2. DRUG AND EXCIPIENT PROFILES AND METHODS USED …shodhganga.inflibnet.ac.in/bitstream/10603/8656/15/15_chapter 2.pdf · 65 2. DRUG AND EXCIPIENT PROFILES AND METHODS USED FOR THE

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2. DRUG AND EXCIPIENT PROFILES AND METHODS USED FOR THE ANALYSIS OF FAMOTIDINE

2.1. Famotidine:

Famotidine is histamine H2 -receptor antagonist.

2.1.1. Synonym: Famotidinum.

2.1.2. Proprietary names1:

Amfamox; Brolin; Dispromil; Famodil; Famodine; Famosan;

Famoxal; Ganor; Gastor; Gastropen; Ifada; Lecedil; Motiax; Pepcid;

Pepcidac; Pepcidin; Pepcidine; Pepdine; Pepdul; Ulcusan; Ulfinol.

2.1.3. Structure of famotidine:

Famotidine is chemically 3-[[[2-[(Aminoiminomethyl) amino]-

4thiazolyl] methyl] thio]-N-(aminosulfonyl) propanimidamide.

2.1.4. Molecular formula: C8H15N7O2S3

2.1.5. Molecular weight: 337.5

2.1.6. Physico-chemical properties:

2.1.6.1. Description:

A white to pale yellowish white crystalline powder with melting

point in the range of 163° C to 164° C.

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2.1.6.2. Solubility:

It is very slightly soluble in water and dehydrated alcohol;

practically insoluble in acetone, alcohol, chloroform, ether and ethyl

acetate; slightly soluble in methyl alcohol; freely soluble in dimethyl

formamide and glacial acetic acid. It dissolves in dilute mineral acids.

2.1.6.3. Storage:

It should be stored in well closed, light resistant container.

2.1.6.4. Dissociation constant:

pKa = 7.06

2.1.6.5. Partition coefficient :

Log P (octanol/water) = −0.64

2.1.7. Pharmacokinetics:

2.1.7.1. Absorption:

Famotidine is readily but incompletely absorbed after oral

administration. Oral bioavailability of famotidine is about 40–50%2,3.

Peak plasma concentration of famotidine in humans is

70.41±30.39 ng/mL4. Peak plasma levels occur in 1-3 hrs following

intravenous3,5,6 and 1-4 hrs following oral administration3,6,7. The

serum therapeutic concentration of famotidine is 20 - 60 ng/mL1,8.

2.1.7.2. Distribution:

The drug is widely distributed in body tissues like kidney, liver,

pancreas and submandibular gland2 and can be detected in breast

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milk. Plasma protein binding of famotidine is 15–20%2,5 and the volume

of distribution of the drug at steady state ranges from 1.0 to 1.3 L/Kg9.

2.1.7.3. Metabolism:

It is metabolized in the liver to form inactive famotidine S-oxide

(S-famotidine). It undergoes minimal first-pass metabolism5.

2.1.7.4. Excretion:

Principally it is excreted in urine2,5,10. 25–30% of famotidine is

excreted as unchanged after oral administration and 65–80% after

intravenous administration2,10. Famotidine has an elimination half life

of 2.5-3.5 hrs2,5,10. A prolongation of elimination half life and a decrease

in total body clearance and renal clearance are observed in patients

with renal failure indicating that dosage adjustment may be necessary

in patients who have renal insufficiency.

2.1.8. Mechanism of action:

H2-receptor antagonists inhibit acid production by reversibly

competing with histamine for binding to H2-receptors on the basolateral

membrane of parietal cells11. Famotidine competitively inhibits

histamine actions at all H2-receptors but its main clinical use is

inhibition of gastric acid secretion. It inhibits histamine stimulated and

gastrin stimulated acid secretion. It decreases both basal and food

stimulated acid secretion by 90% or more, but promotes healing of

duodenal ulcers as shown by numerous clinical trials12.

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2.1.9. Indications and usage:

Famotidine is indicated13 in the following conditions like,

� Short term treatment of active duodenal ulcer.

� Maintenance therapy for duodenal ulcer patients at reduced

dosage after healing of an active ulcer.

� Short term treatment of active benign gastric ulcer.

� Short term treatment of gastro oesophageal reflux disease

(GERD).

