片剂辅料
Excipient and their functionalities
(13-15)
Excipient means any component other than the active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Many guidelines exist to aid in selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS (Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others. While selecting excipients for any formulation following things should be considered wherever possible: keep the excipients to a minimum in number minimize the quantity of each excipients and multifunctional excipients may be given preference over unifunctional excipients.
Excipients play a crucial role in design of the delivery system, determining its quality and performance. Excipients though usually regarded as nontoxic there are examples of known excipient induced toxicities which include renal failure and death from diethylene glycol, osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from lanolin and cardiotoxicity induced by propylene glycol.
Excipients are chosen in tablet formulation to perform a variety of functions like i)For providing essential manufacturing technology functions (binders, glidants, lubricants may be added),
ii)For enhancing patient acceptance (flavors, colourants may be added), iii)For providing aid in product identification (colourants may be added), iv)For Optimizing or modifying drug release (disintegrants, hydrophilic polymers, wetting agents, biodegradable polymers may be added),
v)For enhancing stability (antioxidant, UV absorbers may be added) [edit]
Various excipients used in tablet formulation and their functionalities.
(1, 4, 16)
TABLE.2. EXCIPIENT WITH THEIR FUNCTIONS IN TABLET FORMULATION
EXCIPIENT FUNCTION
Diluents or Fillers Diluents make the required bulk of
the tablet when the drug dosage
itself is inadequate to produce
tablets of adequate weight and
size.
Binders or Granulating agents or Adhesives Binders are added to tablet
formulations to add cohesiveness
to powders, thus providing the
necessary bonding to form
granules, which under compaction
form a cohesive mass or a compact
which is referred to as a tablet.
Disintegrants A disintegrant is added to most
tablet formulations to facilitate a
breakup or disintegration of the
tablet when placed in an aqueous
environment.
Antifrictional Agents
Lubricants Lubricants are intended to reduce
the friction during tablet formation
in a die and also during ejection
from die cavity.
Antiadherents Antiadherents are added to reduce
sticking or adhesion of any of the
tablet granulation or powder to the
faces of the punches or to the die
wall.
Glidants Glidants are intended to promote
the flow of tablet granulation or
powder mixture from hopper to the
die cavity by reducing friction
between the particles.
MISCELLANEOUS
Wetting agents Wetting agents are added to tablet
formulation to aid water uptake
during disintegration and assist
drug dissolution.
Dissolution retardants Dissolution retardants as the name
suggest, retards the dissolution of
active pharmaceutical
ingredient(s).
Dissolution enhancers Dissolution enhancers as the name
suggest, enhance the dissolution
rate of active pharmaceutical
ingredient(s).
Adsorbents Adsorbents are capable of
retaining large quantities of liquids
without becoming wet; this
property of absorbent allows many
oils, fluid extracts and eutectic
melts to be incorporated into
tablets.
Buffers Buffers are added to provide
suitable micro environmental pH to
get improved stability and / or
bioavailability.
Antioxidants Antioxidants are added to maintain
product stability, they act by being
preferentially oxidized and
gradually consumed over shelf life
of the product.
Chelating agents Chelating agents are added to
protect against autoxidation; they
act by forming complexes with the
heavy metal ions which are often
required to initiate oxidative
reactions.
Preservatives Preservatives are added to tablet
formulation in order to prevent the
growth of micro-organisms.
Colours Colours are added to tablet
formulation for following
purposes: to disguise off colour
drugs, product identification and
for production of more elegant
product.
Flavours Flavours are added to tablet
formulation in order to make them
palatable enough in case of
chewable tablet by improving the
taste.
Sweeteners Sweeteners are added to tablet
formulation to improve the taste of
chewable tablets.
[edit]
Key Phrases
, Tablet formulations are usually designed to
satisfy following criteria-Patient acceptability;
accuracy and uniformity of drug
content;manufacturability; optimal drug
dissolution and stability.
, Excipients are any component other than
active pharmaceutical ingredient(s)
intentionally added to the formulation of a
dosage form.
, Excipients play a crucial role in design of the
delivery system, determining its quality and
performance.
, Various excipients used in tablet formulation
are diluents, binders, disintegrants,
lubricants, antiadherents, glidants, wetting
agents, dissolution retardants, dissolution
enhancers, absorbents, buffers, antioxidants,
chelating agents, preservatives, colours,
flavours, sweeteners, etc.
Tablet:Formulation of tablets/Diluents
From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Binders
Previous Page: Excipient
Contents
[hide]
, 1 Introduction
, 2 Classification of diluents
o 2.1 Organic diluents
o 2.2 Inorganic diluents
o 2.3 Co-processed diluents
o 2.4 Key Phrases
[edit]
Introduction
(1, 17)
In order to facilitate tablet handling during manufacture and to achieve targeted content uniformity, the tablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Many potent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in such cases diluents provide the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Usually the range of diluent may vary from 5-80%. Diluents are also synonymously known as fillers. Diluents are often added to tablet formulations for secondary reasons like to provide better tablet properties such as:
i)To provide improved cohesion
ii)To allow direct compression manufacturing
iii)To enhance flow
iv)To adjust weight of tablet as per die capacity
No matter for what purpose they (diluents) are added they must meet certain basic criteria for satisfactory performance in tablet dosage form. They are as follows: Diluent should not react with the drug substance and moreover it should not have any effect on the functions of other excipients, it should not have any physiological or pharmacological activity of its own, it should have consistent physical and chemical characteristics, it should neither promote nor contribute to segregation of the granulation or powder blend to which they are added, it should be able to be milled (size reduced) if necessary in order to match the particle size distribution of the active pharmaceutical ingredient, it should neither support microbiological growth in the dosage form nor contribute to any microbiological load, it should neither adversely affect the dissolution of the product nor interfere with the
bioavailability of active pharmaceutical ingredient, it should preferably be colourless or nearly so.
[edit]
Classification of diluents
(16,17)
Tablet diluents or fillers can be divided into following categories: i)Organic materials - Carbohydrate and modified carbohydrates.
ii)Inorganic materials – Calcium phosphates and others.
iii)Co-processed Diluents.
Carbohydrate substances such as sugars, starches and celluloses may also function as binders during wet granulation process. Whereas when used in direct compression system, they serve as the diluent. The inorganic diluents, do not exhibit binding properties when used in wet granulation and direct compression. Tablet diluent or filler may also be classified on the basis of their solubility in water as soluble and insoluble.
INSOLUBLE TABLET FILLERS OR SOLUBLE TABLET FILLERS OR
DILUENTS DILUENTS
Starch Lactose
Powdered cellulose Sucrose
Microcrystalline cellulose Mannitol
Calcium phosphates, etc. Sorbitol, etc.
Selection of diluent should be done after considering properties of diluent such as: Compactibility, flowability, solubility, disintegration qualities, hygroscopicity, lubricity and stability.
