• Binder can be a sugar and polymer.

• Natural polymers binder: starch, gum (Acacia, tragacanth, gelatin)

• Synthetic polymers binder: PVP, methylcellulose, ethylcellulosa,
hidroxypropylcellulosa\
• Can be used in dry or wet granulation. Wet method requires less material.\
• The amount of binder solution required for the 3 kg of filler are listed in the table

1. Starch (Amylum)
• Can be used as a filler, binder, and the disintegrant
• In the form of starch amili 5-10%
• Preparation :suspend starch 1:1 / 2-1 in cold water, add boiling water 2-4 times with
constant stirring until the starch that can expand into a transparent diluted
• Another way: a suspension of starch in water heated
• Contains 11-14% water content, will cause the tablet disintegrated quickly - The
making must be careful in order to obtain a good starch, is not hydrolyzed, and not
making
• Best Use of a maximum of 30%. If a large dose of active ingredient, starch was replaced
with a better disintegrant, namely Avicel.
• Tablets containing a high concentration of starch tablets showed a fragile and difficult
to be dried
• Unmodified starch does not have good compressibility properties and have a great
friability, and the occurrence of capping in tablets if used in large quantities

As disintegrant:
• Usage: 1-20%, is the most commonly used disintegrant
• Mechanism of action by forming hydrogen bonds during compression and rupture or
expand when water entered Mell pore (capillary)
• Use is tailored to the type of starch, compression pressure, and water content of the
mass
• C to remove absorbed water°Caution: before use, starch must be dried at a temperature
of 80-90

2. Starch 1500
• Can be used as a binder in wet & dry granulation, and disintegrant
• Starch 1500 containing 20% maximum water-soluble fraction that functions as a binder
while the rest are as disintegrant
• Starch 1500 takes ± 3-4 times as much starch amylum to produce tablets with the same
hardness
• Should not be used as a filler in wet granulation because it will produce a gel that serves
as a powerful binder
• As disintegrant, can be added in dry state, in the outer phase.
• The good flow is directly compressible starch
• Can be compressed own, but if mixed with 5-10% of drugs requires additional lubricant
(eg, 0.25% colloidal silicon dioxide)
• Containing 10% moisture and cause the tablets become soft when combined with
magnesium stearate> 0.5%, stearic acid used as a substitute
As disintegrant:
• Represents good disintegrant and added to the dry mixture (in inner phase or outer
phase in dry granulation or direct compression, or in the external phase on the wet
granulation method)
• Caution: should not be given to the wet mass

3. Pregelatinized Starch
• It is a starch that has been cooked and dried again. Can be used as a substitute for starch
paste is more easily soluble in warm water without heating
• Can be added to dry into a powder and then moistened with water to form moist mass

4. Gelatin
• Used at a concentration of 5-10% as much as 1-5% of the formula
• It is rarely used, replaced by PVP, MC. Tends to produce hard tablets and requires
active disintegrant
• Can be used to compound that difficult to bind
• Weaknesses: vulnerable to bacterial and fungal
• If you still needed a stronger binder, can be used a solution of gelatin in water 2-10%,
which is made with gelatin hydrate in cold water for several hours / overnight and then
heated to boiling, the solution must be kept warm until gelatin is used because it will be a
gel at refrigeration

5. Sucrose solution
• Establish a hard granule, hardness set of sucrose concentrations 20-85%
• Very good as a bearer of soluble dyes and produces a variety of colors
• Used to granulate tribasic phosphate binder which generally require a more cohesive
than amylum starch; on ferrous sulphate tablets, acting as a binder and protective
oxidation ferrosulfat
• Other compounds which can be a sugar fastening: aminophylline, asetopheretidin,
acetaminophen, meprobamate

6. Acacia solution
• Used at a concentration of 10-25%; to reduce mephenesin (large doses and difficult to
granulate)
• Generate a hard granules but does not harden in storage
• Weaknesses: can be contaminated with microbes
• Sometimes the liquid lubricant plus PEG 6000 to help the tablet compressing and tablet
disintegration

7. PVP
• Trade name: Kollidone or Plasdone
• Inert, water-soluble and alcohol, used in concentrations of 3-15%, slightly hygroscopic,
does not harden during storage (good for chewable tablets)
• Effervescent Tablets can be made using PVP in anhydrous ethanol. Do not use
anhydrous isopropanol for leaving the smell of the granules.
• The concentration of 5% produces good compressibility of powder sodium bicarbonate
and citric acid so that the tablet to react faster and faster dissolution.
• PVP is good for chewable tablets in particular for aluminum hydroxide, Mg (OH) 2

8. Cellulose
a. Methyl cellulose
• 1-5% water solution, a solution of 5% produces the same hardness with amylum starch
• Can be used to granulate soluble / insoluble powder, a good binder for the excipients
such as lactose, mannitol, and sugar
• Advantage: can be compressed quickly, do not harden on storage
b. CMC Na
• 5-15%
• Incompatible with Mg, Ca, Al, and their salts
• Generate more fragile granules of PVP is a tendency to harden; tablets generally have a
longer disintegration time
c. Ethyl cellulose
• Solution in alcohol. Low grades are used as binder 2-10% in ethanol
• Can be used for powders that are difficult to granulate: acetaminophen, caffeine,
meprobamat, ferofu, arat, and can be used as a non-binding water to powder which is not
waterproof like ascorbic acid
• Can slowing the disintegration time

9. Polyvinyl alcohol
• water soluble, like acacia but not very susceptible to bacterial
• Establish a softer granules from Acacia, yielding faster disintegration of tablets and did
not harden in storage

10. PEG 6000

• As an anhydrous binder, where water and alcohol can not be used
• PEG 6000 is a white solid that melts at 70-750C and hardened at 56-630C

11. N-HPC (Nisso-HPC)

• Soluble in water and organic solvent alcohol, propylene glycol, methylene chloride,
acetone and chloroform. If used as a solvent in the wet granulation N-HPC dissolve in
water or alcohol.
• Preparation :
a. Dissolve in water
- N-HPC added bit by bit into the water while stirring strong
- 20-30% of water heated to 600C and the N-HPC added slowly while stirring. After that,
add the remaining water. In this way more rapid dissolution.
a. Dissolve in organic solvents
DISINTEGRANT USED IN WET GRANULATION
Function: to split tablets
How to use: - when granulation
- Before compressing (the best)

1. Starch (Amylum)

2. Starch 1500

3. Sodium starch glycolate (primogel, explotab)

• Usage: 1-20% with optimum concentration : 4%
• Explotab can not be use as disintegrant in inner phase
• Mechanism similar to starch in general, is a modified starch that can absorb water 200-
300%
• Disintegration time is determined also by the amount of compression pressure
• Attention: at high temperature and high humidity can prolong disintegration time,
slowing down the dissolution time

4. Cellulose (cellulose, methylcellulose, CMC, CMC-Na, Avicel, Acdisol)

• Acdisol is crosslinking of CMC-Na and excellent for use as disintegrant because water
soluble and has a great affinity to water.
• Acdisol is listed on the super disintegrant. Usage: 2-5%.

