1. MULTIVITAMIN PRODUCTS Department of Pharmaceutics Hindu College of Pharmacy

2. MULTIVITAMIN A multivitamin is a preparation intended to supplement a human diet with vitamins, dietary minerals and other nutritional elements. A multivitamin/mineral supplement is defined as the supplement containing 3 or more vitamins and minerals but does not include herbs, hormones, or drugs with each nutrient at a dose below the tolerable upper level determined by the Food and Drug Board and the maximum daily intake to not cause a risk for adverse health effects. Such preparations are available in the form of tablets, capsules,pastilles,powders,liquids and injectable formulations.

3.  The optimized formulations and manufacturing process are required in order to ensure acceptable appearance quality levels The basic taste characteristics of various vitamins follows  Vitamin A acetate, vitamin D 2, and vitamin E – “substantially tasteless”  Vitamin B 1 – “yeasty” bitter  Vitamin B 6 – taste less  Niacinamide- very bitter  Vitamin C –sour  Calcium pantothenate- bitter  Biotin- tasteless  Folic acid- nearly bitter

4. CHEWABLE TABLETS  Chewable tablets when chewed produce a pleasant tasting residue in the mouth that when swallowed does not leave a bitter or unpleasant after taste.  These tablets have been used in the tablet formulation for children, especially multivitamin formulations and for the administration of antacids and selected anti- biotics.  Chewable tablets prepared by compression usually contain manitol, sorbital or sucrose as binders and fillers and flavors to enhance their appearance and taste.

5. ADVANTAGES OF CHEWABLE TABLETS  Patient convenience  use as a substitute for liquid dosage forms.  Improved patient acceptance  better bioavailability. DISADVANTAGES OF CHEWABLE TABLETS  Bad tasting drugs should not be suitable,  Drugs having high dosage levels should be difficult to formulate.

6. Flow chart of various aspects to be considered in connection with chewable tablets TYPICAL PRODUCTS Vitamins Antacids Analgesics Cold Remedies EVALUATION Taste panels Blood levels (for adsorbed drugs) In vitro vs. in vivo correlation for antacids Stability (chemical, physival, organoleptic) Quality control and assurance DESIRED PRODUCT ATTRIBUTES Good taste and mouthfeel Acceptable bioavailabilityand bioactivity ", Acceptable stability and quality Economical formula and process FORMULATION FACTORS Amount of active substances as a percent of total tablet weight Flow Lubrication Disintegration Compressibility Compactability-Stability Organoleptic considerations FORMULATION TECHNIQUES AND APPROACHES Microencapsulation Solid dispersions Ion exchange Spray congealing and coating Granulation and Coating Use of amino acid and protein hydrolysates Inclusion complexes Molecular complexes Formation of salts or derivatives Excipients Artificial sweeteners Flavoring Coloring

7. FORMULATIO N FORMULATIO N FACTORS

8. TASTE AND FLOVOR: Salt and sour tastes are derived form substances capable of ionizing in solution. The term flavor generally refers to a specific combined sensation of taste and smell. EX: sugars has a sweet taste but no flavor whereas honey has a sweet taste and a characteristic smell – the combination of the two being known as honey flavor AROMA: Pleasant smells are generally referred as aromas EX well formulated orange- flavored chewable tablets should have a characteristic sweet and sour taste and aroma of fresh orange.

9. MOUTH -FEEL The term mouth feel is related to the type of sensation or touch that a tablet produces in the mouth upon chewing AFTER –EFFECTS  iron salts leave a rusty after taste  saccharin in high amounts tends to leave a bitter after taste  Another common after effect is a numbing sensation of a portion of the whole surface of the tongue and mouth

10. PHYSICAL PROPORTIES color,odor,taste,after taste, and mouth feel Physical form: crystal, powders, amorphous solid, oily liquid etc Melting or congealing temperature Existing of polymers, Moisture content Aqueous solubility. Active drug stability on its own Compressibility if applicable CHEMICAL PROPERTIES  Chemical structure and chemical class  Major reactions of this chemical class  Major incompatible compounds or class of compounds  Drug dose and any limit on the final dosage size

11. Assessment of the Formulation Problems  The first step in the formulation of a chewable tablet is to obtain a complete profile of the active drug.The drug profile should eliminate potentially incompatible excipients, flavors, and the like at the outset, leading to the use of excipients that would best compliment the drug chemically, physically and organoleptically.