[edit]
Organic diluents
(1,17-20)
Carbohydrates
Sugar and Sugar alcohols
Lactose α-lactose monohydrate, spray dried lactose and anhydrous lactose are widely used as diluent.
Characteristics of α -Lactose monohydrate (hydrous)
Lactose monohydrate is not directly compressible and therefore it is suitable for use in wet granulation.
It has poor flow properties.
α-lactose monohydrate is water soluble.
It produces a hard tablet and the tablet hardness increases on storage. Disintegrant is usually needed in lactose containing tablets.
Drug release rate is usually not affected.
It is usually unreactive, except for discoloration when formulated with amines and alkaline materials (i.e. browning or maillard reaction).
It contains approximately 5% moisture and hence is a potential source of instability especially with moisture sensitive drugs.
It is inexpensive.
It is commercially available under the trade name of: Pharmatose? and Respitose? manufactured by DMV International.
Characteristics of Lactose spray dried
It is directly compressible diluent.
It exhibits free flowing characteristics.
It needs high compression pressures in order to produce hard tablets. Its compressibility is adversely affected if dried below 3% moisture. It has high dilution potential.
It is more prone to darkening in the presence of excess moisture, amines and other compounds due to the presence of a furaldehyde.
Usually, neutral or acid lubricant should be used when spray dried lactose is employed.
Expensive compared to anhydrous and hydrous lactose.
It is commercially available as Spray Process 315? manufactured by Foremost Farms USA.
Characteristics of Lactose anhydrous
Lactose anhydrous is a directly compressible diluent.
It does not exhibit free flowing property.
It can pick up moisture at elevated humidity as a result of which changes in tablet dimensions may occur.
It does not undergo a maillard reaction to the extent shown by spray dried lactose,
although this may occur in some cases to a slight degree.
It is inexpensive.
It is commercially available as Pharmatose? DCL 21 manufactured by DMV Pharma.
Sucrose
Characteristics of Sucrose or sugar
It requires high machine pressures, especially in cases with over wetted granulations.
It is water soluble.
It possesses good binding properties.
It is slightly hygroscopic.
It is inexpensive.
It produces gritty mouth feel (i.e., it is not free from grittiness). It is a calorie contributor and is cariogenic.
Mannitol
Characteristics of Mannitol
Mannitol a sugar alcohol is an optical isomer of Sorbitol.
It exhibits poor flow properties.
It requires high lubricant content.
It is probably the most expensive sugar used as a tablet diluent and is water soluble. It is widely used in chewable tablets because of its negative heat of solution, its slow solubility and its mild cooling sensation in mouth.
It can be used in vitamin formulation, where moisture sensitivity may create a problem.
It is comparatively non hygroscopic.
It is free from grittiness.
It possesses low caloric value and is noncariogenic.
It is commercially available under the brand name Parteck?M manufactured by EMD Chemicals .Other commercial products are Pearlitol? and Mannogem?. Sorbitol
Characteristics of Sorbitol
Sorbitol is often combined with mannitol formulations in order to reduce diluent cost.
It is highly compressible diluent and is water soluble.
It is hygroscopic in nature.
It has good mouth feel and sweet cooling taste.
It is free from grittiness.
It possesses low caloric value and is noncariogenic.
It is commercially available as Sorbifin? and Neosorb? .
Poorly absorbed sugar alcohols such as Sorbitol and mannitol can decrease small intestinal transit time. Therefore absorption may be altered for the drugs that are preferentially absorbed from this region.
Celluloses (1,17, 21)
Powdered cellulose
Characteristics of Powdered cellulose
Powdered cellulose products consist of finely divided amorphous and crystalline α-cellulose particles.
Powdered cellulose may be used alone or together with other fillers such as lactose, calcium phosphates, dextrans and others.
It possesses poor compressibility and exhibits poor flow properties. It has poor binding properties and low dilution potential.
It is water insoluble.
It possesses some degree of inherent lubricity.
It is inexpensive.
It is commercially available under the trade name of Elcema?G-250 manufactured by Degussa Corporation.
Microcrystalline cellulose
Characteristics of Microcrystalline cellulose
Microcrystalline cellulose (MCC) is highly compressible and is perhaps the most widely used direct-compression tablet diluent.
Hard tablets, at low compression pressures, are usually obtained when MCC is used as tablet diluent.
It undergoes plastic deformation on compression and hence it is more sensitive to lubricants.
It exhibits fair flowability.
It exhibits binding properties.
It also possesses disintegrant activity and thus promotes fast tablet disintegration.
It is water insoluble.
) provides increased compactibility, enhanced,Silicified MCC (SMCC- Prosolv flow
and improved uniformity compared to MCC (Avicel? manufactured by FMC Biopolymer)
SMCC is more suitable for cohesive poorly compressible ingredients in direct compression formulation.
Other commercial product is Emcocel? manufactured by Penwest Pharmaceutical Co.
[edit]
Inorganic diluents
(17,22)
Calcium phosphates
The calcium phosphates, here includes, the dihydrate and anhydrous form of dibasic calcium phosphate and tribasic calcium phosphate. They are granular insoluble materials. They are widely used both as wet granulation and direct compression diluents in tablet formulation. Bulk density of calcium phosphates is higher than that of organic fillers. They are used extensively in vitamin and mineral preparations. Dibasic calcium phosphate dihydrate is also commonly known as dicalcium phosphate, calcium hydrogen phosphate dihydrate and secondary calcium phosphate dihydrate.
Dibasic calcium phosphate is available commercially under the trade name (Manufactured by,Di-Tab? (manufactured by Rhone-Poulenc) and Emcompress E.Mendell Co.).An anhydrous form of dibasic calcium phosphate is available commercially under the trade name A-Tab? (manufactured by Rhone-Poulenc). Fujicalin?, a novel commercially available free flowing spherically granulated dicalcium phosphate anhydrous (SGDCPA) for direct tableting was compared with directly compressible dicalcium phosphate dihydrate (DCPD) and it was found that SGDCPA exhibited same good flowability and better compactibility. Whereas in contrast to DCPD, SGDCPA exhibited significant uptake of moisture when exposed to relative humidity exceeding 70 %.Tribasic calcium phosphate is also commonly referred as tricalcium phosphate, tricalcium orthophosphate and hydroxyapatite. Tribasic calcium phosphate is available under the trade name Tri-Tab?. Characteristic of Calcium Phosphates
They are directly compressible and are characterized by brittle fracture on compression during tableting process.
Hard tablets are produced when calcium phosphates are used as diluents. They exhibit good flow properties.
They are non hygroscopic.
They are inexpensive.
