CHAPTER 1

1.1 INTRODUCTION

Dosage forms refer to the different means by which drugs are being taken into the body in

order to exert specific functions. They may be classified according to the route of

administration or physical form. Among different choices, oral dosage forms are usually the

most convenient choice. As known worldwide, taking a medicine via oral route is one of the

best options. As it is the simplest and easiest way for any patient to take a medication.

Advantages of using the oral route of administration include:

Appropriate for any patient, whatever the age is.

The most natural and easiest route of administration.
Includes a big variety of dosage forms.
Economical and safe to the patient.
No nursing is required, which means the patient can take it with no assistance.
Toxicity is delayed due to the late onset of action which permits easier recovery than

is the case with other dosage forms.

The disadvantages of oral dosage form use include:

Delayed onset of action because absorption takes time.

Not suitable for unconscious patients.
Not convenient for a patient with a gastrointestinal disorder such as diarrhoea,

constipation, ulceration, and hyperacidity in stomach.

Sometimes, the medication itself is the cause of such problems in the GIT like aspirin

and many NSAIDs which may lead to ulcers in the stomach upon recurrent usage on

the long run.

Not convenient if the patient suffers malabsorption syndrome in which absorption

through small intestine is impaired.

Not adequate for medications liable to inactivation or destruction in the GIT. E.g.

insulin is a protein, if taken orally, its digested in the stomach like the protein present

in food such as meat and fish.

1
 Not a good choice in case of uncooperative patients as children and infants.
Not appropriate if the patient suffers chronic vomiting.

The most common oral dosage forms are tablets. There are various shapes, sizes and colours

of tablets. They are present in different forms such as the chewable, or the simple one you

swallow. (Taha, 2014)

1.1.1 SURFACTANTS

Some compounds, like short-chain fatty acids, are amphiphilic or amphipathic, i.e., they have

one part that has an affinity for nonpolar media and one part that has an affinity for polar

media. These molecules form oriented monolayers at interfaces and show surface activity (i.e.

they lower the surface or interfacial tension of the medium in which they are dissolved). In

some cases, surfactants are defined as molecules capable of associating to form micelles.

These compounds are termed surfactants, amphiphiles, surface-active agents, tensides, or, in

the very old literature, paraffin chain salts. (Laurier L. Schramm et al., 2003)

The addition of a surfactant into a tablet formulation appears to be an attractive method of

improving the drug release rate. The improved rate is often associated with the effect of the

surfactant increasing the hydrophilicity of the dosage form thereby promoting drug

dissolution. It follows that the action of surfactant improving drug dissolution from tablets

may be attributed to the action of the surfactant producing fine disintegrated particles with

correspondingly larger surface area for dissolution. Thus this study has been design to

investigate the effect of surfactant on the in vitro dissolution profile of paracetamol relative to

batches formulated without surfactants.

1.2 LITERATURE REVIEW

2
Surfactants otherwise called surface-active agents are molecules and ions that are adsorbed at

the interfaces. An alternative expression is amphiphile, which suggests that the molecule or

ion has a certain affinity for both polar and non-polar solvents. Depending on the number and

nature of the polar and non-polar groups, the amphiphile may be predominantly hydrophilic,

lipophilic or reasonably well-balanced between the two extremes. It is the amphiphilic nature

of surface active agents which causes them to be adsorbed at interfaces, whether these be

liquid/gas or liquid/liquid.

Depending on their charge characteristics, surfactants may be anionic, cationic, zwitterionic

(ampholytic) or non-ionic. Examples of surfactants that are used in pharmaceutical

formulation are as follows:

Anionic surfactants: Sodium Lauryl Sulphate BP: is a mixture of sodium alkyl

sulphates, the chief of which is sodium dodecyl sulphate, C12H25SO4Na+, is very

soluble in water at room temperature, and is used pharmaceutically as a preoperative

skin cleaner, having bacteriostatic action against gram-positive bacteria, and also in

medicated shampoos is a component of emulsifying wax.

Cationic surfactants: The quaternary ammonium and pyridinium cationic surfactants

are important pharmaceutically because of their bactericidal activity against a wide

range of gram-positive and some gram-negative organisms. They may be used on the

skin, especially in the cleaning of wounds. Their aqueous solutions are used for

cleaning contaminated utensils.

Non-ionic surfactants:
Sorbitan esters are supplied commercially as Spans and are mixtures of the partial

esters of sorbitol and its mono- and di-anhydrides with oleic acid. They are generally

insoluble in water (low hydrophilelipophile balance (HLB) value) and are used as

water-in-oil emulsifiers and as wetting agents.

