INTRODUCTION:

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) member of propionic acid derivate that possesses anti-inflammatory, analgesic, and antipyretic effects through non-selective cyclooxygenase inhibition, resulting in prostaglandin biosynthesis reduction¹. It is indicated mainly in mild to moderated pain, such as headaches, neuralgia, migraine, dental pain, muscular and articular pain, pain relief after surgery, back pain, premenstrual syndrome, common colds and flu, fever, inflammation from rheumatoid arthritis, osteoarthritis, spondylitis ankylosis, tendinitis, tenosynovitis, injuries, pericarditis, ductus arteriousus in premature baby, etc².

It has a good pharmacokinetic profile by achieving peak serum concentration levels 1-2 hours and 99% of bounding with plasma proteins, metabolized and eliminated in the urine in 24 hours³. Ibuprofen is administered orally and parenterally, and from the initially marketed Brufen, there are different generic pharmaceutical products and dose formulations, ranging from gel, suppositories, oral tablets, capsules, suspension, intravenous in different trade names in dosages 200 – 800mg^4,5.

Even though the main side-effect profile is being considered the gastro-toxicity, renal-toxicity, and blood coagulation disorders⁶, it is being considered as one of the most prescribed medications as well⁷. Importantly, the evaluation of quality control as a process that ensured the desired level of product quality to produce drugs with high efficacy, safety, stability contributes to security for patient and healthcare professionals⁸. However, this is sometimes challenging due to the presence of different formulations which makes it essential to ensure the appropriate equivalence of different pharmaceuticals⁹.

According to the international standards in the evaluation of medical products the generic products must ensure the bioequivalence testing and its ongoing evaluation is essential in the post-marketing phases as well¹⁰. In addition, World Health Organization gave the responsibility to manufacturers for the quality of their manufactured drugs¹¹. Regarding this, Ibuprofen is widely manufactured and marketed in the Republic of Kosovo with more than 50 products, and its evaluation for marketing approval is done according to the national standard includes mainly in vitro physiochemical quality testing^12-14. These in vitro quality parameters are weight, friability, disintegration, dissolution, and active substance content tests^15-21. In addition, there are some studies performed in the different countries that examined the in vitro quality of marketed ibuprofen formulations^22-33, and none of them included products from the Kosovo market.

Therefore this study aims to evaluate the in vitro quality of three ibuprofen uncoated tablets 400 mg formulations that are commercially most commonly used in the Republic of Kosovo markets to ensure that these products meet the quality standards based on official pharmacopeia specification for the Kosovo pharmaceutical market. This work will further increase the awareness in the healthcare professionals, national control authority, patients by showing the quality of the manufactured product. In addition, this will increase the knowledge about the in vitro quality testing of Ibuprofen tablets available in our market by comparing these parameters with the official standards.

MATERIAL AND METHODS:

Sampling, Uniformity of weight and Friability:

This study was analyzed in the main laboratory in the national manufactory TRE-PHARM. It included analyses of Ibuprofen 400mg tablets in the generic name Ibuprofen, trade names albadol and suprafen 400 mg. Uniformity of weight was done by weighting twenty tablets randomly from each manufacturer with electronic weight. In addition, the friability was calculated based on loss of percentage from friabilator³⁴.

Disintegration time:

The disintegration times for each brand were determined in a distilled water bath at (37.0±0.5) C using the reference British Pharmacopoeia (BP) disintegration tester (VEEGO, India). The time that is necessary for breaking up the tablets in the tubes into granules was noted as disintegration time.

Content of Active:

UV Assay:

Standard preparation was prepared by dissolving 100mg ibuprofen in 100mL volumetric flask with 0.1mol/L NaOH solution resulting in a final concentration of 10 mg/mL standard solution which was diluted through aliquots in the desired additional concentration. The absorbance of the solution was read at 221nm. The samples of ibuprofen were prepared by weighing and crushing tablets into powder for each brand. Powder equivalent with 100mg ibuprofen was transferred in 100 mL volumetric flask with 0.1mol/L NaOH solution. Additionally, this solution was filtered with filter paper (No.1) and the aliquots from this were used to give a 10 μg/mL solution.

