BRAIN. Broad Research in Artificial Intelligence and Neuroscience, ISSN 2067-3957, Volume 1, July 2010, Special Issue on Complexity in Sciences and Artificial Intelligence, Eds. B. Iantovics, D. Rǎdoiu, M. Mǎruşteri and M. Dehmer STUDY OF THE FORMULATION AND PREPARATION OF CHEWABLE TABLETS WITH A CALCIUM COMPLEX ASSOCIATION AND VITAMIN D3 Mirela Mitu, Ancuţa Fiţa, Teodora Balaci, Andreea Stănescu, Emma Creţu Abstract. The experimental study objective was the development of chewable tablets with the calcium complex association, the minerals and vi- tamin D3 for children, subject to the rules as stipulated by the Romanian Pharmacopoeia Xth edition. Generating sources of calcium, used as raw ma- terials in the preparation of these tablets are natural products represented by complex mineral rich in calcium - Lactoval R© HiCal (ratio of calcium and phos- phorus is 2,2:1, report the same as breast milk) and 30% bovine colostrums [1, 3], making the absorption of calcium should be increased. Also, in order to fix and better absorb calcium in the body was added to make the preparation of these chewable tablets and vitamin D3. Was chosen as a method of preparing direct compression. Excipients for direct compression are diluents-binder-disaggregated. They are unitary ex- cipients or co-processed products, multi-processed excipients together to meet those properties: microcrystalline cellulose (Vivapur 102) Ludipress, lactose (Tablettose 80), Kollidon CL Isomalt DC 100. Was also added to a lubricant (magnesium stearate) and sweetener and flavoring to carry out the preparation of tablets and after 30 days as provided Romanian Pharmacopoeia Xth and its 2001 supplement, which comprises: organoleptic control, uniformity of weight, strength, disintegration and their friability. Working method chosen and make the appropriate choice leads to tablets in terms of quality standards officinal. Keywords: chewable tablets, calcium complex association, vitamin D3, direct compression method. 2000 Mathematics Subject Classification: 92C99. 80 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 1. Introduction Chewable tablets are solid pharmaceutical dosage forms with the follow- ing advantages: an improved bioavailability due to decay in the mouth (an improvement of dissolution); ensure the elimination of the need for available water to swallow the tablet. The administration seeks immediate therapeutic effect, confers an increased level of patient acceptance (especially in pediatrics) by pleasant taste and a commercial presentation through a substitution variant form preparations liquid. Calcium is the most abundant mineral in the human body. An average human body constitution contains calcium ion 1000-1500g, 99% of which is located in the bones and teeth. Besides the ability to give skeletal mechani- cal strength, calcium is essential for transmitting nerve impulses and muscle contraction. The calcium is known as the preventive factor in osteoporosis, in- crease bone density. Milk and milk products constitute one of the main sources of calcium from food, both in childhood and in adolescence, adulthood and old age. Recent studies have shown that immunostimulator effect of vitamin D is higher than that of vitamin C [2]; the likelihood of upper respiratory tract infections is inversely proportional to the concentration of vitamin D in blood. 2. Materials and method Materials: Were used Lactoval R© HiCal, (DMV International), 30% bovine colostrums, vitamin D3 type 100 (DSM), Ludipress (BASF AG, Germany), Kollidon CL- crospovidon (BASF AG, Germany), Isomalt DC 100 (BANEO-Palatinit GmbH, Germany), Tablettose 80 - (Meggle, Wasserburg GmbH), Vivapur 102, veg- etable magnesium stearate (Faci Spa), maize starch (CHEMaster International Inc.), caramel flavor powder (Vegan, Kosher, gluten free), sweetener. All ex- cipients used were pharmaceutical quality and purity analysis. The tablets formulation: In the Table(1) are shown the composition of the studied wording. Mixing for compression was obtained using a cone double homogenizer. In that were loaded materials: that vitamin D3, and sweetener, caramel flavor, and corn 81 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 starch, magnesium stearate, kollidon, vivapur 102, colostrums, isomalt, ludi- press and lactoval. Time is set during the mixing: 20-minutes. The mixture was passed through the sieve VI and compressed. Direct compression mixture was made with a rotary tablet TX 30 equipped with 30 pairs