12. FORMULATION TECHNIQUES

13. Formulation Techniques Coating by Wet Granulation Microencapsulation Solid Dispersions Adsorbate Formation Technique – Solvent method – Melting method Ion Exchange Spray congealing and spray coating Formation of different salts or derivatives Use of Amino acids and protein hydrolysates

14. COATING BY WET GRANULATION  In this technique drug particles to be coated are fluidized by means of suspension in a controlled high –velocity warm air or stream directed through a perforated plate into a coating chamber,  The drug particles undergoes cyclic flow past an atomizing nozzle delivering coating agent in solution or suspension  The sprayer may be mounted either to spray up ward from the bottom or downward from the top

15. (a) Top spray fluidized bed system. (b) Bottom spray f luidized system.

16. MICRO ENCAPSULATION 1.Formation of three immiscible phases i.e. liquid manufacturing vehicle phase, a core material drug phase, and a coating material phase. 2.Depositing the liquid polymer coating by sorption around the core material under controlled physical mixing of the three phases. 3.Rigidizing the coating usually by thermal cross linking or dissolution techniques to form a rigid microcapsule

17. The resultant coated granules not only mask the taste of a drug but also minimize any physical and chemical incompatibility between in gradients The typical coating material include carboxy methyl cellulose. cellulose acetate phthalate Ethyl cellulose. Gelatin Poly vinyl alcohol, gelatin –acacia, shellac.

18. SOLID DISPERSION Bad tasting drugs can be prevented from stimulating the taste buds by adsorption on to substrates capable of keeping the drugs adsorbed while in the mouth but releasing them eventually in the stomach or GIT Good example is the adsorption of dextrometharphan hydro bromide on to magnesium trisilicate substrate

19. ADSORBATE FORMATION TECHNQUES SOLVENT METHOD  The formation of an adsorbate involves dissolving the drug in a solvent,mixing the solution with the substrate and evaporating the solvent –leaving the drug molecules adsorbed upon the substrate

20. MELTING METHOD  Here the drug or drugs and a carrier are melted together by heating, the melted mixture is then cooled and rapidly solidified in an ice bath with vigorous stirring. The product is then pulverized and sized.  Heat liable drugs volatile drugs and drugs that decompose on melting are obviously unsuitable

21. ION EXCHANGE  It is the reversible interchange of ions between a solid and a liquid phase in which there is no permanent change in the structure of the solid. The solid is the ion exchange material and the ion could be a drug  When used as a drug carrier ion exchange materials provides a mean for binding drugs on to an insoluble polymeric matrix and can effectively mask the problems of taste and odor

22. SPRAY CONGELING AND SPRAY COATING Spray congealing involves cooling of melted substance in the form of fine particles during their travel from a spray nozzle to the distant vicinity of a spray chamber held at a temperature below their melting point. It must be noted that the weight of the active substance is approximately one-third that of the spray-congealed preparation. For small-dose entities, such as the vitamins, spray congealing is ideally suited.

23. The spray coating process involves the spraying of a suspension of the drug particles in a solution of the coating material through a atomizer in to a high – velocity stream of warm air The coarse droplets delivered by the atomizer consists of the drug particles enveloped by coating solution, as the solvent evaporates the coating materials encapsulates the drug particles

24. FORMTION OF THE DIFFERENT SALTS OR DERIATIVES It is an attempt made to modifies the chemical composition of the drug include it self so as to render it less soluble in saliva and there by less stimulating for the taste buds or to obtain a taste less or less bitter form

25. USE OF AMINO ACIDS AND PROTIEN HYDROLYSATES By combining amino acids their salts or a mixture of two it is possible to substantially reduce the bitter taste of penicillin. Some of the preferred amino acids are sacrosin, alanine, taurine, glutamine acid and especially glycine.

