Active Pharmaceutical Ingredients (APIs)
Two Broad Classes of APIs in Tablets:
- Insoluble drugs intended to exert a local effect in the GIT such as Antacids, Polymeric resins – Non-systemic drugs
- Soluble drugs intended to exert a systemic drug effect following their dissolution in the gut and subsequent absorption
API Characteristics That Can Affect Formulation:
Particle Size
Affects dissolution rate, flow properties, and content uniformity
Solubility
Determines dissolution characteristics and bioavailability
Crystalline Structure
Impacts stability, compressibility, and dissolution properties
Polymorphic Form
Different crystalline forms with varying properties
Bulk & Tapped Density
Affects flow properties and tablet weight uniformity
Non-active Ingredients/Excipients
Definition:
A pharmaceutical excipient is defined as an inactive ingredient or any component other than the active ingredient added intentionally to the medicinal formulation or everything in the formulation except the active drug. Pharmaceutical excipients are also called additives, pharmaceutical ingredients, or inactive pharmaceutical ingredients.
Role of Excipients:
- Ease of administration to the target patient population(s) by the intended route
- Improved dosing compliance
- Consistency and control of drug bioavailability
- To enable bioavailability
- Improved API stability including protection from degradation
- To ensure a robust and reproducible physical product
Criteria for Selection of Additives/Excipients:
| Criterion | Description |
|---|---|
| Safety | No harmful or toxicological effect and listed as GRAS (generally recognized as safe) |
| Stability | Good stability with drug – excipient incompatibility and by any impurities in the excipients |
| Analytical Compatibility | No interference in quality validation and analytical tests |
| Regulatory Compliance | Satisfaction of regulatory issues and guidelines in all countries where the product is to be marketed |
| Accessibility & Cost | Ease of accessibility, distribution, and economical cost |
| Environmental Considerations | Satisfaction for environmental issues |
| Physiological Inertness | Be physiologically inert |
| Compatibility | Be physically and chemically compatible with the active substance and the other excipients in the formulation |
| Microbiological Quality | No unacceptable microbiological burden |
Classification of Tablet Additives
Two Major Classifications of Additives:
1. Compression Characteristics Affectors
Affect the compressional characteristics of the tablet:
- Diluents - Increase bulk of tablet
- Binders and Adhesives - Provide cohesiveness
- Lubricants - Reduce friction
- Antiadherents - Prevent sticking
- Glidants - Improve flow
2. Biopharmaceutics & Stability Affectors
Affect the biopharmaceutics, chemical and physical stability & marketing considerations:
- Disintegrants - Facilitate breakup
- Colors - Aesthetic appeal
- Flavors - Taste improvement
- Sweeteners - Taste enhancement
- Buffers - pH control
Diluents/Fillers
Definition:
Diluents are the inert substance added to increase the bulk of the tablet.
Objectives of Incorporating Diluents:
- Size Adjustment: To produce tablets of reasonable size
- Bulk Increase: Diluent increases the bulk to make the tablet a practical size for compression
- Chewable Tablets: Certain diluents (mannitol, lactose, sorbitol, sucrose, inositol) when present in sufficient quantity can impart properties that help in disintegration of the tablet in the mouth by chewing
- Flow and Compression: Diluents used for direct compression formulas give the powder mixture necessary flowability and compressibility
- Release Control: To delay or control the rate of release of drug from the tablet
Characteristics of Ideal Diluents:
- Nontoxic and acceptable to drug-regulatory agencies worldwide
- Commercially available in acceptable grade in all manufacturing countries
- Cheap compared to the active ingredients
- Physiologically inert
- Chemically stable alone and/or in combination with drug(s) and other components
- Free of unacceptable microbiologic "load"
- Color-compatible
- No negative effects on bioavailability of the drug(s)
Different Types of Diluents:
| Category | Examples |
|---|---|
| Sugars | Dextrose, Lactose, Sucrose, Mannitol, Sorbitol, Inositol |
| Polysaccharides | Starches, Modified starch (e.g. Pregelatinized Starch, Starch 1500, Sta-RX 1500, Celutab etc.) |
| Cellulose | Cellulose, Cellulose derivatives, Microcrystalline cellulose (MCC) |
| Inorganic Compounds | Calcium phosphate dihydrate, Calcium sulfate dihydrate, Calcium lactate trihydrate, Calcium carbonate, Magnesium carbonate, Magnesium oxide |
Key Diluents in Detail
Lactose:
Lactose is the most widely used diluent in tablet formulation.