They are abrasive in nature and hence can cause wear of tablet tooling. Sometimes their alkalinity is a major source of drug instability.
edit] [
Co-processed diluents
(17,23)
Co-processing means combining two or more materials by an appropriate process. The products so formed are physically modified in such a special way that they do not loose their chemical structure and stability. Now a days direct compression technique has been one of the well-accepted methods of tablet manufacture. An extensive range of materials from various sources have been developed and marketed as directly compressible diluents such as lactose, starch, cellulose derivatives, inorganic substance, polyalcohols, and sugar-based materials. In addition to the development of directly compressible excipients by modifying just a single substance, co-processing of two or more components has been applied to produce composite particles or co-processed excipients. The composite particles or co-processed excipients are introduced in order to provide better tableting properties than a single substance or the physical mixture.
TABLE.4. LIST OF CO-PROCESSED EXCIPIENTS USED TO ACHIEVE BETTER TABLETING PROPERTIES
TRADE NAME MANUFACTURER DESCRIPTION
?Fast Flo lactose Foremost Whey It is spray processed lactose
Products which is a mixture of crystalline
α-lactose monohydrate and
amorphous lactose.
?Microcellac 75% lactose and 25% MCC
(MicroCrystalline Cellulose)
?Ludipress 93% α-lactose monohydrate,
3.5% polyvinylpyrrolidone, and 3.5% crospovidone.
?Nu-Tab Ingredient Technology Sucrose 95-97%, invert sugar
3-4% and magnesium stearate 0.5%
?Di-Pac Amstar Corp. Sucrose 97% and modified
dextrins 3%
?Sugartab E.Mendell Co. Inc. Sucrose 90-93% and invert
sugar 7-10%.
?Emdex E.Mendell Co. Inc. Dextrose 93-99% and maltose
1-7%
?Cal-Tab Ingredient Technology Calcium sulfate 93% and
vegetable gum 7%
?Cal-Carb Ingredient Technology Calcium carbonate 95% and
maltodextrins 5%
?Calcium 90 Ingredient Technology Calcium carbonate (minimum)
90% and Starch, NF (maximum) 9%
[edit]
Key Phrases
, Diluents make the required bulk of the tablet when the drug dosage itself
is inadequate to produce tablets of adequate weight and size. , Diluents are often added to tablet formulations for secondary reasons
like to provide better tableting properties.
, Tablet diluents or fillers can be divided into following categories: i) Organic materials
ii) Inorganic materials
iii) Co-processed diluents
, Tablet diluents or fillers may also be classified on the basis of their
solubility in water as soluble diluent and insoluble diluent.
, Microcrystalline cellulose (MCC) is perhaps the most widely used
direct-compression tablet filler.
, Co-processing means combining two or more materials by an
appropriate process.
, The composite particles or co-processed excipients are introduced to
provide better tableting properties than a single substance or the
physical mixture
Tablet:Formulation of tablets/Binders
From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Disintegrants
Previous Page: Diluents
Binder is one of an important excipient to be added in tablet formulation. In simpler
words, binders or adhesives are the substances that promotes cohesiveness. It is
utilized for converting powder into granules through a process known as
Granulation.
Contents
[hide]
, 1 Why to go for Granulation?
, 2 Granulation Processes
, 3 Types of Binders
o 3.1 Direct compression (DC) Binders
o 3.2 Mechanism of granule formation
o 3.3 Near Infrared (NIR) spectroscopy : A tool for granulation end
point measurement
o 3.4 Factors to be considered in Granulation
, 3.4.1 Compatibility
, 3.4.2 Characteristics of drugs and other excipients
, 3.4.3 Spreading of Binder
, 3.4.4 Type and quantity of Binder
, 3.4.5 Temperature and Viscosity
, 3.4.6 Method of Addition of Binder
, 3.4.7 Mixing Time
, 3.4.8 Material of Construction of Granulator
, 3.4.9 Type of Granulator
, 3.4.10 Process Variables
, 3.4.11 Apparatus Variables
, 3.4.12 Impeller Movement
o 3.5 Evaluation tests for Binders/Granules
, 3.5.1 Particle Size and Particle Size Distribution
, 3.5.2 Surface Area
, 3.5.3 Density
, 3.5.4 % Compressibility
, 3.5.5 Flow Properties
, 3.5.6 Friability
, 3.5.7 Moisture Content
o 3.6 Key Phrases
[edit]
Why to go for Granulation?
(24)
Powders/Granules intended for compression into tablets must possess two essential
properties : flow property and compressibility.
Flow property/Fluidity is required to produce tablets of a consistent weight and uniform strength. Compressibility is required to form a stable, intact compact mass when pressure is applied. These two objectives are obtained by adding binder to tablet formulation and then proceeding for granulation process. Granules so formed should possess acceptable flow property and compressibility. Some drugs exhibit poor fluidity and compressibility. In such cases binders have to be added for improving flow property and compressibility.
Other reasons for Granulation process are to improve appearance, mixing properties, to avoid dustiness, to densify material, to reduce segregation, in general to either eliminate undesirable properties or to improve the physical and chemical properties of fine powders.
[edit]
Granulation Processes
(24)
The standard methods frequently used today in tablet manufacturing are granulation and direct compression. Granulation technique includes wet granulation
and dry granulation/slugging methods wherein binders are added in
solution/suspension form and in dry form respectively. In Direct Compression, binders possessing direct compressibility characteristics are used. Binder when used in liquid form gives better binding action as compared to when used in dry form.
[edit]
Types of Binders
(18,25-28)
TABLE.5. CLASSIFICATION OF BINDERS
SUGARS NATURAL BINDERSYNTHETIC/SEMISYNTHETIC POLYME
S R Sucrose Acacia Methyl Cellulose
Liquid glucosTragacanth Ethyl Cellulose
e
Gelatin Hydroxy Propyl Methyl Cellulose ( HPMC)
Starch Paste Hydroxy Propyl Cellulose
Pregelatinized StarcSodium Carboxy Methyl Cellulose
h
Alginic Acid Polyvinyl Pyrrolidone (PVP)
Cellulose Polyethylene Glycol (PEG)
Polyvinyl Alcohols
Polymethacrylates
TABLE.6. COMMONLY USED BINDERS BINDER CATEGORY MANUFACTURER
Partially Pregelatinized Maize Starch 1500 Colorcon Starch
Methocel Hydroxy Propyl Methyl Cellulose Dow Chemicals
Wolff-Cellulosics Walocel Hydroxy Propyl Methyl Cellulose Natural Starch and Chemical C
ompany
Luvitec Polyvinylpyrrolidone BASF Company Luvicross Polyvinylpyrrolidone BASF Company LuvicaprolactPolyvinylcaprolactam BASF Company am
TABLE.7. CHARACTERISTICS OF COMMONLY USED BINDER
COMMENTS BINDER SPECIFIED
CONCENTRATION
Starch Paste 5-25%w/w - Freshly prepared starch paste is used
as a binder.
- Its method of preparation is very
crucial.
Pregelatinized 5-10%w/w It is starchthat have been processed Starch (PGS) chemically and/ormechanically to (Direct Compression) rupture all or part of the granules in [Partially and Fully 5-75%w/w the presence of water and PGS] subsequently dried. (Wet Granulation )
- It contains 5% free amylose, 15%
free amylopectin and
80%unmodifiedstarch.
