International Journal of Applied Research in Natural Products Vol. 4 (3), pp. 22-26, Sep-Oct 2011 Directory of Open Access Journals ©2011. IJARNP-HS Publication

Original Article An investigation on physical quality control parameters of dietary supplements tablets commercially available on the Kingdom of Saudi Arabia Maswadeh HM*, Al-Jarbou AN Qassim University, College of Pharmacy, P.O. Box 6800, Buraidah 51452, Kingdom of Saudi Arabia Summary: The goal of this study was to investigate the physical quality control parameters of dietary supplements tablets commercially available on the Kingdom of Saudi Arabia by using weight variation, friability and disintegration tests. The impact of immersion medium pH and the use of disk during disintegration test of dietary supplements as well as a price comparison with respect to quality were investigated. All products were found to fulfill the USP weight variation and friability tests of dietary supplements. Results for disintegration test by using phosphate buffer or distilled water without disk showed that nine of seventeen tablets did not disintegrate within 30 minutes. Wile by using 0.1 HCl pH = 1.1 without disk 6 of seventeen tablets did not disintegrate. In all disintegration tests with different immersion medium in which disk has been used, only one of seventeen tablets did not disintegrate. The results of the disintegration study indicated that pH of immersion medium as well as the use of disk in the observation cylinder has an important impact on the ability of products to pass the disintegration test. Price comparison showed that product with higher price is not necessary to be the best. Some products with low price were shown rapid disintegration in different pH and they have higher number of tablets, vitamins and minerals in each container than other more expensive products that did not pass the disintegration test. Industrial relevance: Content uniformity requirement for drug product is an acknowledgment of the existence of a welldefined dose-response curve and, thus, dosing intervals, such a requirement is not possible for multivitamin-mineral combination products used as nutritional supplements. Alternatively, weight variation, friability and disintegration tests could be used to ensure that the product was indeed manufactured under good manufacturing practices. Keywords: dietary supplements; disintegration; friability.

Introduction The quantitative evaluation and assessment of a tablet's chemical, physical and bioavailability properties are important in the design of tablets and to monitor product quality. These properties are important since chemical breakdown or interactions between tablet components may alter the physical tablet properties, and greatly affect the bioavailability of the tablet system. There are various standards that have been set in the various pharmacopoeias regarding the quality of pharmaceutical tablets. These include the diameter, size, shape, thickness, weight, hardness, friability, disintegration and dissolution characters. The diameters and shape depends on the die and punches selected for the compression of tablets. The remaining specifications assure that tablets do not vary from one production lot to another (Lachman L et al, 1987). To ensure that the manufacturers control the variation in the weight of dosage units such as tablets, capsules, and solids in single-unit containers, the drug content of each unit in a lot should be distributed in a narrow range around the label strength. For this purpose, there are two tests, the content uniformity test and an alternative simplified test, the weight variation test. Weight variation test based on a comparison of the weight of the individual tablets (xi) of a sample of tablets with an upper and lower percentage limit of the observed sample average (mean). ______________________ *Corresponding Author: E-mail: [email protected] Tel:+9666-596897289, Fax: +96663802268 Available online http://www.ijarnp.org

