FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS

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MICROCRYSTALINE CELLULOSE:
Synonym:
Avicel, celphere, emocel, cellulose gel, crystalline cellulose

Chemical name: Cellulose

Structural formula:

Functional category: Adsorbent, Suspending Agent, Diluent, Disintigrant.

Applications in pharmaceutical formulations:
·         MCC is widely used in pharmaceutical formulation as a binder, diluent in tablet and capsule preparations.
·         It also used as a disintegrant and lubricant.

Table 3.3: Uses of MCC

Use

Concentration (%)

Adsorbent

20-90

Antiadherent

5-20

Capsule binder/diluent

20-90

Tablet disintegrant

5-15

Tablet binder/diluent

20-90

Description:
It is a white, odorless, tasteless, crystalline powder composed of porous particles. It is commercially available different particle sizes and moisture grades that have different properties and applications

Solubility:
MCC is slightly soluble in 5%sodium hydroxide solution. Practically insoluble in water, dilute acids and most organic solvents.

Stability and storage conditions:
MCC is a stable though hygroscopic material. The bulk material should be stored in a well-closed container in a cool, dry place.

TRIETHYL CITRATE:
Synonyms:
Citric acid, ethyl ester

Chemical Name:2-Hydroxy-1,2,3-propanetricarboxylic acid, triethyl ester

Structural Formula:

Functional Category: Plasticizer.

Description: Triethyl citrate is a clear, odorless, practically colorless, oilyliquid.

Solubility: soluble 1 in 125 of peanut oil, 1 in 15 of water. Miscible with ethanol (95%), acetone, and propan-2-ol.

Viscosity (dynamic): 35.2 mPa s (35.2 cP) at 250C

Stability and Storage Conditions: Triethyl citrate should be stored in a closed container in a cool, dry location. When stored in accordance with these conditions, triethyl citrate is a stable product.

Incompatibilities: Triethyl citrate is incompatible with strong alkalis andoxidizing materials.

Safety: Triethyl citrate is used in oral pharmaceutical formulations andas a direct food additive. It is generally regarded as a nontoxicand nonirritant material.

Applications:
·         Triethyl citrate and the related esters acetyltriethyl citrate, tributyl citrate, and acetyltributyl are used to plasticize polymers in formulated pharmaceutical coatings.
·         The coating applications include capsules, tablets, beads, and granules for taste masking, immediate release, sustainedrelease, and enteric formulations.
·         Triethyl citrate is also used as a direct food additive for flavoring, for solvency, and as a surface active agent.

TRIACETIN:
Synonyms:
Glycerol triacetate; glyceryl triacetate; triacetylglycerine.
Chemical Name:1,2,3-Propanetriol triacetate
Molecular weight:218.21

Structural formula:

Functional category: Humectant; plasticizer; solvent.
Description: Triacetin is a colorless, viscous liquid with a slightly fatty odor.
Stability and Storage Conditions:Triacetin is stable and should be stored in a well-closed,nonmetallic container, in a cool, dry place.
Incompatibilities:Triacetin is incompatible with metals and may react withoxidizing agents. Triacetin may destroy rayon fabric.
Applications:
·         Triacetin is mainly used as a hydrophilic plasticizer in both aqueous and solvent-based polymeric coating of capsules, tablets, beads, and granules; typical concentrations used are 10–35% w/w.
·         Triacetin is used in cosmetics, perfumery, and foods as a solvent and as a fixative in the formulation of perfumes and flavors.

TITANIUM DIOXIDE:
Synonyms:
Anatase titanium dioxide; brookite titanium dioxide; rutile titanium dioxide; titanic anhydride.

Molecular Weight:79.88

Structural Formula:TiO2

Functional Category:Coating agent; opacifier; pigment.

Description: White, amorphous, odorless, and tasteless nonhygroscopicpowder. Although the average particle size of titanium dioxidepowder is less than 1 mm, commercial titanium dioxidegenerally occurs as aggregated particles of approximately100 mm diameter.Titanium dioxide may occur in several different crystallineforms: rutile; anatase; and brookite. Of these, rutile and anataseare the only forms of commercial importance.

Solubility: practically insoluble in dilute sulfuric acid, hydrochloric acid, nitric acid, organic solvents, and water. Soluble in hydrofluoric acid and hot concentrated sulfuric acid.

Stability and Storage Conditions: Titanium dioxide is extremely stable at high temperatures. Thisis due to the strong bond between the tetravalent titanium ionand the bivalent oxygen ions. Titanium dioxide should be stored in a well-closed container, protected from light, in a cool, dry place.

