone K-29/32.

Melting point:

softens at 150°C.

Moisture content:

Povidone is very hygroscopic, significant amounts of moisture being

absorbed at low relative humidities.

Solubility:

freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and water;

practically insoluble in ether, hydrocarbons, and mineral oil. In water, the

concentration of a solution is limited only by the viscosity of the resulting solution,

which is a function of the K-value.

44

Viscosity (dynamic):

The viscosity of aqueous povidone solutions depends on both the

concentration and the molecular weight of the polymer employed.

STABILITY AND STORAGE CONDITIONS

Povidone darkens to some extent on heating at 150°C, with a reduction in

aqueous solubility. It is stable to a short cycle of heat exposure around 110–

130°C; steam sterilization of an aqueous solution does not alter its properties.

Aqueous solutions are susceptible to mold growth and consequently require the

addition of suitable preservatives.

Povidone may be stored under ordinary conditions without undergoing

decomposition or degradation. However, since the powder is hygroscopic, it should

be stored in an airtight container in a cool, dry place.

Incompatibilities

Povidone is compatible in solution with a wide range of inorganic salts,

natural and synthetic resins, and other chemicals. It forms molecular adducts in

solution with sulfathiazole, sodium salicylate, salicylic acid, phenobarbital, tannin,

and other compounds. The efficacy of some preservatives, e.g. thimerosal, may be

adversely affected by the formation of complexes with povidone.

Regulatory Status

Accepted for use in Europe as a food additive. Included in the FDA Inactive

Ingredients Guide (IM and IV injections; ophthalmic preparations; oral capsules,

drops, granules, suspensions, and tablets; sublingual tablets; topical and vaginal

preparations). Included in nonparenteral medicines licensed in the UK. Included in

the Canadian List of Acceptable Non-medicinal Ingredients.

45

CROSPOVIDONE

NONPROPRIETARY NAMES

• BP: Crospovidone

• PhEur: Crospovidonum

• USPNF: Crospovidone

Synonyms

Crosslinked povidone; E1202; Kollidon CL; Kollidon CL-M; Polyplasdone

XL; Polyplasdone

Chemical Name and CAS Registry Number

1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]

Empirical Formula and Molecular Weight

(C6H9NO)n >1 000 000

Functional Category

Tablet disintegrant.

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.

46

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.

Description

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

practically tasteless, odorless or nearly odorless, hygroscopic powder.

TYPICAL PROPERTIES

Acidity/alkalinity:

pH = 5.0–8.0 (1% w/v aqueous slurry)

Density:

1.22 g/cm3

Loss on drying:

Less than 5%

Particle size distribution:

Less than 400 μm for Polyplasdone XL; less than 74 μm 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.

Solubility:

Practically insoluble in water and most common organic solvents.

47

STABILITY AND STORAGE CONDITIONS

Since crospovidone is hygroscopic, it should be stored in an airtight

container in a cool, dry place.

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; see Povidone.

Regulatory Status

Accepted for use as a food additive in Europe. Included in the FDA Inactive

Ingredients Guide (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.

LACTOSE

NONPROPRIETARY NAMES

• BP: Anhydrous lactose

• JP: Anhydrous lactose

• PhEur: Lactosum anhydricum

• USPNF: Anhydrous lactose

Synonyms

Anhydrous Lactose NF 60M; Anhydrous Lactose NF Direct Tableting;

Lactopress

48

Anhydrous; lactosum; lattioso; milk sugar; Pharmatose DCL 21; Pharmatose DCL

22;

saccharum lactis; Super-Tab Anhydrous.

Chemical Name and CAS Registry Number

O-β-D-galactopyranosyl-(1→4)-β-D-glucopyranose [63-42-3]

Empirical Formula and Molecular Weight

C12H22O11 342.30

Structural Formula

The PhEur 2005 describes anhydrous lactose as O-β-D-galactopyranosyl-

(1→4)-β-Dglucopyranose; or a mixture of O-β-D-galactopyranosyl-(1→4)-α-D-

glucopyranose and O-β- D-galactopyranosyl-(1→4)-β-D-glucopyranose. The

USPNF 23 describes anhydrous lactose as being primarily β-lactose or a mixture of

α- and β-lactose. The JP 2001 describes anhydrous lactose as β-lactose or a mixture

of β-lactose and α-lactose.

Functional Category

Binding agent; directly compressible tableting excipient; lyophilization aid;

tablet and capsule filler.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Anhydrous lactose is widely used in direct compression tableting

applications and as a tablet and capsule filler and binder. Anhydrous lactose can be

used with moisture-sensitive drugs due to its low moisture content.

49

Description

Lactose occurs as white to off-white crystalline particles or powder. Several

different brands of anhydrous lactose are commercially available which contain

anhydrous β-lactose and anhydrous α-lactose. Anhydrous lactose typically contains

70–80% anhydrous β-lactose and 20–30% anhydrous α-lactose.

TYPICAL PROPERTIES

Angle of repose:

39° for Pharmatose DCL 21 and 38° for Super-Tab Anhydrous.

Density :

1.589 g/cm3 for anhydrous β-lactose; 1.567 g/cm3 for Super-Tab

Anhydrous.