- Obtained from maize, potato or rice
starch.
- It is multifunctional excipient used as
a tablet binder, diluent, disintegrant
and flow aid.
- They enhance both flow and
compressibility and can be used as
binders in Direct Compression as well
as Wet Granulation.
- High purity PGS allow simplified
processing as they swell in cold water
and therefore reduce time/costs
compared with traditional starch paste
preparation.
Hydroxypropyl 2-5%w/w - Comparable to Methyl Cellulose.
Methyl Cellulose - Used as a binder in either wet or dry (HPMC) granulation processes.
Polyvinyl 0.5-5%w/w - Soluble in both water and alcohol.
Pyrrolidone (PVP) - Used in wet granulation process.
- It is also added to powder blends in
the dry form and granulated in situ by
the addition of water, alcohol or
hydroalcoholic solution.
- Valuable binder for chewable tablets.
- The drug release is not altered on
storage.
Polyethylene 10-15%w/w - Used as a meltable binder.
Glycol (PEG) 6000 - Anhydrous granulating agent where
water or alcohol cannot be used .
- It may prolong disintegration time
when concentration is 5% or higher
- It improves the plasticity of other
binders.
[edit]
Direct compression (DC) Binders
(29)
Due to ease of manufacture, product stability and high efficiency, the use of Direct Compression for tableting has increased. For Direct Compression, directly compressible binders are required which should exhibit adequate powder compressibility and flowability. Direct Compression binders should be selected on the basis of compression behavior, volume reduction under applied pressure and flow behavior in order to have optimum binding performance. The choice and selection of binders is extremely critical for Direct Compression tablets. TABLE.8. COMMONLY USED DC BINDERS
DC BINDER CLASS MANUFACTURER
aAvicel (PH 101) MCC FMC Corporation
bSMCC (50) SMCC Penwest Pharmaceutical
cUNI-PURE(DW) Partially PGS National Starch
& Chemical
UNI-PURE (LD) Low density starch National Starch & Chemica
DC Lactose DC lactose anhydrous Quest International Group
dDI TAB DC-DCPD Rhodi
a – Microcrystalline Cellulose, b – Silicified Microcrystalline Cellulose, c –
Pregelatinized Starch, d – Dibasic Calcium Phosphate Dihydrate
TABLE.9. CHARACTERISTICS OF DC BINDERS
Flow Behavior DI TAB > SMCC(50) > DC Lactose , UNI PURE(DW) >
Avicel (PH 101) > UNI PURE(LD)
Compressibility UNI PURE(LD) > SMCC(50) , Avicel (PH 101) > UNI
PURE(DW) , DC Lactose > DI TAB
Crushing Strength UNI PURE(LD) > SMCC(50) >
UNI PURE(DW) > Avicel(PH 101) > DC Lactose >
DITAB
[edit]
Mechanism of granule formation
(30)
Granules are formed in three stages:
Nucleation: Here, the particles adhere due to liquid bridges which are the initiation step of Granulation. These adhered particles play a role of nucleus for further enlargement of granules.
Transition: Enlargement of nucleus takes place by two possible mechanisms. Individual particle adhere to the nucleus or two or more nuclei combine among themselves.
Ball growth or enlargement of the granule: Ball growth occurs either by
Coalescence or Breakage or Abrasion Transfer or Layering. In Coalescence a larger granule is formed when two or more granules are united. In Breakage granules break and the fragments of granule adhere to other granules. This forms a layer of material over intact granules. In Abrasion Transfer granule material are abraded through attrition by the agitation of granule bed and abraded material adheres to other granules resulting into enlarged granules. In layering particles adheres to the already formed granules increasing their size.
edit] [
Near Infrared (NIR) spectroscopy : A tool for
granulation end point measurement
(31)
NIR Spectroscopy is applicable for monitoring of wet granulation process when impeller torque method cannot be applied. Watano et al determined the granulation end point using agitated fluidized bed where in IR moisture sensor was installed. The properties of the wet mass obtained from NIR are independent of granulator equipment variables such as impeller design. Even the powder blending efficiency in
the dry mixing phase can be monitored inline by NIR. NIR spectroscopy could be an excellent tool in wet granulation measurement.
[edit]
Factors to be considered in Granulation
(24,30,32)
[edit]
Compatibility
The primary criteria is the compatibility of binder with the API & other tablet components. This is traditionally found by choosing appropriate stability study design. Currently Differential Scanning Calorimetry (DSC) is used to ascertain compatibility.
[edit]
Characteristics of drugs and other excipients
The drugs characteristics like its compressibility, particle size, surface area, porosity, hydrophobicity, solubility in binder are important while fixing a granulation process. The drug that exhibits poor compressibility requires the use of a strong binder (liquid glucose, sucrose, etc.) while the drugs that exhibit good compressibility can be successfully handled using a weak binder ( starch paste etc.,). Fine and porous particles requires higher amount of liquid binder as compared to coarse particles. Hydrophilic drug/excipients exhibiting absorption characteristics require higher volume of binder as compared to hydrophobic drug/excipients. The granule quality (size , friability) is governed by the solubility of the drug in the granulation solution.
[edit]
Spreading of Binder
Spreading of binder/granulation solution on the powder blend is of paramount importance in successful granulation. A binder that spreads easily on particles is superior as compared to that which shows poor wetting quality. HPMC is a superior binder for paracetamol as compared to PVP.
[edit]
Type and quantity of Binder
The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation. As for example hard granulations results due to stronger binder or a highly concentrated binder solution which require excessive compression force during tableting. On the other hand, fragile granulations results due to insufficient quantity of binder which segregates easily. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore the optimum quantity of liquid needed to get a given particle size should be known in order to keep a batch to batch variations to a minimum.
[edit]
Temperature and Viscosity
The temperature and viscosity of binder is also important. Fluid (less viscous) binder exhibit good spreading behavior.
[edit]
Method of Addition of Binder
The method of addition of binder is also important. PVP can be used as solution as a binder or it may be dry blended with powders and later activated by adding water. Distribution of binder is favored if it is dispersed instead of pouring it. [edit]
Mixing Time
The mixing time also determines quality of granules. If the wet massing time is higher (resulting into hard granules), the tablets may fail the dissolution test in certain cases since drug release from hard granules is altered.
[edit]
Material of Construction of Granulator
The material of construction of granulator determines the volume of binder required as well as granule size distribution. Any vessel wall which are wetted easily by binder demands the need of higher volume of binder. As for example vessel wall
made up of Stainless Steel require higher volume of binder as compared to vessel made up of plastics (PMMA – Polymethylmethacrylate and PTFE –
Polytetrafluoroethylene i.e. Teflon). In case of PMMA and PTFE due to high contact angle, all granulating liquid is forced immediately into the powder bed and gives narrow particle size distribution. While in case of steel, due to less contact angle liquid layer formed on the wall surface which in turn causes inhomogeneous distribution of liquid over the powder bed resulting into broader granule size. edit] [
Type of Granulator
Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators.