of stainless pon- sons flat edge, with edges intact, with a diameter of 15mm. Were obtained uncoated tablets, uniform appearance, as a disk, compact structure, with smooth, flat and edges intact 15 mm; • Color - white, mottled with yellow pigment; • Odor - weak characteristic odor; • Taste - sweet, refreshing; After preparation of chewable tablets were determined: • Uniformity of mass; • Friability; • Mechanical strength (diameter, height of tablets); • Disintegration. Determinations were performed in accordance with F.R. X., and E. Ph. 5 [4, 5, 6]. All calculations were performed on 20 or 10 (friability test) tablets. Equipment: • Balance Mettler - Toledo - for uniformity of mass; • The apparatus Pharmatest PTF 10/ER for friability test; • Pharmatest PTB 311E device for mechanical strength (diameter, thick- ness of tablets); • Pharmatest PTZ S device for the test of disruption; 82 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Table 1: The compositions of the chewable tablets with calcium and vitamin D3 ACTIVE SUBSTANCES Ingredients Quantity Lactoval R© HiCal 0,8 mg Colostrum 400 mg Vitamin D3 type 100 (100.000 U I/g) 100 mg EXCIPIENTS Ingredients Quantity Role Ludipress 100,1mg binder,diluent,disintegrant Isomalt DC 100 96,4 mg sweetener Tablettose 80 89,31 mg diluent Kollidon CL 36,4 mg binder Vivapur 102 36,4 mg diluent Magnesium stearate 22,75 mg lubricant Maize starch 18,2 mg lubricant, diluent Caramel flavor 5 mg flavor Sweetener 4,64 mg TOTAL 910 mg 3. Results and Discussions Uniformity of mass: It weighted 20 tablets uncovered and calculated the average mass. The same tablets are weighted individually. Compared to the average mass calcu- lated, the individual mass may submit a deviation: 18 tablets ±5% and just 2 tablets ±7, 5%.The values of individual, average masses and the percentage deviations calculated are shown in the Table(2) and Figure 1 Conclusion: It is noted that the tablets meet standards officinal regard- ing individual mass, masses limits of the tablets which can vary are between 0,866-0,957, and has the corresponding percentage deviations range from: - 2.19% and 2.64%. 83 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 The friability: A loss of less than 1% is considered acceptable for most products. From the experimental results, show that the formulation studied requirement as regards friability. For studied wording, weight loss is less than 1%. To test using 10 chewable tablets are dusting with a soft brush. The drum introduced in tablets, previously weighed, to secure the cover and fasten the drum unit. The drum starts to rotate with the rotation speed of 25 rpm default operating mode. The determination is made after 100 revolutions, respectively after 4 minutes, the tablets are removed and remove all dust again any tablet is broken away. Weigh the tablets, then friability calculated using the formula: Friability = [(Mi-Mf ) / Mi] x 100 where, Mi = initial weight of tablets Mf = final mass of tablets The test is done once. If results are not satisfactory or if weight loss is less than 1%, repeat the test twice and calculate the average of three determina- tions. Results: Mi = 893.786 mg Mf = 890.777 mg Friability = 0.33% < 1%. Conclusion: It is noted that the friability for 10 chewable tablets is less than 1%, so the tablets meet USP requirements. The mechanical resistance, the diameter and the thickness of tablets: To test were using 10 chewable tablets. Each tablet was placed in the de- vice (Pharmatest PTB 311E), after which values were determined for the three parameters (diameter,height and hardness).The tests led to following results and are shown in the Table(3)and Figures(2, 3). Conclusion: The data in the table above and Figures(2, 3) observed that chewable tablets have values very close in terms of their size (diameter, height) 84 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Table 2: The values of individual, average masses and the percentage devia- tions of tablets Crt.No. Individual Mass (g) Percentage deviation(%) 1. 0,909 -0,11 2. 0,896 -1,54 3. 0,892 -1,98 4. 0,921 +0,10 5. 0.902 -0,88 6. 0,934 +2,64 7. 0,916 +0.66 8. 0,911 +0,11 9. 0,923 +1,43 10. 0,899 -1,21 11. 0,893 -1,87 12. 0,917 +0,77 13. 0,925 +1,65 14. 0,913 +0.33 15. 0,890 -2,19 16. 0,899 -1,21 17. 0,901 -0,99 18. 0,887 -2,53 19. 0,920 +1,10 20. 