Melting point:

• 223.0°C for anhydrous α-lactose;

• 252.2°C for anhydrous β-lactose;

• 232.0°C (typical) for commercial anhydrous lactose.

Stability and Storage Conditions

Mold growth may occur under humid conditions (80% RH and above).

Lactose may develop a brown coloration on storage, the reaction being accelerated

by warm, damp conditions. At 80°C and 80% RH, tablets containing anhydrous

lactose have been shown to expand 1.2 times after one day.

Lactose anhydrous should be stored in a well-closed container in a cool, dry

place.

50

Incompatibilities

Lactose anhydrous is incompatible with strong oxidizers. When mixtures

containing a hydrophobic leukotriene antagonist and anhydrous lactose or lactose

monohydrate were stored for six weeks at 40°C and 75% RH, the mixture

containing anhydrous lactose showed greater moisture uptake and drug

degradation.

Studies have also shown that in blends of roxifiban acetate (DMP-754) and

lactose anhydrous, the presence of lactose anhydrous accelerated the hydrolysis of

the ester and amidine groups.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections;

oral capsules and tablets; inhalation preparations; rectal, transdermal, and vaginal

preparations). Included in nonparenteral and parenteral medicines licensed in the

UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

PROPYLENE GLYCOL

NONPROPRIETARY NAMES

• BP: Propylene glycol

• JP: Propylene glycol

• PhEur: Propylenglycolum

• USP: Propylene glycol

Synonyms

1,2-Dihydroxypropane; E1520; 2-hydroxypropanol; methyl ethylene glycol;

methyl glycol; propane-1,2-diol.

51

Chemical Name and CAS Registry Number

1,2-Propanediol [57-55-6]

(−)-1,2-Propanediol [4254-14-2]

(+)-1,2-Propanediol [4254-15-3]

Empirical Formula and Molecular Weight

C3H8O2 76.09

Functional Category

Antimicrobial preservative; disinfectant; humectant; plasticizer; solvent;

stabilizer for vitamins; water-miscible cosolvent.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Propylene glycol has become widely used as a solvent, extractant, and

preservative in a variety of parenteral and nonparenteral pharmaceutical

formulations. It is a better general solvent than glycerin and dissolves a wide

variety of materials, such as corticosteroids, phenols, sulfa drugs, barbiturates,

vitamins (A and D), most alkaloids, and many local anesthetics.

As an antiseptic it is similar to ethanol, and against molds it is similar to

glycerin and only slightly less effective than ethanol.

Propylene glycol is commonly used as a plasticizer in aqueous film-coating

formulations. Propylene glycol is also used in cosmetics and in the food industry

as a carrier for emulsifiers and as a vehicle for flavors in preference to ethanol,

since its lack of volatility provides a more uniform flavor.

52

TYPICAL PROPERTIES

Autoignition temperature:

371°C

Boiling point:

188°C

Density:

1.038 g/cm3 at 20°C

Solubility:

Miscible with acetone, chloroform, ethanol (95%), glycerin, and water;

soluble at 1 in 6 parts of ether; not miscible with light mineral oil or fixed oils, but

will dissolve some essential oils.

Viscosity (dynamic):

58.1 mPa s (58.1 cP) at 20°C

STABILITY AND STORAGE CONDITIONS

At cool temperatures, propylene glycol is stable in a well-closed container,

but at high temperatures, in the open, it tends to oxidize, giving rise to products

such as propionaldehyde, lactic acid, pyruvic acid, and acetic acid. Propylene

glycol is chemically stable when mixed with ethanol (95%), glycerin, or water;

aqueous solutions may be sterilized by autoclaving. Propylene glycol is

hygroscopic and should be stored in a well-closed container, protected from light,

in a cool, dry place.

Incompatibilities

Propylene glycol is incompatible with oxidizing reagents such as potassium

permanganate.

53

Method of Manufacture

Propylene is converted to chlorohydrin by chlorine water and hydrolyzed to

1,2-propylene oxide. With further hydrolysis, 1,2-propylene oxide is converted to

propylene glycol.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the

FDA Inactive Ingredients Guide (dental preparations, IM and IV injections,

inhalations, ophthalmic, oral, otic, percutaneous, rectal, topical, and vaginal

preparations). Included in nonparenteral and parenteral medicines licensed in the

UK. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.

TITANIUM DIOXIDE

NONPROPRIETARY NAMES

• BP: Titanium dioxide, JP: Titanium oxide, PhEur: Titanii dioxidum, USP:

Titanium dioxide

Synonyms

Anatase titanium dioxide; brookite titanium dioxide; color index number

77891; E171;

Chemical Name and CAS Registry Number

Titanium oxide [13463-67-7]

Empirical Formula and Molecular Weight

TiO2 79.88

54

Structural Formula

TiO2

Functional Category

Coating agent; opacifier and pigment.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Titanium dioxide is widely used in confectionery, cosmetics, and foods, in

the plastics industry, and in topical and oral pharmaceutical formulations as a white

pigment. Owing to its high refractive index, titanium dioxide has light-scattering

properties that may be exploited in its use as a white pigment and opacifier. The

range of light that is scattered can be altered by varying the particle size of the

titanium dioxide powder. For example, titanium dioxide with an average particle

size of 230 nm scatters visible light, while titanium dioxide with an average

particle size of 60 nm scatters ultraviolet light and reflects visible light.

