CHAPTER I

Scenario The Pharmacy student in faculty of medicine & health science UMY was given the assignment to made an effervescent tablet of vitamin C. But after evaluation, that tablet is not fastly dissolve in water.

Step 1 Clarification of Term 1. Effervescent tablet : tablets that are compressed from effervescent granules and generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use. Step 2 Defyning The Problem 1. What is the evaluation of effervescent tablet? 2. What is the advantage and disadvantage of effervescent tablet? 3. Whyd the effervescent tablet in the scenario cant be dissolve in water? 4. What is the critical points of effervescent tablet? 5. What is the general formula of effervescent tablet? 6. What is the manufacturing method of effervescent tablet? Step 3 - Brainstorming 1. A. Physic evaluation : Clarity of solution Uniformity of weight and size Hardness Friksibility Friability Disintegration time B. Chemical evaluation : pH solvent Uniformity of active ingredient 2. The advantage of effervescent tablet : Fast onset of action Accurate dosing Good stomach and intestinal tolerance

 More portability Improved portability No need to swallow tablet because we need to dissolved it first in water The disadvantage of effervescent tablet : The complicacy to produce a chemically stable product Humidity during manufacturing may be sufficient to initiate the reactivity of effervescent 3. The effervescent tablet in the scenario cant be dissolve in water maybe due to the influence of other substances, whether is active ingeredient or excipient, that affect solubility 4. Critical points : The amount levels of acids and bases Air humidity when products made Dissolution and disintegration time of tablets The size of the granules 5. R/ Active ingredient x% Tartaric acid Citric acid 100-x-y NaHCO3 =z% Diluent Binder y% Water Lubricant 6. Manufacturing method : Wet granulation - Heating method - Granulation with reactive fluids. - Non reactive granulation with fluid. Dry granulation - Slugging - Compacting Fluidization Step 4 Problem Analysis Effervescent Tablet requires special conditions and methods for its production because there are two ingredients that can not be united which is salt sodium bicarbonate and organic acid as a producer of carbon dioxide. The second reaction, this material will be accelerated by the presence of water, therefore Effervescent tablet during its journey from the end of production into the hands of patients should not be the slightest contact with water. In addition, high temperatures can also accelerate the Effervescent tablet-making process requires special conditions, humidity should be relatively low and the

temperature must be cold to prevent the granules or tablets attached to the machine because of the effect of moisture from the air. The active ingredient category of effervescent tablet : Those that are difficult to digest or disruptive to the stomach. pHsensitive, such as amino acids and antibiotics. oxygen, or moisture. The excipient ingredient of effervescent : o Should be hydrophilic o Should be compatible with the active ingredient o The water amount is an important component o Should be anhydrous o If the molecule is bound in hydrate should be stable o Solubility is an important properties of the effervescent tablet component and its a critical point Critical point of speed disolve : o Granules size o Binder o Diluent o Lubricant o Tablet compression o The amount of water which used to dissolve the effervescent tablet Effervescent reaction H3C6H5 + 3NaHCO3 Na3C6H5O7 + 4H20 + 3CO2 Formulation example: 1 effervescent tablet, made with amount 1,5 gram R/ Vit. C 500 mg Pyridoxine 20 mg PVP 3% 45 mg Sukrosa 15% 225 mg Asam sitrat monohidrat 208 mg Asam tartrat 222,9 mg Natrium bikarbonat 248,5 mg PEG 8000 30 mg

Step 5 Learning Objection 1. General formula of effervescent tablet vitamin C 2. The manufacturing methods of effervescent tablet which can affect the dissolve speed effervescent 3. Calculations, dosage weight 1,5 grams 4. Tablet and granule evaluation 5. Stoikiometri reaction of effervescent 6. Humidity requirements for effervescent tablets 7. The identification of effervescent ingredient 8. Solution if there is an error in the method of manufacture 9. Effervescent packaging Step 7 - Reporting 1. The general formula of effervescent : R/ Active ingredient Tartaric acid Citric acid NaHCO3 Diluent Binder Water Lubricant

x% 100-x-y =z% y%

2. The methods that we used is dry granulation. It offers advantages compared with wet granulation for processing physically or chemically moisture-sensitive materials since a liquid binder is not required. It does not require a drying stage and is therefore suitable for use with compounds that either have a low melting point or degrade rapidly upon heating making it a cost-effective manufacturing option 3. Formulation : 1 effervescent tablet, made with weight 1,5 gram R/ Vit. C 500 mg Pyridoxine 20 mg PVP 3% 45 mg Sukrosa 15% 225 mg Asam sitrat monohidrat 208 mg Asam tartrat 222,9 mg Natrium bikarbonat 248,5 mg PEG 8000 30 mg