� Treatment of pathological hypersecretory conditions

(e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas).

2.1.10. Contraindications:

Famotidine should not be administered to patients with a history

of hypersensitivity to other H2-receptor antagonists.

2.1.11. Drug interactions:

No drug interactions have been identified. Studies with

famotidine in man, in animal models and in vitro have shown no

significant interference with the disposition of drug.

2.1.12. Adverse reactions11:

The overall incidence of adverse effects is low (<3%) and well

tolerated. The most frequent adverse effects include diarrhoea,

dizziness, fatigue, muscle pain, transient rashes, hypergastrinemia.

Less common adverse effects include those affecting the CNS

(confusion, delirium, hallucinations, slurred speech and headache)

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which occur primarily with intravenous administration of the drug. No

major teratogenic risk has been associated with famotidine; caution is

nevertheless warranted when they are used in pregnancy.

2.1.13. Over dosage:

Oral doses of up to 640 mg/day have been given to adult patients

with pathological hyper secretory conditions with no serious adverse

effects.

2.1.14. Dosage and administration:

2.1.14.1. Duodenal ulcer:

In acute therapy, the recommended adult oral dose for active

duodenal ulcer is 40 mg once a day at bedtime. A regimen of 20 mg

twice daily is also effective. For the maintenance therapy an adult dose

of 20 mg once a day at bedtime is recommended.

2.1.14.2. Benign gastric ulcer:

The recommended adult oral dosage for active benign gastric

ulcer is 40 mg once a day at bedtime.

2.1.14.3. Gastro oesophageal reflux disease (GERD):

The recommended oral dosage for adult patients with GERD

symptoms is 20 mg twice daily for up to 6 weeks. The recommended

oral dosage for adult patients with oesophagitis including erosions,

ulcerations and accompanying symptoms due to GERD is

20 or 40 mg twice daily for up to 12 weeks.

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Oral suspension of 0.5 mg/kg up to 8 weeks once daily for

patients less than 3 months of age and twice daily for patients of age

above 3 months up to 1 year.

2.2. Excipients used in the present study:

2.2.1. Polyethylene oxide (PEO)14:

In recent years polyethylene oxide (PEO) has attracted much

attention as a polymeric excipient that can be used in formulations for

different purposes. Formulations with PEO have been extruded to make

different products such as swellable and erodible implants15, scaffolds

for tissue engineering16 or in the production of micelles with

amphiphilic drugs17.

However, PEOs are mostly used to produce

controlled release solid dosage forms such as matrices, reservoirs or

coated cores18-20. PEOs control the release of the active moiety either by

swelling (large molecular weight, >2 MDa) or by eroding and swelling

(small molecular weight, <0.9 MDa), forming a hydrogel in the water. In

both cases, water triggers the process of erosion and/or swelling.

Due to physical and chemical stability, compressibility, high

swelling ability and good solubility in water, PEOs have been proposed

as alternatives to cellulose or other ethylene glycol derivatives in the

production of tablets or granules.

Recently, PEOs have been used in mixtures processed by hot

melt extrusion for the preparation of sustained release mucoadhesive

matrix films21,22. PEO was selected for the development of floating

tablets in combination with sodium bicarbonate due to its high swelling

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ability which facilitate the release of drug through diffusion in a

controlled manner. In the present study, for the first time PEO is being

evaluated as controlled release hydrophilic polymer for the development

of effervescent gastric floating matrix tablets of famotidine.

2.2.1.1. Non proprietary names23:

Polyethylene oxide (USP)

2.2.1.2. Synonyms:

Polyox, Polyoxirane, Polyoxyethylene

2.2.1.3. Description:

It is a white to off-white, free flowing powder with slight

ammonical odor.

2.2.1.4. Formula: C2nH4n+2On+1

PEO is a nonionic homopolymer of ethylene oxide, where ‘n’

represents the average number of oxyethylene groups (about 2000 to

over 100000). It may contain up to 3% of silicon dioxide.

2.2.1.5. Typical properties:

Angle of repose : 34°

Density(true) : 1.3 gm/cc

Melting point : 65-70° C

Moisture content : <1%

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2.2.1.6. Solubility:

It is soluble in water and in a number of common organic

solvents such as acetonitrile, chloroform and methylene chloride and

insoluble in aliphatic hydrocarbons, ethylene glycol and most alcohols.

