FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS

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3.1.1 DRUG PROFILE:

Table 3.1: Test, Specification and Result of Amoxicillin trihydrate as per IP.

Sr. No.

TEST

SPECIFICATION

RESULT

1

Description

White or almost white, crystalline powder

White crystalline powder

2

Solubility

Slightly soluble in water, methanol and ethanol (95%), soluble in dilute solutions of acids and of alkali-hydroxides. Practically insoluble in chloroform, in ether and in fixed oils.

Slightly soluble in water, methanol and ethanol (95%), soluble in dilute solutions of acids and of alkali-hydroxides. Practically insoluble in chloroform, in ether and in fixed oils.

3

Identification

a) I.R absorption spectrum

 

b) By HPLC

IR spectrum of sample as KBr pellet should be concordant with the spectrum obtained with working standard.

 

In the assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the reference solution.

IR spectrum of sample as KBr pellet should be concordant with the spectrum obtained with working standard.

 

In the assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the reference solution.

4

pH

Between 3.5 and 5.5

4.42

5

Water content (by KF, % w/w)

11.5 % to 14.5 % w/w

13.14

6

Specific optical rotation (20% w/v solution in co2 free water

Between +2900 and +3150

(on anhydrous basis)

+303.5

7

 Heavy metals

Not more than 20 ppm

Less than 20

8

Sulphated ash (%w/w)

Not more than 1% w/w

0.09

9

Assay (by HPLC)

Not less than 95.0% and

Not more than 100.5% w/w

99.3

3.2 REVIEW OF EXCIPIENTS

EXCIPIENTS PROFILE34

HYDROXY PROPYL METHYL CELLULOSE:
Synonym
: Hypromellose, Methocel, Methylcellulose, HPMC

Chemical name: Cellulose, 2-hydrxy propyl methyl ether.

Chemical Formula:   HPMC is a partially o-methylated and o-(2-hydroxypropylated) cellulose. It is available in several grades; vary in viscosity and extent of substitution.

Structural formula:

Molecular Weight:  10 000 – 1 500 000

Functional category: Tablet binder, suspending agent, coating agent, thickening agent, viscosity increasing agent.

Description:
HPMC is an odourless and tasteless, white or creamy with fibrous or granular powder.

Solubility:
Soluble in cold water forming a viscous colloidal solutions practically insoluble in chloroform, ethanol but soluble in mixtures of ethanol. Certain grades of HPMC are soluble in aqueous acetone solution.

Viscosity:
A wide range of viscosity types is commercially available. Aqueous solutions are most commonly prepared. Increasing concentration also produce more viscous solutions.

Stability and storage conditions: HPMC powder is stable material. Solutions are stable at PH 3-11. Aqueous solutions are comparatively enzyme resistant providing good viscosity stability during long-term storage. Hypromellose powder should be stored in a well-closed container.

Incompatibilities: It is incompatible with some oxidizing agent. Since it is nonionic, it will not complex with metallic salts and ionic organics to form insoluble precipitates.

Safety:  It is generally regarded as a nontoxic and non-irritant material although excessive oral consumption may have a laxative effect.

Applications in pharmaceutical formulation:
·         HPMC is widely used in oral, ophthalmic and topical formulations. Concentrations between 2% and 5% w/w may be used as a binder in either wet- or dry-granulation processes. High-viscosity grades may be used to retard the release of drugs from a matrix at levels of 10–80% w/w in tablets and capsules.
·         HPMC is primarily used as tablet binder and as a matrix for use in extended release tablet formulation.
·         Lower viscosity grades used in aqueous film coating solutions while higher viscosity grades are used with organic solvents.
·         HPMC is also used as a suspending agent and thickening agents in topical formulations.
·         HPMC at concentrations between 0.45%-1.0%w/w may be added as a thickening agent to vehicles for eye drops

ETHYL CELLULOSE
Synonyms:
Ethocel, surelease, aquacoat ECD.

Structural formula:

Chemical Formula:Cellulose ethyl ether. A long chain polymer consisting of anhydroglucose units joined together by acetal linkages.

Description:  Ethyl cellulose is a tasteless, free-flowing, white to light tan colored powder.

Functional Category:  Coating agent, tablet binder, viscosity increasing agent.

Solubility:  Practically insoluble in glycerin, propylene glycol, and water. It is freely soluble in chloroform, methyl acetate, tetrahydrofuran, and in mixtures of aromatic hydrocarbons with ethanol, methanol, and toluene.

Stability and Storage Conditions: Ethyl cellulose is a stable, slightly hydroscopic material. It is chemically resistant to alkalis, both dilute and concentrated, and to salt solutions, although it is more sensitive to acidic materials than cellulose esters. It is subject to oxidative degradation in the presence of sunlight or UV light at elevated temperatures.

The bulk material should be stored in a dry place, in a well closed container at the temperature between 7-32 °C.

Incompatibilities: It is incompatible with paraffin wax and microcrystalline wax.

Safety:  It is widely used in oral and topical pharmaceutical formulations. It is also used in food products. It is generally regarded as a nontoxic, nonallergic and nonirritant material. Parenteral used may be harmful to the kidneys.

Applications:
·         Ethyl cellulose is widely used in oral and topical pharmaceutical formulations.