The calculation : The tablet weight of effervesent 1500 mg Inner phase weight 98% = 98/100 x 1500 mg = 1470 mg Outer phase (consist of glidant) weight 2% = 2/100 x 1500 mg = 30 mg Inner phase consist of active ingredient, acid, base, binder, and diluent. Acid and base weight = inner phase (active ingredient + binder + diluent) = 1470 mg ( 520 + 45 + 225 ) mg = 680 mg Citric acid monohydrate, molecular weight = 210,14 Equivalent number = 3 Equivalent weight = 210,14/3 = 70,04 Tartaric acid, molecular weight = 150,09 Equivalent number = 2 Equivalent weight = 150,09/2 = 75,05 Natrium bicarbonate, molecular weight = 84,01 Bilangan ekivalen = 1 Equivalent number = 84,01/1 = 84,01 70,04 mol equivalent + 75,05 mol equivalent + 84,01 mol equivalent = 680 mg 229,1 mol equivalent = 680 mg mol equivalent = 2,97 Citric acid monohydrate = 70,04 x 2,97 = 208 Tartaric acid = 75,05 x 2,97 = 222,9 mg Natrium bicarbonate = 84,01 x 2,97 = 249,5 mg 4. Granule evaluation : Angle of repose Granules were carefully poured through the funnel until the apex of the conical pile just touches the tip of the funnel Apparent bulk density an accurately weighed sample of granulation was carefully added to the measuring cylinder with the aid of funnel. then the volume was noted. the volume of the packing was determined in an apparatus consisting of a graduated cylinder mounted on a mechanical tapping device Packed bulk density The final volume was tapped till no further reduction in volume was noted Percent compressibility

Tablet evaluation : tablet shape & dimensions hardness thickness friability weight variations disintegration time content uniformity of active ingredients 5. Stoikiometri reaction of effervescent tablet : (1) H3C6H5O7.H2O + 3NaHCO3 Citric acid (2) Na3C6H5O7 + 4H20 + 3CO2

Na-bicarbonate Na2C4H4O6 + 2H2O + 2CO2

H2C4H4O6.H2O + 2NaHCO3 Tartaric acid Na-bicarbonate

So, to neutralize 1 molecule of citric acid, natrium bicarbonate takes 3 molecules. And to neutralize 1 molecule of tartaric acid, 2 molecules of natrium bicarbonate needed. 6.The manufacture of effervescent tablets require special conditions and method of manufacture because it contains acid and base ingredients, where with the presence of water these two materials will react and produce CO2. Therefore, before the tablet used there should be no water at all in contact with the tablet. Also the high temperature will harm the tablet so the temperature of the room should also be low. Terms of indoor relative humidity for the manufacture of effervescent tablets is 25% and the room temperature should be less than 25 C (Lachman tablet h.294). 7. The identification : Appearance.............................................................................................. White to yellowish, granular powder Odor..........................................................................................................Characteristic pH............................................................................................................. 6,0 - 8,0 (1g/ 100ml of water) Flash point................................................................................................ Not flammable Auto ignition temperature......................................................................... Not available Flammability............................................................................................. Not flammable Upper/ Lower flammable limit.................................................................. Not explosive Rate of burning......................................................................................... Not available Sensitivity to static.................................................................................... Not available Sensitivity to impact.................................................................................. Not available Solubility................................................................................................... Freely soluble in water.

8. Once the tablet effervescence is damage, theres no way to fix it again. So we need to extra careful to make this effervescent tablet. And also the critical point which are humidity and temperature should be concerned.

9. The packaging of effervescent tablet Blisters and tubes are commonly used for packaging. Aluminum, which has a lesser water permeability, can be used instead of standard polymer blister materials. If ten or even more individual tablets are packed into one tube very dry air can be added. Silica gel or other drying agents can be also incorporated into most tube lids.

CHAPTER II

CHAPTER III
Ingredient description of effervecent tablet of vitamin c: R/ Ascorbit acid PVP 3% Sucrose 15% Citric Acid Monohirat Tartrate Acid sodium bicarbonate PEG 8000

Monographs of materials a. Ascorbic Acid Description Empirical Formula Synonim Information C6H8O6 C-97; lactone; E300; 3-oxo-L-gulofuranolactone, enol form; vitamin C. Chemical Name Molecular Weight Structural Formula L-()-Ascorbic acid 176.13 cevitamic acid; 2,3-didehydro-L-threo-hexono-1,4-

Description

Ascorbic acid occurs as a white to light-yellow-colored, nonhygroscopic, odorless, crystalline powder or colorless crystals with a sharp, acidic taste. It gradually darkens in color upon exposure to light.