Different Grades of Lactose:
- Lactose Monohydrate
- Anhydrous Lactose
- Lactose (Fine) #100 mesh, #200 mesh
- Lactose Coarse (suitable for direct compression)
- Spray-dried Lactose
Important Note:
Lactose may discolor in the presence of amine drug bases or salts and alkaline lubricants. Brownley and Lachman reported that care must be taken in using spray-dried lactose since it tends to become brown due to the presence of 5-(hydroxymethyl)-2-furaldehyde, when combined with moisture, amines, phosphates, lactates, and acetates.
The employment of neutral or acid lubricants such as stearic acid appears to retard the discoloration, while alkaline lubricants (e.g., Magnesium stearate) accelerate the darkening. Bases as well as drugs which release radicals (e.g., amino salts) can bring about this browning, known as the Maillard reaction.
Microcrystalline Cellulose (MCC):
Trade Name: Avicel – is a directly compression material
Two Grades Available: PH 101 (powder) and PH 102 (granules)
Advantages: Widely used as diluent and disintegrating agents
Starch:
Starch may come from corn, wheat or potatoes and is used as a tablet diluent. It is one of the most widely used diluents in tablet formulation.
Types:
- The USP grade of starch has poor flow and compression characteristics and possesses a high typical moisture content of between 11 and 14%
- Specially dried types of starch have a standard moisture level of 2 to 4% (available at a premium price)
- Directly compressible starches are now available commercially (e.g., Sta-Rx1500, Starch 1500)
Properties:
- Free-flowing
- Directly compressible
- Used as a diluent, binder, disintegrating agent
- Also used as self-lubricating
- Contains about 10% moisture and is prone to softening when combined with excessive amount (more than 0.5%) of Magnesium Stearate
Hydrolyzed Starches:
Two hydrolyzed starches are Emdex and Celutab, which are basically 90 to 92% Dextrose and about 3 to 5% Maltose.
Properties:
- Free-flowing and directly compressible
- Used in place of Mannitol in chewable tablets because of their sweetness and smooth feeling in the mouth
- Contain about 8 to 10% moisture and may increase in hardness after compression
Binders
Definition:
Agents used to impart cohesive qualities to the powdered material are referred to as binders or granulators.
Objectives of Incorporating Binders:
- Cohesiveness: Impart cohesiveness to the tablet formulation (both direct compression and wet-granulation method) which ensures the tablet remaining intact after compression
- Flow Improvement: Improve the free-flowing qualities by the formation of granules of desired size and hardness
Selection Criteria:
The primary criterion when choosing a binder is its compatibility with the other tablet components. Secondarily, it must impart sufficient cohesion to the powders to allow for normal processing (sizing, lubrication, compression, and packaging), yet allow the tablet to disintegrate and the drug to dissolve upon ingestion, releasing the active ingredients for absorption.
Examples of Typical Granulating Systems:
| Material | System Normally Used (% of granulating) | Concentration Used (% of formula) |
|---|---|---|
| Acacia | 10-25 | 2-5 |
| Cellulose derivatives | 5-10 | 1-5 |
| Gelatin | 10-20 | 1-5 |
| Gelatin-acacia | 10-20 | 2-5 |
| Glucose | 25-50 | 2-25 |
| Polymethacrylates | 5-15 | 5-20 |
| Polyvinylpyrrolidone (PVP) | 3-15 | 2-5 |
| Starch paste | 5-10 | 1-5 |
| Sucrose | 50-75 | 2-25 |
| Sorbitol | 10-25 | 2-10 |
| Pregelatinized starch | 2-5 | 1-10 |
| Tragacanth | 3-10 | 1-4 |
| Sodium alginate | 3-5 | 2-5 |
Key Binders in Detail:
Starch Paste:
Starch as a paste forms tablets which are generally soft and brittle. It requires heat to facilitate manufacture. Depending on the amount of heat employed, starch undergoes hydrolysis to dextrin and then to glucose. Thus, care in preparation of starch paste is necessary to produce a correct and consistent ratio of starch and its hydrolysis products, as well as to prevent charring.
Polyvinylpyrrolidone (PVP):
PVP is an alcohol-soluble material which is used in concentrations between 3 and 15%. Granulations using a PVP-Alcohol system process (granulate) well, dry rapidly, and compress extremely well. PVP finds particular application in multivitamin chewable formulations where moisture sensitivity can be a problem.