Applications:
·         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.
·         Titanium dioxide is also used in dermatological preparations and cosmetics, such as sunscreens.

MAGNESIUM STEARATE
Synonyms:
Magnesium octadecanoate; octadecanoic acid, magnesium salt, stearic acid, magnesium salt.

Chemical name:Octadecanoic acid magnesium salt

Empirical Formula: C36H70MgO4

Molecular weight: 591.34

Structural Formula: CH3(CH2)16COO)2Mg

Functional Category: Tablet and capsule lubricant.

Description: Magnesium stearate is a fine, white, precipitated or milled, impalpable powder of low bulk density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin.

Solubility: practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in warm benzene and warm ethanol (95%).

Stability and storage conditions: Magnesium stearate is stable and should be stored in a well closed container in a cool, dry place.

Incompatibilities: Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with strong oxidizing materials. Magnesium stearate cannot be used in products containing aspirin, some vitamins, and most alkaloidal salt.

Applications: Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams.

TALC
Synonyms:
Hydrous magnesium calcium silicate; hydrous magnesium silicate; magnesium hydrogen metasilicate; MagsilOsmanthus.

Functional Category: Anticaking agent; glidant; tablet and capsule diluents and lubricant.

Empirical Formula: Talc is a purified, hydrated, magnesium silicate, approximating to the formula Mg6 (Si2o5)4 (OH)4. It contains small, variable amounts of aluminum silicate and iron.

Description: Talc is a very fine, white to grayish- white, odorless, impalpable, unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness.

Stability and storage conditions: Talc is a stable material and may be sterilized by heating at 160oC for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation.Talc should be stored in a well-closed container in a cool, dry place.

Applications: Talc was once widely used in oral solid dosage formulations as a lubricant and diluent. It is widely used as dissolution retardant in the development of controlled-release products.

3.3 REVIEW OF DOSAGE FORM:
1.      MiddleBrook Pharmaceuticals, Inc
. has developed a delivery technology called PULSYS, which enables pulsatile delivery or delivery in rapid bursts of certain drugs. The technology provides the prolonged release and absorption of a drug. The company’s PULSYS product MOXATAG (amoxicillin extended-release) tablets, 775 mg are used for the treatment of pharyngitis/tonsillitis secondary to Streptococcus pyogenes, commonly known as strep throat, for adults and pediatric patients age 12 and older.35

2.      K. Mallikarjuna Rao et al(2011) prepared floating microspheres of amoxycillin trihydrate agaistH.pylorias model drug for prolongation of gastric residence time. The microspheres were prepared by the Non Aqueous solvent diffusion method using polymers hydroxypropylmethyl cellulose and ethyl cellulose.In vitro drug release studies were performed, and drug release kinetics was evaluated using the linear regression method. The prepared microspheres exhibited prolonged drug release (10 h).36

3.      JayeshParmaret al(2010) worked onMultiparticulate systems for oral extended release have been successfully developed and marketed due to their unique manufacturer and patient benefits that are realized. The formulation advantages are release profile modulation and combination therapy, and clinical benefits are ease of swallowing (paediatric and geriatric focus), consistent release profiles and minimal risk of dose dumping. This article will review the critical formulation aspects of multiparticulate core manufacturing considerations with emphasis on barrier membrane coating using ethylcellulose for oral extended release applications.37

4.      Amnon Hoffman et al(1998) developed an oral sustained-release formulation for amoxicillin that maximize the duration of active drug concentration, thus increasing the dosing interval. Due to short biological half-life and limited ‘absorption window’ (confined to the small intestine) with poor colonic absorption, the matrix tablet formulation, composed of hydrophilic (hydroxypropyl methyl-cellulose) polymer. The results suggest that in order to achieve a twice daily dosing regimen that will provide therapeutic concentrations for the whole 12 h dosing intervals, a larger dose of the new formulation should be given (e.g. 750 mg or even 1g twice daily).23

5.      Singhal M. et al(2011) developed extended release antipsychotic oral solid dosage formulation which exhibited better stability, high production feasibility and excellent patient acceptability compared to existing formulation. In the present study, Perphenazine depot tablets were formulated which included aqueous granulation as well as aqueous sustained release coating using different approaches in which different grades of Eudragits.38

6.      Shiva Kumar Yellankiet al (2010) developed a mucoadhesive microsphere which improved drug delivery systems to gastro intestinal tract for treatment of Helicobacter pylori induced peptic and duodenal ulcers, In an effort to augment the anti-Helicobacter pylori effect of Amoxicillin trihydrate mucoadhesive microspheres, which have the ability to reside in the gastrointestinal tract for an extended period. Cumulative percent drug release was found to be maximum for FI (91.12 %). Formulation FII found to follow Higuchi matrix with the regression value of 0.9985.39