Read more »
Labels: disintegrant, Tablet, Wet Granulation

BINDER USED in WET GRANULATION

• Binder can be a sugar and polymer.
• Natural polymers binder: starch, gum (Acacia, tragacanth, gelatin)
• Synthetic polymers binder: PVP, methylcellulose, ethylcellulosa,
hidroxypropylcellulosa\
• Can be used in dry or wet granulation. Wet method requires less material.\
• The amount of binder solution required for the 3 kg of filler are listed in the table

1. Starch (Amylum)
• Can be used as a filler, binder, and the disintegrant
• In the form of starch amili 5-10%
• Preparation :suspend starch 1:1 / 2-1 in cold water, add boiling water 2-4 times with
constant stirring until the starch that can expand into a transparent diluted
• Another way: a suspension of starch in water heated
• Contains 11-14% water content, will cause the tablet disintegrated quickly - The
making must be careful in order to obtain a good starch, is not hydrolyzed, and not
making
• Best Use of a maximum of 30%. If a large dose of active ingredient, starch was replaced
with a better disintegrant, namely Avicel.
• Tablets containing a high concentration of starch tablets showed a fragile and difficult
to be dried
• Unmodified starch does not have good compressibility properties and have a great
friability, and the occurrence of capping in tablets if used in large quantities

As disintegrant:
• Usage: 1-20%, is the most commonly used disintegrant
• Mechanism of action by forming hydrogen bonds during compression and rupture or
expand when water entered Mell pore (capillary)
• Use is tailored to the type of starch, compression pressure, and water content of the
mass
• C to remove absorbed water°Caution: before use, starch must be dried at a temperature
of 80-90

2. Starch 1500
• Can be used as a binder in wet & dry granulation, and disintegrant
• Starch 1500 containing 20% maximum water-soluble fraction that functions as a binder
while the rest are as disintegrant
• Starch 1500 takes ± 3-4 times as much starch amylum to produce tablets with the same
hardness
• Should not be used as a filler in wet granulation because it will produce a gel that serves
as a powerful binder
• As disintegrant, can be added in dry state, in the outer phase.
• The good flow is directly compressible starch
• Can be compressed own, but if mixed with 5-10% of drugs requires additional lubricant
(eg, 0.25% colloidal silicon dioxide)
• Containing 10% moisture and cause the tablets become soft when combined with
magnesium stearate> 0.5%, stearic acid used as a substitute

As disintegrant:
• Represents good disintegrant and added to the dry mixture (in inner phase or outer
phase in dry granulation or direct compression, or in the external phase on the wet
granulation method)
• Caution: should not be given to the wet mass

3. Pregelatinized Starch
• It is a starch that has been cooked and dried again. Can be used as a substitute for starch
paste is more easily soluble in warm water without heating
• Can be added to dry into a powder and then moistened with water to form moist mass

4. Gelatin
• Used at a concentration of 5-10% as much as 1-5% of the formula
• It is rarely used, replaced by PVP, MC. Tends to produce hard tablets and requires
active disintegrant
• Can be used to compound that difficult to bind
• Weaknesses: vulnerable to bacterial and fungal
• If you still needed a stronger binder, can be used a solution of gelatin in water 2-10%,
which is made with gelatin hydrate in cold water for several hours / overnight and then
heated to boiling, the solution must be kept warm until gelatin is used because it will be a
gel at refrigeration

5. Sucrose solution
• Establish a hard granule, hardness set of sucrose concentrations 20-85%
• Very good as a bearer of soluble dyes and produces a variety of colors
• Used to granulate tribasic phosphate binder which generally require a more cohesive
than amylum starch; on ferrous sulphate tablets, acting as a binder and protective
oxidation ferrosulfat
• Other compounds which can be a sugar fastening: aminophylline, asetopheretidin,
acetaminophen, meprobamate

6. Acacia solution
• Used at a concentration of 10-25%; to reduce mephenesin (large doses and difficult to
granulate)
• Generate a hard granules but does not harden in storage
• Weaknesses: can be contaminated with microbes
• Sometimes the liquid lubricant plus PEG 6000 to help the tablet compressing and tablet
disintegration

7. PVP
• Trade name: Kollidone or Plasdone
• Inert, water-soluble and alcohol, used in concentrations of 3-15%, slightly hygroscopic,
does not harden during storage (good for chewable tablets)
• Effervescent Tablets can be made using PVP in anhydrous ethanol. Do not use
anhydrous isopropanol for leaving the smell of the granules.
• The concentration of 5% produces good compressibility of powder sodium bicarbonate
and citric acid so that the tablet to react faster and faster dissolution.
• PVP is good for chewable tablets in particular for aluminum hydroxide, Mg (OH) 2

8. Cellulose
a. Methyl cellulose
• 1-5% water solution, a solution of 5% produces the same hardness with amylum starch
• Can be used to granulate soluble / insoluble powder, a good binder for the excipients
such as lactose, mannitol, and sugar
• Advantage: can be compressed quickly, do not harden on storage
b. CMC Na
• 5-15%
• Incompatible with Mg, Ca, Al, and their salts
• Generate more fragile granules of PVP is a tendency to harden; tablets generally have a
longer disintegration time
c. Ethyl cellulose
• Solution in alcohol. Low grades are used as binder 2-10% in ethanol
• Can be used for powders that are difficult to granulate: acetaminophen, caffeine,
meprobamat, ferofu, arat, and can be used as a non-binding water to powder which is not
waterproof like ascorbic acid
• Can slowing the disintegration time

9. Polyvinyl alcohol
• water soluble, like acacia but not very susceptible to bacterial
• Establish a softer granules from Acacia, yielding faster disintegration of tablets and did
not harden in storage

10. PEG 6000

• As an anhydrous binder, where water and alcohol can not be used
• PEG 6000 is a white solid that melts at 70-750C and hardened at 56-630C

11. N-HPC (Nisso-HPC)

• Soluble in water and organic solvent alcohol, propylene glycol, methylene chloride,
acetone and chloroform. If used as a solvent in the wet granulation N-HPC dissolve in
water or alcohol.
• Preparation :
a. Dissolve in water
- N-HPC added bit by bit into the water while stirring strong
- 20-30% of water heated to 600C and the N-HPC added slowly while stirring. After that,
add the remaining water. In this way more rapid dissolution.
a. Dissolve in organic solvents

FILLER/DILUENT FOR WET GRANULATION

Is an inert substance that is added in tablet formula intended to create a tablet weight as
expected.
Usually tablets containing the active substance with a small dose requires a lot of filler
material. If the tablet has big dose of active substance, the filler slightly or not at all.