Hydroxypropylmethylcellulose (HPMC) and Hydroxypropylcellulose (Klucel):
These are soluble in various organic solvents or cosolvent systems, as well as water. L-HPC is a low molecular weight, cross-linked form of Klucel. It functions not only as a tablet binder but also a tablet disintegrant. Unlike Klucel, it is not soluble in water. It has tremendous swelling capability which accounts for its disintegration property. L-HPC may be used in both direct-compression as well as wet granulation tablet formulas. Various grades of L-HPC may be used depending on whether the tablet is to be wet-granulated or directly compressed.
Pregelatinized Starch:
Pregelatinized starch (National 1551 and Starch 1500) can be blended dry with the various components of a tablet formula and activated with water at the desired time of granulation. In a direct-compression formulation, no more than 0.5% Magnesium Stearate should be used to prevent softening of the tablets.
Lubricants, Antiadherents and Glidants
Lubricants:
Objectives:
- Prevent adhesion of the tablet material to the surface of dies and punches
- Reduce inter-particular friction; improve the rate of flow of tablet granulation
- Facilitate ejection of the tablets from the die cavity
Examples: Talc, Magnesium Stearate, Calcium Stearate, Stearic Acid, Hydrogenated Vegetable Oils and Polyethylene Glycols (PEG)
Lubricants are included to reduce the friction during tablet ejection between the walls of the tablet and the wall of the die in which the tablet was formed.
Antiadherents:
Antiadherents are used for the purpose of reducing the sticking or adhesion of any of the tablet ingredients or powder to the faces of the punches or to the die wall.
Glidants:
Glidants are intended to promote flow of the tablet granulation or powder materials by reducing the friction between the particles.
Water Insoluble Lubricants:
| Lubricant | Percentage |
|---|---|
| Stearates (Mg, Ca & Na) | 0.25-2 |
| Stearic acid | 0.25-2 |
| Sterotex | 0.25-2 |
| Talc | 1-5 |
| Wax | 1-5 |
Water Soluble Lubricants:
| Lubricant | Percentage |
|---|---|
| Boric acid | 1 |
| Sodium benzoate | 5 |
| Sodium acetate | 5 |
| Sodium oleate | 5 |
| PEG 4000, 6000 | 1 – 4 |
Antiadherent Materials:
| Materials | Usual Range (%) |
|---|---|
| Talc | 1-5 |
| Corn starch | 3-10 |
| Cab-O-Sil | 0.1-0.5 |
| Syloid | 0.1-0.5 |
| DL-leucine | 3-10 |
| Sodium Lauryl sulphate | < 1 |
| Metallic Stearates | < 1 |
Glidant Materials:
| Materials | Usual Range (%) |
|---|---|
| Talc | 5 |
| Cab-O-Sil | 0.1-0.5 |
| Syloid | 0.1-0.5 |
| Aerosil 200 | 1-3 |
Disintegrants
Purpose:
The purpose of a disintegrant is to facilitate the breakup of a tablet after administration in the GIT.
Addition Methods:
Disintegrating agent may be added:
- Prior to granulation (Intra-granular)
- During the lubrication step prior to compression (Extra-granular)
- At both processing steps
Role of Disintegrants:
Disintegrating agents are substances included in tablet formulations and in some hard shell capsule formulations to promote moisture penetration and dispersion of the matrix of the dosage form in dissolution fluids. An oral solid dosage form should ideally disperse into the primary particles from which it was prepared.
Characteristics of Ideal Disintegrant:
- Poor solubility
- Poor gel formation
- Good hydration capacity
- Good compressibility and flow properties
- No tendency to form complexes with the drugs
Factors Affecting Action of Disintegrants:
Starch as Disintegrant:
Traditionally, starch has been the disintegrant of choice in tablet formulations, and it is still widely used. Starch generally has to be present at levels greater than 5% to adversely affect compactibility, especially in direct compression. Moreover, intra granular starch in wet granulations is not as effective as dry starch.
Mode of Action:
Starch has a great affinity for water and swells when moistened, thus facilitating the rupture of the tablet matrix. Others have suggested that the spherical shape of the starch grains increases the porosity of the tablet, thus promoting capillary action.
Concentration: Normally 5% w/w is suggested. For rapid disintegration 10 – 15% w/w may be taken.