3
 Polysorbates are complex mixtures of partial esters of sorbitol and its mono and di-

anhydrides condensed with an approximate number of moles of ethylene oxide. They

are supplied commercially as Tweens. The polysorbates are miscible with water, as

reflected in their higher HLB values, and are used as emulsifying agents for oil-in-

water emulsions. (Martin)

Paracetamol (Acetaminophen):

Figure 1. Chemical structure of paracetamol

Paracetamol, acetaminophen of chemical name N-acetyl-p-aminophen is one of the most

commonly used over-the-counter (OTC) medications for the relieve of pain; in which it

serves as an analgesic and also for relieve of fever; in which it serves as an anti-pyretic. In

combination with opioid analgesics, paracetamol can also be used in the management of more

severe pain such as post-surgical pain and providing palliative care in advanced cancer

patients. Though paracetamol is used to treat inflammatory pain, it is not generally classified

as an NSAID because it exhibits only weak anti-inflammatory activity.

4
While generally safe for use at recommended doses (1,000 mg per single dose and up to

4,000 mg per day for adults), even small overdoses can be fatal.

The onset of analgesia is approximately 1129.5 minutes after oral administration of

paracetamol and its half-life is 14 hours.

Paracetamol (Acetaminophen) was considered as one of the safest and most frequently used

analgesic and antipyretic drug all over the world. However, many problems and concerns

associated with its use appeared with time.

Paracetamol during pregnancy and risk of male foetus infertility:

A controversial issue suggested by a new European study about paracetamol and other mild

analgesics that women who use these drugs during pregnancy may increase the risk that their

male children will grow up to be infertile. The prospective cohort study included 2297

Danish and Finnish pregnant women reporting on their use of mild analgesics during

pregnancy. The testicular position of new-borns was assessed by trained paediatricians. The

study concluded that there was an association between the timing and the duration of mild

analgesic use during pregnancy and the risk of cryptorchidism. These findings were

supported by anti-androgenic effects in rat models leading to impaired masculinization. The

results suggest that intrauterine exposure to mild analgesics is a risk factor for development

of male reproductive disorders. (KADIC, 2010)

Acetaminophen toxicity:

Acetaminophen is metabolised in the liver. Acetaminophen (paracetamol) toxicity is a

common cause of drug-induced hepatotoxicity in children and adults. N-acetylcysteine

(NAC) has been used for several decades and has proven to be the antidote of choice in

treating acetaminophen-induced hepatotoxicity. (Algren, 2008) Acetaminophen-induced

5
hepatotoxicity is usually related to exceeding the maximum daily dose which is 4grams. It is

a leading cause of drug-induced liver injury. (Pan, 2009)

Paracetamol has a melting point of 169oC and a density of 1.263g/cm3

1.2.1 Mechanism of action of Paracetamol:

As an antipyretic:

The antipyretic effects of acetaminophen is complex and repress inflammatory signals at

many levels. Although COX enzyme inhibition plays a central role in the antipyretic actions

of this drug, other immune-modulatory actions appear to contribute.

As our understanding of these medications deepens, indications for its use in treating febrile

patients may also change. (David M. Aronoff, 2001)

As an analgesic:

The precise analgesic action of acetaminophen remain unsure but its becoming clear that the

predominant mechanisms largely responsible for acetaminophens analgesic activity are

located in the CNS. Also, it appears that there may be multiple mechanisms (which may be

interlinked) which may contribute to acetaminophens analgesic activity. A greater

understanding of how acetaminophen provides pain relief may lead to optimal analgesia as

well as improved utilization of analgesic polypharmacy. (Smith, 2009)

1.2.2 Pharmacokinetics of Paracetamol:

Acetaminophen has low first-pass metabolism and the hepatic extraction ratio is 0.110.37 in

adults. The relative bioavailability of rectal compared with oral acetaminophen formulations

(rectal/oral) has been reported as 0.52 (range 0.240.98) and even as low as 0.3. The relative

6
bioavailability is higher in neonates and approaches unity. The relative bioavailability of

rectal formulations appears to be age related.

Rate of absorption Acetaminophen has a pKa of 9.5 and in the alkaline medium of the

duodenum, acetaminophen is non-ionized. Consequently, absorption of the non-ionized form

from the duodenum to the systemic circulation is rapid in children have reported rapid

absorption (T1/2abs 2.7, se 1.2 min; Tlag 4.2, se 0.4 min) parameters in febrile children given

elixir orally. Similar absorption half-lives have been estimated in children given

acetaminophen as an elixir before tonsillectomy (T1/2abs 4.5 min, CV 63%, Tlag 0).