In pharmaceutical formulations, titanium dioxide is used as a white pigment

in film-coating suspensions, sugar-coated tablets, and gelatin capsules. Titanium

dioxide may also be admixed with other pigments.

Titanium dioxide is also used in dermatological preparations and cosmetics,

such as sunscreens.

Description

White, amorphous, odorless, and tasteless nonhygroscopic powder.

Although the average particle size of titanium dioxide powder is less than 1 μm,

commercial titanium dioxide generally occurs as aggregated particles of

approximately 100 μm diameter.

55

Titanium dioxide may occur in several different crystalline forms: rutile; anatase;

and brookite. Of these, rutile and anatase are the only forms of commercial

importance. Rutile is the more thermodynamically stable and is used more

frequently than the other crystalline forms.

Melting point:

1855°C

Moisture content:

0.44%

Particle size distribution:

Average particle size = 1.05 μm.5

Solubility:

Practically insoluble in dilute sulfuric acid, hydrochloric acid, nitric acid,

organic solvents, and water. Soluble in hydrofluoric acid and hot concentrated

sulfuric acid. Solubility depends on previous heat treatment; prolonged heating

produces a less-soluble material.

STABILITY AND STORAGE CONDITIONS

Titanium dioxide is extremely stable at high temperatures. This is due to the

strong bond between the tetravalent titanium ion and the bivalent oxygen ions.

However, titanium dioxide can lose small, unweighable amounts of oxygen by

interaction with radiant energy. This oxygen can easily recombine again as a part

of a reversible photochemical reaction, particularly if there is no oxidizable

material available. These small oxygen losses are important because they can cause

significant changes in the optical and electrical properties of the pigment.

56

Titanium dioxide should be stored in a well-closed container, protected from

light, in a cool, dry place.

Incompatibilities

Owing to a photocatalytic effect, titanium dioxide may interact with certain

active substances, e.g. famotidine. Studies have shown that titanium dioxide

monatonically degrades film mechanical properties and increases water vapor

permeability of polyvinyl alcohol coatings when used as an inert filler and

whitener.

Titanium dioxide has also been shown to induce photooxidation of

unsaturated lipids.

Safety

Titanium dioxide is widely used in foods and oral and topical

pharmaceutical formulations. It is generally regarded as an essentially nonirritant

and nontoxic excipient.

Regulatory Status

Accepted as a food additive in Europe. Included in the FDA Inactive

Ingredients Guide (dental paste; intrauterine suppositories; ophthalmic

preparations; oral capsules, suspensions, tablets; topical and transdermal

preparations). Included in nonparenteral medicines licensed in the UK. Included in

the Canadian List of Acceptable Non-medicinal Ingredients.

57

HYPROMELLOSE

NONPROPRIETARY NAMES

• BP: Hypromellose, JP: Hydroxypropylmethylcellulose, PhEur: Hypromellosum,

USP: Hypromellose

Synonyms

Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; Methocel;

methylcellulose propylene glycol ether; methyl hydroxypropylcellulose; Metolose;

Tylopur.

Chemical Name and CAS Registry Number

Cellulose hydroxypropyl methyl ether [9004-65-3]

Empirical Formula and Molecular Weight

The PhEur 2005 describes hypromellose as a partly O-methylated and O-(2-

hydroxypropylated) cellulose. It is available in several grades that vary in viscosity

and extent of substitution. Grades may be distinguished by appending a number

indicative of the apparent viscosity, in mPa s, of a 2% w/w aqueous solution at

20°C. Hypromellose defined in the USP 28 specifies the substitution type by

appending a four-digit number to the nonproprietary name: e.g., hypromellose

1828. The first two digits refer to the approximate percentage content of the

methoxy group (OCH3). The second two digits refer to the approximate percentage

content of the hydroxypropoxy group (OCH2CH(OH)CH3), calculated on a dried

basis. It contains methoxy and hydroxypropoxy groups conforming to the limits for

the types of hypromellose stated in Table I. Molecular weight is approximately 10

58

000–1 500 000. The JP 2001 includes three separate monographs for

hypromellose: hydroxypropylmethylcellulose 2208, 2906, and 2910, respectively.

Functional Category

Coating agent; film-former; rate-controlling polymer for sustained release;

stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent.

APPLICATIONS IN PHARMACEUTICAL FORMULATION OR

TECHNOLOGY

Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical

formulations.

In oral products, hypromellose is primarily used as a tablet binder,1 in film-

coating,2–7 and as a matrix for use in extended-release tablet formulations.8–12

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 filmcoating materials that are commercially

available include AnyCoat C, Spectracel, and Pharmacoat.

Hypromellose is also used as a suspending and thickening agent in topical

formulations.

Compared with methylcellulose, hypromellose produces aqueous solutions

of greater clarity, with fewer undispersed fibers present, and is therefore preferred

in formulations for ophthalmic use. Hypromellose at concentrations between 0.45–

59

1.0% w/w may be added as a thickening agent to vehicles for eye drops and

artificial tear solutions.

Hypromellose 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.

Description

Hypromellose is an odorless and tasteless, white or creamy-white fibrous or

granular powder.