2.2.1.7. Pharmaceutical applications:

� Used as a tablet binder at a concentration range of 5- 85%

� The higher molecular weight grades provide delayed drug

release via the hydrophilic matrix approach.

� As an excellent mucoadhesive polymer.

� Low levels of PEO are effective thickeners.

� PEO films demonstrate good lubricity when wet. This property

has been utilized in the development of coatings for medical

devices.

� PEO can be radiation cross linked in solution to produce a

hydrogel. The hydrogels so produced have been used in

wound-care applications.

2.2.1.8. Storage conditions:

It should be stored in tightly sealed container in a cool and dry

place.

73

In the present study, effervescent gastric floating matrix tablets

were prepared using two viscosity grades of PEO as matrix forming

polymer for controlled release of famotidine. The grades of polyethylene

oxides used in the present study and their viscosities24 are:

PEO grade Mol. Wt. Viscosity (cps)

WSR 303 7,000,000 7,500 – 10,000 (1% solution)

WSR N-12K 1,000,000 400-800 (2% solution)

2.2.2. Glyceryl behenate25:

Glyceryl behenate is a hydrophobic, non swelling, wax material

commonly used as a lubricant. It consists of a mixture of mono-,

di- and tribehenate of glycerol (18%, 52% and 28% in weight,

respectively). Over the past decade, glyceryl behenate has been used for

controlled release applications by direct compression and more recently

by hot melt coating26-28, melt granulation or pelletization29,30 or the

formation of solid–lipid nanoparticles31. Due to its low density

(0.942 g/cm3) and controlled release nature, it is used for development

of gastric floating matrix tablets of famotidine without the use of

effervescent.

GRAS committee accepted it for use as a food additive in Europe.

Glyceryl behenate was included in the FDA’s inactive ingredients guide

(capsules and tablets) and in the Canadian list of acceptable non-

medicinal ingredients.

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2.2.2.1. Nonproprietary names32:

Glyceryl behenate (USP-NF)

2.2.2.2. Synonyms:

Compritol 888 ATO; 2,3-dihydroxypropyl docosanoate;

docosanoic acid, 2,3-dihydroxypropyl ester; glyceryl monobehenate.

2.2.2.3. Description:

Glyceryl behenate occurs as a fine white to off-white free flowing

powder or hard waxy mass with a faint odor, tasteless, non-reactive

with other formulation ingredients.

2.2.2.4. Formula: C69H134O6

The USP NF 23 describes glyceryl behenate as a mixture of

glycerides of fatty acids, mainly behenic acid. It specifies that the

content of 1-monoglycerides should be 12.0–18.0%.

2.2.2.5. Typical properties:

Molecular weight : 1059.8 gm/mole

Melting point : 65–77° C

Water content (%) : Not more than 0.5%

Acid value : ≤4

Iodine value : ≤3

Saponification value : 145–165

Residue on ignition : ≤0.1%

Heavy metals : ≤0.001%

Content of 1-monoglycerides : 12.0–18.0%

Free glycerin : ≤1.0%

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2.2.2.6. Solubility:

Glyceryl behenate is soluble, when heated, in chloroform and

dichloromethane. It is practically insoluble in ethanol (95%), hexane,

mineral oil and water.

2.2.2.7. Pharmaceutical applications:

Glyceryl behenate is used in cosmetics, foods and oral

pharmaceutical formulations. In cosmetics, it is mainly used as a

viscosity-increasing agent.

Table 2.1: Uses of glyceryl behenate

Use Concentration (%)

Lipophilic matrix or coating for sustained released tablets and capsules

>10.0

Tablet and capsule lubricant 1.0–3.0

Viscosity-increasing agent in silicon gels (cosmetics)

1.0–15.0

Viscosity-increasing agent in w/o or o/w emulsions (cosmetics)

1.0–5.0

In pharmaceutical formulations, glyceryl behenate is mainly used

as a tablet and capsule lubricant33 and as a lipidic coating excipient. It

has been investigated for the encapsulation of various drugs such as

retinoids34. It has also been investigated for use in the preparation of

sustained release tablets35-38, as a matrix-forming agent for the

controlled release of water-soluble drugs38 and as a lubricant in oral

solid dosage formulations and it can also be used as a hot-melt coating

agent sprayed onto a powder39.