1. Avicel (Microcrystalline Cellulose)

• Avicel 103 has the advantage compared with 101, 102 because of small specific
volume, better flow and a shorter disintegration time.
• Insoluble, non-reactive, the flow is not good, hold 50% capacity.
• Generate a hard tablet with a small pressure (compressibility good) and low friability
tablets, long-time stability.
• Generate a fast wetting and thus distribute the liquid evenly to the entire mass of
powder; produce drug distribution and a uniform color.
• Acting as an auxiliary binding, resulting in a hard granules with minimal fines.
• Can be act as dry binder, disintegrant, lubricant and glidan.
• Its use requires a lubricant; its use can be combined with lactose, mannitol, starch,
calcium sulfate.
• Helps overcome substances that if overwetting (too wet) to something like "clay" is
difficult and when dry granulated , the granule becomes hard and resistant to
disintegration. Example: kaolin, calcium carbonate.
• Avicel in wet granulation improve ties in the compression, reducing the capping and
friability of tablets.
• Avicel assist with water-soluble drugs for homogeneous, preventing migration of water
soluble dyes and helps for quick evaporation and uniform.
• For drugs with small doses, Avicel used as a filler and binder addition.
• 60% Avicel PH 101 and 40% amylum as 10% starch as a paste made easy moist
granulated mass, forming a strong granules on drying with less fine than that just paste
made from starch.
• Form PH 101: powder, PH 102: granule, PH 103: powder

As disintegrant:
- It is a very good disintegrant, especially at concentrations of 10% or higher.
- In wet granulation method, Avicel don’t have disintegrant properties.
- Attention: at high concentrations, Avicel can cause sticky on the tongue.

2. Calcium sulfate trihydrate

• Used as a filler for granulation with the amount of active ingredient 20-30%.
- Synonym: terra alba, snow white filler.
- Insoluble, non-hygroscopic.
- The higher the grade, increasingly white, most inexpensive filler, the active substance
can be used for acidic, neutral, alkaline, have high absorban capacity for oil.
- Binder suggested: PVP, Croscarmellose, starch paste.

3. Calcium phosphate dibasic

• Used as a filler and binder for direct compression with the smallest in size, not
expensive, can not be used with acid compounds or acid salt
• If you use a liquid binder that is too much then so sticky and hard, can not be granulated
so that the solution combined with the starch / Avicel

4. Lactose
• Incompatible with: highly alkaline compound, ascorbic acid, salicylamide, pyrilamine
maleate, phenilephrine HCl
• lactose hydrate granules contain 4-5% moisture content
• Lactose is the reductor sugar, reacts with amines to produce Maillard reaction
• Isomers: α and β (in the mixture are in equilibrium both forms)
• The most common filler, there are 2 forms: hydrated and anhydrous
• Rarely reacts with the drug (hydrated and anhydrous)
• For wet granulation use lactose hydrate. Anhydrous lactose did not experience Maillard
reaction (with an active substance containing amines in the presence of metal stearate),
but it absorbs moisture.
• In general, tablets show a good release rate, the granule quick to dry, disintegration of
the tablets are not much affected by hardness.
• Disadvantages : lactose can change color in the presence of alkaline amines and Mg-
stearate
• Known 4 kinds of forms: coarse granules (60-80 mesh), fine granules (80-100 mesh),
spray dried granules (100-200 mesh), and anhydrous lactose
• Known as sugar milk.

Spray-dried Lactose
• use as filler for direct compression, usually combined with Avicel. If it’s singular, used
in a concentration of 40-50% as the carrier
• The nature of its direct compression is reduced if the water content <3%, can be mixed
with 20-25% active substance without losing its properties of direct compression
• The capacity to hold the active substance 20-25%; have good flow and binding
characteristics of lactose better than usual
• Disadvantages : can be blackened with a moist, amen, or other compounds containing
furaldehid
• Use a neutral or acid lubricant

5. Sucrose

• Can act as filler or binder

• If used as sole binder, sucrose form hard granules and tablets were more likely be
dissolved than disintegrated. Therefore, many in combination with other insoluble fillers
• If used as dry filler, usually granulated with water-soluble binder or hydroalcohol.
Granules hardness depend on the amount of binder used. The mixture of water and
alcohol will produce a softer granules.
• It has many forms, most commonly used form of "confectioner" for wet granulation
containing 3% corn starch to prevent caking
• Sucrose is used as a sweetener in chewable tablet and is used as a binder to improve
tablet hardness
• Disadvantages : tablets made with the composition of most of the sucrose will harden in
storage. Sucrose rather than reducing sugars but become brown on storage and
hygroscopic
• Derivatives of sucrose that can be used for direct compression:
a. Sugartab: 90-93% sucrose, 7-10% invert sugar
b. In the Pac: 97% sucrose, 3% modified dextrins
c. Nu Tab: 95% sucrose, 4% invert sugar, 1% corn starch, magnesium stearate

6. Dextrose

• Its application limited to wet granulation as filler and binder

• Used similar to sucrose, which tends to produce hard tablets, especially if using
dextrose anhydrous
• To become brown on storage

7. Mannitol
• Good filler for chewable tablet because it’s taste good, slightly sweet, smooth, cool
(negative heat solution)
• Non-hygroscopic, the flow is poor, needs more liquid binder
• Can be used for formulation of vitamins, produce finer granules than sucrose or
dextrose
• Levels of moist granules are made from sucrose, dextrose, and mannitol after drying
overnight at 140-150 0F is 0.2%
• Only a few absorbed in the gastrointestinal tract, if used a lot to be laxative

8. Emdex and Celutab

• Can react with amines at high temperature and high humidity

• Free flowing and can be compressed directly, containing 8-10% moisture, tablet
hardness can be increased after compression
• Hydrolyzed starch containing 90-92% dextrose and 3-5% maltose
• Can be used as a substitute for mannitol in the chewable tablet as sweet and smooth
taste.

Properties of Some Tablet Ingredients

1. Fines
The maximum amount of fines is 30% of the weight of the tablet, including the outer
phase. If the total amount of fines more than 30% big possibility capping will occur.
Different amounts, different distributions can be resolved by Hoover that does not vibrate
and / or a add stirrer on the compression machine.

2. Eksplotab
Eksplotab is not an acid-resistant ingredient and only use as disintegrant in the outer
phase, can not be able to be used for wet granulation. Use 3-5%, maximum 25%.

3. Starch 1500
Filler for direct compression tablets. If there is water, it going into gel so that the active
substances are blocked, power expands less so disintegrant time will be long. Use as
tablet filler : no more than 30%.

4. Avicel pH 101,102,103 good for direct compression tablet

5. If the active ingredients amount is small and the form is crystal, the risk of content
uniformity to be not same is high if made by direct compression, because it is less
homogeneous.

6. For direct compression, use a fine active substance with a good flow.
7. If the base coarse and the fine active substance fine, the distribution becomes uneven
due to a particle size distribution is uneven, especially when compression process, due to
vibration.

8. Vitamin B12 for direct compression must be smoothed first. Use mannitol as filler, not
Saccharum Lactis.

9. If you want to develop antibiotics, select binding that does not change the potential.

10. Common mechanism of disintegration for tablet is wetting, water penetration,

swallowing, and destroying. For direct compression, if the print mass flow rate of 1.5 g /
sec or more is good enough.

11. If the active ingredient amount is 200 mg per tablet, get ready to be made by
directcompression.

12. The tablet disintegration time of evaluation, review mechanisms disintegration time,
surfactant. Hydrophobic disintegrant would be better.

13. PVP easily penetrated by water.

14. Ac di sol 3% as outer disintegrant to improve the disintegration time.

Granulation is made separately by considering the number of granules as much, the
distribution of the same granule in which the ratio of granule A and B together, the
distribution of weakness is not always the same.

