Tablet:Formulation of tablets/Diluents
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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.
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 DILUENTS |
SOLUBLE TABLET FILLERS OR DILUENTS |
|
Starch Powdered cellulose Microcrystalline cellulose Calcium phosphates, etc. |
Lactose Sucrose Mannitol Sorbitol, etc. |
Selection of diluent should be done after considering properties of diluent such as: Compactibility, flowability, solubility, disintegration qualities, hygroscopicity, lubricity and stability.
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.
Silicified MCC (SMCC- Prosolv) provides increased compactibility, enhanced 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.
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 Di-Tab® (manufactured by Rhone-Poulenc) and Emcompress (Manufactured by 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.
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 Products |
It is spray processed lactose 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% |
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
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