0,894 -1,76 Average 0,8584 85 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Figure 1: Percentage deviation of invidual mass of tablet but also in terms of mechanical strength. This is due largely to correct adjust- ment tablet machine. The disintegration of chewable tablets: For chewable tablets disintegration test were used 6 tablets at the same time absolutely the same conditions, so that all samples are inserted into the same water bath maintained at 36-38◦C; arm support device with baskets of moving up and down control by a microprocessor running 30 races per minute over a distance of 55 mm. It is preferable that chewable tablets correspond to the dissolution test for uncoated tablets, which must be disintegration, more than 15 minutes. The following table IV shows disintegration times for the disintegration six chew- able tablets under test. Conclusion: Chewable calcium tablets correspond officinal disintegration rules for uncoated tablets (disintegration time 8-8, 4 min. <15 min., Figure(4). 86 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Table 3: The diameter (mm), the thickness (mm) and the mechanical resis- tance (N ) of the studied formulation Crt.No. Diameter (mm) Height (mm) Hardness (N ) 1. 15.02 3.94 123.5 2. 14.99 3.98 115.0 3. 14.99 3.95 120.5 4. 15.01 3.93 109.5 5. 14.98 3.97 125.1 6. 14.99 3.95 113.8 7. 15.00 3.94 119.3 8. 14.99 3.97 113.7 9. 14.99 3.93 131.9 10. 14. 8 3.97 120.8 Average 14.99 3.95 119.31 4.Conclusions Two natural products represented the calcium complex association used for preparation of chewable tablets: a Lactoval R© HiCal, rich in minerals, with a high content of calcium, and bovine colostrums. To obtain chewable tablets, direct compression method was used to very good because it eliminates the presence of high temperature and humidity, which are risk factors, using di- rect compression excipients coprocessor, which ensured the stability of active components. Working method chosen and make the appropriate choice leads to tablets in terms of officinal quality standards. Following the test of stability is seen that after 30 days the average weight values, individual mass, diameter, thickness, resistance and disintegration in- creases and decreases relative to the friability tablets made initial determi- nations. This is due hygroscopicity of some excipients, which may adversely affect the stability of chewable tablets. Therefore, preparation of these tablets should be made under controlled conditions followed by blister or filling their bottles with a desiccant substance. 87 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Figure 2: The hardness of tablets (N ) Figure 3: Diameter (mm) and height (mm) of tablets 88 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Table 4: Time of disintegration of chewable tablets Crt. Time of disintegration(min) Time of disintegration(sec) 1. 8 480 2. 8.32 499,2 3. 8.2 492 4. 8.04 482,4 5. 8.18 490,8 6. 8.4 504 Figure 4: The disintegration time of chewable tablets 89 M. Mitu, A. Fiţa, T. Balaci, A. Stănescu, E. Creţu - Study of chewable tablets with a calcium complex association and vitamin D3 Experimental study has shown the possibility to obtain film-based natural products that have an appreciable content of calcium and other trace elements, minerals and vitamin D3, an important role in returning stability excipients used. Children having a pleasant taste will more easily accept the chewable tablet flavor and active substances are more easily disposed of pharmaceutical form as the tablets are broken in the mouth and are more easily absorbed and metabolized in the body, with the development of therapeutic, to the tablets are swallowed. References [1] Buckley J, Abbott M, Martin S, Brinkworth G, Whyte P.” Effect on an oral bovine colostrums supplement on running performance”. Abstract from: 1998 Australian conference of science and medicine in sport, Ade- laide, South Australia, October 1999; [2] Grant WB, Holick MF (2005). ”Benefits and requirements of vitamin D for optimal health: a review”. Altern Med Rev 10 (2): 94-111; [3] Gregory S. Kelly, (nov.2003). ”Bovine colostrums: a review of clinical uses” Altern Med Rev 2003;8(4):378-394; [4] xxxEuropean Pharmacopoeia 5th edition, Council of Europe, Strasbourg, 2004; [5] xxxFarmacopeea Română, ediţia a X-a, Editura Medicală, Bucureşti, 1993; [6] xxxUnited States Pharmacopoeia, USP 27, United States Pharmacopoeia Convention Inc, Rockville Md, 2004. Mirela Mitu, Ancuţa Fiţa, Teodora Balaci, Andreea Stănescu, Emma Creţu Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy ”Carol Davila” - Bucharest contact e-mail: aastanescu@gmail.com 90