Solubility

In powder form, ascorbic acid is relatively stable in air. In the absence of oxygen and other oxidizing agents it is also heat stable. Ascorbic acid is unstable in solution, especially alkaline solution, readily undergoing oxidation on exposure to the air. The oxidation process is accelerated by light and heat

and is catalyzed by traces of copper and iron. Ascorbic acid solutions exhibit maximum stability at about pH 5.4. Solutions may be sterilized by filtration. The bulk material should be stored in a well-closed nonmetallic container, protected from light, in a cool, dry place. Incompatibilities Incompatible with alkalis, heavy metal ions, especially copper and iron, oxidizing materials, methenamine, phenylephrine hydrochloride, pyrilamine maleate, salicylamide, sodium nitrite, sodium salicylate, theobromine salicylate, and

picotamide. Stability Gradually darkened by exposure to light, however slight discoloration does not affect the treatment effect. Ascorbic acid oxidizes rapidly in air or atmosphere basa.Pada concentration> 100 mg / ml, vitamin C to decompose through the production of carbon dioxide. Functional Category Applications Pharmaceutical Formulation Antioxidant; therapeutic agent. in Ascorbic acid is used as an antioxidant in aqueous pharmaceutical formulations at a concentration of 0.010.1% w/v. Ascorbic acid has been used to adjust the pH of solutions for injection, and as an adjunct for oral liquids. It is also widely used in foods as an antioxidant.

b. PVP Description Empirical Formula Synonim Information (C6H9NO)n_(C4H6O2)m poly(1-vinylpyrrolidoneco-vinyl acetate); polyvinylpyrrolidonevinyl acetate copolymer; PVP/VA; PVP/ VA copolymer. Chemical Name Acetic acid ethenyl ester, polymer with 1-ethenyl-2-

pyrrolidinone Molecular Weight 45 00070 000

Structural Formula

Description

Copovidone is a white to yellowish-white amorphous powder. It is typically spray-dried with a relatively fine particle size. It has a slight odor and a faint taste.

Solubility

greater than 10% solubility in 1,4-butanediol, glycerol, butanol, chloroform, dichloromethane, ethanol (95%), glycerol, methanol, polyethylene glycol 400, propan2-ol, propanol, propylene glycol, and water. Less than 1% solubility in cyclohexane, diethyl ether, liquid paraffin, and pentane.

Incompatibilities

Copovidone is compatible with most organic and inorganic pharmaceutical ingredients. When exposed to high water levels, copovidone may form molecular adducts with some materials; see Crospovidone and Povidone.

Stability

Copovidone is stable and should be stored in a well-closed container in a cool, dry place.

Functional Category Applications Pharmaceutical Formulation

Film-former; granulating agent; tablet binder. in In tableting, copovidone can be used as a binder for direct compression(13) and as a binder in wet granulation

c. Sucrose Description Empirical Formula Synonim Information C12H22O11 Beet sugar; cane sugar; a-D-glucopyranosyl-b-D-

fructofuranoside; refined sugar; saccharose; sugar. Chemical Name Molecular Weight b-D-fructofuranosyl-a-D-glucopyranoside 342.30

Structural Formula

Description

Sucrose is a sugar obtained from sugar cane (Saccharum officinarum Linne (Fam. Gramineae)), sugar beet (Beta vulgaris Linne (Fam. Chenopodiaceae)), and other sources. It contains no added substances. Sucrose occurs as colorless crystals, as crystalline masses or blocks, or as a white crystalline powder; it is odorless and has a sweet taste

Solubility Incompatibilities

Practically insoluble in clorofom, etanol and solubel in water Powdered sucrose may be contaminated with traces of heavy Metals

Stability

Sucrose has good stability at room temperature and at moderate relative humidity

Functional Category

Base for medicated confectionery; coating agent; granulating agent; sugar coating adjunct; suspending agent; sweetening agent; tablet binder; tablet and capsule diluent; tablet filler; viscosity-increasing agent. in In the powdered form, sucrose serves as a dry binder (220% w/w) or as a bulking agent and sweetener in chewable tablets and lozenges.