Physical Quality Control Parameters of Dietary Supplement

The strength of a tablet plays a very important role in its marketing and dissolution. The mechanical strength of tablet can be determined by its hardness and through friability test. Measuring the hardness of a tablet is not a reliable indicator for tablet strength as some formulations when compressed into very hard tablets tend to cap or lose their crown portions on attrition. (Pisek R et al. 2002, Du J SW. 2003). Tablet friability test is a method to determine the physical strength of uncoated tablets upon exposure to mechanical shock or attrition. Friability test is carried out in an instrument called a friabilator. A friability testing apparatus should stimulate the conditions that the product will be exposed to during the process of production. (Lachman L et al, 1987). Disintegration test is a measure of the time required under a given set of conditions for a group of tablets to disintegrate into particles which will pass through a 10 mesh screen. Generally, the test is useful as a quality assurance tool for conventional dosage forms. Active ingredients can only be absorbed if they are released into solution from the dosage form. Disintegration is the first step in this process for immediate release dosage forms. It has to be pointed out that a product which fails disintegration will presumably fail dissolution criteria (Du et al., 2003). It is evident that content uniformity requirement for dietary supplements is not easy possible due to the presence of multiple ingredients such as vitamins, minerals, herbs or other botanicals, and amino acids. Alternatively, weight variation, friability and disintegration tests could be used to ensure that the product was indeed manufactured under good manufacturing practices. The goal of this study was to investigate the physical quality control parameters of dietary supplements tablets commercially available on the Kingdom of Saudi Arabia by using weight variation, friability and disintegration tests. The impact of immersion medium pH and the use of disk during disintegration test of dietary supplements as well as a price comparison with respect to quality were investigated. Materials and methods Products where purchased from commercial outlets are listed in Tables 1.Friability, weight variation and disintegration test were done according to US Pharmacopeia for friability, for weight variation and for disintegration test. Friability test: The friability of tablets was determined according to US Pharmacopeia using Roche friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100 revolutions. The % friability was then calculated by using the following equation: F=Winitial–Wfinal/Winitial X 100……. (1) Where, F= friability (%), Winitial = initial weight, Wfinal = Final weight The requirements are met if the friability is not more than 1.0%.(USP 2005). Weight variation test: To study weight variation, 20 tablets of each formulation were weighed using an electronic balance (Denver APX-100, Arvada, Colorado) and the test was performed according to the US Pharmacopeia . The requirements are met if the weights of not more than 2 of the tablets differ from the average weight by more than the percentage listed in the US Pharmacopeia and no tablet differ in weight by more than double that percentage (USP 2005). Disintegration test: The disintegration test was done using a disintegration tester ED 2L (Electrolab, Mumbai, India) which complies with USP standards. The test units were inserted into the observation cylinder and the basket assembly was attached to the test apparatus. The appropriate immersion medium 800ml was filled into each beaker, and the test was started immediately after the basket assembly was attached (USP, 2005). Disintegration test with and without disk was performed for 17 products using 800ml of three different immersion medium. The first disintegration test was performed using 0.1N HCl with pH = 1.1 (Simulated gastric fluid without enzyme), the second was performed using distilled water with pH = 5.6 (USP disintegration conditions for dietary supplements) and the third test was performed using phosphate buffer with pH = 7.4 (Simulated intestinal fluid without enzyme) for 30 minutes. The acceptance criteria for a successful test are the same for pharmaceutical and dietary supplements preparations. If all six tablets disintegrate, the test is passed. If one or two tablets do not fully disintegrate, then twelve additional tablets are tested. Only two tablets out of the total of eighteen tested tablets are allowed to fail complete disintegration. Results and discussion: The characterization and quality control of pharmaceutical dosage forms is much more closely controlled compared to dietary supplements (USP 2005 and Lobenberg et al., 2006). There are no dissolution requirements specified for most minerals and vitamins. Also content uniformity requirements for drug products is an acknowledgment of the existence of a well-defined dose-response curve and, thus dosing intervals, such a requirement is not possible for multivitamin-mineral combination products used as nutritional supplements. Alternatively, weight variation and friability requirements could be used to ensure that the product was indeed manufactured under good manufacturing practices.

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Hamzah MM ;Ahmed AA

It could be observed that all products fulfill the USP weight variation and friability tests of dietary supplements as shown in Table 1 which indicate that products used in this study were manufactured under good manufacturing practices. Table 1. Tested mineral and vitamin tablets: Brand name/ manufacturer, lot no., hardness, weight, friability, component, number of tablets in each container and their price in USD. Brand Name/ Manufacturer MATERNA/ Wyeth, Canada

Lot No. D76595

CEBROVIT/ Sun Naturals, USA

807455

FERROVIT/ Arnet Pharmaceutical, USA

907420

ZINC-ACE/ Surepharm Services Ltd, UK

37207/A

OSTEOCARE/ Vtabiotic Ltd, UK

OE062P

MIXAVIT/Julphar, U.A.E

515

NEURORUBINEFORT/ Mepha, Switzerland GINKGO-VIT/Arnet Pharmaceutical, U.S.A

1050115

907416

Hardness (N) 247.8 +4.7% -16.4% 176.6 +11% -14.9%

Weight (mg) 1352.32 +1.3% -0.9% 448.00 +6.3% -3.2%

Friability % 0.03

0.02%

Each tablet contains 13 Vitamins & 10 Minerals 7 Vitamins 3 Minerals & others 12 Vitamins & 4 Minerals 11 Vitamins & 2 Minerals 1 Vitamins & 3 Minerals 6 Vitamins

37.8 +17.4% -16.9% 134.8 +29.8% -13.0% 226 +28.9 -27.6 128.1 +10.2 -14.6 116.9 +8.4% -7.0% 252.3 +12.5% -6.4% 168.3 +23.7% -38% 266.2 +12.4% -8.8% 199.5 +23.2% -14.5%

419.20 +4.3% -5.7% 535.60 +2.6% -2.8% 1551.13 +1.6% -1.9% 185.2 +4.3 -2.8 459.9 +1.2 -1.2 1269.6 +1.9 -1.2 2008.7 +1.0% -1.2% 1754.8 +2.3% -2.8% 557.8 2.0% -1.6%