Absorption in infants under the age of 3 months was delayed 3.68 times, consistent with

delayed gastric emptying in young infants. Oral absorption was considerably delayed in

premature neonates in the first few days of life. Rectal absorption is slow and erratic with

large variability. For example, absorption parameters for the triglyceride base were T1/2abs

1.34 h (CV 90%), Tlag 0.14 h (31%). The absorption half-life for rectal formulations was

prolonged in infants under 3 months (1.51 times greater) compared to those seen in older

children. Several clearance studies confirm sulphate metabolism to be the dominant route of

elimination in neonates.

Glucuronide/sulphate ratios range from 0.12 in premature neonates of 2832 weeks post-

conception, 0.28 in those at 3236 weeks post-conception to 0.34 in term neonates 02 days

old. Ratios of 0.75 in children 39 years, 1.61 in those aged 12 years and 1.8 in adults are

reported. Approximately 4% of acetaminophen is excreted in urine unmetabolized and the

amount is dependent on urine flow. A total body clearance in full-term neonates of 4.9 (CV

38%) L/h/70kg after enteral acetaminophen has been reported using an allometric 3/4 power

model. This clearance is approximately 40% that of older children (215 years). Clearance

over the first year of life reaches 80% of that seen in older children by 6 months. Further

investigation using published data from premature neonates confirmed this trend in the very

7
young. Clearance increased from 28 weeks post-conception (0.74 L/h/70 kg) with a

maturation half-life of 11.3 weeks to reach 10.9 L/h/70 kg by 60 week. Volume of

distribution. The population distribution volumes in children are similar to those reported in

adults (5670 L). The volume of distribution for acetaminophen in mammals, including

humans, is 4970 L/70 kg as we would expect from the allometric size model with a power

function of 1. The volume of distribution decreases exponentially with a maturation half-life

of 11.5 weeks from 109.7 L/70 kg at 28 weeks post-conception to 72.9 L/70 kg by 60 weeks.

Foetal body composition and water distribution alter considerably during the third trimester

and over the first few months of life, probably reflecting neonatal body composition and the

rapid changes in body water distribution in early life. Parenteral formulation Propacetamol

(N-acetylparaaminophenoldiethyl aminoacetic ester) is a water-soluble pro-drug of

acetaminophen that can be administered intravenously over 15 min. It is rapidly hydroxylated

into acetaminophen (1 g propacetamol = 0.5 g acetaminophen). An alternative intravenous

acetaminophen formulation is now available that does not require hydrolysis and is associated

with less pain on injection. (Brian J. Anderson, 2007)

1.2.3 Below is a summarized product description of paracetamol:

Common use:

Paracetamol is applied as an analgesic and antipyretic. It reduces fever and relieves pain.

8
In combination with other medicines paracetamol could be used in other cases. It can be also

prescribed to patients for whom NSAIDs are contraindicated.

Dosage and direction:

Take Paracetamol by mouth with a glass of water, with or without food. Avoid cutting,

crushing or chewing this medicine.

Do not take the medicine more often than it is prescribed. Do not give up taking it except on

the advice of your doctor.

It may need time for the medicine to help.

Consult your doctor concerning proper dose for you.

Precautions:

Before taking Paracetamol tell your doctor or chemist if you are allergic to it; or if you have

other allergies.

Avoid drinking alcohol and smoking while being treated with this medication.

Aged people can be more sensitive to side effects of the medicine.

Inform your doctor if you have kidney or liver problems, high blood pressure; if you are

pregnant or breast-feed.

Contraindications:

Paracetamol should not be used by patients having demonstrated a reaction of

hypersensitivity to it.

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Possible side effect:

The usage of Paracetamol rarely brings to side effects. But prolonged or habitual use of it

may lead to liver damage or failure.

Many people using this medicine do not have serious side effects.

Turn to your doctor or pharmacist for more details.

In case you notice the effects not listed here, contact your doctor or pharmacist.

Drug interaction:

Tell your doctor or pharmacist of all prescription and non-prescription/herbal products you

may use before using this medication.

Paracetamol can interact with:

* NSAIDs of the salicylate family (Aspirin)

* medicines for pain and inflammation (ibuprofen or naproxen)

* medicines that treat or prevent blood clots (warfarin)

* oral contraceptives.

Turn to your doctor or pharmacist for more details.

Missed dose:

If you have missed your dose, take it as soon as you remember. If you see that it is near the

time for the next dose, skip the missed dose and resume your usual dosing schedule. Do not

take your dose twice.

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Overdose:

If you think you have used too much of this medicine seek emergency medical attention right

away. The symptoms of overdose usually include chest pain, nausea, irregular heartbeat, and

feeling light-headed or fainting.