Superdisintegrants:
Three Major Types:
- Crosscarmelose - cross linked cellulose
- Crospovidone - cross linked polyvinyl pyrrolidone
- Sodium starch glycolate - cross linked starch
Mode of Action:
| Superdisintegrant | Mode of Action |
|---|---|
| Croscarmelose | Swelling (4 to 8 fold in less than 10 seconds) |
| Crospovidone | Wicking or capillary action |
| Sodium starch glycolate | Swelling (7 to 12 folds in less than 30 seconds) |
Classification of Superdisintegrants:
| Type | Description | Trade Names |
|---|---|---|
| Modified Starches (Sodium starch glycolate, NF) |
Sodium carboxy methyl starch; the carboxy methyl groups induces hydrophilicity and cross-linking reduces solubility | Explotab®, Primojel®, Tablo® |
| Modified Cellulose (Croscarmellose, NF) |
Sodium carboxymethyl cellulose which has been cross-linked to render the material insoluble | AcDiSol®, Nymcel ZSX®, Primellose® |
| Cross-linked PVP (Crospovidone, NF) |
Cross-linked poly vinyl pyrrolidone; cross-linking render the material insoluble in water | Crospovidone M®, Kollidon CL® |
Colouring Agents
Objectives of Using Colors:
- Impart color to the tablets
- Make the tablet more aesthetic in appearance
- Help the manufacturer to identify the product during its preparation
Regulatory Note:
All colorants used in pharmaceuticals must be approved and certified by the FDA (Food & Drug Administration). Dyes are generally listed as FD&C (Food, Drug & Cosmetic Dyes) and D&C (Drug & Cosmetic Dyes).
Common Colorants:
| Colour | Other Names | Color Index (CI, 1971) |
|---|---|---|
| D&C Red 22 | Eosin Y | 45380 |
| FD&C Yellow 5 | Tartrazine | 15985 |
| FD&C Yellow 6 | Sunset Yellow FCF | 19140 |
| FD&C Blue 1 | Brilliant Blue FCF | 42090 |
| FD&C Blue 2 | Indigocarmine | 73015 |
| FD&C Green 3 | Fast Green FCF | 42035 |
| Caramel | Burnt sugar | - |
| Titanium dioxide | - | 77891 |
Forms of Colorants:
Dyes
Dyes are dissolved in the binding solution prior to the granulating process. However, during drying their color may migrate to the surface and may produce mottling of the tablet. Another approach is to adsorb the dye on starch or calcium sulfate from its aqueous solution; the resultant powder is dried and blended with other ingredients.
Color Lakes
Color lakes are dyes which are adsorbed onto a hydrous oxide of a heavy metal (like aluminium) resulting in an insoluble form of the dye.
Flavours and Sweeteners
Flavours:
Flavours are usually limited to chewable & effervescent tablets or other tablets intended to dissolve in the mouth.
Purposes:
- Improve acceptability among pediatric and geriatrics patients
- Enhance patient compliance
Application Methods:
- Added to tablet granulations in solvents
- Dispersed on clays and other adsorbents
- Emulsified in aqueous granulating agents (i.e., binder)
Concentration: Should be used only in the concentration range of 0.5 to 0.75% w/v.
Examples: Citrus oil, Cardamom tincture, etc.
Sweeteners:
Mainly used in chewable, effervescent & mouth dissolving tablets for improvement of taste.
Common Sweeteners:
| Sweetener | Properties |
|---|---|
| Sugar | Natural sweetener |
| Mannitol | 72% as sweet as sugar, cooling & mouth filling effect |
| Saccharin | Artificial sweetener (500 times sweeter than sucrose). Disadvantages: bitter after taste, potential carcinogenic concerns |
| Cyclamate | Either alone or with saccharin – it is banned |
| Aspartame (Searle) | Widely replacing saccharin & approved by FDA. Disadvantage: lack of stability in presence of moisture & discoloration in presence of ascorbic acid & tartaric acid |
Co-processed Excipients
Definition:
Co-processed excipients are mixtures of one or more excipients used in combination to improve their characteristics.
Advantages:
- Reduces the number of excipients in a formulation
- Reduces the overall cost and time for processing
- Improves functionality and performance
Examples of Co-processed Excipients:
| Co-processed Excipients | Brand Name |
|---|---|
| Cellulose and Lactose | Cellactose |
| Lactose and MCC | Microcelac 100 |
| Lactose and Maize starch | Starlac |
| Lactose and PVP | Ludipress |
| MCC and Sodium CMC | Avicel CL-611 |
Formulation Strategy:
The selection and combination of appropriate excipients is critical to developing a successful tablet formulation. Understanding the properties, functions, and interactions of each excipient type allows formulators to create robust, effective, and patient-friendly tablet products.