0.03%

0.03%

0.14%

0.02%

0.02%

0.08%

0.08%

Number of Tablets 100

Price (USD) 7.4

30

9.3

30

10.6

30

16.0

30

9.0

40

1.6

3 Vitamins

20

2.6

12 Vitamins & 12 Minerals 8 Vitamins & 6 Minerals 1 Vitamins & 1 Minerals 7 Vitamins & 3 Minerals

30

18.6

30

10.6

60

11.7

30

21.3

CALCITONE/Arnet Pharmaceutical, U.S.A

907417

Ar-D-Cal/ Arnet Pharmaceutical. U.S.A

908407

SILICA-OK/Surepharm Services Ltd for Wassen international, UK

38521

Dynamisan / Farmar Italy for Novartis Consumer Health SA, Switzerland Stresstabs / Wyeth. Canada

Jo9006

263.8 +13.8% -10.3%

1523.4 +1.7% -1.9%

0.06%

11 Vitamins 13 Minerals & others

30

11.9

E32945

299.1 +0.3% -0.2% 120.2 +16.1% -7.5%

1308.2 +1.3% -0.9% 795.4 +4.1% -2.4%

0.05%

9 Vitamins & 2 Minerals 7 Vitamins 5 Minerals & others

30

3.6

30

10.4

296.6 +1.1% -8.1% 110.7 +28.2% -16.1% 231.5 +27.3% -51.4%

1401.3 +0.6% -1.0% 703.3 +7.4% -9.0% 1448.1 +1.2% -2.7%

60

13.3

20

3.7

30

2.8

Vita Ladies / Arnet Pharmaceutical, U.S.A

005438

Century 2000 / Arnet Pharmaceutical U.S.A

811428

Neurobion / Merck, Austria

375109

Centrum / Lederle laboratories division, Amirican cyanamide company, U.S.A

28406

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0.05%

0.03%

0.01%

0.05%

0.01%

0.03%

12 Vitamins & 13 Minerals 3 Vitamins

Not Mentioned

Physical Quality Control Parameters of Dietary Supplement

Disintegration test with and without disk was performed for 17 products using 800ml of three different immersion medium. The first disintegration test was performed using 0.1N HCl with pH = 1.1 (Simulated gastric fluid without enzyme), the second was performed using distilled water with pH = 5.6 (USP disintegration conditions for dietary supplements) and the third test was performed using phosphate buffer with pH = 7.4 (Simulated intestinal fluid without enzyme) for 30 minutes. Table 2 showed that nine of seventeen tablets did not disintegrate within 30min when phosphate buffer or distilled water without disk has been used as immersion medium during the disintegration test. Wile by using 0.1 HCl pH = 1.1 without disk 6 of seventeen tablets did not disintegrate. In all disintegration tests with different pH, when disk has been used, only one of seventeen tablets did not disintegrate. Table 2. Disintegration test for mineral and vitamin tablets in three different immersion medium without disk.

D76595

Disintegration test (0.1N HCl, pH = 1.1) Pass

Disintegration test ( H2O, pH = 5.6) Pass

Disintegration test ( Phosphate buffer, pH = 7.4) Pass

CEBROVIT/ Sun Naturals, USA

807455

Not pass

Not pass

Not pass

FERROVIT/ Arnet Pharmaceutical, USA

907420

Not pass

Not pass

Not pass

ZINC-ACE/ Surepharm Services Ltd, UK

37207/A

Pass

Not pass

Not pass

OSTEOCARE/ Vtabiotic Ltd, UK

OE062P

Pass

Not pass

Not pass

MIXAVIT/Julphar, U.A.E

515

Pass

Pass

Pass

NEURORUBINE-FORT/ Mepha, Switzerland

1050115

Pass

Pass

Pass

GINKGO-VIT/Arnet Pharmaceutical, U.S.A

907416

Not pass

Not pass

Not pass

CALCITONE/Arnet Pharmaceutical, U.S.A

907417

Pass

Pass

Pass

Ar-D-Cal/ Arnet Pharmaceutical. U.S.A

908407

Pass

Pass

Pass

SILICA-OK/Surepharm Services Ltd for Wassen international, UK

38521

Not pass

Not pass

Not pass

Dynamisan / Farmar Italy for Novartis Consumer Health SA, Switzerland

J09006

Pass

Pass

Pass

Stresstabs / Wyeth. Canada

E32945

Pass

Pass

Pass

Vita Ladies / Arnet Pharmaceutical, U.S.A

005438

Not pass

Not Pass

Not pass

Century 2000 / Arnet Pharmaceutical U.S.A

811428

Not pass

Not pass

Not pass

Neurobion / Merck, Austria

375109

Pass

Not pass

Not pass

Centrum / Lederle laboratories division, Amirican cyanamide company, U.S.A

28406

Pass

Pass

Pass

Brand Name/ Product Manufacturer

Lot No.