TYPICAL PROPERTIES

Acidity/alkalinity:

pH = 5.5–8.0 for a 1% w/w aqueous solution.

Ash:

1.5–3.0%, depending upon the grade and viscosity.

Density :

1.326 g/cm3

Melting point:

browns at 190–200°C; chars at 225–230°C. Glass transition temperature is

170–180°C.

60

Moisture content:

Hypromellose absorbs moisture from the atmosphere; the amount of water

absorbed depends upon the initial moisture content and the temperature and

relative humidity of the surrounding air.

Solubility:

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. Certain grades of hypromellose are soluble in

aqueous acetone solutions, mixtures of dichloromethane and propan-2-ol, and other

organic solvents

Specific gravity:

1.26

Viscosity :

A wide range of viscosity types are commercially available. Aqueous

solutions are most commonly prepared, although hypromellose may also be

dissolved in aqueous alcohols such as ethanol and propan-2-ol provided the alcohol

content is less than 50% w/w. Dichloromethane and ethanol mixtures may also be

used to prepare viscous hypromellose solutions. Solutions prepared using organic

solvents tend to be more viscous; increasing concentration also produces more

viscous solutions.

STABILITY AND STORAGE CONDITIONS

Hypromellose powder is a stable material, although it is hygroscopic after

drying. Solutions are stable at pH 3–11. Increasing temperature reduces the

viscosity of solutions. Hypromellose undergoes a reversible sol–gel transformation

upon heating and cooling, respectively. The gel point is 50–90°C, depending upon

the grade and concentration of material. Aqueous solutions are comparatively

61

enzyme-resistant, providing good viscosity stability during long-term storage.

However, aqueous solutions are liable to microbial spoilage and should be

preserved with an antimicrobial preservative: when hypromellose is used as a

viscosity-increasing agent in ophthalmic solutions, benzalkonium chloride is

commonly used as the preservative. Aqueous solutions may also be sterilized by

autoclaving; the coagulated polymer must be redispersed on cooling by shaking.

Hypromellose powder should be stored in a well-closed container, in a cool, dry

place.

Incompatibilities

Hypromellose is incompatible with some oxidizing agents. Since it is nonionic,

hypromellose will not complex with metallic salts or ionic organics to form

insoluble precipitates.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the

FDA Inactive Ingredients Guide (ophthalmic preparations; oral capsules,

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.

62

4.0 MATERIALS AND METHODS

4.1 LIST OF EQUIPMENTS

S.No Equipments Name Make Specification/Capacity

1 Electromagnetic sieve

shakerElectro lab EMS-8

2 Fluid Bed Dryer Alliance 5.0kg/L

3 UV apparatus Shimadzu -

4 Rotary Tablet compression

machineCadmach 23 Station

5 Portable Stirrer Remi -

6 Electronic Balance Mettler 3.0Kg

7 Bulk density Apparatus Campbell electronics -

8 Humidity Chamber

(400C ± 20C/75% ±5%RH)Thermo Lab 200L

9 Monsanto Hardness Tester Tab-Machines -

10 Vernier Caliper (Thickness) Mitutoyo -

11 Moisture Balance Citizen -

12 Fribilator Electrolab -

13 Dissolution apparatus Lab India Disso 2000

14 HPLC Shimadzu -

15 Coating Pan 5 L

63

4.2 LIST OF INGREDIENTS

The following materials were obtained from the commercial source and used as

received.

S.No. INGREDIENTS NAME MANUFACTURER

1 Doxycycline Hyclate Husasdha Pharma

2 Microcrystalline Cellulose Vijlak Pharma

3 Lactose DMV International

4 Povidone Zhangiagang hope

chemical

5 Isopropyl Alcohol Shell Relene

6 Starch Maize Products

7 Croscarmellose Sodium Mingtai Chemicals

8 Talc Indian Chemicals

9 Magnesium Stearate Harihar Organics

10 Hypromellose 15 cps Shangdong Head Co.

Ltd

11 Propylene Glycol Manali Petro

Chemicals

12 Titanium Dioxide Merck

13 Quinoline Yellow Lake Roha Dye Chem

14 Methylene Chloride Chemplast Sanmar

64

4.3 SELECTION OF EXCIPIENTS

Excipients selection will be made based on the excipients used by the

marketed preparations available in regulated markets such as US, UK and

Germany. The inactive ingredients used in the formulation shall be retrived from

the literature through internet (rx list website for product from USA, emc website

for UK and vidal website for Germany). Based on the available excipients

preformulation study will be conducted to selected the final manufacturer / grade

of excipients.

The preformulation studies will be conducted by uniform mixing of drug and

other excipients in a specific ratio and subject them to stability study. The final

excipients will be selected based on stability observation and the performance of

these excipients in various trials.

65

4.4 EVALUATION OF MARKET SAMPLES

The fast moving brand is purchased from the market and is analysed for its

physical and chemical characteristics such as average weight, Description, DT,

Thickness, Diameter, Loss on drying, Assay, Dissolution, Packing details, Storage

conditions, Shelf life and Product details.

66

4.5 OUTLINE OF MANUFACTURING PROCEDURE AND OUTLINE

OF COATING PROCEDURE:

Sifting:

The weighed raw materials (Doxycycline Hyclate, Microcrystalline

cellulose, Lactose monohydrate, Povidone, Isopropyl Alcohol, Starch,

Crospovidone, Talc and Magnesium Stearate) are sifted through appropriate sieve.