15. Size (mesh) 18-20, 20-22; the usual 16-16

If the granules had weak binding, use sieve with mesh size equal

16. Active substances with high specific gravity (generally inorganic substances),
granulation as usual, inner phase as small as possible.

17. CaCO3 can be used as a disintegrant an work in the stomach which will absorb
stomach acid and converted to CO2.

Tablets Effervecent Ingredients

It should be noted that the ingredients used in tablet effervescent
should have the contents moist very low and when the manufacture of this preparation
must be done in a dry place.

Characteristic of Effervescent tablet ingredients:

1. In many ways, the principles used in producing Effervescent tablets similar to those
used for conventional tablets. Many of the processes and tools the same process.
Likewise, the general nature of granules required for obtaining tablets according to the
requirements such as:

• Particle Size
• Particle shape
• Granulometri
• Uniformity of distribution
• Free flow of granules
• Granules must be compressed

2. The nature of raw materials selected for use in Effervescent Tablets that more
important than tablets conventional is the moisture content, which means the raw
materials used must be dry.
If the raw material used is not dry (containing moisture), then acid reaction will occur the
carbonate will cause the product to be physically unstable and decompose. Once started
the reaction it will continue much faster because the byproducts reaction is water added.

Example:
CH2COOH CH2COONa
CH2COOH + 3NaHCO3 CHCOONa + 3 CO2 + 3 H2O
CH2COOH CH2COONa

Therefore, the raw materials used must be in anhydrous (dry) with a few levels humid
absorbed. The water molecule is still there but very little because it takes a little water to
bind the granules because if the granules too dry, granules can not be compressed.

3. Solubility is the nature of the raw materials that are important in Effervescent Tablets.
If the components of the tablet does not dissolve, the Effervescent reaction will not
happen and tablets will not be disintegrated rapidly. The speed of dissolving is more
important than the solubility due to substances that dissolve slowly to impede
disintegration of tablets and dissolve slowly to produce residue that is not favored after
tablet disintegration.

Sources of Carbon Dioxide

Sources of carbon dioxide from Effervescent Tablets obtained from carbonate salts
because this salt to generate 53% carbon dioxide. Salt is often used is sodium bicarbonate
and sodium carbonate. Sodium bicarbonate with a concentration in water 0.85% showed
pH 8.3. sodium carbonate with a concentration of 1% in water has a pH of 11.5. Sodium
carbonate shows also the effect of stabilization in Effervescent Tablets for its ability to
absorb moisture in advance can prevent the onset response Effervescent. Oxygen can be a
source of Effervescent with sources can be used sodium perborates anhydrous.
Acid Source
Source of acid commonly used in Effervescent Tablets can be classified into;
a. Acid Foods, among others:

1. Citric acid, an acid used most often because the price is cheap. Citric acid can
dissolve easily and quickly, and in the form of granules can flow freely. There is
also a form of anhydrate form, and it’s hygroscopic.
2. Tartaric acid, this acid has a solubility of higher than of citric acid.

b. Anhydrous Acid
If the acid anhydride is dissolved in the water there will be a liberating form of acid
hydrolysis which can react with carbon dioxide source. Example : succinic anhydride.

c. Acid Salt
This salt can be used because in solution, this salt can produce protons and produce a
solution with a pH below 7. Examples : sodium hydrogen phosphate, sodium dihydrogen
phosphate, and sodium bisulfite.

Other Ingredients for Effervescent Tablet

Other additives in Effervescent Tablets, among others, such as binders, fillers, and
lubricants. However, these materials use in limited amounts. As with any filler, only used
a little, because the formula Effervescent Tablets already contains a lot of carbonate and
acid.

a.Binder and Wetting agent

To manufacture Effervescent Tablets with the method of granulation using, a binder such
as gelatin, starch and gums can not be used because the solubility is slow or because the
content of residual water is high that can accelerate the instability of Effervescent
Tablets. Effective binder for Effervescent Tablets is PVP. PVP added to the powder
which is granulated in a dry state and then wetted by wetting agent, isopropanol, ethanol
or hydro-alkohol. Alcohol is not binding but added as wetting agent to dissolve PVP.

b. Filler
Usually, it takes only a little filler because substance that produces effervescent already
quite large. Sodium bicarbonate is a good filler. Other fillers are Na. Chloride, Na.
Sulfate and Na. Bicarbonate.

c. Lubricants
Lubricants that are water soluble or substance that can be dispersed in water can be used
as a lubricant. Powder of sodium benzoate and PEG 8000 is an effective, water soluble
lubricant.
Effervescent Tablet : Developing and Method of
Manufacturing
Effervecent tablets made by some method, that is by wet granulation, dry granulation,
and the method of fluidization. Fluidization method wurster method, using a special spray
equipment complete with channels spray binder and air duct heating.

Effervescent Tablet requires require 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.

WET GRANULATION
Generally the same as conventional tablets

The process:

1. Heating method
Usually the acid component is heated. Because this process is not constant and difficult to
control is rarely used.

Granulation with Reactive Fluids.

Effective materials for granulating is water. The process by adding a little water (0.1 to
0.5%) is sprayed on the resulting reaction mixture to produce granules. Granules are still
damp and then transferred to a tablet machine and compressed tablets into the oven
drying process occurs to remove water so that the tablet becomes stable.

Non Reactive granulation with fluid.

The liquid used is ethanol or isopropanol. The liquid is added slowly to the mixture in a
mixer. In this regard need to be added dry binder such as PVP. After that the granule is
inserted into the oven and then dried. Again smoothed then compressed.
DRY GRANULATION

Done in two ways:

Slugging
Created chunks large size tablets using a tablet machine and then the tablet is inserted
into the granulating machine to be mashed into a desired size

Compacting
Using a special machine, clamp roller compactor which compact premix powder into the
form of tape / plate between two rollers which rotate counterclockwise. Materials crushed
into granules in granular machine.

Vitamin C Effervescent Tablet : Formula, Manufacturing

and Consideration of Material and Method of
Manufacture Selection
Formulation
One effervescent tablet made with weights 1.5 grams (1500 mg).
Formula for 1 piece of Vitamin C effervescent tablets:

• Vitamin C 500 mg
• Pyridoxine 20 mg
• PVP 3% 45 mg
• Sucrose 15% 225 mg
• Citric Acid Monohydrate 208 mg
• Tartaric Acid 222,9 mg
• Sodium Bicarbonate 249,5 mg
• PEG 8000 30 mg

Read more about :Effervescent Tablet Formulation and Manufacture

Calculation

Weight of effervescent tablet = 1500 mg

Inner Phase weight (consist of active ingredient, acid, base, binder and filler) (98%) =
1500 mg = 1470 mg× 98/100

1500 mg = 30 mg× Outer Phase (consists of glidant) (2%) = 2/100

Acid and Base weight = Inner phase– (active ingredient + binder +filler)
= 1470 mg – ( 520 + 45 + 225 ) mg = 680 mg
Citric acid monohydrate:
Molecular weight = 210,13
Equivalent number = 3
Equivalent weight = 210,13/3 = 70,04

Tartaric Acid :
Molecular weight = 150,09
Equivalent number = 2
Equivalent weight = 150,09/2 = 75,05

