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 3.0

PLAN OF WORK DRUG SPECIFIC REVIEW

3.1

LITERATURE REVIEW

24 25 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 OUTLINE OF MANUFACTURING PROCEDURE & OUTLINE OF COATING PROCEDURE PRE COMPRESSION PARAMETER

66

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

4.5 4.6

S.No. 4.7

TITLE

67 69

PAGE No.

POST COMPRESSION PARAMETER

71

4.7.1

DESCRIPTION

72

4.7.2

WEIGHT VARIATION TEST

72

1

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 5.1

RESULTS AND DISCUSSION MANUFACTURING OF TRIALS

78

5.2

EVALUATION OF MARKET SAMPLE

80

5.3

INCOMPATIBILITY STUDIES

82

5.4

FORMULATION OF DOXYCYCLINE HYCLATE

84

5.5

TABLETS EVALUATION OF DOXYCYCLINE HYCLATE

87

5.6

TABLETS & GRANULES COMPARATIVE DISSOLUTION STUDY FOR

89

5.7

DOXYCYCLINE HYCLATE TABLET STABILITY STUDY

90

6.0

SUMMARY AND CONCLUSION

91

7.0

BIBLIOGRAPHY

92

LIST OF ABBREVATIONS USED

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

2

78

No

-

Number

g

-

Gram

ml

-

milliliter

IPA

-

Isopropyl Alcohol

JP

-

Japan Pharmacopoeia

Ph Euro

-

European Pharmacopoeia

o

C

-

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: 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 .

3

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 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 4

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 2. Vaginal tablets

(D) Tablets used to prepare solution 1. Effervescent tablets 2. Dispensing tablets 3. Hypodermic tablets 4. Tablet triturates

5

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 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

6

•

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 ). 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.

7

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 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.

8

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 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 9

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 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

10

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 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.

11

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

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 watersolubility or pH -dependent solubility iii) Capacity to produce an elegant looking product 12

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. 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)

13

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 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.

14

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. EudragitIt is marketed under the name of Eudragit E is freely soluble in gastric fluid up to pH 5 andco-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 RLdispersion. 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 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

15

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 (200400 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. 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

16

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) andintestinal track. Opasray (complete film coating concentrate) are promoted as achieving lessOpadry 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 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. 17

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.

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 18

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.

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

19

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.

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.

20

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 retest 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.

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 21

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.

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

22

*

Preformulation Studies

*

Formulation development of core tablets

*

Analysis of Trials

*

Coating of final formula

*

Comparative Study

*

Stability study of final formula

2.1

PLAN OF WORK Literature Collection

Evaluation of Market Sample

Selection of Excipients

23

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

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.

24

Standard pH Water Molecular Weight Molecular Formula Chemical Name

2.0 to 3.0 in solution contains 10mg of Doxycycline per ml 1.4% to 2.8% 512.94 & C22H24HClN2O8½ C2H6O.½ H2O Doxycycline hydrochloride hemi ethanolate hemi hydrate 110°C NMT 0.5%

Melting Point Loss On Drying Pharmacokinetics Route of administration Absorption T max t½ Effect of food Plasma protein binding Metabolism at Excretion US Innovator Product Observations Storage 3.1

Oral Completely absorbed 2.6µ g / ml 12 to 24 Hours Food does not affected the extent and absorption 80 to 95% Liver Through facieses Vibramycin Store in air tight containers

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 25

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 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 26

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 2octyl 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 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 nonexistent levels in the serum indicate that this biodegradable controlled-release 27

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 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

28

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 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

29

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 highperformance 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(0infinity) 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(0t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were within the range 80125% 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(0infinity) 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 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

30

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. 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.

31

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.

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:

32

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. 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.

33

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

STRUCTURAL FORMULA

Functional Category Disinfectant; solvent. APPLICATIONS

IN

PHARMACEUTICAL

TECHNOLOGY 34

FORMULATION

OR

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.

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.

35

Autoignition temperature: Boiling point:

425°C

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.

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

36

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.

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. 37

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.

STARCH NONPROPRIETARY NAMES • BP: Maize starch • Potato starch • Rice starch • Tapioca starch • Wheat starch 38

• 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; PureCote; 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.

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 39

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.

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:

40

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 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.

41

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]

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 42

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 viscosityincreasing 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.

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: 43

• 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.

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.

44

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. 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 45

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. 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) 46

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.

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, 47

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 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

48

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-Dglucopyranose 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.

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 : 49

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.

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 50

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. 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.

51

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.

