Comparison of double dose of Paracetamol tablets 500mg with one Paracetamol tablet 1000mg

Baraa Daghman¹, Nisrin Kaddar², Mohammed Ayyed Najm³, Hala Barakat⁴

¹MD, Department of Pharmaceutical Chemistry and Quality Control, Faculty of Pharmacy, Tishreen University, Lattakia, Syria.

²PhD, Department of Pharmaceutical, Faculty of Pharmacy, Tishreen University, Lattakia, Syria.

³Assistant Professor, College of Medicine, Ibn Sina University of Medical and Pharmaceutical Sciences, Baghdad, Iraq.

⁴PhD, Department of Pharmaceutical Chemistry and Quality Control, Faculty of Pharmacy,

Al-Sham Private University (ASPU), Lattakia, Syria.

*Corresponding Author E-mail: baraadaghman@gmail.com

ABSTRACT:

Various geometrical shapes of paracetamol tablets are available, which play an important effect on the speed and quantity of drug release and swallow ability. Patients with swallowing disorders experience difficulties taking large dose (1000mg), which may lead to take two smaller tablets 500mg. This study purposes to investigate the impact of doubling dose and different geometrics on drug release, depending on dissolution test and surface area to volume ratio (SA/V). First, all the studied companies were confirmed to the required constitutional specifications. Then, the dimensions of different shapes of tablets and SA/V ratio were calculated by using Solid Works program. Finally, the dissolution test was performed in a medium of phosphate buffer (pH=5.8) for 30 minutes. All tablets were accepted in term of uniformity of content and weight and showed acceptable friability, with suitable hardness and the disintegration time was less than 30 minutes. After half an hour of beginning the dissolution test, over 80% of the paracetamol from all the tablets examined was found to have been released. The release rates were approximately constant for the various shapes of tablets with the same rate of SA/V. Drug release from two tablets of 500mg was faster than that from one tablet of 1000mg, this offers a therapeutic benefit to achieve the analgesic effect more quickly.

KEYWORDS: Double dose, Drug release, Surface area, SA/V ratio, Paracetamol tablet.

1. INTRODUCTION:

Paracetamol is commonly used as a drug for pain reliever and fever reduce. It is an over-the-counter medication, used alone and in combination with several other drugs. It is also the first choice for many patients, including children, pregnant women, and the elderly. The half-life of the oral forms (tablets, syrups) is approximately 4-6 hours. Paracetamol is a Class III of Biopharmaceutical Classification System (BCS) compound, and achieves the relationship of In Vitro - In Vivo Correlation (IVIVC)^1-6.

Many companies manufacture paracetamol tablets under different generic trade names, at different doses and geometrics. They would have to be bio-equivalent to the reference product (Doliprane) to be interchangeable^4,7-17.

Paracetamol tablets are used extensively, but there are concerns about their shape and size. Unfortunately, there is not enough knowledge about the effort required by patients to swallow certain tablets, which could have an impact on treatment outcomes (e.g., prescription medication adherence or causing clinical complications). Most patients preferred consuming multiple medium-sized tablets rather than a single large tablet (e.g., patients have difficulty swallowing large 1000mg tablets of paracetamol, so they take two 500mg tablets) or may dividing or crushing the bulky tablet, inducing consequent effects and risks related to changing the pharmacokinetics of the drug. The (EMA) European Medical Agency and the (FDA) Food and Drug Administration have published guidelines according to which differences in the physical properties of a drug should be considered^18-20.

Some patients are facing swallowing difficult, especially children and the elderly, as a result of some physiological changes^21,22. Size of tablet affects the passage of the product across the esophagus and pharynx, and the large tablets require a longer time to pass throughout the esophagus, thus causing esophagitis and other risks. Understanding how a patient’s gender, body size, age, and medical conditions impact swallowing capabilities. It would be appropriate for all oral medications to have a medium size, with a tablet diameter ranging between 6 and 13, just like the dimensions of capsules and tablets that were found to cause less difficulties according to a study conducted by Jeremy^{18, 22-26}.

The geometry of tablets has an impact on drug release. Certain attempts have been made to regulate dissolving behavior by controlling tablet geometry, which includes shape and volume. Some authors discovered that the ratio of surface area-to-volume (SA/V) is more significant in influencing drug release than the actual surface area of the tablet. The FDA proposes that consistent drug release mechanisms can be achieved by stabilizing the SA/V ratio ^27-29. The main aim of the studyis to investigate how the surface area to volume ratio (SA/V) affects the release of drugs from different shapes of paracetamol tablets and compare double doses of 500 mg tablets with a single 1000 mg tablet.