Sodium Bicarbonate:
Molecular weight = 84,01
Equivalent number = 1
Equivalent weight = 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 mg

Tartaric Acid = 75,05 x 2,97 = 222,9 mg
Sodium Bicarbonate = 84,01 x 2,97 = 249,5 mg

Read more about :Effervescent Tablet Formulation and Manufacture

Consideration of Materials in The Formula And Method Of Manufacture Selection

• The weight of tablet is 1500 mg because the weight is adequate for the weight of
effervescent tablets
• The selected dose of ascorbic acid is 500 mg / day because the dose can be used
for the treatment of canker sores due to deficiency of vitamin C.
• Number of pyridoxine consumed per day should be fulfilled as much as 2.2 mg
for men and 2 mg for women. Pyridoxine is used therapeutically to treat anemia
sideroblastik and metabolic disorders due to deficiency of pyridoxine, has a dose
of 100-400 mg per day. Pyridoxine dose selected in this formula is 20 mg / day
because it still includes a range of doses that can be used for prophylaxis and
pyridoxine deficiency, also to meet the effervescent tablet weight of 1.5 grams.
• Binder used is PVP because PVP is a water soluble binder and a selected
concentration of 3% for PVP which is used as a binder in pharmaceutical
formulations and technology for 0.5 to 5%
• Fillers used is sucrose, because filler used in the effervescent tablet is sugar.
Concentrations of the selected is 15% because sucrose is used as filler in
pharmaceutical formulations and technology is 20-20%.
• The acid used is a combination of citric acid monohydrate and tartaric acid as
would be obtained good effervescent tablets. When used citric acid monohydrate
only, granules produced would be sticky and soft, so it can not be compressed,
 whereas when used in single-tartaric acid it will produce effervescent tablets are
hard and cracked.
• Base used is sodium bicarbonate because the base is usually used in combination
with tartaric acid.
• lubricant used should be water soluble so that the selected PEG 8000
• The method chosen was the manufacture of dry granulation because the active
substance is a vitamin that can not stand the heat so that it is not necessary dry
granulation drying process that requires heat.

Weighing to Make 1000 Effervescent Tablets

Asam askorbat 500 mg x 1000 = 2500 g

Pyridoxine 20 mg x 1000 = 100 gr
PVP 3% 45 mg x 1000 = 225 gr
Sukrosa 15% 225 mg x 1000 = 1125 gr
Asam sitrat monohidrat 208 mg x 1000 = 1040 gr
Asam tartrat 222,9 mg x 1000 = 1114.5 gr
Natrium bikarbonat 249,5 mg x 1000 = 1247.5 gr
PEG 8000 30 mg x 1000 = 150 gr

Procedures

Dry Granulation Method

1. Active Ingredient and excipients each were sieved in separated place.

2. Mixed together and then mixed until homogeneous.
3. Powder mass was slugged (5 kg/cm2), and then crushed/sieved trough mesh 12
and mesh 20 siever.
4. Granular flow test obtained. The flow must be obtained at 10 g / sec. If not
obtained, the flow of it, should be slugging back up to obtain the desired flow.
5. Once the granules have a flow of 10 g / sec, the granules added lubricants.
Granules ready to be compressed into tablets weighing 1.5 grams.

Effervescent Tablet Formulation and Manufacture

What you should know about effervescent forms before formulate and
manufacture it? As per revised definition proposed to US FDA, Effervescent tablet is a
tablet intended to be dissolved or dispersed in water before administration. Effervescent
tablets are uncoated tablets that 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. You will find
the process of Effervescent Tablet Formulation and Manufacture here.

Many studies have demonstrated that effervescent tablets and powders enhance
absorption of a number of active ingredients, such as disulfiram and caffeine. That’s
because the carbon dioxide created by the effervescent reaction can induce enhanced
active-ingredient permeability due to an alteration of the paracellular pathway. It is
theorized that the carbon dioxide alters (widens) the intercellular space between cells,
which leads to greater absorption of active ingredients (both hydrophobic and
hydrophilic).

Read more about :Vitamin C Effervescent Tablet : Formula, Manufacturing and

Consideration of Material and Method of Manufacture Selection
There are several categories of active ingredients: Those that are difficult to digest or
disruptive to the stomach, calcium carbonate for example. In a normal tablet or powder,
the calcium carbonate dissolves in the stomach acid and is carried into the digestive
system for absorption. However, calcium carbonate releases carbon dioxide when it
dissolves in the GI, which usually produces gas in the stomach. As people age, they have
less acid in the stomach, and thus a calcium carbonate tablet may pass through the
stomach without dissolving. That, in turn, may lead to constipation. However, if the
calcium carbonate is taken in an effervescent formulation, the calcium dissolves in water,
is readily available for the body to absorb, and there is no risk of excessive gas in the
stomach or of constipation.

The low pH in the stomach can cause active ingredients to become denatured, lose
activity, or cause them to remain inactive, such as Amino acid and vitamins. Effervescent
ingredients, however, can buffer the water-active solution so that the stomach pH
increases and thus prevent the degradation or inactivation of the active ingredient. This
buffering effect induces the stomach to empty quickly, usually within 20 minutes into the
small intestine. The result is maximum absorption of the active ingredient.

A typical effervescent tablet (1 inch in diameter weighting 5 grams in total weight) can
include more than 2,000 milligrams of water soluble active ingredients in a single dose. If
the required dose is larger than that, the sachet (powder form) is a common means of
delivery.

Those that are susceptible to light, oxygen, or moisture. Typical effervescent

formulations have less than 0.5 percent of free moisture. To maintain that level and
prevent other damage from the ambient environment, the formulation’s package should
be 0.001-inch-thick aluminum that completely blocks light, oxygen, and moisture.

Effervescence Tablet Formulation

Acid Reaction. Effervescence is the reaction (in water) of acids and bases producing
carbon dioxide. Typical acids used in this reaction are citric, malic, tartaric, adipic, and
fumaric.

• Citric acid is the most commonly used. It taste like citrus.

• Malic acid used in effervescent formulas for a Smoother aftertaste, but the price of
malic acid is higher than citric acid.
• Tartaric, adipic, and fumaric had low water solubilities and used sparingly.

Bases Reaction. Typical bases used in the effervescent reaction are sodium bicarbonate,
potassium bicarbonate, sodium carbonate, and potassium carbonate. Sodium bicarbonate
is very common in effervescent formulas and produces a clear solution after tablet
disintegration. When sodium levels are a concern, potassium bicarbonate is used. Both
types of carbonates are used mainly as desiccants.

Binders. Binders in effervescent tablets use to bring the tablet hardness to a point where
handling is possible. These binders should be water-soluble and include dextrose,
sorbitol, xyitol, and lactose. Be careful, binders can carry free moisture into the tablet,
which is undesirable and can increase disintegration times when used in large quantities.
The ideal amount of binder is one that makes the tablet hard enough to handle, but soft
enough to disintegrate and dry enough to be stable.

Sweeteners and Flavors. Depending on the product, formulators can use color (artificial
or natural), sweeteners (acesulfame potassium, sodium saccharin, aspartame, and
surcalose), and flavors (artificial or natural) to enhance a product or to mask off-notes
derived from the active ingredients.