MATERNA/ Wyeth, Canada

The present study showed that the pH of immersion medium as well as the use of disks in the observation cylinder had an important impact on the ability of products to pass the disintegration test. More specific, the use of 0.1N HCl as immersion medium for disintegration was more effective than the use of distilled water or phosphate buffer. It is important to remind that the use of 0.1N HCl as immersion medium is closer to the reality, because tablets is expected to disintegrate inside the stomach within a reasonable time to release the active ingredient or nutrient. This disintegration will facilitate further dissolution in the biological fluids before gastrointestinal absorption. Also it is important to note that if a vitamin or mineral is poorly soluble or its dissolution is slow, then dissolution and not disintegration is the most critical parameter. Yet, it has to be pointed out that a product which fails disintegration will presumably fail dissolution criteria. Furthermore, if a mineral has to be absorbed within an absorption window and the dosage form does not release its content in a timely manner, then the therapy might be compromised or fail (Lobenberg et al., 2006 and Thakker et al., 1987). The present study showed that the disintegration was also effected significantly by using disk. Only one of

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Hamzah MM ;Ahmed AA

seventeen tablets did not disintegrate when disk was used. Recent studies (Kamba et al.2002, 2003) investigated the mechanical forces applied in the disintegration apparatus showed that a tablet might undergo two defined impulsive forces in the basket assembly: one when the disk hits and one when it hits the basket screen while the basket-rack assembly is moving up and down. Such forces might apply to the dosage form for each movement cycle of the basket assembly. The disintegration of the products with and without disk showed that fluid forces combined with additional forces of the disks can increase disintegration significantly. Motility forces of healthy human intestine were reported to be up to 1.2 N. ( Lobenberg et al., 2006 and Aytug et al. 2001). Recent studies have shown that there are several diseases which impact motility like Parkinson’s disease, diabetes mellitus and thyroid diseases. (Aytug et al. 2001 and Kerbs et al., 2001). Therefore, many patients which have such diseases and take mineral supplements might have compromised motility. This might influence the disintegration of the administered dosage form. Such products, and those needing higher mechanical forces to disintegrate (use of disk), might therapeutically fail in patients due to insufficient motility forces (Lobenberg et al., 2006 and Kuemmerle et al., 2000). Price comparison showed that product with higher price is not necessary to be the best (Table1 and Table 2). Some products with low price, much more number of tablets, vitamins and minerals in each container were passed the disintegration test, while other more expensive products did not passed the disintegration test. References Aytug N, Giral A, Imeryuz N, 2001. Gender influence on jejunal migrating motor complex. Am J Physiol Gastrointest Liver Physiol 280:G255-63. Du J, Hoag SW. 2003. Characterization of excipient and tableting factors that influence folic acid dissolution, friability, and breaking strength of oil- and water-soluble multivitamin with mineral tablets. Drug Dev Ind Pharm 29:1134–47. Kamba M, Seta Y, Kusai A. 2002: Comparison of the mechanical destructive force in the small intestine of dog and human. Int J Pharm 237:139-149. Kamba M, Seta Y, Takeda N, 2003. Measurement of agitation force in dissolution test and mechanical destructive force in disintegration test. Int J Pharm 250:99-109. Krebs NF. 2001. Bioavailability of dietary supplements and impact of physiologic state: infants, children and adolescents. J Nutr 1351S–4S. Kuemmerle J: 2000. Motility disorders of the small intestine: new insights into old problems. J Clin Gastroenterol 31:276-81. Lobenberg R, Steinke W. 2006. Investigation of vitamin and mineral tablets and capsules on the Canadian market. J Pharm Pharmaceut Sci 9(1):40-49. Lachman L, Lieberman H, Kanig J. 1987.The theory and practice of industrial pharmacy. Varghese publication house, 3rd edition, page-299. Pisek R, Korselj V,Vrecer F. 2002. Comparison of Direct Rotor Pelletization(Fluid Bed) and Hign Shear Pelletization Method for Pellet Production. Pharm and Biopharm (53): 327-333. Thakker KM, Sitren HS, Gregory JF III, Schmidt GL, Baumgartner TG. 1987. Dosage form and formulation effects on the bioavailability of vitamin E, riboflavin, and vitamin B-6 from multivitamin preparations. Am J Clin Nutr 45:1472–9. United States Pharmacopeia: 2005. Friability and weight variation of dietary supplements. Rockville, MD: US. Pharmacopeial convention, Inc United States Pharmacopeia: 2005. Disintegration and dissolution of dietary supplements. Rockville, MD: US. Pharmacopeial convention, Inc.

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