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2.2.2.8. Storage conditions:

Glyceryl behenate should be stored in a tightly sealed container

below 35° C temperature.

2.3. Estimation of famotidine:

Analytical methods for the estimation of famotidine that are

available for the estimation in pharmaceutical formulations and

biological fluids include high performance liquid chromatography

(HPLC)40-46, thin layer chromatography47-49, mass spectrometry50-52,

UV-Visible Spectrophotometric method53,54.

2.3.1. Method used for estimation of famotidine in the present study:

UV spectrophotometric method based on the measurement of

absorbance at 265 nm was selected for the in vitro analysis of

famotidine in the present work55. The calibration curve was constructed

in 0.1 N HCl.

2.3.1.1. Stock solution:

50 mg of famotidine was dissolved in sufficient amount of 0.1N

HCl in a 50 mL volumetric flask and the solution was made up to the

mark with 0.1N HCl.

2.3.1.2. Standard solution:

The stock solution was diluted subsequently with 0.1N HCl to get

a series of dilutions containing 2, 4, 6, 8 and 10 µg/mL. The

absorbance of these solutions was measured at 265 nm against blank.

77

All the estimations were done in triplicate and average values are

reported.

2.3.1.3. Results and discussion:

Famotidine is freely soluble in 0.1 N HCl. The concentrations of

famotidine and the corresponding absorbance values are given in

Table 2.2. The standard curve for famotidine was plotted against

concentration and the calibration curve is shown in Fig. 2.1.

Table 2.2: Concentration versus absorbance values for the estimation of famotidine

Concentration (µg/mL)

UV Absorbance (mean ± s.d.)

2 0.090 ± 0.02

4 0.170 ± 0.03

6 0.233 ± 0.12

8 0.314 ± 0.21

10 0.386 ± 0.18

y = 0.0283x + 0.0077r = 0.9989

0.00

0.10

0.20

0.30

0.40

0 2 4 6 8 10

Absorbance

Concentration (µg/mL)

Fig. 2.1: Calibration curve for the estimation of famotidine

The present analytical method obeyed Beer’s law in the

concentration range 2-10 µg/mL and is suitable for the estimation of

78

famotidine. The correlation coefficient (r) was found to be 0.9989,

indicating positive correlation between the concentration of famotidine

and the corresponding absorbance values.

2.3.2. HPLC method for the estimation of famotidine in human plasma samples:

Few HPLC methods have been reported for the estimation of

famotidine in human plasma samples40-46. Most of them are

complicated due to the extraction and evaporation processes.

The HPLC method of Zarghi et al.43, was modified and used for

the estimation of famotidine in human plasma samples obtained in the

in vivo study. In the present study, plasma samples were processed by

protein precipitation method instead of extraction method in order to

avoid the use of organic solvents and protein free plasma samples were

directly injected into the HPLC column.

2.3.2.1. Instrument details:

A gradient HPLC (Shimadzu, Class VP series) with two

LC-10AT VP pumps, variable wavelength programmable Photo Diode

Array (PDA) detector, SPD-M10A VP was used. The HPLC system was

equipped with the Shimadzu LC Solution software (Version 1.12).

Samples were chromatographed on a reversed phase C18 column

(GeminiTM 5µ, 250 x 4.6 mm).

2.3.2.2. Chromatographic conditions:

Methanol and disodium hydrogen phosphate (30 mM, adjusted to

pH 6.8 with phosphoric acid) in the ratio of 75:25 %v/v were used as

79

mobile phase. The mobile phase components were filtered before use

through a 0.45 µm membrane filter and pumped from the respective

solvent reservoirs at a flow rate of 1.0 mL/min. Eluents were monitored

using UV detection at a wavelength of 286 nm. The volume of injection

port was 20 µL.

2.3.2.3. Preparation of stock solution of famotidine:

Stock solution of famotidine was prepared by dissolving 50 mg of

famotidine with methanol in a 50 mL volumetric flask. This stock

solution was suitably diluted with mobile phase to give 100 µg/mL

(intermediate stock solution).