Lubricants. Lubrication of effervescent tablets has historically been the main stumbling
block to an acceptable, marketable product. Typical lubricants such as magnesium
stearate are not useful due to their insolubility in water. Most formulators have to use
water-soluble lubricants such as sodium benzoate, polyethylene glycol, and adipic acid.
But, There are tablet presses that use lubrication spray on the punches so that the formula
does not require lubrication.

Effervescent Tablet Manufacture and Production

Basically, the manufacture of effervescent tablets are identical to used for making
conventional tablets and powders, but production must occur in very low humidity areas.
Effervescent granulations can be mixed in conventional blending equipment, such as
ribbon, twin-cone, drum mixer and V-type blenders. All equipment should be well
grounded and absolutely dry after wash-down. Any traces of moisture in the equipment
will give erratic granulation results and most likely result in lost batches of product.

Read more about :Vitamin C Effervescent Tablet : Formula, Manufacturing and

Consideration of Material and Method of Manufacture Selection

Wet Granulation. Wet granulation of the effervescent base can be performed by

carefully adding 0.1 to 1.0 percent water (weight-to-weight basis) to the chosen blending
equipment. The granulation steps must be precisely timed and the ingredients mixed
thoroughly to distribute the solvent or binder solution evenly in the blend. The mix is
then quickly discharged to drying ovens. You must constantly monitor the operational
parameters of all equipment, especially drying equipment, as variations in drying times
and temperatures can affect the finished product. While stable granulations will
ultimately be made, vast differences in tablet hardness and disintegration times can result
from over- or under-reacting the granulation.

After drying, the granulation is sized, and a final mix is performed. Fluid-bed dryers have
been used for many years to make effervescent granulations. Basically, the water or
binder solution is sprayed onto the effervescent mixture while it is suspended in a stream
of hot, dry air. The humidity and temperature of the air serve to stop the effervescent
reaction quickly and uniformly. To ensure that you produce a free-flowing granulation,
chose the particle sizes carefully and monitor all systems closely. Vacuum granulators
have also been used to make effervescent granulations. This equipment gives you a very
controlled granulation of the product and allows a dustfree environment. The equipment
also generally requires less power and less operating space than other types of
granulators. In operation, the water or binder solution is sprayed onto the effervescent
mixture during blending.

Drying occurs by placing the granulation under vacuum and heating it via a thermal
jacket. Effervescent products normally require tablet presses that can deliver high
compression forces. If the tablets are to be wrapped in foil or placed into a tube, give
careful attention to the tablet parameters during Compression. Monitor the tablet
thickness to ensure the wrapping or packaging equipment can handle the tablets. Strict
control of temperature and humidity in all areas is a must (65 to 75ºF, relative humidity
of 10 percent), or the formulation will begin a chemical reaction after it’s packaged. In
essence, the tablet will self-destruct because the byproducts of an effervescent reaction
are water and carbondioxide.

The best way to stabilize an effervescent product is to produce it in an environment

where humidity is under strict control and to package it in a suitable moisture barrier. All
ingredients in the formulation must be anhydrous. Your contractor should test for free
moisture before packaging.

Packaging Materials of Effervescent Tablet

Many effervescent product failures occur each year due to inadequate packaging
materials. Why? Because many pharmaceutical industries purchase those materials based
on pricing, rather than its stability. The most common types of packaging are foil packets
and tubes. Pinholes are a common problem in foil packets. By going to a heavier-gauge
foil (usually more expensive), you will greatly reduce the number of pinholes.

The area within the packet should be large enough to hold the tablets without creating
stress on the foil and as small as possible to minimize the amount of “room-air” that it
can trap inside with the tablets. Given the very low humidity of effervescent tabletting
operations, the tablets are so dry that a relative humidity of even 10 percent is fairly high
when it’s trapped in close contract with tablets. Tubes are made of plastic, glass, or
extruded aluminum with fitted caps containing desiccants. Desiccants are used to “bind-
up” any free moisture in the tablet or in the air to prevent the effervescent reaction from
starting prematurely. Be sure to conduct well-performed stability studies on tubes and
any other packaging you are considering. Figure 2 shows a packaging machine wrapping
effervescent tablets.

Stability Testing of Effervescent Tablet.

After packaging, effervescent products should be placed in a test chamber set at 40ºC and
75 percent relative humidity for at least 3 months to determine whether they will be
stable. At the end of the third month, you should perform physical tests (package leak
test, tablet appearance, disintegration time, tablet hardness, and sensory evaluation of the
product) to determine whether any off-notes developed during testing. You should also
perform chemical assays (HPLC/MS) to test the actives in the tablet. Has there been any
product degradation? If so, why?

The common reasons for degradation of an effervescent product are :

• The packaging material does not have a moisture vapor transmission rate of 0.
Moisture vapor can enter the package.
• The seal of the foil pouch is compromised. This can happen when there is too
much dust in the packaging area or when a machine malfunctions during
wrapping of the product.
• There are ingredients in the formula that are not compatible with each other or
with the effervescent components chosen for the product. Here, the
pharmaceutical or nutraceutical company should ensure that its R&D department
collaborates closely with the contract manufacturer. Each staff member must learn
which raw materials are suitable for a successful effervescent product and which
are not.

Problems In Preparation Tablets

Problems that may arise is with regard to how to make good preparations and in
accordance with their intended use.

To make good preparations needed pre-formulation data covering stability, organoleptic,

physicochemical properties, and other data that can be expected to support the raw
materials that are suitable for the formation of a preparation is good and the achievement
of the intended use.

As for the problems that may occur:

1. Incompatible active substance (melting, change color, decompose, and so on).

2. Stability of active ingredient:

a. For substances that are damaged by the presence of water, made with a tablet-making
methods that do not use water and need to be considered solvent used for granulation.

b. For substances that are easily oxidized by heating and UV light, used in tablet
manufacturing method that does not use heat and UV rays in the process.

c. For substances that are hygroscopic, do not use a wet granulation method used amyli
mucilago because it’s difficult to be dried. This can be overcome by the addition of
adsorbents such as Aerosol <3%. d. For substances that are not waterproof and heat, can
be used method of making tablets by direct compression or dry granulation • For
substances with a small amount (the amount of fines <30%) can be made by Direct
Compression • For substances with a large number (the number of fines> 30%) can be
made by Dry Granulation.

3. Selection of suitable materials

For the determination of excipient should be note the incompatibility with the active
ingredient. In addition, the materials used should have a melting point high enough, so
that the compressing process does not melt.

4. The number of total fines

The number of fines were added at the time of compressing is maximum of 30%, ideally
15%. If a bigger nuisance in the compressing of tablets.

5. Comparison of specific gravity of the active ingredient with the carrier (if too much
should the amount of the fine as little as possible)

6. The concentration of Mg stearate as a lubricant maximum of 2%. If it's too big will
happen laminating.

7. Use of mucilago amyli as a binder in tablet manufacturing process will complicate the
dissolution of the active substance in the granules because mucilago amyli of dried water
impenetrable. To fix this, need to be added wetting agent(Tween 80 0.05% -0.15%) so
that the tablet has a disintegration time better.

