Physiological Analysis of Different Brands of Paracetamol Tablets in the Market
Chapter One
Aim and Objectives of the Study
Aim
The aim of this study is to evaluate the bioequivalence of six brands of Paracetamol usingin vitro dissolution profile as surrogate to in vivo bioequivalence studies.
Objectives
The objectives of the study are to;
- randomly select six different brands of Paracetamol using systematic random sampling.
- conduct quality control studies on Paracetamol tablets sampled (BP and USP, 2009).
- develop and validate UV methods for determination of Paracetamol in simulated physiological media pH 1.2, 4.5, 6.8 and 7.4
- determine the dissolution profiles of the individual brands in each of the simulated physiological media.
- evaluate the bioequivalence of the six brands using difference factor (f1), similarity factor (f2) and dissolution efficiency (D.E.).
CHAPTER TWO
LITERATURE REVIEW
Reported methods of analysis from literature
Ultraviolet spectroscopy
Literature survey showed that, severalUltraviolet spectroscopy methods were developed for assaying Paracetamol in drug substances, pharmaceutical formulations and biological fluids. Ultraviolet derivative method can also be used to assay Paracetamol in urine. Rojanarataet al., (2010) reported a green bienzymatic UV‐spectrophotometric method based on two enzymatic reactions in which, d‐4‐hydroxy phenyl glycine side chain of Paracetamol was selectively cleaved off by penicillin acylase and subsequently, reacted with 2‐oxoglutarate, by the catalysis of d‐phenyl glycine aminotransferase, to yield 4‐hydroxy benzoyl formate and absorbance measured at 335 nm. While,Nagaralli et al.,(2002) reported a sensitive spectrophotometric method for Paracetamol based on the measurement of absorbance of tris(o‐phenanthroline) iron(II) [method A] and tris (bipyridyl) iron(II) [method B] complexes at 510 and at 522 nm, respectively.
Colorimetric methods
Amin et al., (1994) reported a selective colorimetric method based on the reaction of Paracetamol with 4‐nitrophenol (I), 2,4‐dinitrophenol (II), 3,5‐dinitrobenzoic acid (III) or 3,5‐dinitrosalicylic acid (IV) in alkaline medium. The method is selective for the determination of Paracetamol in the presence of its degradation products, other antibiotics and different amines that are normally encountered in dosage forms.
High performance liquid chromatography methods
Torres et al.,(2010)developedan accurate and sensitive reversed‐phase high‐performance liquid chromatography–diode array–fluorescence (RP‐HPLC –DAD–FLD)for the quantitative determination of Paracetamol along with 10 other antibiotics and their main metabolites in urine has been using, diode array (DAD) and fluorescence (FLD) detectors for analysis. The separation of the analyzed compounds was conducted by means of a C18 (150mm×4.6mm I.D.,particle size 5μm) analytical column with C18 (4mm×4mm, particle size 5μm) guard column. Analyzed drugs were determined within 34 minutes using formic acid 0.1% in water and acetonitrile in gradient elution mode as mobile phase.
Structure Activity Relationship
All penicillins have the basic structure of a thiazolidine ring (A) attached to a β-lactam ring (B) that carries a secondary amino group (RNH–) substituents R can be attached to the amino group (Daniel and Lisa, 2012). Structural integrity of the 6-aminopenicillanic acid nucleus (rings A and B) is essential for the biologic activity of these compoundsand chemical substituent attached to the nucleus can influence the stability of penicillin as well as spectrum of activity, substitution on R-group of the primary amine with electron withdrawing group decreases the electron density on the side chain carbonyl and protect these penicillins, in part, from acid degradation this property has clinical implication, because these compound survive passage through stomach better and many can be given orally for systemic purpose whereas hydrolysis of the β-lactam ring by bacterial β-lactamases yields penicilloic acid, which is deficient in antibacterial activity.(Lester et al., 2008 and Daniel and Lisa 2012).
Pharmacokinetics
Paracetamol is resistant to inactivation by gastric acid, it is rapidly and almost completely absorbed when given orally(Sean et al., 2009). Presence of food in the stomach does not reduce the total amount absorbed (Daniel and Lisa, 2012). Peak plasmaParacetamol concentrations of about 4-8 micrograms/ml,after 500 mg dose (Daniel and Lisa, 2012). With traceable amounts present for up to 8 hours, doubling the dose can double the concentration(Sean et al., 2009). Concentrations of Paracetamol after intramuscular injection are similar to those achieved with oral doses, plasma proteins binding is about 20– 30% and plasma half-lives of 1 to 1.5 hours (Daniel and Lisa, 2012). Paracetamol is widely distributed at varying concentrations in body tissues and fluids(Sean et al., 2009). It crosses the placenta; small amounts are distributed into breast milk. Little Paracetamol passes into the CSF unless the meninges are inflamed(Sean et al., 2009).