[edit]
Process Variables
Higher degree of densification of the granules results due to higher impeller speed as well as longer wet massing time. And also there is tendency of agglomeration since liquid saturation increases. Consequently, impeller speed and wet massing time affect the granule size.
[edit]
Apparatus Variables
The apparatus variables in High Shear Mixer have a larger effect on granule growth than in Fluidized Bed Granulators because the shear forces are dependent on the mixer construction. The size and shape of the mixing chamber, impeller and chopper vary in different High Shear Mixers.
[edit]
Impeller Movement
Adhesion of wetted mass to the vessel is less if impeller movement is helical. This gives a narrower granule size and few lumps. In case of High Shear Mixers, adhesion of wetted mass to the vessel is a problem which can be reduced by proper construction of the impeller or by coating the vessel with Polytetrafluoroethylene i.e. Teflon.
[edit]
Evaluation tests for Binders/Granules
(1)
Compactness, physical and chemical stability, rapid production capability, efficacy are some of the characteristics that make tablet a ruling dosage form. These characteristics depend on the quality of granules from which it is made. The characteristics of granules produced are affected by formulation and process variables. So it becomes essential to evaluate the granule characteristics to monitor its suitability for tableting.
edit] [
Particle Size and Particle Size Distribution
The particle size of granules affect the average tablet weight, tablet weight variation, disintegration time, granule friability, granulation flowability and the drying rate kinetics of wet granulations. Therefore the effects of granule size and size distribution on the quality of tablet should be determined by formulator. The methods usually adopted for measurement of particle size and particle size distribution includes Microscopy, Sieving, Conductivity test.
[edit]
Surface Area
Surface area of the drug effects upon dissolution rate especially in cases where drug have limited water solubility. The two most common methods for surface area determination are Gas Adsorption and Air Permeability.
[edit]
Density
Granule density, True Density, Bulk Density may influence compressibility, tablet porosity, flow property, dissolution and other properties. Higher compression load is required in case of dense and hard granules which in turn increases the tablet disintegration and drug dissolution times. Density is usually determined by pycnometer.
[edit]
% Compressibility
Compressibility is the ability of powder to decrease in volume under pressure. Compressibility is a measure that is obtained from density determinations. % Compressibility = (Tapped density – Bulk density/Tapped density)*100
Compressibility measures gives idea about flow property of the granules as per CARR’S Index which is as follows :
TABLE.10. CARR’S INDEX
% COMPRESSIBILITY FLOW DESCRIPTION
5 – 15 Excellent
12 – 16 Good
18 – 21 Fair
23 – 28 Poor
28 – 35 Poor
35 – 38 Very Poor
> 40 Extremely Poor
[edit]
Flow Properties
It is very important parameter to be measured since it affects the mass of uniformity of the dose. It is usually predicted from Hausner Ratio and Angle Of Repose Measurement.
Hausner Ratio = Tapped Density / Bulk Density
TABLE.11. HAUSNER RATIO
HAUSNER RATIO TYPE OF FLOW
Less than 1.25 Good Flow
1.25 – 1.5 Moderate
More than 1.5 Poor Flow
Angle of Repose (Φ) is the maximum angle between the surface of a pile of powder and horizontal plane. It is usually determined by Fixed Funnel Method and is the measure of the flowability of powder/granules.
-1Φ = tan (h / r) where, h = height of heap of pile
r = radius of base of pile
TABLE.12.ANGLE OF REPOSE (Φ)
ANGLE OF REPOSE TYPE OF FLOW
< 25 Excellent
25 – 30 Good
30 – 40 Passable
> 40 Very Poor
[edit]
Friability
Friability is important since it affects in particle size distribution of granules affecting compressibility into tablet, tablet weight variation, granule flowability. Friability is determined carrying out Tumbler Test or using Friability Tester ( Roche Friabilator ) and % loss is determined.
edit] [
Moisture Content
It affects the granule flowability, compressibility as well as the stability of moisture sensitive drug and therefore should be determined to evaluate the quality of granule.
[edit]
Key Phrases
, Binders are added in tablet formulation to have required flow property
and compressibility of powders.
, Wet Granulation, Dry Granulation/Slugging, Direct Compression are
major granule manufacturing methods.
, Direct Compression Binders are more efficient than conventional binders.
, Pregelatinized Starch is used as multifunctional excipient: tablet binder
(wet granulating agent as well as direct compression binder), diluent,
disintegrant and flow aid.
, Polyethylene Glycol used as meltable binder.
, Granules are formed in three stages: Nucleation, Transition and Ball
Growth.
, NIR a tool for granulation end point measurement. However, it was
shown to work only for fluid-bed granulation. Torque impeller method
and power consumption are still the best methods for high-shear and
planetary mixer-granulators.
, Compatibility of binder with API and other excipients, characteristics of
binder, process variables, and apparatus variables affects the quality of
granules.
, Granules have to be evaluated in order to measure its suitability for
tableting.
Tablet:Formulation of tablets/Disintegrants
From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Antifrictional Agents
Previous Page: Binders
Contents
[hide]
, 1 Introduction
, 2 Mechanism of tablet disintegrants
, 3 Methods of addition of disintegrants
, 4 Types of disintegrants
o 4.1 Starch
o 4.2 Pregelatinized starch
o 4.3 Modified starch
o 4.4 Cellulose and its derivatives
o 4.5 Microcrystalline cellulose (MCC)
o 4.6 Alginates
o 4.7 Ion-exchange resin
o 4.8 Miscellaneous
o 4.9 Superdisintegrants
, 5 Factors affecting disintegration
o 5.1 Effect of fillers
o 5.2 Effect of binder
o 5.3 Effect of lubricants
o 5.4 Effect of surfactants
, 6 Key Phrases
[edit]
Introduction
Boavailability of a drug depends in absorption of the drug, which is affected by
solubility of the drug in gastrointestinal fluid and permeability of the drug across gastrointestinal membrane. The drugs solubility mainly depends on physical –
chemical characteristics of the drug. However, the rate of drug dissolution is greatly influenced by disintegration of the tablet.
The drug will dissolve at a slower rate from a nondisintegrating tablet due to exposure of limited surface area to the fluid. The disintegration test is an official test
and hence a batch of tablet must meet the stated requirements of disintegration. Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrants.
The objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet.
FIGURE.16. SCHEMATIC REPRESENTATION OF TABLET DISINTEGRATION AND
SUBSEQUENT DRUG DISSOLUTION
[edit]
Mechanism of tablet disintegrants
(16,29,33-39)
The tablet breaks to primary particles by one or more of the mechanisms listed below:-
I.By capillary action
II.By swelling
III.Because of heat of wetting
IV.Due to disintegrating particle/particle repulsive forces
V.Due to deformation
VI.Due to release of gases
VII.By enzymatic action
BY CAPILLARY ACTION
Disintegration by capillary action is always the first step. When we put the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug /excipient and on tableting conditions. For these types of disintegrants maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles.