Applications Pharmaceutical Formulation

d. Citric acid monohydrate Description Empirical Formula Synonim Chemical Name Information C6H8O7_H2O 2-hydroxypropane-1,2,3-tricarboxylic acid monohydrate. 2-Hydroxy-1,2,3-propanetricarboxylic acid monohydrate

Molecular Weight Structural Formula

210.14

Description

Citric acid monohydrate occurs as colorless or translucent crystals, or as a white crystalline, efflorescent powder. It is odorless and has a strong acidic taste. The crystal structure is orthorhombic.

Solubility Incompatibilities

easily soluble in water, very hygroscopic Citric acid is incompatible with potassium tartrate, alkali and alkaline earth carbonates and bicarbonates, acetates, and sulfides. Incompatibilities also include oxidizing agents, bases, reducing agents, and nitrates

Stability

Citric acid monohydrate loses water of crystallization in dry air or when heated to about 408C. It is slightly deliquescent in moist air. Dilute aqueous solutions of citric acid may ferment on standing

Functional Category

Acidifying agent; antioxidant; buffering agent; chelating agent; flavor enhancer.

Applications Pharmaceutical Formulation

in Citric acid monohydrate is used in the preparation of effervescent granules, while anhydrous citric acid is widely used in the preparation of effervescent tablets.

e. Tartaric acid Description Empirical Formula Synonim Information C4H6O6 L-()-2,3-Dihydroxybutanedioic dihydroxybutane1,4-dioic acid; 2,3-dihydroxysuccinic acid; E334; dtartaric acid; L-()-tartaric acid. acid; (2R,3R)-2,3-

Chemical Name Molecular Weight Structural Formula

[R-(R*,R*)]-2,3-Dihydroxybutanedioic acid 150.09

Description

Tartaric acid occurs as colorless monoclinic crystals, or a white or almost white crystalline powder. It is odorless, with an extremely tart taste.

Solubility

Incompatibilities

Tartaric acid is incompatible with silver and reacts with metal carbonates and bicarbonates (a property exploited in

effervescent preparations). Stability The bulk material is stable and should be stored in a wellclosed container in a cool, dry place. Functional Category Applications Pharmaceutical Formulation Acidifying agent; flavor enhancer; sequestering agent. in In pharmaceutical formulations, it is widely used in combination with bicarbonates, as the acid component of effervescent granules, powders, and tablets.

f.

Sodium bicarbonate Description Empirical Formula Synonim Information NaHCO3 Effer-Soda; monosodium carbonate; Sal de Vichy; sodium acid carbonate; sodium hydrogen carbonate Chemical Name Molecular Weight Structural Formula Description Carbonic acid monosodium salt 84.01 NaHCO3 Sodium bicarbonate occurs as an odorless, white, crystalline

powder with a saline, slightly alkaline taste. The crystal structure is monoclinic prisms. Grades with different particle sizes, from a fine powder to free-flowing uniform granules, are commercially available Solubility

Incompatibilities

Sodium bicarbonate reacts with acids, acidic salts, and many alkaloidal salts, with the evolution of carbon dioxide. Sodium bicarbonate can also intensify the darkening of salicylates. Sodium bicarbonate reacts with acids, acidic salts, and many alkaloidal salts, with the evolution of carbon dioxide. Sodium bicarbonate can also intensify the darkening of salicylates.

Stability

Sodium bicarbonate powder is stable below 76% relative humidity at 258C and below 48% relative humidity at 408C.(24) At 54% relative humidity, the degree of pyrolytic decarboxylation of sodium bicarbonate should not exceed 4.5% in order to avoid detrimental effects on stability.

Functional Category Applications Pharmaceutical Formulation

Alkalizing agent; therapeutic agent. in Sodium bicarbonate is generally used in pharmaceutical formulations as a source of carbon dioxide in effervescent tablets and granules.

g. PEG 8000 Description Empirical Formula Synonim Information HOCH2(CH2OCH2)mCH2OH Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; PEG; Pluriol E; polyoxyethylene glycol. Chemical Name Molecular Weight a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl) 7 0009 000

Structural Formula

Description

Solid grades (PEG>1000) are white or off-white in color, and range in consistency from pastes to waxy flakes. They have a faint, sweet odor. Grades of PEG 6000 and above are available as free-flowing milled powders

Solubility

all grades of polyethylene glycol are soluble in water and miscible in all proportions with other polyethylene glycols (after melting, if necessary). Aqueous solutions of higher-molecular-weight grades may form gels. Liquid polyethylene glycols are soluble in acetone, alcohols, benzene, glycerin, and glycols. Solid polyethylene glycols are soluble in acetone, dichloromethane, ethanol (95%),

Incompatibilities

The chemical reactivity of polyethylene glycols is mainly confined to the two terminal hydroxyl groups, which can be either esterified or etherified. However, all grades can exhibit some oxidizing activity owing to the presence of peroxide impurities and secondary products formed by autoxidation.