·         The main use of ethyl cellulose in oral formulations is as a hydrophobic coating agent for tablets and granules. Ethyl cellulose coatings are used to modify the release of a drug, to mask an unpleasant taste, or to improve the stability of a formulation; for example, where granules are coated with ethyl cellulose to inhibit oxidation.

·         Modified release tablet formulations may also be produced using ethyl cellulose as a matrix former.

·         Higher-viscosity ethyl cellulose grades tend to produce stronger and more durable films.

·         An aqueous polymer dispersion (or latex) of ethylcellulose such as Aquacoat ECD (FMC Biopolymer) or Surelease (Colorcon) may also be used to produce ethyl cellulose films without the need for organic solvents.

·         Drug release through ethyl cellulose-coated dosage forms can be controlled by diffusion through the film coating. This can be a slow process unless a large surface area (e.g. pellets or granules compared with tablets) is utilized. In those instances, aqueous ethyl cellulose dispersions are generally used to coat granules or pellets.

·         Ethyl cellulose produces hard tablets with low friability, although they may demonstrate poor dissolution.

·         In topical formulations, ethyl cellulose is used as a thickening agent in creams, lotions, or gels, provided an appropriate solvent is used. Ethyl cellulose has been studied as a stabilizer for emulsions.

EUDRAGIT
Nonproprietary Name:
NF: Methacrylic acid copolymer; polymeric methacrylates.

Chemical name:Poly(methacrylic acid, methyl methacrylate) 1 : 1 (Eudragit L 100),  Poly(methacrylic acid, methyl methacrylate) 1 : 2  (Eudragit S 100)

Functional Category: Film former, tablet binder

Synonyms: Eudragit, polymeric methacrylates.

Molecular Weight: ≥ 100, 000

Solubility: Type E, L and Type S – soluble in polar organic solvents, such as alcohols (ethanol, isopropanol), acetone, esters, chloroform, etc. Insoluble in water, petroleum ether, and saliva. Swells and dissolves in acidic media.

Type RL and RS – soluble in isopropanol and ethanol in combination with acetone or methylene chloride;also in methanol, chloroform, trichloroethylene, ethyl acetate, and glycolmonomethyl ether.

Eudragit L 100 Powder Soluble in intestinal fluid from pH 6, Eudragit S 100 Powder Soluble in intestinal fluid from pH 7

Safety: Acute toxicity studies have been performed in rats, rabbits, and dogs. No toxic effects were observed with Type L30D, E, L, S, RS, and RL at doses of dry   lacquer substance ranging from 6-28 g/ kg body weight over a two- week period.

Applications:

  • Binder – It has been used as a granulation binder in concentration between 5 to 20%.
  • Film former – Eudragit E is used as film coating agent, soluble in gastric fluid. Eudragit RL and RS form water- insoluble film coat for delayed- release products.

PVP
Synonym
: poly [1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone; polyvinylpyrrolidone; 1-vinyl-2-pyrrolidinone polymer.

Chemical name: 1-Ethenyl-2-pyrrolidinone homopolymer

Molecular weight: 2500–3 000 000

Structural formula:

Functional Category:  Disintegrant; dissolution aid; suspending agent; tablet binder.

Description: Povidone occurs as a fine, white to creamy-white colored, odourless or almost odourless, 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.

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.Dynamic viscosity of 5% w/v Povidone K-30 (Kollidon) solutions in ethanol (95%) is 3.4mPas and in propan-2-ol is 5.8mPas at 250C.

Applications:
·         Intableting, povidone solutions are used as binders in wetgranulation processes.
·         Povidone is used as a solubilizer in oral and parenteral formulations and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms.
·         Povidone solutions may also be used as coating agents.
·         Povidone is additionally used as a suspending, stabilizing, or viscosity-increasing agent in a number of topical and oral suspensions and solutions.
·         The solubility of a number of poorly soluble active drugs may be increased by mixing with povidone.

Table 3.2: Use of povidone

Use

Concentration (%)

Carrier for Drugs

10-25

Dispersing agent

Upto 5

Eye Drops

2-10

Suspending Agent

Upto 5

Tablet binder

0.5-5

COLLOIDAL SILICON DIOXIDE:
Synonyms:
Aerosil, colloidal silica, cab-o-sil, fumed silica; light anhydrous silicic acid; silicic anhydride

Chemical formula: Sio2

Functional category: Adsorbent, anticaking agent, glidant, suspending agent, viscosity improving agent.

Description: It is a light, loose, bluish-white colored, odorless, tasteless, nongritty amorphous powder.

Solubility: Practically insoluble In organic solvents, water and acids. It is soluble in hot solutions of alkali hydroxide.

Stability and storage conditions: Aerosil is hygroscopic but absorbs large quantities of water without liquefying. Aerosil should be stored in well-closed container.

Applications in pharmaceutical formulations:
·         Colloidal silicon dioxide improves the flow properties of the dry powders. Aerosil also act as a thickening agent and suspending agent in gels and semisolid preparations.
·         In aerosols Aerosil is used to promote particulate suspension, eliminate hard settling.
·         It is also used as a tablet disintegrant.
·         Aerosil is frequently added suppository formulations containing lipophilic excipients to increase viscosity, prevent sedimentation.

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