TYPICAL PROPERTIES Autoignition temperature: 371°C Boiling point: 188°C Density: 1.038 g/cm3 at 20°C Solubility:

52

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. 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

53

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 Structural Formula TiO2 Functional Category Coating agent; opacifier and pigment. APPLICATIONS

IN

PHARMACEUTICAL

TECHNOLOGY

54

FORMULATION

OR

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. 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: 55

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. 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.

56

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.

HYPROMELLOSE NONPROPRIETARY NAMES • BP: Hypromellose, JP: Hydroxypropylmethylcellulose, PhEur: Hypromellosum, USP: Hypromellose Synonyms

57

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-(2hydroxypropylated) 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 10 000–1 500 000. 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

TECHNOLOGY 58

FORMULATION

OR

Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical formulations. In oral products, hypromellose is primarily used as a tablet binder,1 in filmcoating,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– 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.

59

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.

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 60

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 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.

61

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.

4.0

MATERIALS AND METHODS

4.1

LIST OF EQUIPMENTS

S.No 1

Equipments Name Electromagnetic sieve shaker 62

Make

Specification/ Capacity

Electro lab

EMS-8

2

Fluid Bed Dryer

3

UV apparatus

4

Rotary Tablet compression

5

machine Portable Stirrer

6

Electronic Balance

7

Bulk density Apparatus

8

Humidity Chamber 0

Alliance

5.0kg/L

Shimadzu

-

Cadmach

23 Station

Remi

-

Mettler

3.0Kg

Campbell electronics

-

Thermo Lab

200L

0

(40 C ± 2 C/75% ±5%RH) 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

4.2

5L

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 63

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

4.3

12

Titanium Dioxide

Merck

13

Quinoline Yellow Lake

Roha Dye Chem

14

Methylene Chloride

Chemplast Sanmar

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.

64

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.

65

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:

66

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.

DIRECT COMPRESSION METHOD: Sifting Mixing Compression Coating

WET GRANULATION METHOD: Sifting Dry mixing Binder preparation

67

Granulation Drying Sifting and Fine blending Lubrication Compression Coating solution preparation

4.6

Coating 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 68

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.

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 69

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.

SIEVE NO.

TARE WEIGHT OF SIEVES

WEIGHT OF GRANULES AFTER 5MINUTES

20 30 40 50 60 100 120

4.7

POST COMPRESSION PARAMETER

•

Description 70

QUANTITY OF GRANULES RETAIN

CUMULATIVE GRANULES RETAIN

•

Thickness & diameter

•

Hardness

•

Friability

•

Disintegration test

•

In-vitro dissolution test

•

Assay

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.

71

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.

WEIGHT VARIATION TOLERANCES FOR UNCOATED TABLETS WEIGHT VARIATION SPECIFICATION

Average weight

Maximum percentage

Of Tablet (mg)

Difference Allowed

<80

10

80-250

7.5

>250

5

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 72

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 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

73

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.

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: 74

Medium

:

Water 900ml

Apparatus

:

II (paddle)

RPM

:

75

Time

:

90 minutes

Bottom to Paddle Length :

4.5 ± 0.5 cm

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

75

DISSOLUTION ACCEPTANCE CRITERIA Stage

Number of Stages

S1

6

Acceptance Criteria Each Unit is NLT Q +5% Average of 12 Unit (S1 + S2) is equal to

S2

6

greater than to Q and no unit is less than Q-15%

S3

12

Average of 24 Unit (S1+S2+S3) is equal to greater than to Q

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:

76

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

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. microcrystalline cellulose is replaced with lactose anhydrous.

77

Half of

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.

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.

78

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 79

Packing details

:

10 tablets packed in a 0.04mm Alu/Alu strip.

Storage conditions

:

Store below 25°C, protect from light & moisture.

Shelf life

:

36 months

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

PRODUCT DETAILS

Titanium dioxide IP

80

81

5.3 INCOMPATIBILITY STUDIES

Sl. DRUG + EXCIPIENTS No. 1 Lactose monohydrate

RATIO

RT

40°C

50°C

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.

DOXYCYCLINE HCLATE

No.