8. On the use of PVP as a binder, PVP should be dissolved in alcohol 95%. But in the
early stages, the volume of alcohol used is not known so it can be given as a powder.

9. Use of Amylum that too much (maximum 30%) causing the tablet can not be
compressed because the compressibility is very ugly.

10. Amylum used as a disintegrant in outer phase should be dry Amylum because the
presence of water would reduce its stability as disintegrant. Amylum drying should be
performed at 700C because at this temperature does not occur gelatin from Amylum.

11. In the manufacture of tablets with direct compression method, the diluents can be
used the combination of Primogel with Avicel or Avicel with Starch 1500 with a ratio of
7:3 or 3:1. Since Avicel has good compressibility but the flow is not good, then to
improve the flow can be used Primogel or Starch 1500.

12. To cope with drought granules due to uncontrolled drying it is necessary to increase
humectan namely glycerin or propylene glycol 1-4% calculated on mucilago.

Glycerin is added to the mucilago (binder) to facilitate the homogeneity of glycerin on

the tablets, as well as the addition of Tween to the hydrophobica active substance in
mucilago.

The addition of glycerin and Tween is for the purpose of:

- Glycerin: fear on the drying time of water lost / evaporate all
- Tween: worry about the composition of the used water-repellent, making it necessary
for the addition of Tween so the tablets are not broken.

The exact amount of Tween depends on:

• The amount of active ingredients
• The amount of ingredients used

13. Number of Aerosil are added should be no more than 3% because of Aerosil are
voluminous and absorb water so tablet had longer disintegration time.

14. When the weight of the tablet is too high and varied

Probably caused by:

• Distribution at Hoover caused the vibration. So a little push, large granules will come
out first, because there is a process of consolidation. Therefore needs to be put a uniform
granule size.
• The flow of granules is less well
• particle distribution is not normal, because the specific gravity is so different, so the
flow is bad.
• less lubricant so the flow is bad.

15. If the active ingredient water-soluble :

• Do not granulate it with water
• As a binder, use a solvent which does not dissolve the tablet mass.
Conditions: eg used solvents X, there may be substances that dissolve in solvent X used
as solvent bonding, but a maximum of 30%.
Labels: Problems in Tablet Formulation, Tablet Formulation

Tablet Weight Variation: What Causes It and How to Deal

Weight Variations
In the process of compressing a tablet, of course there are problems,
one of them is the weight variation. Usually, the range is still tolerable for large-sized
tablets (diameter> 10 mm) was 3%, while for small tablet (diameter <7mm) is 5%.
However, this specification ranges vary depending on the respective industry and the
active ingredient of the drug. If the active ingredient is an extremely potent drug, in terms
of the number of doses are very small (microgram scale) has a large effect, then the range
specifications for tablet weight variation would be minimized.
Tablet weight variation in compressing process is not a trivial thing. Moreover, when
affecting the uniformity of dosage units.

Tablet weight variation may be caused by:

• Distribution at Hoover caused the vibration. So, small granule pushed, large
granules will come out first, because there is a process of consolidation.
Therefore, needs to be put a uniform granule size. So, before the compressing
process begins, better evaluation the particle size distribution first.
• The flow of granules is not good / not free-flowing granules
• particle distribution is not normal, because the specific gravity is different, so that
the flow is bad.
• Keep the uniform of particle size distribution. Not too many fines and not too
many granules. Granules with a large particle diameter which causes the resultant
tablet has a variety of unsightly weight, while too fine granules which causes
unsightly flow time.
• lubricant or glidant less or not mixed evenly.

How to overcome the weight variation of tablets:

1.Particle size distribution is uneven

Evaluate the particle size first. If too many fines, then you need to do is create a number
of more granular. This case is commonly found on the direct compression process. This
need not happen if are careful in choosing excipient for direct compression. The problem
is excipient for direct compression is usually relatively more expensive.

If the active ingredient of the drug is stable to heat and humidity, then an easier way is to
produce by wet granulation. Through granulation, drying and sifting, which formed
granules can be more evenly. Critical points that need more attention is the moisture
content and size of mesh used at the time of sifting.

If the active ingredients of drugs are not stable to heat and humid, then try to dry
granulation, compaction with the compactor machine or slugging. Note the size of mesh
used to sift.

What if large granule size is more? It is certainly easier to handle. You can resolve it by
way of sifting the granules. Usually the size of mesh used to sift in the drying phase is the
mesh 12. If the granules are still considered too large, you can sift it twice with 12 mesh
sieve with a mesh or smaller, the mesh 20. Check again whether the particle size
distribution was uneven.

2. Lubricant or glidant less or not mixed evenly.

To solve tablet weight variation, you also can add excipient Aerosil or colloidal Silicon
Dioxide. This excipient was added to the external phase. The amount used is usually 1-
2% of the total weight of the tablet. Mixing for 10-15 minutes. If you need to add
lubricant (Magnesium Stearate) as much as 0.5% -1%. But, keep in mind lubricant is
hydrophobic, may interfere with dissolution of tablets.

3. Specific gravity too different

This case often occurs in the manufacture of tablets that contain more than one type of
granules. Two or more active ingredients each made in separate granules (usually
because of incompatible), then at the time of compression into one, and coupled with the
outer phase. Or two granules remain separate, but when compression using two different
hopper, then compress into one tablet.

Two different granule must have the same specific gravity/ almost the same in order to
avoid variations in weight.

Special Problem in Compressing Tablet Process

1. Sticky on Die

Manifestations:

• Inherent in the die and difficult to remove

• Loud noise in engine
• Tablet brittle, ugly, rough side of the tablet, sometimes black

Cause:

• Antidherent less
• lack of or improper lubricant
• Example: Tablet aspirin sticky with Magnesium stearate, stearic acid should be
used (which micronize because the function of lubricant between the particles are
so fine that will be covered by the lubricant).
• Water content is high will cause the attachment or sticky on the die, while low
water levels can cause the laminating or capping.
• The possibility of chemical or physical interaction, example :physical interaction
between etoxy benzamin with caffeine, glyceryl guaiacolate with promethazine
HCl, which are melting so high adhesives and eventually become sticky.
• Raw materials with very low melting point. Example: Ibuprofen, glyceryl
guaiacolate, Ciprofloxacin (antibiotic imidazole derivatives).
Settlement Issues/Problem Solution:

• Improve antiadherent and lubricants

• Replacement of a suitable lubricant
• Reduce the number of coarse granules
• Reduce the amount of water but do not get under the optimum, because the tablet
becomes less good. If you already know the amount of wetting agent, carried out
by adding the wetting agent to a binder solution, ie materials that do not evaporate
but wet, for example : Propylene glycol or glycerin.
• If there is sticky because of the punch and die may be damaged, because if defects
in the punch, it will be attached so that the smooth punch and die.
• If possible compressing at low temperature and low humidity due specifically to
the active ingredient with a low melting point or eutectic mixture occurs, the
eutectic mixture of substances more easily absorb water. Example: The
combination of ampicillin with Clavulanic acid, where clavulanic acid easily
destroyed by high humidity and temperature. Therefore, the manufacturing is
done in a low temperature and RH.
• Change of filler, filler material with high melting point and can adsorbing, such as
SiO2 and Aerosil (adsorbent). Aerosil Addition in tablet tablets will cause the
appearance of good, clear and shiny, but the longer the disintegration time.