Stability

Polyethylene glycols should be stored in well-closed containers in a cool, dry place. Stainless steel, aluminum, glass, or lined steel containers are preferred for the storage of liquid grades.

Functional Category

Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant

Applications Pharmaceutical Formulation

in Polyethylene glycol grades with molecular weights of 6000 and above can be used as lubricants, particularly for soluble tablets. The lubricant action is not as good as that of magnesium stearate, and stickiness may develop if the material becomes too warm during compression. An antiadherent effect is also exerted, again subject to the avoidance of overheating.

Tablet effervecent of Vitamin C 500 mg with weight 2000 mg,will be made with the following formula: R/ Vitamin C 500 mg PVP 3% Sucrose 15% Citric Acid monohydrate Tartaric Acid Sodium bicarbonate PEG 8000 2% The calculation is: Weight of effervescent tablet Weight of inner phase 98% (98/ 100 x 2000 mg) Weight of outer phase 2% (consisting of a lubricant) (2/ 100 x 2000 mg )

= 2000 mg = 1960 mg = 40 mg

In the manufacture of effervescent tablets, inner phase consists of active substances, acid, base, binder, and filler/diluent: Weight of acids and bases = Inner phase - (active substance binder + diluent) = 1960 mg (500 + 60 + 300) mg = 1100 mg The calculation to determine the weight of acids and bases used in formula preparation, calculated with mole equivalent of each of the acids and bases, so the stoichiometric reaction to form CO2 gas is: H3C6H5O7 . H2O + 3NaHCO3 Citric Acid monohydrate Na. bicarbonate H2C4H4O6 + 2NaHCO3 Tartaric Acid Na. bicarbonate The calculation are: Citric acid monohydrate: molecular weight = equivalent number = equivalent weight = Tartaric acid: molecular weight = equivalent number = equivalent weight = Sodium bicarbonate: molecular weight = Equivalent number = equivalent weight = Na3C6O7 + 4H2O + 3CO2 Na. Citric Water carbon dioxide 2H2O Water + 3CO2 carbon dioxide

Na2C4H4O6 + Na. Tartaric

210,14 3 210,14/ 3 = 70,04 150,09 2 150,09/2 84,01 1 84,01/1

= 75,05

= 84,01

The total mole equivalents of acid-base = 229,1 mole equivalent of formula preparation = 1100/ 229,1 = So, weight of acids and bases used in the formula:

4,80

Citric acid monohydrate Tartaric acid Sodium bicarbonate

= 70,04 x 4,80 = = 75,05 x 4,80 = = 84,01 x 4,80 =

336,19 mg 360,24 mg 403,25 mg

The formulation of effervescent tablet of vitamin C with weight 2000 mg/ tablet is: R/ Vitamin C 500 mg PVP 60 mg Sucrose 300 mg Citric acid monohydrate 336,19 mg Tartaric acid 360,24 mg Sodium bicarbonate 403,25 mg PEG 8000 40 mg 1999,69 mg 2000 mg Consideration in the selection of materials and methods of manufacture of effervescent tablet :
The tablets weight 2000 mg are chosen because the weight is adequate for the

effervescent tablet The selected dose ascorbic acid 500 mg / day because the dose can be used for the treatment of stomatitis caused by deficiency of vitamin C. The Binder that being used is PVP because it is a water - soluble binder. The concentration that selected is 3% because the PVP concentration that used as a binder in Pharmaceutical formulations and technologies is 0.5-5 % . And PVP selected because it can bind with other ingredients in powder form. The diluent that being used is sucrose because the diluent using for effervescent tablet is sugar . The concentration that selected is 15 % because the sucrose concentration used in the formulation and technology Pharmaceuticals is 2-20 % The acid that being used is combination of citric acid monohydrate and tartaric acid because if its being combined, they will be make a better formulation . If the citric acid monohydrate is used alone, the granules will be sticky and subdued so it cant be compressed , whereas if the tartaric acid is used alone it will be easily crushed The base that being used is sodium bicarbonate because its common in combination with tartaric acid .

DAPUS : http://www.faqs.org/patents/app/20120283668, diakses pada 10 november 2013 Material Safety Data Sheet of Effervescent Tablet