26. NAMESOURCE PARTICLE SIZE LOD BROWN SUGAR AMSTAR 92%ON 50 MESH 0.7% MOLASSES GRANULES AMSTAR 100%ON 12 MESH 1% COMPRESSIBL E MOLASSES INGREDIENT TECHNOLOGY 50% ON 60 MESH 4% COMPRASSI BLE HONEY INGREDIENT TECHNOLOGY 50% ON 60 MESH 4% EXCIPIENTS

27. COMPRESSIBL E SUGAR AMSTAR 75% ON 100 MESH 0.5% DEXTRON/FR UCTOSE/MALT OSE MENDELL 3% ON 20 MESH 7% 7% DEXTRONEMENDELL 3% ON 20 MESH 9% LACTOSESHEFFIELD 20 % ON 60 MESH 1 % MANNITAL _ 75% ON 80 MESH 0.3% SORBITALPFIZER 33%ON 60 MESH 1 %

28. SWEETENERS MATERIALS RELATIVE SWEETNESS RELATIVE SWEETNESS ASPARTAME 200 200 CYCLAMATES 30 – 50 GLYCYRRHIZIN 50 50 SACCHARIN450 DEXTRON(GLUCOSE)0.7 FRUCTOSE(LEVULOSE)1.7 LACTOSE0.2 MALTOSE0.3 MANNITOL0.5-0.7 SORBOTALO.5-0.6 SUCROSE1

29. FLAVORS SWEET VANILLA, STONE FRUITS, GRAPE,BERRIES,MAPLE SOUR CITRUS,CHEERY,RASHBERRY,STRAW BEERY SALTYNUTTY,BUTTERY,SPICE,MELON BITTER LICORICE,ANISE,CHERRY,NUT,GRAPE FRUIT LICORICE,ANISE,CHERRY,NUT,GRAPE FRUIT ALKALINE MINT, CHOCOLATE, CREAM METALIC GRAPE, LEMONE-,LIME

30. COLORANTS Colorants are used in the manufacturing of the chewable tablets for the following reason 1.To increase aesthetic appeal to the consumer 2.To aid in product identification and differentiation 3.To mask unappealing or non uniform color of raw materials 4.To complement and match the flavor used in the formulation

31. Two main forms of colorants are 1.DYES  chemical compounds that exhibit their coloring power when dissolved in a solvent,  cheaper and available in a wide range of shades with higher coloring power than the natural pigments 2.LAKES  Lakes have been defined by the FDA as the “aluminum salts of fd&c water soluble dyes  fd&c lakes are available in six basic colors one :yellow, one :orange, two reds (a pink red and orange red) and two blues (a green blue, and royal blue)  concentration range of 0,1 to 0,3%

32. MANUFACTURING PROCESS

33. Four important aspects of the chewable tablet manufacture are the 1. Proper incorporation of the coloring agent 2. Assurance of necessary particle size distribution 3. Maintenance of correct moisture content 4. Achievement of the proper tablet hardness

34. If the granulation process involves wet granulation the extent of wetting and the rate and extent of drying should be considered. Over wetting can expected to produce hard granules that may have poor compression characteristics resulting in more softer and friable tablets. So care must be taken The method and appropriate order for the addition of the flavor and color must be determined if wet granulation is being used.

35. Since most flavor substances are volatile they can not be subjected to elevated temperatures for this reason they can not be incorporated in wet granulation flavors can be added in the final blending operation of the process The color if in the form of a lake would be incorporated in the same step The concentration of these ingredients would not exceed 0.1% An important consideration is the assurance of the uniform blending During compression the granules fracture and release fresh white material on to the surface resulting in white spots on the colored back ground called “speckling”.