+ EXCIPIENTS

1

DOXYCYCLINE HYCLATE

RATIO 1:10

RT

40°C

No change in colour No change in colour

+ Hypromellose 15 cps

50°C No change in colour

(Source-1) 2

DOXYCYCLINE HYCLATE

1:10

No change in colour No change in colour

+ Hypromellose 15 cps

No change in colour

(Source-2) 3

DOXYCYCLINE HYCLATE

1:10

No change in colour No change in colour

+ HPC

No change in colour

83

5.4 FORMULATION OF DOXYCYCLINE HYCLATE TABLETS SL. NO.

INGREDIENTS

TRIAL I Qty/TAB (mg)

TRIAL I Qty/500Tab (g)

TRIAL II Qty/TAB (mg)

TRIAL II Qty/500Tab (g)

1

Doxycycline Hyclate

115.40

57.70

115.40

57.70

2

Microcrystalline (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:

cellulose

Sticking is observed

84

Sticking is rectified

5.4 FORMULATION OF DOXYCYCLINE HYCLATE TABLETS SL. NO. 1 2

INGREDIENTS

Doxycycline Hyclate Microcrystalline cellulose (DC 102 grade) 3 Lactose Anhydrous 4 Sodium Starch Glycolate 5 Povidone 6 Isopropyl Alcohol 7 Starch 8 Croscarmellose Sodium 9 Talc 10 Magnesium Stearate 11 Microcrystalline cellulose (DC 112 grade) 12 Aerosil 13 Crospovidone 14 TOTAL COATING FORMULA: 1 Hypromellose 15 cps 2 Propylene Glycol 3 Titanium Dioxide 4 Talc 5 Quinoline Yellow Lake 6 Methylene Chloride 7 Isopropyl Alcohol

TRIAL III Qty/TAB (mg) 119.00 62.00

TRIAL III Qty/500Tab (g) 595.00 310.00

62.00 18.00 2.00

90.00 90.00 10.00 400 ml 50.00 75.00 30.00 30.00

10.00 15.00 6.00 6.00 300.00 6.20 1.20 0.20 0.20 0.20

24.80 4.80 0.80 0.80 0.80 385 ml 256 ml 85

TRIAL IV Qty/TAB (mg) 127

TRIAL IV Qty/500Tab (g) 63.5

40 ml 3.00 3.00 147.50

1.50 1.50 73.75

4.50 15.00 300.00

2.25 7.50

5.4 FORMULATION OF DOXYCYCLINE HYCLATE TABLETS SL. NO. 1 2 3 4 5 6 7 8 9

INGREDIENTS

Doxycycline Hyclate Microcrystalline cellulose Lactose monohydrate Povidone Isopropyl Alcohol Starch Crospovidone Talc Magnesium Stearate TOTAL COATING FORMULA: 1 Hypromellose 15 cps 2 Propylene Glycol 3 Titanium Dioxide 4 Talc 5 Quinoline Yellow Lake 6 Methylene Chloride 7 Isopropyl Alcohol

TRIAL V Qty/TAB (mg) 127.00 68.00 62.00 3.00 10.00 18.00 6.00 6.00 300 6.50 1.40 0.20 0.20 0.20

86

TRIAL V Qty/1000Tab (g) 127.00 68.00 62.00 3.00 80 ml 10.00 18.00 6.00 6.00 6.50 1.40 0.20 0.20 0.20 130 ml 86 ml

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

5–6

3–4

4–5

4–5

4–5

0.1

0.26

0.16

0.1

0.17

4–5

4–5

3–4

1–2

4–5

Hardness Test (kg/cm2) Friability D.T. with Disc (min)

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 40# 8.4%

Sieve Analysis

--

--

(Cumulative Retained)

--

--

60# 27.3% 80# 31.6% 100# 32.7%

88

5.6 COMPARATIVE DISSOLUTION STUDY FOR DOXYCYCLINE HYCLATE TABLETS

NO. OF BASKE

DOXIT TABLET (BRAND) # D 80292

TRIAL-II

TRIAL-III

TRIAL-IV

TRIAL-V

87.53

42.19

87.27

98.08

100.37

89.61

79.64

94.72

98.38

102.90

91.02

89.72

95.36

101.18

103.94

91.41

91.08

96.73

103.77

106.04

91.95

98.01

97.25

104.18

108.23

T 15 Min. % Release 30 Min. % Release 45 Min. % Release 60 Min. % Release 90 Min. % Release

89

5.7 STABILITY STUDY

40°C / 75% RH PARAMETERS Description

Initial

1 Month

30°C / 65% RH 2 Month

2 Month

Yellow coloured, slightly biconvex, film coated tablets 2.56

Yellow coloured, slightly biconvex, film coated tablets 2.61

Yellow coloured, slightly biconvex, film coated tablets 2.94

Yellow coloured, slightly biconvex, film coated tablets 2.51

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

Water Content D.T.

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