7.      Grimmettet al (2005)developed tablet containing a coated core. A tablet formulation which comprises a core containing amoxicillin trihydrate, coated with a release retarding coating, surrounded by a casing layer which includes a another active pharmaceutical substance i.e. potassium clavulanic acid. It such that there is an initial quick release of amoxicillin from the casing layer and a sustained release of amoxicillin and clavunate from the core.40

8.      Ramarajuet al (2011) developed multi-layered modified release formulation comprising amoxicillin and clavulanate. The multilayered modified release formulation comprises: an immediate releae layer comprising amoxicillin and clavulanate; and a slow release layer comprising amoxicillin and one or more release retarding agents; and one or more non-release controlling inert barrier layers placed in between the immediate release layer and slow release layer and comprising one or more pharmaceutically acceptable excipients.41

9.      Gregory E. Amidon, PhD. et al (2007) described different types of diluents, glidants, polymers and surfactants. The properties of excipients that ensure satisfactory and consistent performance often depend on the dosage form, the product, the manufacturing process, and the dosage form performance requirements.42

10.  Igor Legenet al (2006) were worked on different pharmaceutically acceptable excipients as permeation enhancers for a low permeability drug, amoxicillin. As a model for the intestinal epithelium excised rat jejunum, mounted in side-by-side diffusion cells, was used. Among the tested pharmaceutically acceptable excipients only sodium lauryl sulfate (0.2 mg/ml) increased the permeability of amoxicillin in the mucosal-to-serosal direction, which was accompanying with the abolishment of the secretory oriented transport of amoxicillin. Other excipients (0.072 mg/ml Pluronic F68, 0.2 mg/ml Lutrol F127, 0.2 mg/ml Cremophor EL or 0.2 mg/ml Carbopol 934) have no influence on the permeability of amoxicillin.43

11.  M.K.Goyalet al (2010) were preparedfloating microspheres consisting of (i) calcium silicate (CS) as porous carrier; (ii) famotidine and (iii) Hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) as polymers. The floating microspheres were evaluated for particle size, micromeritic properties, percent drug content, in vitro floating behavior, and in vitro drug release. In Vitro Buoyancy percentage of the microspheres was found to be 98.75±3.62 At pH 1.2, drug release from floating microsphere containing amoxicillin formulation AM4 was found to be 98.87 ± 0.67 % at the end of 12 hr. While at pH 7.4, Formulation AM4 released 99.23 ± 0.94 % of drug at 12 hr respectively.44

12.  Raxit Y. Mehta et al (2010) worked on the Utility of Ultra-High Viscosity Hypromellose in Extended Release Matrix Formulations. Hypromellose (HPMC) high viscosity grades K100M and K200M were used to formulate ketoprofen and metformin HCl extended release (ER) tablets. The effects of these two viscosity grades of HPMC on drug release profiles and tablet properties were investigated using 20% to 30% polymer levels. Results indicated that HPMC viscosity did not affect the drug release profiles at either polymer level. The use of HPMC K100M resulted in similar or superior tablet properties compared to HPMC K200M.45

13.  KultidaSongsuranget al (2011) produced Sustained release mucoadhesive amoxicillin tablets with tolerance to acid degradation in the stomach were studied. The sustained-release tablets of amoxicillin were prepared from amoxicillin coated with ethyl cellulose (EC) and then formulated into tablets using chitosan (CS) or a mixture of CS and beta-cyclodextrin (CD) as the retard polymer. The effects of various (w/w) ratios of EC/amoxicillin, the particle sized of EC coated amoxicillin and the different (w/w) ratios of CS/CD for the retard polymer, on the amoxicillin release profile were investigated. The result showed that the release profiles of amoxicillin were greatly improved upon coating with EC, while the inclusion of CD to the CS retardant additionally prolonged the release of the drug slightly. 46

14.  HN Shivakumaret al(2006) were prepared pH sensitive multi-particulate system intended to approximate the chronobiology of angina pectoris is proposed for colonic targeting. The system comprising of Eudragit S-100 coated pellets was designed for chronotherapeutic delivery of diltiazem hydrochloride. The drug loaded core pellets were produced by aqueous extrusion spheronization technique using microcrystalline cellulose as a spheronizing aid and PVP K 30 as a binder. Different coat weights of Eudragit S-100 were applied to the drug loaded pellets in an automatic coating machine to produce the pH sensitive coated pellets. In vitro dissolution studies of the coated pellets performed following pH progression method showed that the drug release from the coated pellets depended on the coat weights applied and pH of the dissolution media.47