2. MATERIALS AND METHODS:

2.1. Study area and design:

This research was carried out between August 2021 and June 2022 at Tishreen University and Al-Manara University in Lattakia - Syria.

An in-vitro study was conducted to assessquality control parameters of Syria's commercially available paracetamol 500 mg and innovator brand (Doliprane) 500 mg and 1000 mg tablets. The study included different quality control assessments such as uniformity of weight, hardness, friability, disintegration time, dissolution test, and uniformity of content. The SA/V ratio was calculated by using solid Works program, and dissolution test was used to investigate the effect of different geometrics and SA/V values of paracetamol 500 mg and 1000 mg tablets on drug release. The evaluation was done according to United State pharmacopoeia standards.

2.2. Instruments, materials and reagents:

Sensitive Balance (Precisa XB220A/Germany), a machin for testing hardness (Erweka TBH200/ Germany), another for testing friability (Logan Instruments Crop/ Germany), and for testing disintegration (Erweka ZT-52/Germany), dissolution test apparatus (Erweka DT), and UV-spectrophotometer (D - Lab), Gilbert digital electronic caliper.

Standard paracetamol (Ibn Hayan Company, Syria), mono sodium phosphate dihydrate (NaH₂PO₄.2H₂O) (Titan Biotich Ltd, India), di-sodium hydrogen orthophosphate (dihydrate) (Na₂HPO₄.2H₂O) (Titan Biotich Ltd, India), sodium hydroxide (Eurolab).

2.3. Samples description:

Four different brands paracetamol tablets were purchased from the drug stores in Syria, which had different shapes. Studied companies were coded as A1, B1, C1, D1 for paracetamol tablets containing 500 mg whereas the innovator was coded as I1, and coded as I2 for the paracetamol tablets of innovator containing1000 mg (Table 1).

Table 1. Code, dosage, manufacturing and expiration date of paracetamol tablets

Code	Dosage (mg)	Mfga. Date	Expb. Date
A1	500	Apr-20	Apr-23
B1	500	Apr-21	Mar-24
C1	500	Mar-20	Mar-24
D1	500	Mar-20	Apr-23
I1	500	Sep-20	May-23
I2	1000	Sep-20	Aug-23

^a= Manufacturing date of paracetamol

^b= Expiring date of paracetamol

2.4. Preparation of calibration curves:

2.4.1. In sodium hydroxide

The calibration curve was created using different concentrations of the standard stock solution of paracetamol prepared in 0.1 M sodium hydroxide. The equation of regression obtained was Y= 0.712X + 0.0225.R² = 0.9955 signifies a strong correlation between absorbance (Y) and concentration (X) of the reference sample.

2.4.2. In phosphate buffer (pH=5.8)

The calibration curve was createdusing different concentrations of the standard stock solution of paracetamol prepared in a phosphate buffer with a pH of 5.8. The equation of regression obtained was = 0.715X + 0.023. The correlation coefficient R2 = 0.9989 signifies a strong correlation between absorbance and concentration of the reference sample.

2.5. Uniformity of weight test:

20 tablets were chosen randomly and their weight was measured using a sensitive balance. The average and standard deviation were computed. The formula used for calculating the weight variation as a percentage was: % of weight variations = (X̅ – Xi) / X̅ ×100, where X̅:the average weight of tablets and Xi: the individual weight of tablet. Studied tablets have an average weight more than 250 mg, so the acceptable limit should not exceed 5% for the deviation of weight for tablets.

2.6. Hardness test:

10 tablets were determined their hardness by using a hardness tester for both doses (500 mg and 1000 mg). Average values were calculated and expressing in Kpa. Tablets should not be very hard to permit their appropriate dissolution. On the other hand, the tablets should not be very soft to prevent premature disintegration during processing and transport.

2.7. Friability test:

10 tablets of 1000 mg and 20 tablets of 500 mg were weighed separately. The tablets were dedusted meticulously prior to testing. The friabilator was operated at 25 rev/min for 4 min. The tablets were flicked and weighed again. Friability expresses as the percentage loss in tablets weight was calculated by using the following equation:

% 𝐹𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =(W1-W2) / W1×100, where

W1 is weight before test and

W2 is weight after test.

2.8. Disintegration test:

6 tablets were selected randomly. The medium of disintegration was 900 mL distilled water at 37±0.5°C. The amount of time it took to crackeach tablet and navigate through the net was recorded, and an average time was determined.