BY SWELLING
Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration is again slows down.
FIGURE.17. DISINTEGRATION OF TABLET BY WICKING AND SWELLING
Because of heat of wetting (air expansion)
When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet. This explanation, however, is limited to only a few types of disintegrants and can not describe the action of most modern disintegrating agents.
Due to disintegrating particle/particle repulsive forces
Another mechanism of disintegration attempts to explain the swelling of tablet made with ‘non-swellable’ disintegrants. Guyot-Hermann has proposed a particle
repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets. The electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking.
Due to deformation.
Hess had proved that during tablet compression, disintegranted particles get deformed and these deformed particles get into their normal structure when they come in contact with aqueous media or water. Occasionally, the swelling capacity of starch was improved when granules were extensively deformed during compression. This increase in size of the deformed particles produces a break up of the tablet. This may be a mechanism of starch and has only recently begun to be studied.
FIGURE.18. DISINTEGRATION BY DEFORMATION AND REPULSION
Due to release of gases
Carbon dioxide released within tablets on wetting due to interaction between bicarbonate and carbonate with citric acid or tartaric acid. The tablet disintegrates due to generation of pressure within the tablet. This effervescent mixture is used when pharmacist needs to formulate very rapidly dissolving tablets or fast disintegrating tablet. As these disintegrants are highly sensitive to small changes in humidity level and temperature, strict control of environment is required during manufacturing of the tablets. The effervescent blend is either added immediately prior to compression or can be added in to two separate fraction of formulation.
By enzymatic reaction
Here, enzymes presents in the body act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration.
TABLE.13. DISINTEGRATING ENZYMES
ENZYMES BINDER
Amylase Starch
Protease Gelatin
Cellulase Cellulose and it’s derivatives
Invertase Sucrose
[edit]
Methods of addition of disintegrants
The method of addition of disintegrants is also a crucial part. Disintegrating agent can be added either prior to granulation (intragranular) or prior to compression (after granulation i.e. extragranular) or at the both processing steps. Extragranular fraction of disintegrant (usually, 50% of total disintegrant requires) facilitates breakup of tablets to granules and the intragranular addition of disintegrants produces further erosion of the granules to fine particles.
[edit]
Types of disintegrants
(34,40-42)
[edit]
Starch
Starch was the first disintegrating agent widely used in tablet manufacturing. Before 1906 potato starch and corn starch were used as disintegrants in tablet formulation. However, native starches have certain limitations and have been replaced by certain modified starches with specialized characteristics.
The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid and in doing so release of certain amount of stress which is responsible for disruption of hydrogen bonding formed during compression.
Lowenthal & Wood proved that the rupture of the surface of a tablet employing starch as disintegrant occurs where starch agglomerates were found. The conditions best suited for rapid tablet disintegration are sufficient number of starch agglomerates, low compressive pressure and the presence of water.
The concentration of starch used is also very crucial part. If it is below the optimum concentration then there are insufficient channels for capillary action and if it is above optimum concentration then it will be difficult to compress the tablet. [edit]
Pregelatinized starch
Pregelatinized starch is produced by the hydrolyzing and rupturing of the starch
grain. It is a directly compressible disintegrants and its optimum concentration is 5-10%. The main mechanism of action of Pregelatinized starch is through swelling. [edit]
Modified starch
To have a high swelling properties and faster disintegration, starch is modified by carboxy methylation followed by cross linking, which is available in market as cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even low
and,substituted carboxymethyl starches are also marketed as Explotab Primojel?. Mechanism of action of this modified starches are rapid and extensive swelling with minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its limit, then it produces viscous and gelatinous mass which increases the disintegration time by resisting the breakup of tablet. They are highly efficient at low concentration because of their greater swelling capacity.
TABLE.14. LIST OF DISINTEGRANTS
DISINTEGRANTS CONCENTRATION IN SPECIAL COMMENTS
GRANULES
(%W/W)
Starch USP 5-20 Higher amount is required,
poorly compressible
Starch 1500 5-15 -
?Avicel(PH 101, PH 102) 10-20 Lubricant properties and
directly compressible
?Solka floc 5-15 Purified wood cellulose
Alginic acid 1-5 Acts by swelling
Na alginate 2.5-10 Acts by swelling
?Explotab 2-8 Sodium starch glycolate,
superdisintegrant.
?Polyplasdone(XL) 0.5-5 Crosslinked PVP
?Amberlite (IPR 88) 0.5-5 Ion exchange resin
Methyl cellulose, Na CMC, 5-10 -
HPMC
?AC-Di-Sol 1-3 Direct compression
2-4 Wet granulation
Carbon dioxide _ Created insitu in
effervescent tablet
[edit]
Cellulose and its derivatives
Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water.
[edit]
Microcrystalline cellulose (MCC)
MCC exhibit very good disintegrating properties because MCC is insoluble and act by wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of MCC. It also serves as an excellent binder and has a tendency to develop static charges in the presence of excessive moisture content. Therefore, sometimes it causes separation in granulation. This can be partially overcome by drying the cellulose to remove the moisture.
[edit]
Alginates
Alginates are hydrophilic colloidal substances which has high sorption capacity. Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in water, slightly acidic in reaction. Hence, it should be used in only acidic or neutral granulation. Unlike starch and MCC, alginates do not retard flow and can be successfully used with ascorbic acid, multivitamin formulations and acid salts of organic bases.
[edit]
Ion-exchange resin
Ion exchange resin (Ambrelite?IPR-88) has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain drugs.
[edit]
Miscellaneous
This miscellaneous category includes disintegrants like surfactants, gas producing disintegrants and hydrous aluminium silicate. GAS PRODUCING DISINTEGRATING AGENTS IS used in soluble tablet, dispersible tablet and effervescent tablet. Polyplasdone?XL and Polyplasdone?XL10 act by wicking, swelling and possibly some deformation recovery. Polyplasdone?XL do not reduce tablet hardness, provide rapid disintegration and improved dissolution. Polyplasdone? as disintegrating agent has small particle size distribution that impart a smooth mouth feel to dissolve quickly. Chewable tablet does not require addition of disintegrant. [edit]
Superdisintegrants
As day’s passes, demand for faster disintegrating formulation is increased. So,
pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. But have one drawback that it is hygroscopic therefore not used with moisture sensitive drugs.
And this superdisintegrants act by swelling and due to swelling pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration.