Storage:

Store your medicines at room temperature between 68-77F (20-25C) away from light and

moisture. Do not store your drugs in the bathroom. Keep all drugs away from reach of

children and pets. (Pharma, 2013)

1.2.4 REVIEW OF PREVIOUS RELATED STUDIES

A. The effect of various surfactants on release behaviour of Procainamide

Hyrdochloride from ethylcellulose-based matrices:

Matrices containing 100mg Procainamide Hydrochloride were prepared using different

percentages of surfactants, anionic (sodium lauryl sulphate and sodium stearate) cationic

(cetylpyridinium chloride and cetyltrimethyl ammonium bromide) and non-ionic (span 60

and tween 80). Dissolution studies alone were done using paddle method at 501 rpm.

Dissolution media were 1000ml 0.1N HCl (pH=1.2) and phosphate buffer solution (pH=7.2)

at 370.5C. Anionic surfactants with good solubility can improve the wettability of tablets in

the dissolution medium. Cationic surfactants lower the interfacial tension between the tablet

matrix and the dissolution medium, also they act as wicking agents, causing fluid to enter the

dosage form, it may then dissolve and form pores, through which the drug release may be

affected. Use of different percentages of span 60 has no effect on release rate constant, this

can be due the lower solubility and wettability of this surfactant.

11
In summary, the release rate of the drug was distinctly reduced by incorporation of anionic

surfactants in matrix formulations. This is because SLS and SS are able to form poorly water-

soluble complexes with the drug. In the case of cationic surfactants, the drug release rate was

significantly increased. Non-ionic surfactants had no notable effect on the release rate

although the release rate was dependent on the HLB values, as found to increase slightly in

the presence of hydrophilic non-ionic surfactants. (Noushin Bolourtchian et al., 2005)

B. In-vitro release of Paracetamol from suppocire suppositories; role of additives:

The following surfactants were used:

Sodium lauryl sulphate (0.5% and 1%)

DOSS (0.5% and 1%)
CPGMC (2% and 5%)
Span 80 (2%)
Labrasol (2% and 5%)

on suppocires D, C, NCX and CP bases in white coloured suppositories containing 250mg of

Paracetamol.

Upon melting point determination of the suppositories, addition of surfactants did not show

and change in melting point of suppositories prepared using suppocire D and NCX but in the

case of suppocire C, it was marginally increased compared to that of plain suppocire C

suppositories. In the case of suppocire CP, the melting point range was decreased by addition

of CPGMC up to 37-38C and for other additives, it remained the same.

Upon hardness testing, addition of surfactants showed a decrease in hardness of suppository

whereas it remained unaffected for some suppocire suppositories

Upon dissolution testing, addition of surfactants markedly increased the drug release.

Addition of Labrasol with increasing concentration from 2% to 5% was associated with a

significant increase in drug release. (Shegokar Ranjita and Kamalinder, 2010)

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 C.
Effect of various surfactants and their concentration on controlled release of

captopril from polymeric matrices:

Surfactants used include SLS, CTAB and Arlacel 60. The release rate of captopril from the

matices was generally decreased by the anionic surfactant. As captopril has two pKa values

3.7 (weak acid) and 9.8 (very weak acid) the drug will be in cationic form (about 99%) at pH

1.2 possessing the ability of complex formation with anionic surfactant SLS. Thus SLS is

expected to retard the release rate of captopril at pH 1.2. At pH 6.8, captopril has a negative

charge on the carbonyl group and a positive charge on the nitrogen. Therefore, SLS is still

able to interact with the cationic group to make a complex. In addition, the enhanced

viscosity of the gel layer surrounding the matrix, which leads to the reduction in the release

rate of drugs.

The release of captopril from matices containing Arlacel 60 as non-ionic surfactant was not

affected significantly, it could be concluded that wetting doesnt play a significant role in the

dissolution process and that the minor acceleration or retardation observed with the

incorporation of CTAB and SLS might be due to the surfactant dissolving and forming

pores/channels which increases the effective surface area by a method other than wetting.

Two possible mechanisms have been postulated as to why surfactants increase the rate of

drug release from matrix formulations. Firstly, it is possible that the surfactant lower the

interfacial tension between the product and the dissolution fluid, secondly, it is possible that

the surfactant acts as a wicking agent, causing the fluid to enter the dosage form, the

surfactant may then dissolve and form pores (or other disruptions) from which the drug

release may be affected. (Nokhodchi Ali et al., 2008)

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1.3 AIMS AND OBJECTIVES

Aim: To investigate the effect of surfactants on the in-vitro release of paracetamol tablets.

Objective:

Formulation of paracetamol tablets containing different surfactants.

Carrying out quality tests on the formulated tablets.

Investigate the effect of anionic, cationic and non-ionic surfactants on the release of

paracetamol from the formulated tablets.