This was accompanied by reading as the standard with 221nm wavelength was used for UV spectrophotometric experiments and the percentage of the content was calculated (Shimadzu UV-visible spectrophotometer, model UV-1800).

HPLC Assay:

The High-Performance Liquid Chromatography (HPLC equipped with Diode Array Detector, Shimadzu USA MFG Inc.) was used for HPLC Assay analysis and validated as previously described (12). The stationary phase included the chromatography column Ascentis Supelco 100A C18 column (5μm particle size, 250x4.6 mm), with the flow rate was 1.0mL/min (phosphate buffer and methanol mobile phase 34:66) and UV detection was performed at 254nm. The standard preparation was done by weighting Ibuprofen powder (160mg) into a 100mL volumetric flask with 70mL HPLC grade methanol by sonication for 30minutes. The 5mL aliquot of the solution was further diluted into 100 mL to get the concentration of 80mg/mL and the standard which contained 4μg/mL were automatically injected into HPLC. Three injections were run for each standard to ensure system suitability and calibrate. However, the samples were prepared through pulverizing tablets from each brand and transferring the related powder equivalent to 400mg Ibuprofen into a 100 mL volumetric flask filled with 70mL methanol. This was sonicated as in the standard preparation. The solution was filtered with filter paper 0.45 nm and a further 1 mL was taken and diluted with 50 mL methanol to get a test solution of 80mg/mL. The sample was automatically injected in HPLC 20μL and 3 injections were done for each brand.

The area of the HPLC peak of ibuprofen was quantified with integration through LabSolutions Software (Shimadzu) according to its standard. Chromatograms for each standard and sample were shown in (Fig. 1).

RESULTS:

All the Ibuprofen 400 tablets analyzed were within their shelf lives. These were the most common brands, including one of them produced within the national level. Some physicochemical parameters of these brands were included in Table 1.

The weight uniformity testing indicated no significant changes in the weight of tablets (P>0.05), and confirmed the BP standards 95,0-105,0% for ibuprofen). Moreover, there was no significant weight variation among the analyzed brands. All the samples showed friability values below 1%. Even though there was significant variation of the disintegration times for the first brand (P<0.001), the disintegration times of all samples meet the BP requirements (within 15 min for uncoated tablets) Table 1.

In addition, the results of the assay of chemical content using UV-VIS and HPLC analysis for the determination of ibuprofen in the analyzed brands in our study were further demonstrated in Table 2, Fig. 1 and 2. All the brands meet the BP specification in the UV and HPLC assay methods (95-105% of active drug content).

Table 2. Assay the result of the amount of ibuprofen obtained from UV and HPLC analysis.

Sample	Labeled	Amount (mg/tablet) UV HPLC (RSD)	Label Claim (%) UV HPLC (% RSD)
E01	400	387.64 402.56	96.91 100.64 (0.605)
E02	400	403.80 419.72	100.95 104.93 (0.154)
E03	400	395.80 405.16	98.95 101.29 (1.484)

DISCUSSION:

We have evaluated the physicochemical quality control analysis of the three brands of ibuprofen containing tablets (400mg), designated as E01, E02, and E03, and obtained from the Republic of Kosovo Market. All of the analyzed brands were compared with BP specification (variation limits of ± 5.0%.), regarding the performed tests such as uniformity of weight, friability, disintegration times, and active drug content.