2.9. Uniformity ofcontent test:

The purpose of this test is to determine the drug substance's individual content in a number of tablets. 10 tablets were crushed individually and analyzed for theircontent as a percentage in a medium of 0.1 M sodium hydroxide after filtering. The absorbance of the filtered samples was determined using U.V. Spectroscopy at λ_max 257 nm. The Acceptance Value (AV) was calculated.

2.10. In-vitrodissolution test:

The test was conducted following the guidelines outlined in the USP 36[30], by using Apparatus 1 (paddle method), at rotation speed of 50 rpm, at λ_max = 243 nm, 37 ± 0.5 °C in 900 ml of phosphate buffer (pH=5.8) for 30 minutes. A volume of 5 ml was withdrawn using a syringe at specified time intervals (5,10,15,20,30) min and filtered. To keep a constant volume, the same amount of new dissolution medium was added to maintain the overall volume.

2.11. In-vitro dissolution test for double dose:

Two 500 mg paracetamol tablets placed together in the flask under the same conditions, and a comparison was made with one 1000 mg paracetamol tablet of the innovator drug.

2.12. Measuring the appearance and dimensions:

Before conducting the dissolution studies, the shape and size of the 500 mg and 1000 mg tablets were examined, and the dimensions of each brand’s tablets were recorded. Using SolidWorks TM software 2016 SP 2.0 (Dassault Systems 3DS, France), calculations were performed for surface area, volume, and SA/V ratiobased on these dimensions.

3. RESULTS AND DISCUSSION:

3.1 Measurement of tablet characteristics:

The initial focus of the research was to assess the quality criteria of various brands of paracetamol (500 mg and 1000 mg) with the innovator (Doliprane). The results of uniformity of weight, hardness, friability, disintegration time, uniformity of content, and dissolution test of the studied companies of paracetamol tablets are displayed in Table 2.

Table 2 shows the physical parameters test results of studied tablets. The results show that all the studied generic companies conform to the required specifications. The uniformity of weight test of tablets indicates that the active ingredients are evenly dispersed throughout the entire batch. The USP states that there should be no more than a 5% difference in weight between individual tablets and the average tablet weight.

Table 2. The results of physical parameters, and dissolution test of studied tablets contained 500 mg and 1000 mg paracetamol

Code	Dosage (mg)	Uniformity of weight (%) ± SDa (g)	AVd n= 10	Hardness Kpa± SDc	Friability (%loss)	Disintegration Time (min) ± SDa	Dissolution Test n= 6 Drug release after 30 min (%)
A1	500	0.55 ± 2.8	12.79	± 1.9824.035	0.0	± 0.102 5.29	94.78
B1	500	0.55 ± 0.8	6.43	0.647 ± 23.201	0.1	3.31 ± 0.007	93.59
C1	500	2.2 ± 0.59	11.5	0.738 ±12.585	0.1	3.04 ± 0.0265	95.06
D1	500	0.58 ± 2.95	3.57	22.484 ± 1.516	0.2	4.52 ± 0.0107	95.57
I1	500	0.54 ± 1.11	9.7	0.724 ±15.969	0.0	± 0.0221.29	87.93
I2	1000	1.09 ± 2.07	9.8	1.33 ±18.806	0.0	3.26 ± 0.021	89.22

^c: Standard Deviation

^d: Acceptance Value

All tablets (generics and innovator) have passed the uniformity of weight test (the standard deviation did not exceed 5%). This guideline helps assess how evenly paracetamol is distributed in the tablets.The degree of hardness of a tablet is a crucial factor to consider when evaluating its crush strength. According to the results, all paracetamol brands had acceptable and desirable crushing strength and passed the test (ranged between 12.58 kpa and 24.03 kpa for 500 mg tablets). In the friability test, the results were matched with hardness results and all brands showed accepted friability values (The friability percentage ranged from 0 to 0.2%). In all formulations the percentage of friability was less than 1% which ensures that all the tablets were mechanically stable and complied with USP 36^[30].Another physical parameter is disintegration test, the disintegration time was satisfactory according to USP^[30], and ranged from 1.29 to 5.29 min. Uniformity of content refers to the consistency in the quantity of the drug substance across different units and determines whether the individual content is within the limits set. Dosage of uniformity requirements are satisfied when the acceptance value of the initial 10 tablets is 15 or less according toUSP^[30]. The acceptance values were calculated for each generic and innovator brand, and according to the results, all of them were smaller than 15.

3.2. In vitro dissolution study results

Dissolution is a parameter related to the drug's absorption and bioavailability. In vitro dissolution is used to determine compliance with the pharmacopeial in vitro drug release requirements. Table 2 indicated that each tablet had released over 80% of the active ingredient after 30 minutes, which is acceptable according to the requirements of the USP 36^[30]. Various paracetamol brands exhibit release rates ranged from 87.93% to 95.57% (figure 1) for 500 mg tablets.