2.3.2.4. Preparation of stock solution of internal standard (IS):

50 mg of the ranitidine (as IS) was dissolved in triple distilled

water in a 50 mL volumetric flask and the solution was made up to

mark. This IS stock solution was diluted with mobile phase to get

10 µg/mL.

2.3.2.5. Procedure:

Plasma standard solutions (15, 30, 45, 90, 180, 270, 360, 450

and 500 ng/mL) of famotidine were prepared by taking 900 µL of drug

free human plasma in 5 mL polyprolylene tubes and 100 µL of

famotidine working standard solutions containing 150, 300, 450, 900,

1800, 2700, 3600, 4500 and 5000 ng/mL (prepared from intermediate

stock solution). 50 µL of IS (10 µg/mL) was added to above solutions

and vortex mixed for 30 seconds using a Remi cyclo mixer. 1 mL of

acetonitrile and 0.5 mL of methanol were added to the above mixtures,

80

for precipitation of plasma proteins. The samples were vortex mixed for

10 minutes and then centrifuged at 4000 rpm for 30 min using Remi

centrifuge. The clear supernatant solution was separated, filtered with

0.45 µm membrane filter and an aliquot of 20 µL was injected directly

into the HPLC loop injector. Similarly, controls of blank plasma (free

from drug) and blank plasma with IS were also processed in same

manner as described above and analyzed.

The quantification of chromatogram was performed using peak

area ratio of the drug to the IS and the average value for five such

determinations is taken. Calibration curve was constructed between the

plasma concentration of famotidine and peak area ratio.

2.3.2.6. Precision, accuracy and recovery:

The intra- and inter-day precision and accuracy of the present

HPLC method were estimated by subjecting the famotidine standard

solutions (30, 180 and 450 µg/mL) to HPLC for five different times on

five different days to HPLC. Precision was calculated by using the

percent relative standard deviation (% RSD or % C.V. = 100 s.d./M

where, M is the mean of the experimentally determined concentrations

and s.d. is the standard deviation of M). Accuracy is defined as the

percent relative error (% RE) and was calculated using the following

formula % RE = 100(E-T)/T where E is the experimentally determined

concentration and T is the theoretical concentration.

The relative analytical recovery for plasma at three different

concentrations of famotidine (30, 180, 450 ng/ml) was determined.

81

Known amounts of famotidine were added to drug free plasma and the

internal standard was then added. The relative recovery of famotidine

was calculated by comparing the peak areas for extracted famotidine

from spiked plasma and a standard solution of famotidine in methanol

containing internal standard with the same initial concentration (five

samples for each concentration level).

2.3.2.7. Results and discussion:

Optimum resolution of famotidine with no interference from other

components in plasma was achieved with the mobile phase used for the

assay. Ranitidine was used as an internal standard. The

chromatograms obtained for blank plasma and plasma spiked with IS

and different concentrations of famotidine are shown in Fig. 2.2.

Retention times of famotidine and IS were found to be 6.45 ± 0.05 and

8.35 ± 0.05 min respectively. The results of peak area ratio of the drug

to the IS are represented in Table 2.3. A representative calibration

curve of famotidine peak area ratio to the IS over the famotidine

concentration range of 0 to 500 ng/mL is shown in Fig. 2.3. The

calibration curve resulted in the linear least squares regression

equation: y = 0.007x - 0.0003, where x is the concentration of

famotidine (ng/mL) and y is the peak area ratio of famotidine to the IS.

A good linear relationship was observed as indicated by correlation

coefficient (r=0.9999) and the limit of detection was found to be

2 ng/mL. This calibration curve was used for the estimation of

famotidine in plasma samples of in vivo studies.

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Fig. 2.2: HPLC Chromatograms of a) human blank plasma, b) plasma spiked with IS, c) famotidine at 15 ng/mL, d) 270 ng/mL and

e) 500 ng/mL

(a)

(c)

(d)

(e)

(b)

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Table 2.3: Concentration versus peak area ratio

of famotidine in human plasma

Concentration of famotidine (ng/mL)