FIGURE.19. Mechanism of superdisintegrants by swelling
TABLE.15. LIST OF SUPERDISINTEGRANTS
SUPERDISINTEGRANTS EXAMPLE MECHANISM SPECIAL
OF OF ACTION COMMENT
?Crosscarmellose Crosslinked -Swells 4-8 -Swells in two
cellulose folds in < 10 dimensions. seconds. -Direct ?Ac-Di-Sol -Swelling and compression or
wicking both. granulation
?Nymce ZSX
?Primellose
?Solutab
?Vivasol -Starch free
Crosspovidone Crosslinked -Swells very -Water insoluble
PVP little and and spongy in ?Crosspovidon M returns to nature so get ?Kollidon original size porous tablet
?after Polyplasdone
compression
but act by
capillary action
Sodium starch glycolate Crosslinked -Swells 7-12 -Swells in three
starch folds in dimensions and ?Explotab <30 seconds high level serve ?Primogel as sustain release
matrix
Alginic acid NF Crosslinked -Rapid swelling -Promote
alginic acid in aqueous disintegration in ?Satialgine medium or both dry or wet
wicking action granulation
Soy polysaccharides Natural -Does not contain
super any starch or ?Emcosoy disintegrant sugar. Used in
nutritional
products.
Calcium silicate -Wicking action -Highly porous,
-light weight
-optimum
concentration is
between 20-40% [edit]
Factors affecting disintegration
[edit]
Effect of fillers
(43,44)
The solubility and compression characteristics of fillers affect both rate and mechanism of disintegration of tablet. If soluble fillers are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants. Chebli and cartilier proved that tablets made with spray dried lactose (water soluble filler) disintegrate more slowly due to its amorphous character and has no solid planes on which the disintegrating forces can be exerted than the tablet made with crystalline lactose monohydrate. [edit]
Effect of binder
As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid disintegration. Even the concentration of the binder can also affect the disintegration time of tablet.
[edit]
Effect of lubricants
(16,34)
Mostly lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This hydrophobic coating inhibits the wetting and consequently tablet disintegration.
Lubricant has a strong negative effect on the water uptake if tablet contains no disintegrants or even high concentration of slightly swelling disintegrants. On the contrary, the disintegration time is hardly affected if there is some strongly swelling disintegrants are present in the tablet. But there is one exception like sodium starch glycolate whose effect remains unaffected in the presence of hydrophobic lubricant unlike other disintegrants.
[edit]
Effect of surfactants
TABLE.16. THE EFFECTS OF VARIOUS SURFACTANTS
SURFACTANT REMARKS
Sodium lauryl sulfate Good-various drugs
Poor - various drugs
Polysorbate 20 Good
Polysorbate 40 & 60 Poor
Polysorbate 80 Good
Tweens Poor
Poly ethylene glycol Poor
(Good – decrease in disintegration time, Poor – increase in disintegration time)
Sodium lauryl sulphate increased absorption of water by starch or had a variable effect on water penetration in tablets. Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time. Aoki and fukuda claimed that disintegration time of granules of water-soluble drugs did not seem to be greatly improved by the addition of nonionic surfactant during granulation , but the desired effect of a surfactant appeared when granule were made of slightly soluble drugs. The speed of water penetration was increased by the addition of a surfactant.
[edit]
Key Phrases
, Disintegrants are added to tablet to induce breakup when it comes in
contact with aqueous fluid.
, Disintegration by capillary action or by swelling is the major mechanism
for disintegrants.
, Disintegrant can be added intragranular or extragranular or at both
stages.
, Superdisintegrants have greater efficiency at low concentration and
hence, their demand is increasing day by day.
Tablet:Formulation of tablets/Antifrictional Agents
From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Miscellaneous Excipients
Previous Page: Disintegrants
Contents
[hide]
, 1 Lubricants
o 1.1 Classification of lubricants
, 1.1.1 Water Insoluble Lubricants
, 1.1.2 Water Soluble Lubricants
, 2 Antiadherents
, 3 Glidants
, 4 Key Phrases
[edit]
Lubricants
(4,16)
Lubricants are the agents that act by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection. Solid lubricants, act by boundary mechanism, results from the adherence of the polar portions of molecules with long carbon chains to the metal surfaces to the die wall. Magnesium stearate is an example of boundary lubricant. Other is hydrodynamic mechanism i.e. fluid lubrication where two moving surfaces are separated by a finite and continuous layer of fluid lubricant. Since adherence of solid lubricants to the die wall is more than that of fluid lubricants, solid lubricants are more effective and more frequently used.
Since primarily lubricants are required to act at the tooling or material interface, lubricants should be incorporated in the final mixing step, after granulation is complete. When hydrophobic lubricants are added to a granulation, they form a coat around the individual particles (granules), which may cause an increase in the disintegration time and a decrease in the drug dissolution rate. Presence of lubricants may results in a less cohesive and mechanically weaker tablet because it may interfere with the particle – particle bonding.
Surface area is important parameter for deciding lubricant efficiency. Lubricants
with high surface area are more sensitive to changes in mixing time than lubricant with low surface area. Therefore lubricant mixing time should be kept minimum. Tooling used to compress the tablet is important for deciding type and level of lubricant used. Additional lubricant is often added to the tablet formulations that are to be compressed with curved face punches. Further, the amount of lubricant increases as the particle size of the granulation decreases but its concentration should not exceed to 1% for producing maximum flow rate.
Lack of adequate lubrication produces binding which can results in tablet machine strain and can lead to damage of lower punch heads, lower cam track, die seats and the tooling itself. And it may also yield tablets with scratched edges and are often fractured at the top edges. With excessive binding the tablet may be cracked and fragmented by ejection.
[edit]
Classification of lubricants
Lubricant are classified according to their water solubility i.e. water insoluble and water soluble. Selection of lubricant is depends partly on mode of administration, type of tablet, desired disintegration and dissolution properties, physicochemical properties of granules or powder and cost.
[edit]
Water Insoluble Lubricants
Water insoluble lubricants are most effective and used at reduced concentration than water soluble lubricants. Since these lubricants function by coating , their effectiveness is related with their surface area, extent of particle size reduction, time, procedure of addition and length of mixing.
TABLE.17. LIST OF INSOLUBLE LUBRICANTS
INSOLUBLE CONCENTRATION COMMENTS LUBRICANTS
Stearates(Magnesium Reduce tablet
Stearate, Calcium strength; prolong 0.25 -1 Stearate, Sodium disintegration;
stearate) widely used.
Insoluble but not
hydrophobic; Talc 1 -2 moderately
effective.
Sterotex 0.25 – 1 -
Waxes 1 - 5 -
Stearowet 1 - 5 -
Glyceryl Both lubricant and 1 - 5 ?behapate(Compritol888) binder;
Dispersion
Liquid paraffin Up to 5 problem; inferior to
stearates
[edit]
Water Soluble Lubricants
Water Soluble Lubricants are used when a tablet is completely soluble or when unique disintegration and dissolution characteristics are required. Tablet containing soluble lubricant shows higher dissolution rate than tablet with insoluble lubricants. Physical mixture of this lubricant i.e. SLS or MLS with stearates can lead to the best compromise in terms of lubricity, tablet strength and disintegration.