CHAPTER THREE
MATERIALS AND METHOD
Drug Sampling
10 brands of paracetamol tablets (500mg)having different manufacturing dates were purchased from various registered pharmacies within Lagos, Nigeria and labeled with the code A, B, C, D, E, F,G, H, I and J.
Method
The following were carried out on the brands of paracetamol tablets:
- Physical
- Chemical
- Microbiological
Physical Examination
The physical examination being carried out the brand paracetamol was sub divided into the following;
Uniformity of weight test
Twenty tablets were randomly selected from each brand and weighed individually using the analytical weighing balance (Shimadzu ATX224). The weight of 20 tablets altogether was also weighed and the mean weight was calculated. The weight variation was calculated as mean ±5% of the mean. If two tablets out of 20 are outside the range, the tablets are considered to have failed the test. (BP 2012).
Hardness test
The crushing strength of 5 tablets from each brand were determined with a tablet hardness tester and the average were calculated. If the tablets are outside the range of 4 Kgf – 12 KgF, they are considered to have failed the test
CHAPTER FOUR
RESULT
Physical examination result
Tables 1-3 and Figures 1-3 shows the physical parameters of the various brands of paracetamol tablets. The hardness test on the tablets shows that only 2 tablets are outside the range of 4KgF – 12KgF (BP 2012). All the tablets have a friability of ≤1% which also conforms to BP 2012. Table 1 also shows that the uniformity of weight test on the tablets indicated no significant variations in the weights of tablets within the different brands but there were significant weight variations among tablet of the same brands. Hence, all the brands conformed to the British pharmacopoeia specification which recommends that not more than 2 of the individual tablet weight should deviate from the average weight by more than ±5% and none should deviate by more than ±10%. The disintegration times of all the tablets are also within 15 minutes (BP 2012) except brand E with disintegration time of 27 minutes 44 seconds
CHAPTER FIVE
DISCUSION AND CONCLUSION
DISCUSSION
The investigation shows that 8 out of the 10 brands of paracetamol tablets analyzed passed the physical test. Tablet is defined as a compressed dosage form containing medicaments with or without excipients. According to the Indian Pharmacopoeia, pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drug or a mixture of drugs, with or without diluents. They vary in shape and differ greatly in size and weight, depending on amount of medicinal substances and the intended mode of administration. Tablet hardness test measures the crushing strength of a tablet. The crushing strengths shown by the tablet will ensure resistance to damage during handling, packaging and transportation. Although only 8 brands passed the hardness test, this could be as a result of moisture gain and subsequent loss on storage under varying humidity conditions. A high crushing strength in turn could lead to a high disintegration time which lead to brand E having a high disintegration time.
Friability is the tendency for a tablet to chip, crumble or break following compression. This tendency is normally confined to uncoated tablets and surfaces during handling or subsequent storage. It can be caused by a number of factors including poor tablet design (too sharp edges), low moisture content, insufficient binder, etc.
For obvious reasons, tablets need to be hard enough such that they do not break up in the bottle but friable enough that they disintegrate in the gastrointestinal tract. All the tablets passed friability test according to BP 2012. The uniformity of weight of the tablets is a measure of drug content and release of the tablets. However, variation among the brands of tablets is as a result of different excipients used by the companies.
From the findings made in this study, it could be inferred that very small level of microbial contamination of the tablets in this investigation were observed. Tablets are compacts drug delivery systems with low water content which usually afford them good protection against microbial contamination. Spoilage and clinical infections resulting from microbial contamination of tablets under hot and humid conditions of the tropics have been reported. Tablets also undergo deleterious changes as discoloration, weakening of tablets matrixes and decreases in the potency of active ingredients when improperly stored. Potential contamination of tablets may arise from heavy microbiological burden in raw materials, though this is usually drastically reduced by lethal drying stage of wet granulation. However, the decreasing use of direct compression in manufacturing of tablets in pharmaceutical industries implies that some contaminants may survive up to the compression stage.
The assay result shows that the percentage content of acetaminophen as an active ingredient in the paracetamol tablets met compedial requirement which means that the drug is in the right prescription.
CONCLUSIONS
All the brands of paracetamol tablets analyzed passed the official requirements for microbiological quality (BP 2012). The assay result also shows that the percentage content of paracetamol in all the brands analyzed ranges from 90.0-110% as per USP 2007 specifications. 8 out of 10 brands passed the physical parameters tests according to the BP 2012 except 2 brands. It is therefore suggested that for better patient acceptability, the quality of product as well as Good Manufacturing Practice should be enforced and maintained so as to prevent antibiotic resistivity and access to safe and quality drugs. Also, a routine market surveillance of pharmaceutical product is encouraged so as to discourage marketing of poor quality products.
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