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1.4 JUSTIFICATION

Algesia is a very common phenomenon to everyone irrespective of age, owing firstly to the

fact that it is a common symptom of almost all diseases ranging from non-communicable to

communicable diseases. Algesia in itself can be mild and self-limiting but in some cases, it

progresses into serious pain and also sometimes, it can be over-looked by a patient during

which it progresses into serious diseases such as rheumatoid arthritis, osteoarthritis etc. Drugs

used to treat Algesia are generally classified as analgesics for which paracetamol

(acetaminophen) is a common example.

Due to the uncomfortable nature of algesia, it becomes imperative that medications are

produced which offer a quicker relief. The addition of surfactants to paracetamol tablets is a

very good measure to achieving this.

CHAPTER 2

2.1 Materials and Methodology:

Table 1. Formula for the preparation of paracetamol tablets

Ingredient 1 tablet 700 tablets

Paracetamol 300mg 210g
Surfactant 5%w/w 22.75g
Acacia mucilage 20%w/w 39ml
Starch 5%w/w 22.75g
Lactose 267.5mg 187.6g

15
Weight of acacia used:

Density of acacia = Mass/Volume

Density = 1.075g/ml

Mass of acacia = Xg

Volume of acacia used = 39ml

Therefore; Mass or weight of acacia used = Density Volume = 1.075 39 = 41.925g.

Formulations:

Batch 1: Tablets without surfactant.

Batch 2: Tablets with Cetryltrimethylammoniumbromide (CTAB)
Batch 3: Tablets with Sodium Stearate (SS)
Batch 4: Tablets with Tween 80.

2.1.1 GRANULATION (WET GRANULATION) AND COMPRESSION:

Pure Paracetamol powder, starch and Lactose weighing 210g, 22.75mg and 187.6g

respectively were transferred into a porcelain mortar to produce different batches of the

Paracetamol tablets with 22.75g, 22.75g, 21.20ml of CTAB, SS and tween 80 used as

surfactants in 3 batches respectively. The wet mass of granules were screened using sieve of

mesh number 8 and dried in a hot-air oven at 30C for 30 minutes. The dry mass of granules

were screened using sieve of mesh number 16 and dried in the hot-air oven at 50C for 1

hour. 1% Talc was added to the different batches of granules after which the granules were

compressed into tablets using the DP30 Single Punch Tablet Press.

16
(Pharmacopoeia, 2013)

2.1.2 PREPARATION OF PHOSPHATE BUFFER OF pH 5.8:

Solutions containing 225ml of 0.2M sodium dihydrogen orthophosphate and 16.74ml of

standardized 0.2M sodium hydroxide were measured with volumetric flasks and diluted to

900 ml in a 900ml measuring cylinder with water. (Pharmacopoeia, 2013)

PREPARATION OF 0.1M Sodium Hydroxide (NaOH):

40g of NaOH in 1000ml = 1M NaOH

4g of NaOH in 100ml = 1M NaOH

0.4g of NaOH in 100ml = 0.1M NaOH

PREPARATION OF 0.2M Sodium dihydrogen orthophosphate (NaH2PO4.H2O):

156g of NaH2PO4.H2O in 1000ml = 1M NaH2PO4.H2O

15.6g of NaH2PO4.H2O in 100ml = 1M NaH2PO4.H2O

3.12g of NaH2PO4.H2O in 100ml = 1M NaH2PO4.H2O

PREPARATION OF 0.2M Sodium Hydroxide (NaOH):

40g of NaOH in 1000ml = 1M NaOH

4g of NaOH in 100ml = 1M NaOH

0.8g of NaOH in 100ml = 0.2M NaOH

2.1.3 DISSOLUTION TEST:

A solution containing 900ml of phosphate buffer pH 5.8 was prepared to be used as the

dissolution medium, one tablet was placed in each basket of the Erweka DT6 dissolution

tester and the paddle rotated at 50 revolutions per minute at a temperature of 370.1C (under

sink conditions). 20 ml samples were withdrawn from the medium and filtered at times 10,

17
20, 30, 40, 50 and 60 minutes. The absorbance of the solutions, diluted with 0.1M NaOH,

were measured at the maximum at 257 nm using 0.1M sodium hydroxide in the reference cell

in a T90+ UV/VIS spectrophotometer.

2.1.4 FRIABILITY TEST:

Whole tablets from each batch were dusted and weighed and placed in the drum of the

Erweka TA20 friability tester. The drum was rotated for 4 minutes and the whole tablets

removed, dusted and weighed again. The percentage friability was calculated using the

equation:

(W1 W2) / W1 100

Where;

W1 = Weight of tablets before testing.

W2 = Weight of tablets after testing.

According to the United States Pharmacopoeia, the limit is not more than 4%.