2. Sticky in the pons

Manifestation:

• Peeled of the tablet because the tablet surface attached to the pons. Cause the
same as earlier
• Lack of anti adherent
• high water content
• Sticky at puncher

Overcome the same:

• Change the size of the granules

• Add adsorbent
• Fix tool
• Tools polished, so that the adhesives are very small on tablets and pons.

3. Capping / Laminating
Capping = detached
Laminating = split
Cause:

• Air trapped in tablets because granules are very fine

• Porosity is high, especially in the use of a new puncher, with that air is trapped
between the punch and die
• The hardness tablet is too low or too high (there is optimal)
• The granules that are too dry. Solution: add the ingredients that are not easily
evaporated in the solvent liquid binder
• Substances that are less precise fastener.
• Binder whose numbers are too small (right but the numbers are small)

Abatement

• Preparation of granules repeated if the cause is excess or shortage of suitable

binder or not.
• Add dry binder such as gum arabic, sorbitol, PVP, saccharin, NHPC, LHPC 21,
methylcellulose with high consistency, thus increasing the cohesiveness of the
tablet.
• Reduction of particle size of the granules, because the specification must be the
same size.

4. Cleft or cracks on the surface of the tablet

Manifestations:
As a result of the three previous issues: laminating, sticky or sometimes because of the
pons that are too deep.

Completion:

• Polish pons and die

• For large granule size, reduce the particle granules.
• Replaced punch and die
• Add dry binder

5. Weight uniformity

First Cause:

• The flow is poor

 • Distribution of granule size that is not appropriate, because with such a high
porosity may arise, which can not guarantee the uniformity of weight because of
the new distribution at the time ofcompressing.
• Mixing system that is notright, so the machine must be locked down as well,
especially the pons can vary so that different weights.

Problem solving:

• Fix or repeat the process of making granules, granule size improvement, binders,
granulation, blending repair compressed mass.
• Repair engine tablets tablets ie validating machine.
• The speed of flow can lead to different weight of tablets. The cause of the flow
velocity: water content is so high and the flow adhesivity become less; high
porosity, the air trapped because of fines and binder are many who do not fit or
less. The number of fines increased, the porosity increases, the flow is not good.

The second reason: the distribution of granules is not good.

Settlement Issues:

• Reduce the moisture content

• Creation of new granule, causing a small porosity, the distribution of fine granules
optimal flow.

6 The uniformity of content

Done when:

• Levels below 50 mg of active ingredient

• When comparing levels of active ingredients by weight of the tablet is less than
the 50%

Causes of poor uniformity of content:

• Due to poor flow

• Mixing of pre-granulation is not right then used to determine the homogeneity of
the active substance in the granules (in factory)
• Because of the high fines content, the high porosity (weights vary)
• High water content so that the flow is less well
• The condition of the engine is not right.
Problem solving :

• Improvements include the mixing of granule size, binder changes, granulation.

• Calibration of the machine.

Pre-Formulation, Formulation and Manufacturing of

Aspirin Chewable Tablet for Children
Acetylsalicylic Acid, also known by trade name Aspirin, is an acetyl
derivative of salicylic acid that is a white, crystalline, weakly acidic substance, with
melting point 137°C. It is useful in the relief of headache and muscle and joint aches.
Aspirin is also effective in reducing fever, inflammation, and swelling and thus has been
used for treatment of rheumatoid arthritis, rheumatic fever, and mild infection. Large
doses cause acid-base imbalance and respiratory disturbances and can be fatal, especially
in children. Acetaminophen (known by trade name Tylenol), which does not cause gastric
irritation but does lower fever and relieve pain, is often substituted for Aspirin.

Chewing chewable tablets of aspirin produces the most rapid and biggest absorption
compared to swallowing solid tablets or chewing and then swallowing solid tablets.

Formulation of Aspirin Chewable Tablet

Aspirin Chewable Tablet per Tablet

AlOH (Dried gel) 6.5 % 13 mg
Aspirin 40.5% 81 mg
Talc 1% 2 mg
Primogel 4% 8 mg
NuTab 46.7% 93.4 mg
Mafco Magna Sweet 0.3% 0.6 mg
Orange Flavor 1% 2 mg

Preparation an Manufacturing
1. Mix NuTab and AlOH, add aspirin and mix again (1)
2. Mix primogel, talc, flavor, and Magna Sweet and sifted 16 mesh (2)
3. Add (2) to (1), mix and press into tablet

Combination NuTab and Magna Sweet as a sweetener to reduce the sour taste of aspirin,
as well as the orange flavor. In the dry state, there is no incompatibility between aspirin
reaction with alkaline AlOH. Primogel (Sodium Starch Glycolate) used as disintegrant
and Talc as antiadherent.

Pre-Formulation
ASPIRIN
Physical State : white crystalline powder or needle-shaped crystals with sweetish taste,
Odorless, Colourless
Melting Point : 136 C (with decomposition)
Boiling Point : 140 C
Specific Gravity : 1.35
Solubility : Soluble in acetone, ether, alcohol, boiling water, benzene and turpentine,
sparingly soluble in chloroformbenzene, slightly soluble in water; melts at 158°C.
Solubility In Water: 1g/100g water @ 37C
Stability : Stable in dry air (hydrolyzes in moist air, decomposes in hot water)

Aspirin is unstable in the presence of alkaline compounds, such as alkaline stearate

lubricants. Its replacement could be used talk.

The sodium salt form (sodium salicylate) is common commercially, prepared from
mainly sodium phenolate with carbon dioxide under heating and pressure. It contains
both a hydroxyl and a carboxyl group, which react with either an acid or an alcohol. The
carboxyl group forms esters with alcohols; e.g. methyl salicylate is formed with
methanol, which used in food flavorings and preservatives; menthyl salicylate is formed
with methanol, which is used in suntan lotions. The hydroxyl group reacts with acetic
acid to form acetylsalicylic acid (called aspirin) which is the most widely common
antiseptic and antipyretic agent. Phenyl salicylate (called salol) is formed with phenol,
which is also used as an antiseptic and antipyretic agent.

NU-Tab (Compressible Sugar)

is used in a wide range of chewable applications, including children's vitamins and
medications and for taste masking bitter or unpleasant drugs.
Description: White, granular, free-flowing powder with the sweet taste of sucrose. Very
soluble in water, non-hygroscopic, non-reactive with other tablet ingredients. Slightly
soluble in alcohol. Nutritional information: 100% carbohydrate with a caloric content of
4 kcal/g.

Physical Characteristics:
Moisture Content (%) : NMT 1%
Bulk Density (g/cc) 0.69
retained on US 40 mesh: NMT 1%
retained on US 100 mesh: NMT 90%
through US 200 mesh: NMT 5%

Applications:
• In Chewable Tablet : coarse mesh size makes it an excellent carrier for materials with
compresion problems
• In Direct Compression : excellent flowability, high compressibility, low hygroscopicity,
sweet and non-reactive.
• Sweetener
• Taste Masking