Peak area Peak area ratio Famotidine IS

15 3506 33065 0.11

30 6193 29614 0.21

45 9364 29838 0.31

90 19619 31308 0.63

180 42848 34190 1.25

270 56357 29461 1.91

360 81623 32979 2.47

450 96523 30790 3.13

500 113579 32354 3.51

Fig. 2.3: Calibration curve for the estimation of famotidine in human plasma samples

y = 0.007x - 0.0003r = 0.9999

0

0.5

1

1.5

2

2.5

3

3.5

4

0 200 400

Peak area ratio

Plasma concentrations of famotidine (ng/mL)

84

The results of precision and accuracy are represented in

Table 2.4. High precision and accuracy of the present precipitation

method was confirmed with low percent C.V. values (<5%) and low

% RE values (within ±2) respectively in intra- and inter-day estimation

of famotidine. The percentage recovery values represented in Table 2.5

revealed that this procedure is suitable for the precipitation of plasma

proteins. The results of the study indicated that the method was

sensitive, precise and accurate. Hence this method is used for the

estimation of famotidine in human plasma samples during the in vivo

studies.

Table 2.4: Precision and accuracy of the HPLC method used

for the estimation of famotidine in human plasma samples

Concentration of famotidine

(ng/mL)

Intra-day Inter-day

Mean (%, n=5)

% C.V.

% RE Mean

(%, n=5)

% C.V.

% RE

30 100.7 2.19 1.2 100.3 3.12 1.15

180 101.3 0.95 0.4 101.5 1.59 0.54

450 100.1 2.35 0.9 99.7 3.14 -0.15

Table 2.5: Relative recovery of famotidine from plasma

Famotidine spiked

concentration

(ng/mL)

Famotidine

concentration found

(ng/mL, Mean, n=5)

% recovery

(Mean ± s.d.)

30 30.63 102.1 ± 0.98

180 182.16 101.2 ± 1.52

450 449.51 99.89 ± 3.31

2.4. Studies on interference of famotidine with the excipients used

in the present investigation:

85

In the present investigation, PEO and glyceryl behenate are used

as rate controlling polymer and wax material respectively along with

other excipients (like sodium bicarbonate, Aerosil, magnesium stearate

and lactose) for the development of gastric floating matrix tablets

(GFMT) of famotidine. The excipients used could cause interference in

the estimation of famotidine by UV spectrophotometric method. Hence,

a study was made to check for the interference of the proposed

excipients of the formulations with famotidine.

Accurately weighed amounts of drug and excipients (in 1:1 w/w

ratio) separately were mixed thoroughly in a mortar using pestle. From

each mixture, an accurately weighed powder equivalent to 50 mg of

famotidine was transferred into 50 mL volumetric flask. The drug was

extracted with 40 mL of 0.1N HCl with vigorous shaking on mechanical

shaker for 1 hr and filtered into a 50 mL volumetric flask using

0.45 µm Millipore nylon filter disc. The filtrate was made up to the

mark with 0.1N HCl. Then the solution was suitably diluted with

0.1N HCl and assayed for famotidine by the UV spectrophotometric

method described in Sec. 2.3.1.

2.4.1. Results and discussion:

The results of famotidine estimated in interference study are

shown in the Table 2.6. The results indicated that none of the

materials interfered with famotidine estimation in UV spectroscopic

method. Thus the method was found to be suitable in the present

investigation for the estimation of drug in the in vitro samples.

86

Table 2.6: Percent of drug estimated in interference study

Excipient famotidine estimated (%, mean±s.d., n=3)

PEO WSR 303 100.13 ± 1.02

PEO WSR N-12K 99.29 ± 0.92

Glyceryl behenate 99.93 ± 0.38

Sodium bicarbonate 99.75 ± 1.20

Aerosil 99.84 ± 0.84

Magnesium stearate 99.81 ± 1.02

Lactose 99.89 ± 1.28

2.5. Calculation of initial dose and maintenance dose for the

design of gastric floating drug delivery systems of famotidine for 12 hours:

There are no sustained release formulations for famotidine in the

market, hence the total dose (DT) consisting of initial (DI) and

maintenance doses (DM) for formulating the famotidine sustained

release was calculated as per Robinson and Eriksen equation with a

zero order release principle56. In this profile the rate of delivery is

independent of the amount of drug remaining in the dosage form and

constant over time as shown by the Eq. 2.1.

Drug availability rate k0 = Rate in = Rate out Eq. 2.1

Where, k0 is the zero order rate constant for drug release (amount

per time).