(Pharmacopoeia, 2013)

2.1.5 UNIFORMITY OF WEIGHT:

Up to 20 whole tablets were selected at random and the individual weights determined using

the Adam PW124 weighing balance. Not more than 2 of the individual weights deviated from

the average weight by more than the percentage deviation shown in the table below and none

deviated by more than twice that percentage: (Pharmacopoeia, 2013)

Table 2. Allowable percentage deviation of tablets

Average weight of tablets Percentage Deviation

50mg or less 10

18
 More than 80mg or less than 250mg 7.5
250mg or more 5

2.1.6 DISINTEGRATION TEST:

Up to 6 tablets from each batch were placed in each of the six tubes of the basket and a disc

was added to each tube and the Erweka ZT3 disintegrating time tester operated using water

maintained at 372C as the immersion fluid. All the tablets for each batch disintegrated

completely within 15 minutes. (Pharmacopoeia, 2013)

2.1.7 ASSAY OF PARACETAMOL TABLETS:

Up to 20 tablets were powdered and a quantity of the powder containing 0.15g of

paracetamol was weighed and transferred into 50ml of 0.1M NaOH, and then diluted with

100ml of water in a 200ml volumetric flask. The solution was shaken for 15 minutes after

which sufficient water was added to make up to the 200ml mark. The solution was filtered

after which 10ml of the filtrate was diluted with water to 100ml using a 100ml volumetric

flask. 10ml of the solution was measured and added to 10ml of 0.1M NaOH, after which it

was diluted to 100ml with water in a 100ml volumetric flask. The absorbance of the solution

produced was measured using a T90+ UV/VIS Spectrophotometer at the maximum of

257nm. (Pharmacopoeia, 2013)

2.1.8 CALIBRATION OF THE UV/VIS SPECTROPHOTOMETER:

Six concentrations of paracetamol powder calculated to have an absorbance between 0.2-0.8

were prepared and their absorbance read at a wavelength of 257nm.

Preparing concentrations with absorbances between 0.2 and 0.8

A = abc

A = 0.2

19
a = 715

b = 1cm

c=?

Therefore, c = A/ab = 0.2/(715 1) = 0.00028% w /v

If A = 0.8

a = 715

b = 1cm

c=?

Therefore, c = A/ab = 0.8/(715 1) = 0.00012% w /v

Concentrations are then selected from within the range of 0.00028% w /v and 0.00012%

w /v .

CHAPTER 3

3.1 RESULTS

3.1.1 UNIFORMITY OF WEIGHT:

Table 3. Results of the uniformity of weight test on batch 1

Number Weight (g) Deviation Percentage

Deviation (%)
1 0.4557 -0.0532 -10.4539
2 0.4940 -0.0149 -2.9279
3 0.5065 -0.0024 -0.4716
4 0.5076 -0.0013 -0.2555
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5 0.5290 0.0201 +3.9497
6 0.5117 0.0028 +0.5502
7 0.5744 0.0655 +12.8709
8 0.5357 0.0268 +5.2663
9 0.5123 0.0034 +0.6681
10 0.5194 0.0105 +2.0633
11 0.4852 -0.0237 -4.6571
12 0.4585 -0.0504 -9.9037
13 0.5040 -0.0049 -0.9629
14 0.4979 -0.0110 -1.9650
15 0.5862 0.0773 +15.1896
16 0.5070 -0.0019 -0.3733
17 0.5007 -0.0082 -1.6113
18 0.4579 -0.0510 -10.0216
19 0.5467 0.0378 +7.4278
20 0.5039 -0.0050 -0.9825

Average weight of tablets = 0.5089

Table 4. Results of uniformity of weight test on batch 2

Average weight of tablets = 0.5657g

Number Weight (g) Deviation Percentage Deviation (%)

1 0.5564 -0.0093 -1.6715
2 0.5101 -0.0556 -9.8285
3 0.5932 0.0275 +4.8612
4 0.5770 0.0113 +1.9975
5 0.4952 -0.0705 -12.4624
6 0.5841 0.0184 +3.2526
7 0.5044 -0.0613 -10.8361
8 0.5856 0.0199 +3.5178
9 0.5460 -0.0197 -3.4824

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10 0.5862 0.0205 +3.6238
11 0.5848 0.0191 +3.3763
12 0.5481 -0.0176 -3.1112
13 0.6135 0.0478 +8.4497
14 0.5775 0.0118 +2.0859
15 0.5908 0.0251 +4.4370
16 0.5906 0.0249 +4.4016
17 0.5824 0.0167 +2.9521
18 0.5633 -0.0024 -0.4242
19 0.5388 -0.0269 -4.7552
20 0.5871 0.0214 +3.7830

Table 5. Results of uniformity of weight test on batch 3

Average weight of tablets = 0.5746g

Number Weight (g) Deviation Percentage Deviation (%)