TABLE.18. LIST OF SOLUBLE LUBRICANTS
WATER SOLUBLE CONCENTRATION RANGE
LUBRICANTS (%W/W)
Boric acid 1
Sodium benzoate 5
Sodium oleate 5
Sodium acetate 5
Sodium Lauryl sulfate 1 – 5 (SLS)
Magnesium lauryl 1 - 2 sulfate (MLS)
[edit]
Antiadherents
(4, 16)
punches and Some material have strong adhesive properties towards the metal of dies or the tablet formulation containing excessive moisture which has tendency to result in picking and sticking problem. Therefore antiadherents are added, which prevent sticking to punches and die walls.Talc, magnesium stearate and corn starch
have excellent antiadherent properties. Vegan had suggested that silicon oil can be used as antiadherent.
TABLE.19. LIST OF ANTIADHERENTS
ANTIADHERENT RANGE(%W/W) COMMENT
Lubricant with excellent antiadherents Talc 1 – 5 properties
Lubricant with excellent antiadherents Cornstarch 3 – 10 properties
Does not give satisfactory results due to Colloidal silica 0.1 – 0.5 ??small surface area. Cab-O-Sil and Syloid
Water soluble lubricant; excellent DL-Leucine 3 – 10 antiadherents properties
Sodium lauryl <1 Antiadherents with water soluble lubricant sulfate
Antiadherents with water insoluble Stearates <1 lubricant
[edit]
Glidants
(4, 16)
GLIDANTS are added to the formulation to improve the flow properties of the material which is to be fed into the die cavity and aid in particle rearrangement within the die during the early stages of compression. If the flow properties are extremely poor then glidants are ineffective and consideration of force free mechanisms may be necessary. Starch is a popular glidant because it has additional value of disintegrant. Concentration of starch is common up to 10%, but should be
limited otherwise it will worsen the flow of material. Talc is a glidant which is superior to starch; its concentration should be limited because it has retardant effect on dissolution-disintegration profile.
Silaceous material like colloidal silica i.e. syloid, pyrogenic silica (0.25%), hydrated sodium silioaluminate (0.75%) are also successfully used to induce flow. Glidants act by interposing their particles between those of material and lower the overall interparticulate friction of the system by virtue of their reduced adhesive tendencies. Similar to lubricants, they are required at the surface of feed particles and they should be in fine state of division and appropriately incorporated in the mixture.
[edit]
Key Phrases
, Lubricants are added to reduce the friction during compression.
, Antiadherents avoid sticking to die walls and picking by punches.
, Glidants improve the flow property of material/granules.
Tablet:Formulation of tablets/Miscellaneous Excipients
From Pharmpedia
< Tablet:Formulation of tablets
Next Page: Ideal properties of API for formulating tablets
Previous Page: Antifrictional Agents
Contents
[hide]
, 1 Wetting Agents
, 2 Dissolution
Retardants
, 3 Dissolution
Enhancers
, 4 Adsorbents
, 5 Buffers
, 6 Antioxidants
, 7 Chelating Agents
, 8 Preservatives
, 9 Colourants
, 10 Flavours
, 11 Sweeteners
, 12 Key Phrases
[edit]
Wetting Agents
Wetting Agents in tablet formulation aid water uptake and thereby enhancing
disintegration and assisting in drug dissolution. Incorporation of anionic surfactant
like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It has been
established that SLS improves permeation of drug through biological membrane
since it destroys the path through which drug has to pass and thus minimizing the
path length for the drug to travel. Wetting agents are mainly added when
hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl
sulfosuccinate are used as wetting agent in tablet formulation.
[edit]
Dissolution Retardants
Dissolution Retardants are incorporated into tablet formulation only when controlled
release of drug is required. Waxy materials like stearic acid and their esters can be
used as dissolution retardants.
[edit]
Dissolution Enhancers
They are the agents that alter the molecular forces between ingredients to enhance
the dissolution of solute in the solvent. Fructose, Povidone, Surfactants are used as
dissolution enhancer.
[edit]
Adsorbents
(4)
Adsorbents are the agents that can retain large quantities of liquids. Therefore
liquids like Vitamin E can be incorporated into tablets by addition of
adsorbents .Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium
silicate, magnesium oxide and silicon dioxide. Generally the liquid to be adsorbed is
first mixed with the adsorbent prior to incorporation into the formulation. Silicon dioxide when added can play as both glidant and an adsorbent role in the formula. [edit]
Buffers
Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability. Most commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate. [edit]
Antioxidants
Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated Hydroxy Anisole (BHA) , citric acid , and tartaric acid .
edit] [
Chelating Agents
Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments. Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used chelators.
[edit]
Preservatives
Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.
[edit]
Colourants
(1, 4,16)
Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. Most widely used colourants are dyes and lakes which are FD & C and D & C approved. Dyes are generally applied as solution especially in the granulating agent. Lakes are usually employed as dry powders for colouring. In general, direct compression tablets are coloured with lakes because no granulation step is used. Natural colourants can be used and generally they do not require the FDA certification before use in drug products. One of the important advantage in using lakes is reduced risk of interaction between the drug and other ingredients as well as colour development is rapid which reduces processing time .While employing wet granulation , care should be taken to prevent colour migration during drying . In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements and Microreflectance Photometer used to measure the colour uniformity and gloss on a tablet surface.
TABLE.20. SOME COMMONLY USED PHARMACEUTICAL COLOURANTS (SYNTHETIC)
FD & C COLOUR COMMON NAME
Red 3 Erythrosine
Red 40 Allura red AC
Yellow 5 Tartrazine
Yellow 6 Sunset Yellow
Blue 1 Brilliant Blue
Blue 2 Indigotine
Green 3 Fast Green
[edit]
Flavours
(1,4)
Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavors are incorporated either as solids (spray dried
flavors) or oils or aqueous (water soluble) flavors. Solids that is dry flavors are easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added during the lubrication process. The maximum amount of oil that can be added to granulation without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous flavors are less used because of its instability on aging.
edit] [
Sweeteners
(1,4,45)
Sweeteners are added primarily to chewable tablets.
TABLE.21. SOME OF THE SWEETENERS USED IN TABLET FORMULATION
NATURAL SWEETENERS ARTIFICIAL SWEETENERS
Mannitol
Saccharin
Lactose
Cyclamate
Sucrose
Aspartame
Dextrose
Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic. Even cyclamate is
carcinogenic .Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of aspartame is its lack of stability in the presence of moisture. When aspartame is used with hygroscopic components, it will be necessary to determine its stability under conditions in which the product can adsorb atmospheric moisture. Aspartame is manufactured and marketed by,available in market under the brand
Nutrasweet Nutrasweet Company.
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Key Phrases
, Only FD&C and D&C approved colourants can be incorporated into tablet
formulation.
, Flavours and Sweeteners are one of the important ingredients of
chewable and mouth dissolving tablet formulation.
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