DI is required to give initial rapid release of drug so as to attain

the minimum therapeutic level immediately after dosing.

Eq. 2.2 ( )

=

F

VCD dose Initial

davgss

I

87

Where, Cssavg is the average steady state plasma level, Vd is the volume

of distribution and F is the fraction of dose absorbed.

k0 = DIKel Eq. 2.3

Where, Kel is overall first order drug elimination rate constant (per

hour). Hence k0 should be equal to the elimination rate constant so as

to maintain the steady state condition.

In general the total dose required (DT) is the sum of the

maintenance dose (DM) and the initial dose (DI).

DT = DI + DM Eq. 2.4

In practice, DM (mg) is released over a period of time and is equal

to the product of H (the number of hours for which sustained action is

desired after initial dose) and the zero order rate constant, k0 (mg/hr).

Therefore the Eq. 2.4 can be expressed as

DT = DI + k0H Eq. 2.5

Ideally the maintenance dose (DM) is released after DI has

produced a minimum therapeutic blood level of the drug. However due

to the limits of formulations, drug release even starts from DM also from

the beginning i.e. at t=0, thus increasing the initial drug level in the

blood. Hence it is necessary to reduce the initial dose of the drug to

account for the excess release for drug from DM by using a correction

factor, k0tp. This correction factor is the amount of drug provided by DM

during the period from t=0 to the time of the peak drug level, tp. The

corrected initial dose (DI*) becomes DI-(k0tp). Then the total dose is

DT = DI* + k0H = (DI - k0tp) + k0H Eq. 2.6

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2.5.1. Pharmacokinetic parameters of famotidine:

Elimination half life (t1/2) of famotidine is 3 hrs (average of 2.5 to

3.5 hrs), the time to reach peak plasma (tp) is 2 hrs and Vd = 91 L and

F = 0.49,11. From the literature of the PEPCID (innovator product of

famotidine in USA) label and pharmacological review information4,6, it

was found that the plasma levels after multiple doses are similar to

those after single doses indicating the Cmax is similar to Cssavg, therefore

Cmax of 0.07 mg/L was taken as Cssavg.

2.5.2. Calculation of DI and DM:

The initial dose (DI), corrected initial dose (DI*), maintenance dose

(DM) and total dose (DT) were calculated according to calculations

described above.

2.5.2.1. Calculation of elimination rate constant:

Elimination rate constant (Kel) = 0.693/t1/2

= 0.693/3 = 0.231 hr-1

2.5.2.2. Calculation of initial dose:

= (0.07 X 91)/0.4

= 15.93 mg

2.5.2.3. Calculation of desired input rate (k0):

Desired input rate from maintenance dose (k0) = DIKel

( )

=

F

VCD dose Initial

davgss

I

89

= 15.93 X 0.231 = 3.68 mg/hr

2.5.2.4. Calculation of maintenance dose:

Maintenance dose (DM) = k0H (Since, H = the number of hours for

which sustained action is desired after initial dose = (12-1) = 11 hrs)

= 3.68 X 11 = 40.48 mg

2.5.2.5. Calculation of corrected initial dose DI*:

DI* = DI – (k0tp) = 15.93 – (3.68 X 2) = 8.57 mg

2.5.2.6. Calculation of total dose:

Total dose (DT) = DI* + DM

= 8.57 + 40.48 = 49.05 mg

From the above calculations the total dose obtained for sustained

release of famotidine for 12 hrs is 49.05 mg. The total dose was

rounded off to 50 mg for the convenience. Initially the dosage form

should release the total initial dose (i.e. 8.57 mg ~ 9.0 of drug, means

18% of total 50 mg dose) in the first 1 hr followed by maintenance dose

(i.e. 50-9=41 mg of drug) for up to 12 hrs thereafter at a release rate of

3.68 mg/hr (i.e. 7.36% of total 50 mg dose). Based on these

assumptions the theoretical release profile was predicted and shown in

Table 2.7 and Fig. 2.4

90

Table 2.7: Predicted theoretical release profile

Time (hrs) % drug release

1 18 2 25 3 33 4 40 5 47 6 55 8 70 10 84 12 99

Time (hrs)

% drug release

0 3 6 9 120

20

40

60

80

100

Fig. 2.4: Predicted theoretical release profile

91

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