1 0.5584 -0.0162 -2.8193
2 0.5883 0.0137 +2.3843
3 0.5578 -0.0168 -2.9238
4 0.5693 -0.0053 -0.9224
5 0.5666 -0.0080 -1.3923
6 0.5678 -0.0068 -1.1834
7 0.5788 0.0042 +0.7309
8 0.5631 -0.0115 -2.0014

22
9 0.5799 0.0053 +0.9224
10 0.5960 0.0214 +3.7243
11 0.5679 -0.0067 -1.1660
12 0.6038 0.0292 +5.0818
13 0.5998 0.0252 +4.3857
14 0.5802 0.0056 +0.9746
15 0.5825 0.0079 +1.3749
16 0.5929 0.0183 +3.1848
17 0.5523 -0.0223 -3.8810
18 0.5691 -0.0055 -0.9572
19 0.5644 -0.0102 -1.7751
20 0.5613 -0.0133 -2.3146

Table 6. Results of uniformity of weight test for batch 4

Average weight of tablets = 0.5651g

Number Weight (g) Deviation Percentage Deviation (%)

1 0.5085 -0.0566 -10.0159
2 0.5293 -0.0358 -6.3352
3 0.5624 -0.0027 -0.4778
4 0.5799 0.0148 +2.6190
5 0.5285 -0.0366 -6.4767
6 0.5082 -0.0569 -10.0690
7 0.5690 0.0039 +0.6901

23
8 0.5361 -0.0290 -5.1318
9 0.5490 -0.0161 -2.8490
10 0.5644 -0.0007 -0.1239
11 0.5007 -0.0644 -11.3962
12 0.5682 0.0031 +0.5486
13 0.5284 -0.0367 -6.4944
14 0.5833 0.0182 +3.2207
15 0.5044 -0.0607 -10.7415
16 0.5465 -0.0186 -3.2915
17 0.5523 -0.0128 -2.2651
18 0.6032 0.0381 +6.7422
19 0.5877 0.0226 +3.9993
20 0.5691 0.0040 +0.7078

3.1.2 DISINTEGRATION TEST:

Table 7. Results of disintegration tests carried out on each batch of tablets.

Batch Time per tablet

1 12 seconds

2 2 minutes 25 seconds

3 2 minutes 9 seconds

4 1 minute 57 seconds

3.1.3 FRIABILITY TEST:

Sample calculation using batch 1:

Weight before test = 6.5539g

Weight after test = 6.3106g

24
Percentage friability = (6.5539 6.3106)g/6.5539g 100 = 0.2433g/6.5539g 100 = 3.7%

Table 8. Results of the friability test done on each batch of tablets

Batch Percentage friability

1 3.7%
2 1.0%
3 0.2%
4 0.2%

Table 9. Summary of results of some of the quality analysis.

Batch Test
Hardness Friability Uniformity of weight Disintegration
1 Pass 3.7% (failed) Pass Pass
2 Pass 1.2% Pass Pass
3 Pass 0.2% Pass Pass
4 Pass 0.2% Pass Pass

3.1.4 ASSAY OF PARACETAMOL TABLETS:

Sample calculation using batch 1:

0.3g of paracetamol is contained in 0.5089g of paracetamol tablet powder

0.15g of paracetamol is contained in 0.2545g of paracetamol tablet powder

Absorbance: 0.548

Using; A = abc
25
Where;

a = specific absorbance (A 1%, 1cm)

b = thickness of couvette

c = concentration

A = absorbance

Therefore; 0.548 = 715 1 c; c = 0.00077%w/w

Expected concentration = 0.00075%w/w

Percentage content = (0.00077/0.00075)%w/w 100 = 102.7%

Table 10. Percentage content of the paracetamol in the paracetamol tablets

Batch Percentage content

1 102.7%
2 100%
3 103%
4 103%

3.1.5 CALIBRATION CURVE:

Table 11. Absorbance of different concentrations of pure paracetamol

Concentration Absorbance

0.0015 0.664

0.0010 0.443

0.00085 0.400

0.00075 0.362

26
 0.0005 0.259

CALIBRATION CURVE

f(x) = 401.88x + 0.06

R = 1

Figure 2. Calibraion curve for pure paracetamol

3.1.6 DISSOLUTION TEST:

CALCULATION FOR PERCENTAGE RELEASED:

From the calibration curve, the linea equation is;

y = 401.88x + 0.0559

Sample calculation:

Using Batch 1 at 10 minutes;

y; absorbance = 0.362

27
 0.362 = 401.88x + 0.0559

0.362 0.0559 = 401.88x

0.3061 = 401.88x

x = 0.0007617%w/v

Dilution factor at time 10 minutes is 10;

x = 0.0007617 10 = 0.007617

If 100ml contains 0.007617g of paracetamol

Then 900ml will contain 0.06855g of paracetamol

Nominal weight = 0.06855g

Expected weight = 0.3g

Percentage released = (0.06855/0.3)g 100 = 22.85%

Table 12. Percentage release of paracetamol from batch 1 tablets

Time Absorbance (nm) Percentage released (%) Cumulative Percentage

Released
10 0.362 22.85 22.85

20 0.461 30.24 53.09

30 0.563 37.85 90.94

28
 40 0.568 38.23 129.17

50 0.682 46.74 175.91

60 0.762 52.71 228.62

Table 13. Percentage released of paracetamol from batch 2 tablets

Time Absorbance Percentage released (%) Cumulative Percentage Released

(nm)
10 0.385 24.57 24.57
20 0.453 29.64 54.21
30 0.572 57.79 112
40 0.682 70.11 182.11
50 0.692 71.23 253.34
60 0.773 80.30 333.64

Table 14. Percentage released of paracetamol from batch 3 tablets

Time Absorbance Percentage released (%) Cumulative Percentage Released

(nm)
10 0.371 23.52 23.52
20 0.483 47.83 71.35
30 0.592 60.02 131.37
40 0.601 61.03 192.4
50 0.659 67.53 259.93
60 0.741 76.71 336.64

Table 15. Percentage released of paracetamol from batch 4 tablets

Time Absorbance Percentage released (%) Cumulative Percentage Released

(nm)
10 0.382 24.34 24.34
20 0.443 43.34 67.68

29
 30 0.573 57.90 125.58
40 0.686 70.55 196.13
50 0.703 72.46 268.59
60 0.764 79.29 347.88

Table 16. Comparison of the percentage release of the 4 batches.

TIME BATCH 1 BATCH 2 BATCH 3 BATCH 4

(minutes)
10 22.85 24.57 23.52 24.34
20 30.24 29.64 47.83 43.34
30 37.85 57.59 60.02 57.9
40 38.23 70.11 61.03 70.55
50 46.74 71.23 67.53 72.46
60 52.71 80.3 76.71 79.29

3.1.7 RELEASE PROFILE CURVES:

30
 Release Profile Curve

Batch 1
Batch 2
Batch 3
Batch 4

Figure 3. Release profile curve for the different batches

3.2 DISCUSSION

The addition of surfactants to tablet preparations have been known to increase the release of

drugs from the tablet. This like mentioned earlier is most likely due to the ability of the

surfactant to increase the surface area of the drug available for dissolution by disintegrating

the drug into particles which will avail a larger surface area for dissolution.

The addition of surfactants to the tablet formulations as seen for Batches 2, 3 and 4 increased

the disintegrating time of the tablets, this will hence give a slower onset of action and a

possible longer duration of action. To this end, the amount of doses given per day of this

formulations may have to reduced so as to prevent accumulation and its deliterious effects on

the gastro-intestinal tract (GIT). Batch 2 which contained CTAB as surfactant required a

31
longer time for disintegration of the tablets used. All the tablets for each batch disintergated

completely within 15 minutes.

Also the addition of surfactant impacted positively on the friability of the tablets, as seen

from the results above with surfactants CTAB, SS and Tween 80, producing tablets of

percentage friability of 1.0%, 0.2% and 0.2% respectively. This reduced friabilty of the

tablets infers that these tablets will have the required strenght to withstand the processes of

transportation and storage of the drug thus ensuring that drugs of the right quality are used by

clients.

All four formulations of tablets when assayed for the percentage content of pure paracetamol

passed the test, as the acceptable percentage for the content of paracetamol should be

between 95 105%. It was found that batch 2 which contained CTAB actually contains

exactly 100% of pure paracetamol, but not withstanding, the passing of the test by the other

batches including that without surfactants, infers that the tablets if used by a patient will most

likely contain the right amount of active ingredient to perform the required therapeutic action

if all things remain equal.

As seen from Fig. 6, the addition of surfactants increased the percentage of the API released

with time, with Batch 2 producing the highest amount of the API released at the end of a 60

minute duration. Paracetamol is sparingly soluble in water and the addition of cationic

surfactant increased the wetting ability of the compound and hence increased the solubility of

the drug thus increased dissolution. It should be noted however, that inappropriate increase in

concentration of surfactant can result in a decreased dissolution of the drug, therefore, proper

checks should be done to ensure that the right amount of surfactant is added to any

formulation.

32
 CONCLUSION

Inclusion of the surfactants increased the release of paracetamol from the formulated tablets.

The cationic surfactant; cetyltrimethylammoniumbromide was the most effective at

increasing the release rate of paracetamol.

33
 RECOMMENDATION

Tablet preparations should be formulated to contain surfactants as this will cause an increase

in the release of the active ingredient from the dosage form.

34
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