Mixing:

Sifted raw materials are mixed using polybag together to get a uniform

mixture.

Compression:

The mixed blend in compressed into a tablet of average weight 300 mg using

D tooling in a 8 station compression machine. Lubricated granules are compressed

by using 9.1mm SC punches with average weight of 300mg. Then tablets physical

parameters are recorded.

Coating

The compressed bulk tablets are loaded into the R&D model 5L coating pan,

Non-aquous coating solution in prepared Hypromellose 15 cps, Propylene Glycol,

Titanium Dioxide, Talc, Quinoline Yellow Lake, Methylene Chloride and

Isopropyl alcohol are coated to get a weight said up to 2.3% w/w.

67

DIRECT COMPRESSION METHOD:

Sifting

Mixing

Compression

Coating

WET GRANULATION METHOD:

Sifting

Dry mixing

Binder preparation

Granulation

Drying

Sifting and Fine blending

Lubrication

Compression

Coating solution preparation

Coating

68

4.6 PRECOMPRESSION PARAMETER

Loss on drying

Bulk density

Tapped density

Compressibility index

Sieve analysis

4.6.1 LOSS ON DRYING

The prepared granules (5 gm) were taken and the moisture content is determined at

60oC using IR moisture balance.

4.6.2 BULK DENSITY

Quantity of granules sufficient to fill 50ml is taken in a 50ml measuring cyclinder

(having each 1ml reading). The weight of this granules is noted

Bulk density in calculated using

Bulk Density = Mass of Powder (g) .Volume of Powder (ml)

4.6.3 TAPPED DENSITY

After that the measuring cylinder is subjected to 50 tappings or until to get a

constant powder level on a smooth surface.

Tapped Density = Mass of Powder (g) .Volume of Power (ml)

After 50 taps.

69

4.6.4 COMPRESSIBILITY INDEX

Compressibility Index = Vo – Vf

Vo

Vo = Initial Volume

Vf = Final Volume

Compressibility Index (%) Flow Characters

≤ 10 Excellent

11 – 15 Good

16 – 20 Fair

21 – 25 Passable

26 – 31 Poor

32 – 37 Very Poor

> 38 Very Very Poor

4.6.5 SIEVE ANALYSIS

Weighed quantity of granules is loaded into the preweighed stacked sieves in the

electronic sieve shaker (Coarser sieve on top to fine sieve at bottom). The sieves are

clamped tightly and is subjected to electrical vibration after 5minutes vibration is

discontinued and the sieves are reweighed. The quantity of granules retained in the

respective sieve are noted down.

70

SIEVE NO.

TARE WEIGHT OF

SIEVES

WEIGHT OF GRANULES

AFTER 5MINUTES

QUANTITY OF GRANULES

RETAIN

CUMULATIVE GRANULES

RETAIN

20

30

40

50

60

100

120

4.7 POST COMPRESSION PARAMETER

Description

Thickness & diameter

Hardness

Friability

Disintegration test

In-vitro dissolution test

Assay

71

4.7.1 DESCRIPTION

The general appearance of a tablet, its visual identity and overall “elegance” is

essential for consumer acceptance. The color, shape, odor, surface texture and legibility

of any identifying marking are all noted for the tablet prepared.

THICKNESS AND DIAMETER

Thickness depends mainly upon die filling, physical properties of materials to be

compressed and compression force. The thickness and diameter were measured by using

vernier caliper.

4.7.2 WEIGHT VARIATION TEST

It is desirable that every individual tablet in a batch is uniform in weight and

variation it any is within permissible limits. Non uniformity in weights may lead to

variation in dosing. All finished batches of tablets should be sampled and tested for

weight uniformity.

20 tablets were weighed collectively and individually, from the collective weight,

average weight was calculated. Each tablet weight was compared with average weight to

ascertain whether it is within permissible limits or not. The tablets meet the B.P. test if

not more than 2 tablets are outside the percentage limit and if no tablets differs by more

than 2 times the percentage limit.

72

WEIGHT VARIATION TOLERANCES FOR UNCOATED TABLETS

WEIGHT VARIATION SPECIFICATION

4.7.3 HARDNESS

It is defined as force required breaking a tablet in a diametric compression test. To

perform this test Monsanto test is used. It consists of a barrel containing a compressible

spring held between two plungers. The tablet is placed in contact with the lower plunger

and a zero reading is taken. The upper plunger is then forced against a spring by turning a

threaded blot until the tablet fractures. As the spring is compressed a pointer rides along a

gauge in the barrel to indicate the force. The force of fracture is recorded. This parameter

is important to know that the tablet has sufficient strength to withstand mechanical

shocks of handling in manufacturing, packaging and shipping.

4.7.4 FRIABILITY

It is intended to determine the loss of mass under defined conditions. The friability

of uncoated tablets is determined by using roche friabilator in the laboratory. In a wider

Average weight

Of Tablet (mg)

Maximum percentage

Difference Allowed

<80 10

80-250 7.5

>250 5

73

sense chipping and fragmentation can also be included in friability. It reflects cohesion of

tablet ingredients.