The quality control tests (QC) guarantees the quality of final dosage forms through measurements of content uniformity of the product tablets to ensure the precise dose of the medication which ensures the uniform distribution of the main ingredient among the dosage form^8-10. This test is mandatory in EU countries; manufacturers the following Ph. Eur. Standards^35-38. On the other side, the particular generic substitution is present in the pharmaceutical community and varies in different acceptance rates between the patients³⁹. According to WHO the patient should be recommended in a particular brand due to pharmacokinetic variability ⁴⁰. In addition, this switching with bioequivalent drugs might result in different exposure to the active substance and pharmacokinetic variability within-subjects⁴¹, however, this might be improved through implementing interchangeability based on the reference-bioequivalent ⁴², as in the Ibuprofen tablets as well⁴³.

However, the quality control of the uniformity, weight variation of ≤ ±5% from the mean weight, ≤1% friability weight loss of the ibuprofen tablets in our study did not have a degree of variation and passed the BP specification tests⁴⁴, and was in accordance with the quality of Ibuprofen tablets in the other countries as well ^22-33. In addition, the disintegration times of all samples meet the BP requirements (within 15 min for uncoated tablets) within the 30 minutes time frame. This suggested the expected values of the drug release are higher for all of the analyzed products.

Determining the average content of active ingredients in pharmaceutical forms is essential for quality control, and expressed as a percent on the label claim. In this study, the assay was performed with UV-VIS spectroscopic and HPLC-UV chromatographic methods for the quantification of Ibuprofen. The BP specification in the UV and HPLC assay methods recommends the variation limit of 95-105 % of the active drug content^24,42-46.

In our study, the Ibuprofen content in the analyzed tablets meet the BP specification and passed both used assay tests. Therefore, Ibuprofen tablets analyzed in our study had adequate active drug content and were within the limits specified. In addition, most of the available generic formulations of Ibuprofen tablets were acceptable in vitro quality. Therefore, our findings are consistent with other previous consistent studies regarding the appropriate quality control of Ibuprofen tablets API which fulfilled the BP specifications which comply with established limits, showing also the acceptable in-vitro quality of commercially available Ibuprofen tablet brands commercially available in Nigeria^24,27, Zimbabwe²⁵, Bangladesh²⁶, Romania²⁸, Ethiopia⁴⁵, and India⁴⁶ comply with established limits.

It can therefore be summarized that ibuprofen tablets marketed in the Republic of Kosovo do not vary in physicochemical qualities and they are chemically equivalent which could be hypothesized a similar bioavailability and the therapeutic outcome expected would be achieved in the expected time.

Moreover, despite the absence or limitation of the relevant published studies that evaluated the quality of generic drug products marketed in the Republic of Kosovo, the analyzed products provide promising quality assurance, and this work may set the future stage for additional similar investigations on other drug products to confirm the quality of the pharmaceutical products marketed in the Republic of Kosovo.

The limitation of our study is that our findings do not represent all of the Ibuprofen tablet brands in the Republic of Kosovo and our results do not apply to ibuprofen formulation with other than presented strength form in the current study.

CONCLUSION:

The results of the analyzed parameters obtained from our study comply with the pharmacopeial limit and meet the official monograph specifications for the in vitro quality control test. and we can conclude that this Ibuprofen product available in the Republic of Kosovo meets the in vitro quality parameters to provide therapeutic efficacy.

This study can help also the Drug Control Authority regarding the quality status of the marketed Ibuprofen products in the Republic of Kosovo and increase the alertness in extending these findings to ensure the quality of pharmaceutical products to improve the health sector in the country.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

We would like to thank the TreLab Quality Control Laboratory, Trepharm, the Republic of Kosovo for providing laboratory infrastructure.

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Received on 10.12.2021 Modified on 26.02.2022

Research J. Pharm. and Tech. 2022; 15(8):3725-3730.

DOI: 10.52711/0974-360X.2022.00624

Sample	Average Weight (mg)	Standard Deviation (SD)	% Standard deviation (RSD)	Relative Friability (%)	Average Disintegration Time (min)
E01	565.68	5.72	1.04	0.17	10.01 (0.73)
E02	522.63	4.83	0.95	0.09	3.87 (0.24)
E03	651.65	6.19	0.95	0.12	5.89 (1.65)