Figure 1. Comparison of dissolution profile of paracetamol from studied generic and innovator tablets contained 500 mg

3.3. Effect of different shapes and SA/V ratio on drugrelease:

Figure 2 illustrates the various shapes and dimensions of the paracetamol tablets that were analyzed in the study. Table 3 shows the findings from the surface area, volume, and the SA/V ratio measurements of studied tablets. According to the results in table 3, the different shapes of tablets had a constant SA/V ratio. The release rates remained consistent across different tablet shapes that maintained a constant surface area to volume ratio. The release profile was not notably influenced by the varied shapes. This is consistent with a study by researcher Reynolds et al^[27].Multi studied have suggested that the SA/V ratio provides the most accurate representation of tablet geometry when compared to other measurements, especially the diameter^{[28, 31, 32]}.

Figure 2. Geometric shapes of different generic companies and innovator of paracetamol tablets

Table 3. Surface area, volume, SA/V ratio, percent of drug release of paracetamol tablets 500 mg and 1000 mg

Code	Dosage (mg)	SA (mm²)	V (mm³)	SA/V (mm^-1)	Percent of drug release after 30 min (%)
A1	500	379.15	491.65	0.771	94.78
B1	500	398.35	567.55	0.702	93.59
C1	500	404.58	532.38	0.760	95.06
D1	500	396.69	536.96	0.739	95.57
I1	500	382.80	560.04	0.684	87.93
I2	1000	698.81	1261.83	0.554	89.22

3.4. Effect of double dose on therelease of drug:

Figure 3 shows the release profiles vs. time for double dose of 500 mg paracetamol tablets compared to one 1000 mg tablet. Drug release rates, SA, V, SA/V for the tablets are given in Table 4. As seen in table 4, a double dose has greater SA/V values than a one tablet. The expectation is that the rate and velocity of drug release will increase in proportion to the surface area to volume ratio. Refer tofigure 3, the release rate and speed of paracetamol increased with increasing SA/V values of double dose. Drug release from two tablets 500 mg with outer surface ranged from 758.3 mm2 to 809.16 mm2 was faster than that from one tablet 1000 mg with outer surface 698.81 mm2, thus getting the analgesic effect faster. The total surface area accessible for solvent penetration is larger when two tablets are used compared to using just one tablet.Furthermore, the solvent needs to infiltrate a greater distance into the larger tablets. Both factors contribute to a slower drug release rate from the 1000 mg tablets, and this result is consistent with previous research^[33].In addition, it is more desirable for patients to swallow two tablets of Paracetamol 500 mg than one large 1000 mg tablet.

Figure 3. Percentage of drug release from two tablets 500 mg of generic and innovator brands of paracetamol compare to one innovator tablet 1000 mg

Table 4. Surface area, volume, SA/V ratio, and percentage of released of double dose (tow tablets 500 mg) compare to one innovator tablet 1000 mg

Code	Number of tablets	Dosage (mg)	SA (mm²)	V (mm³)	SA/V (mm^-1)	Percentage of released after 5 min (%)	Percentage of released after 30 min (%)
A1	2	500	758.3	983.3	1.542	49.87	93.23
B1	2	500	796.7	1135.1	1.403	48.6	92.74
C1	2	500	809.16	1064.76	1.519	55.46	97.68
D1	2	500	793.38	1073.92	1.477	53.76	95.8
I1	2	500	765.6	1120.08	1.367	50.26	92.7
I2	1	1000	698.81	1261.83	0.554	41.29	89.22

4. CONCLUSIONS:

The ratio ofsurface area to volume of a tablet is a crucial factor in the pharmaceutical field. The ideal release of a tablet can be achieved by choosing the correct SA/V ratio, regardless of the tablet’s shape. This value can be applied to design tablets in different shapes, dosed, sizes, and release profiles simultaneously. It is possible to increase the speed and quantity of drug release by increasing the SA/V ratio, therefore, using a double dose of paracetamol can help to speed up the analgesic effect by increasing the surface area of contact with the solvent, as well as the increase in the ratio of SA/V compared to the value of this ratio for one tablet of 1000 mg. In addition, it is easier to swallow the smaller 500 mg tablets instead of the larger 1000 mg tablets.

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Received on 03.04.2024 Modified on 31.05.2024

Research J. Pharm. and Tech 2024; 17(10):4671-4676.

DOI: 10.52711/0974-360X.2024.00720