The Roche friability test apparatus consists of acicular plastic chamber, divided

into 2 compartments. The chamber was rotated at a speed of 25 rpm and the tablets were

dropped to a 15cm distance. Reweighed tablets were placed in the apparatus which was

given 100 revolutions after which tablets were weighed once again. The difference

between the two weights represents friability. The weight loss should not be more than

1%.

Then the tablets are dusted and reweighed and the friability percentage is calculated

using the formula.

Wo – W

F = (---------------- ) x 100

Wo

Wo – Weight of the 20 tablets before friability

W - Weight of the 20 tablets after friability

Conventional compressed tablets that lose less than 0.5 to 1.0% of their weight are

generally considered acceptable.

When capping is observed on friability testing, the tablet should not be considered

for commercial use, regardless of the percentage of loss seen.

74

4.7.5 DISINTEGRATION TEST

The USP device to test disintegration uses two glass tubes that are 3 inches long,

open at the top, and held against a co-mesh screen at the bottom end of the basket rack

assembly to text for disintegration time, one tablet is placed in each tube, and the basket

rack is positioned in a 1 litre beaker of water, stimulated gastric fluid, or stimulated

intestinal fluid, at 37oC ± 2oC such that the tablets remain 2.5cm below the surface of the

liquid on their upward movement and descend not closer than 2.5cm from the bottom of

the beaker. A standard motor – driver device is used to move the basket assembly

containing the tablets up and down through a distance of 5 to 6 cm at a frequency of 28 to

32 cycles per mins. Perforated plastic disc may also be used in the test. These are placed

on top of the tablets and impart an abrasive action to the all particles must pass through

the 10-mesh screen in the time specified.

4.7.6 IN-VITRO DISSOLUTION TEST

Dissolution Parameters:

Medium : Water 900ml

Apparatus : II (paddle)

RPM : 75

Time : 90 minutes

Bottom to Paddle Length : 4.5 0.5 cm

75

STANDARD PREPARATION:

Weigh accurately about 100mg of Doxycycline Hyclate WS in 100ml volumetric

flask, dissolve and make up the volume with water. Pipette out 10ml of the above

solution and dilute to 100ml with water. Further dilute 10ml of the solution to 100ml

with water.

SAMPLE PREPARATION:

Filter the sample from each vessel and 10ml of the filtrate to 100ml with water.

PROCEDURE:

Measure the absorbance of the standard and sample solution at maximum at 276nm

using water as blank. Calculated the content of Doxycycline.

CALCULATION:

Sample Abs X Std. Wt X 10 X 10 X 900 X 100 X Purity of Std X 100 X 0.87 Std. Abs X 100 X 100 X 100 X Label claim X 10 X 100

= % of Doxycycline / tablet

Dissolution Acceptance Criteria

Stage Number of Stages Acceptance Criteria

S1 6 Each Unit is NLT Q +5%

S2 6

Average of 12 Unit (S1 + S2) is equal to

greater than to Q and no unit is less than

Q-15%

S3 12Average of 24 Unit (S1+S2+S3) is equal to

greater than to Q

76

4.7.7 ASSAY

STANDARD PREPARATION:

Weight accurately about 100mg of Doxycycline Hyclate WS in 100ml

volumetric flask, dissolve and make up the volume with water. Pipette out 10ml of

the above solution and dilute to 100ml with water. Further dilute 10ml of the

solution to 50ml with water.

SAMPLE PREPARATION:

Weigh and finely powder not less than 20 tablets. Transfer an accurately

weighed portion of the powder, equivalent to about 100mg of Doxycycline, to a

100ml volumetric flask, add about75ml of water, sonicate for 5 minutes, shake for

15 minutes, dilute with water to volume, and filter. Pipette out 10ml of the above

solution to 100ml volumetric flask and make up the volume with water. Further

dilute 10ml of the solution to 50ml with water.

PROCEDURE:

Measure the absorbance of the standard and sample solutions at maximum at

276nm using water as a blank. Calculate the content of Doxycycline.

CALCULATION:

Sample Abs X Std. Wt X 10 X 10 X 100 X 100 X 50 X Purity of Std X 100 X Avg Wt of Tablet X 0.87 Std. Abs X 100 X 100X100X 50 X Sample Wt X 10 X 10 X 100 X Label claim

= % of Doxycycline / tablet

77

5.0 RESULTS AND DISCUSSION

5.1 MANUFACTURING OF TRIALS

Trial-I

Direct compression was tried, direct compressible microcrystalline cellulose,

croscarmellose sodium, starch, titanium dioxide, and talc are mixed with

Doxycycline Hyclate for 5minutes. Talc and Magnesium Stearate are added to the

same and mixed for another 2minutes. Sticking was observed.

Trial-II

To avoid sticking, granulation method is adopted in this trial. Half of

microcrystalline cellulose is replaced with lactose anhydrous. Sodium starch

glycollate is also included as a disintegrator. In this trial sticking problem was

rectified. Initial tablet parameters were satisfactory.

Trial-III

Ingredients and granulation are almost similar to Trial-II. Povidone is added

to improve hardness. The tablets were coated with optimized coating formula.

This batch is placed in a PVC by aluminium pouch and was subjected to stability

study. The tablets develop dark spots on stability.