15.  MdARahmanet al(2008) prepared multiparticulate formulation of sodium paraaminosalicylate for oral administration was developed by extrusion spheronization technique. Microcrystalline cellulose was used as filler in concentration of 14.4% w/w. Pellets were coated with Eudragit L 30 D-55 using fluidized bed processor. Different weight gains of acrylic polymer were applied onto the pellets and evaluated for in vitro dissolution behavior in 0.1 N HCl for two hours and then media was changed to phosphate buffer pH 6.8. A 60% w/w coating level of Eudragit L30 D 55 has produced the most acceptable results against the gastric attack.48

16.  Hagstadet al(1984) concluded that the bronchial concentration of amoxicillin (dose 500 mg) exceeded the MIC for the sensitive strains of H.influenza. the penetration of amoxicillin in to bronchial secretions was investigated by bronchioscopy.32

17.  Sj: Ovallet al (1985) studied the disposition kinetics of amoxicillin and ampicillin in human volunteers. There was a tendency to more sustained plasma concentrations after amoxicillin which was also proved by a significantly lower mean plasma clearance.32

18.  Watson et al (1986) studied the effect of ingesta on the systemic availability of different penicillins. In fasted dogs ampicillin showed poorer systemic avaibility than did amoxicillin, with Cmax and AUC values of less than half those of amoxicillin. The solid and liquid preparations of amoxicillin had similar bioavailability.32

19.  Arancibiaet al(1987) studied the pharmacokinetics and bioavailability of a controlled release amoxicillin formulation. The results indicated that there was no correlation between the in-vitro dissolution rate and the pharmacokinetic behaviour in the body.32

20.  Sugawara et al(1990) studied the transport characteristics of aminopenicillins (ampicillin and amoxicillin) and found out that the passive transport mechanism contribute a lot in the intestinal absorption of the beta lactam antibiotics.32

21.  MuniyandySaravananet al(2002) studied the different batches of cephalexin extended release tablet were prepared by wet granulation method by using Eudragit L100. The effect of the concentration of Eudragit L100, microcrystalline cellulose and tablet hardness on cephalexin release was studied. The dissolution results showed that a higher amount of Eudragit in tablet composition and higher tablet hardness resulted in reduced drug release. An increased amount of microcrystalline cellulose in tablet composition resulted in enhanced drug release. Tablet composition of 13.3% w/w Eudragit L100 and 6.6 to 8% w/w microcrystalline cellulose with hardness of 7—11 kg/cm2 gave predicted release for 6 h.49

MATERIALS USED

Table: 4.1 List of ingredients used in the different formulation

Sr. no.

Ingredients name

Manufacturer

Supplier

1

Amoxicillin trihydrate

DSM Antiinfective IND.

Vaishali agencies Pvt. Ltd.

2

HPMC K4M

Colorcon Asia Pvt. Limited

Colorcon Asia Pvt. Limited

3

Ethyl cellulose (ETHOCEL STANDARD 7 PREMIUM ID48253)

Colorcon Asia Pvt. Limited

Colorcon Asia Pvt. Limited

4

METHOCEL E6 PREMIUM LV HPMC

Colorcon Asia Pvt. Limited

Colorcon Asia Pvt. Limited

5

PVP k-30

China

Vishal pharma

6

MCC (101)

Gujarat microwax Ltd.

Vishal pharma

7

Magnesium stearate

Komal pharmaceuticals

Vishal pharma

8

Talc

Gangotrti

Vishal pharma

9

Coating I (OPADRY ENTERIC 940580000 WHITE)*

Colorcon Asia Pvt. Limited

Colorcon Asia Pvt. Limited

10

Coating II (OPADRY ENTERIC 95K580000 WHITE)#

Colorcon Asia Pvt. Limited

Colorcon Asia Pvt. Limited

11

Brilliant blue

Asim product

Centurion lab., baroda.

12

Empty hard gelatin capsule shell

Amit enterprises, pithampur.

Gautampharmachem, Vadodara

13

Isopropyl alcohol

Lee changyung chemical corp.

Shriyogeshwar trading co.

14

Methylene chloride

Gujarat Alkalies  Chemical Ltd.

Shriyogeshwar trading co.

HPMC: Hydroxy Propyl Methyl Cellulose,
PVP: polyvinyl pyrrolidone,
MCC: microcrystalline cellulose

*Coating I:mixture of methacrylic acid copolymer (L-100), triethyl citrate, titanium dioxide, and talc,

#Coating II:Mixture of methacrylic acid copolymer (S-100), titanium dioxide, talc and triacetin.

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