36. CHEWABLE MULTI VITAMIN TABLETS Vitamin A acetate 12.50 mg 12.50 mg Vitamin D 1 4.50mg 4.50mg VitaminD 2 0.58mg 0.58mg Vitamin E. 50 % SD 33.00mg 33.00mg Ascorbic acid 90% 67.00mg 67.00mg Folic acid 0.40mg 0.40mg Vitamin B 2 5.20mg 5.20mg Vitamin B 6 6.00mg 6.00mg

37. Vitamin B 12 6.00 6.00 NIACINAMIDE 60.00 60.00 FERROUS FUMARATE 18.00 18.00 PHARMASWEET POWDER 8.70 8.70 NATURAL ORANGE FLAVOR 10.90 10.90 EMDEX938.52 COLOR ORANGE NO S31282 q,s q,s MAGNESIUM STEARATE 8.70 8.70

38. Mix vitamin D 1.D 2.folic acid and B 12 with niacinamide for 15 min To 1 add vitamin A,E, ascorbic acid,B 2,B 6,ferrous fumarate,small portion of emdex, and mix thoroughly for 15 min To 2 add remaining emdex,flavor, and pharmasweet and mix for 10 to 15 min Add color to 3 and blend thoroughly until it is evenly distributed Add magnesium stearate to 3,blend 5 min and compress

39. EVALUATION OF CHEWABLE TABLETS  Organoleptic evaluation takes place at various stages in the development of a chewable tablets  For example evaluation of dextrometharphan, ephidrine for their bitterness followed by the taste comparison of these drugs after absorption onto a polycarboxylic acid resin

40. CHEMICAL EVALUATION ASSAY FOR DRUG CONTENT  A suitable analytical method (chromatographic, titrimetric, spectrophotometric, etc) is used to determine the active content on a respective sample (usually an aliquot of 20 randomly selected tablets after pulverization)  The recovered amount of the active drug is then expressed as percent of labeled drug content

41. DOSAGE UNIFORMITY As is usually the case with chewable tablets where provision is made for a large use of sweet excipients,coating agents and for taste masking and mouth feel.then individual assay of the given number of randomly selected dosage unit is done to obtain drug content in the various samples

42. PHYSICAL EVALUATION Tablet physical appearance : as one of the quality control procedure tablets should be inspected for smoothness, absence of cracks, chips and undesirable characteristics If the tablets are colored this would include examination for mottling and other evidence of non uniform color distribution except where they are used intentionally

43. HARDNESS  The hardness test is performed to provide a measure of tablet strength. Tablets should be hard enough to with stand packing and shipping but not so hard to create undue difficulty upon chewing FRIABILITY  for chewable tablets friability value of up to 4% are accepted

44. DISINTIGRATION  This test indicate the ability of the tablet to disintegrate and still provide the benefit of the drug if it accidentally swallowed DISSOLUTION  Chewable tablets should be tested in two forms : intact and partially crushed

45. STABLITY TESTING Stability testing of dosage forms or drug products is carried out to evaluate time –dependent changes. Accelerated stability testing is used to predict quickly potential changes that may occur in a product. There are three areas of major concern in the stability testing of chewable tablets : organoleptic, chemical, physical the data obtained from chemical evaluation of the tablets at elevated tem and humidity,stress condition are most useful

46. OTHER TESTS IN THE STABILITY PROGRAM WOULD INCLUDE Active drug content determination. Changes in physical characterization of the tablet Change in the tablet hardness, friability,dissolution rate and extent of dissolution Moisture content of the tablets Stability of the coating systems Stability of the colorants

47. REFERENCES: 1. Pharmaceutical Dosage Forms: Volume 1 second edition,Revised and Expanded Herbert A. Lieberman pg no 176 & 404 to 415 www.imageswww.images. com