78

Trial-IV

Due to dark spots formation of Trial-III, croscarmellose sodium and sodium

starch glycollate are removed and instead crospovidone was used as a disintegrant.

Microcrystalline cellulose alone is used as a diluent. Though the tablet

characteristics are satisfactory. Thickness is found to be higher, which may not be

packed with the existing packaging change parts.

Trial-V

Diluents and lubricants are similar to Trial-III. Crospovidone was used as a

disintegrator instead of croscarmellose sodium and sodium starch glycollate.

Tablets parameters were found to be satisfactory. This batch is placed in a PVC by

aluminium pouch and was subjected to stability study. The tablets develop dark

spots on stability.

79

5.2 EVALUATION OF MARKET SAMPLE

Description : Yellow coloured, round, biconvex, film

coated tablets with 100 on one side and

DOXT on other side.

Average weight (mg) : 295mg

DT : 4 – 5 Minutes

Thickness : 4.35 – 4.50 mm

Diameter : 9.15mm (with film coating)

Loss On Drying : 2.49% w/w

Assay : 98.58%

Dissolution : 88.95 at 90 minutes

Packing details : 10 tablets packed in a 0.04mm

Alu/Alu strip.

Storage conditions : Store below 25C, protect from light

& moisture.

Shelf life : 36 months

80

PRODUCT DETAILS

Brand name & Strength : DOXT 100 Tablets

Batch no : D80090

Manufactured by : Dr.Reddy’s Laboratories Ltd., Yanam

Inactive Ingredients : Lake of Quinoline Yellow WS and

Titanium dioxide IP

81

5.3 INCOMPATIBILITY STUDIES

Sl. No.

DRUG + EXCIPIENTS RATIO RT 40C 50C

1 Lactose monohydrate 1:1 No change in colour No change in colour No change in colour

2 Lactose anhydrous 1:1 No change in colour No change in colour No change in colour

3 Crospovidone 1:1 No change in colour No change in colour No change in colour

4 Titanium dioxide 1:20 No change in colour No change in colour No change in colour

5 Starch 1:1 No change in colour No change in colour No change in colour

6 Talc 1:20 No change in colour No change in colour No change in colour

7 Magnesium Stearate 1:20 No change in colour No change in colour No change in colour

8 HPMC 15 cps 1:20 No change in colour No change in colour No change in colour

9 Sodium Starch Glycolate (1) 1:1 No change in colour No change in colour No change in colour

10 Sodium Starch Glycolate (2) 1:1 No change in colour Change in colour (Black spots)

No change in colour

11 Povidone K30 1:10 No change in colour No change in colour No change in colour

12 Microcrystallinecellulose 1:1 No change in colour No change in colour No change in colour

82

5.3 INCOMPATIBILITY STUDY

Sl.

No.

DOXYCYCLINE HCLATE

+ EXCIPIENTSRATIO RT 40C 50C

1 DOXYCYCLINE HYCLATE

+ Hypromellose 15 cps

(Source-1)

1:10 No change in colour No change in colour No change in

colour

2 DOXYCYCLINE HYCLATE

+ Hypromellose 15 cps

(Source-2)

1:10 No change in colour No change in colour No change in

colour

3 DOXYCYCLINE HYCLATE

+ HPC

1:10 No change in colour No change in colour No change in

colour

83

5.4 FORMULATION OF DOXYCYCLINE HYCLATE TABLETS

SL. NO.

INGREDIENTS TRIAL IQty/TAB (mg)

TRIAL IQty/500Tab (g)

TRIAL IIQty/TAB (mg)

TRIAL IIQty/500Tab (g)

1 Doxycycline Hyclate 115.40 57.70 115.40 57.70

2 Microcrystalline cellulose (DC 102 grade)

142.10 71.05 64.00 32.00

3 Starch 15.00 7.50 9.60 4.80

4 Colloidal silicon dioxide 4.50 2.25 - -

5 Croscarmellose Sodium 15.00 7.50 15.00 7.50

6 Talc 6.00 3.00 6.00 3.00

7 Magnesium Stearate 4.50 2.25 6.00 3.00

8 Lactose Anhydrous (Pharmatose DC 121)

- - 64.00 32.00

9 Sodium Starch Glycolate - - 20.00 10.00

10 Isopropyl Alcohol - - - 35 ml

11 TOTAL 302.50 - 300.00

RAMARKS: Sticking is observed Sticking is rectified

84

5.4 FORMULATION OF DOXYCYCLINE HYCLATE TABLETS

SL. NO.

INGREDIENTS TRIAL IIIQty/TAB (mg)

TRIAL IIIQty/500Tab (g)

TRIAL IVQty/TAB (mg)

TRIAL IVQty/500Tab (g)

1 Doxycycline Hyclate 119.00 595.00 127 63.52 Microcrystalline cellulose

(DC 102 grade)62.00 310.00

3 Lactose Anhydrous 62.00 90.004 Sodium Starch Glycolate 18.00 90.005 Povidone 2.00 10.006 Isopropyl Alcohol 400 ml 40 ml7 Starch 10.00 50.008 Croscarmellose Sodium 15.00 75.009 Talc 6.00 30.00 3.00 1.5010 Magnesium Stearate 6.00 30.00 3.00 1.5011 Microcrystalline cellulose

(DC 112 grade)- 147.50 73.75

12 Aerosil - 4.50 2.2513 Crospovidone - 15.00 7.5014 TOTAL 300.00 300.00

COATING FORMULA:1 Hypromellose 15 cps 6.20 24.802 Propylene Glycol 1.20 4.803 Titanium Dioxide 0.20 0.804 Talc 0.20 0.805 Quinoline Yellow Lake 0.20 0.806 Methylene Chloride 385 ml7 Isopropyl Alcohol 256 ml

85

5.4 FORMULATION OF DOXYCYCLINE HYCLATE TABLETS

SL. NO.

INGREDIENTS TRIAL VQty/TAB (mg)

TRIAL VQty/1000Tab (g)

1 Doxycycline Hyclate 127.00 127.002 Microcrystalline cellulose 68.00 68.003 Lactose monohydrate 62.00 62.004 Povidone 3.00 3.005 Isopropyl Alcohol 80 ml6 Starch 10.00 10.007 Crospovidone 18.00 18.008 Talc 6.00 6.009 Magnesium Stearate 6.00 6.00

TOTAL 300COATING FORMULA:

1 Hypromellose 15 cps 6.50 6.502 Propylene Glycol 1.40 1.403 Titanium Dioxide 0.20 0.204 Talc 0.20 0.205 Quinoline Yellow Lake 0.20 0.206 Methylene Chloride 130 ml7 Isopropyl Alcohol 86 ml

86

5.5 EVALUATION OF DOXYCYCLINE HYCLATE TABLETS

TRIAL-I TRIAL-II TRIAL-III TRIAL-IV TRIAL-V

Average Weight 299 299 300.1 300 299.8

Thickness (mm) 4.55 – 4.60 4.15 – 4.22 4.25 – 4.35 4.8 – 4.9 4.36 – 4.44

Hardness Test (kg/cm2) 5 – 6 3 – 4 4 – 5 4 – 5 4 – 5

Friability 0.1 0.26 0.16 0.1 0.17

D.T. with Disc (min) 4 – 5 4 – 5 3 – 4 1 – 2 4 – 5

87

5.5 EVALUATION OF DOXYCYCLINE HYCLATE GRANULES

TRIAL-I TRIAL-II TRIAL-III TRIAL-IV TRIAL-V

Bulk Density 0.334 0.322 0.302 0.412 0.404

Tapped Density 0.395 0.388 0.364 0.496 0.481

Compressibility Index 15.44 17.44 17.03 15.60 15.90

Sieve Analysis

(Cumulative Retained)

-- -- -- --

40# 8.4%

60# 27.3%

80# 31.6%

100# 32.7%

88

5.6 COMPARATIVE DISSOLUTION STUDY FOR DOXYCYCLINE HYCLATE TABLETS

NO. OF

BASKET

DOXIT TABLET (BRAND) # D

80292TRIAL-II TRIAL-III TRIAL-IV TRIAL-V

15 Min. %

Release

87.53 42.19 87.27 98.08 100.37

30 Min. %

Release

89.61 79.64 94.72 98.38 102.90

45 Min. %

Release

91.02 89.72 95.36 101.18 103.94

60 Min. %

Release

91.41 91.08 96.73 103.77 106.04

90 Min. %

Release

91.95 98.01 97.25 104.18 108.23

89

5.7 STABILITY STUDY

PARAMETERS

40C / 75% RH 30C / 65% RH

Initial 1 Month 2 Month 2 Month

Description Yellow coloured, slightly biconvex, film coated tablets

Yellow coloured, slightly biconvex, film coated tablets

Yellow coloured, slightly biconvex, film coated tablets

Yellow coloured, slightly biconvex, film coated tablets

Water Content 2.56 2.61 2.94 2.51

D.T. 4 – 5 minutes 4 – 5 minutes 4 – 6 minutes 4 – 5 minutes

Dissolution 105.07 103.93 103.06 104.68

Assay 111.13 110.34 110.10 111.26

90

6.0 SUMMARY AND CONCLUSION

The proposed project “formulation and evaluation of Doxycycline

Hyclate tablets” is carried out at Fourrts (India) Laboratories Pvt. Ltd.,

located at Vandalur Road, Kanchipuram District – 603 103. The Corporate

Office is at Okkiyam Thoraipakkam, Chennai – 96.

The project is aimed to develop the formulation of Doxycycline

Hyclate tablets.

Chapter-1 deals with Introduction of the formulation of tablets, film coating

and ICH guidelines on stability study.

Chapter-2 deals with Objective of the work with Plan of work.

Chapter-3 deals with Drug Specific Review with Literature Review and

Excipients Profile.

Chapter-4 provides information regarding Materials and Methods.

Precompression and Post compression parameters.

Chapter-5 provides information regarding formulation and evaluation of

Doxycycline Hyclate tablets.

Through this study a stable formulation of Doxycycline Hyclate

tablets is successfully developed. The stability results reveal that the

developed product is stable. The final formula obeys USP monographs for

Doxycycline Hyclate tablets. In-vitro dissolution study shows the

formulation is comparable with marketed product.

91

7.0 BIBLIOGRAPHY

92