Pharmaceutical Excipients Material

Introduction1-2

Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are include in the manufacturing process or are contained in a finished pharmaceutical product dosage form.1, 2

Excipients play a wide variety of functional roles in pharmaceutical dosage form, including:

· Modulating solubility & bioavailability of APIs,

· Increasing the stability of active ingredients in dosage forms,

· Helping active ingredients maintains preferred polymorphic forms or conformations,

· Maintaining the pH and /or osmolarity of the liquid formulations,

· Acting as antioxidants, emulsifying agents, aerosol propellants, tablet binders, and tablet disintegrants,

· Preventing aggregation or dissociation (e.g. of protein and polysaccharide actives),

· Modulating immunogenic responses of active ingredients (e.g. adjuvants), and more.2

Approval of excipients

Under U.S. law, an experiment, unlike an active drug substance, has no regulatory status and may not be sold

for use in food or approved drugs unless it can be qualified through one or more of the three U.S. Food and Drug administration (FDA) approval mechanisms that are available for components used in food and/or finished new drug dosage forms. These mechanisms are:

· Determination by FDA that the substance is “generally recognized as safe” (GRAS) pursuant to Title 21, U.S. Code of federal regulation, parts 182, 184 or 186 (21 CFR182, 184 & 186) ;

· Approval of food additive petition as set forth in 21 CFR 171: or

· The excipient is referenced in, and part of, an approved new drug application (NDA) for a particular function in that specific drug product. Excipients contained in over-the-counter (OTC) drug products subject to FDA monographs referenced in 21CFR parts 331-358 must comply with the requirements in 21CFR 330.1 (e) which reads as for

“The product contains only suitable inactive ingredients which are safe in the amounts administered & do not interfere with the effectiveness of the preparation or with suitable test or assays to determine if the product meets its professed standards of identity, strength, quality, & purity. Color additives may be used only in accordance with section 721 of the act &

subchapter A

Functionality and performance of excipients

The objective of a medicinal formulation development project is to deliver drug to the patient in the required amount, at the required rate, consistently within a batch, from batch to batch, and over the product’s shelf life.

The US Food & Drug administration’s Quality in the 21st century initiative, which includes the quality by design (QbD) & process analytical technologies (PAT) initiatives, requires that the pharmaceutical industry better understand its product formulations & manufacturing unit processes. In addition, ICH Q8- Pharmaceutical Development (also issued by FDA as Guidance for Industry), links in to the common documents (CTD) & suggest the need for greater understanding in the design & development of pharmaceutical formulation of formulation & processes. Consequently, industry is expected to demonstrate that it understands its formulations & process & can define the appropriate design space that will allow the routine manufacture of pharmaceutical products that deliver the correct amount of drug to the patient, at the required rate, consistently from dose to dose & from lot to lot, over the shelf-life of the product (i.e., “a robust formulation”). A robust formulation may be defined as: A formulation that is able to accommodate the typical variability seen in the API, excipients, & process without the manufacture, stability, or performance of the product being compromised. The larger the design space, the more likely we will produce a robust formulation. Most formulations have three components: the active pharmaceutical ingredient drug (API), the excipients(s), & the manufacturing process (es). In some instances, there is the forth component: the primary packaging. To understand product variability we must understand input variability. The variability of API, excipients & process parameters are obvious components of the overall variability. Nonetheless, other factors could affect the manufacture, stability, or performance of the product. For example, how materials are fed into the unit process, how materials interact together during processing, & how an operator carries out the operations can all affect the final product attributes.

Thus, for a given formulation & process, we must understand variability in the raw materials & their interactions to define the process & then demonstrate sufficient understanding of the process to define the design space for the product.

Two main approaches can be used to achieve consistent products. The traditional approach is to specify the input parameters more tightly, particularly the excipients & process (but also the API), & to limit the product variability by limiting the input variability. This approach does not address the variability in interactions. This interaction factor, the sum of all the interactions, also can cause problems. A second, more modern approach is to accept that there will be input variability & work to gain a sufficient understanding of the process to define an appropriate process end-point. A particular unit process is thus continued until the end-point is achieved. This second approach seems better matched to the intent of the QbD initiative, & also is likely to give a larger design space, & thus, a more flexible formulation & process.

Functionality,functionality-related characteristics,

and excipients performance

Functionality applies equally to APIs & excipients.

Functionality has been defined as:

a desirable property of a [material] that aids manufacturing & improves the manufacture, quality or performance of the drug product.In the context of the pharmaceutical formulation & products, each formulation will have its own peculiar requirements for functionality. Thus, functionality can only be properly tested by the manufacture & subsequent testing of a batch of product. This process is less than desirable. An approach currently in vogue is to identify a surrogate test, usually a physical test, that beers some relations to the required functionality. The European pharmacopoeia defines such properties as they relate to pharmacopoeia materials as follows: physical &/or physicochemical characteristics those are critical to the typical uses of an excipients. Most excipients are included in many different products & may impart several different types of functionality depending on a particular type of application. In some instances, product manufacturers have established a correlation between a product &/or manufacturing performance & some physicochemical property of a key ingredient. In such circumstances, the product manufacture may request an additional test to be included in its specification for that ingredient.

The perils of excipient lot selection

As a short-term fix for existing formulations or, in some cases, as a longer-term strategy, excipients companies are frequently approached by customers to supply material to a tighter specification than regular materiel. It is important to remember that many excipients are not produced using simple batch processing.

Drug-excipient compatibility studies

In the solid dosage form the drug is in intimate contact with one or more excipient; the latter could affect stability of drug. Knowledge of drug excipients interaction is therefore very useful to the formulator in selecting appropriate excipients. These information may already being existence for known drug. For new drug or excipients the preformulation scientist must generate needed information. A typical tablet contains binders, lubricants, disintegrate, fillers etc. compatibility screening for a new drug must consider two or more excipients for each class. The ratio of drug to excipients use in these tests is very much subject to the discretion of the preformulation scientist. It should be consistent with the ratio most likely to be encountered in the final tablet and will depend on the nature of the excipients and the size and the potency of the tablet. Often the interaction is accentuated for easier detection by compressing or granulating the drug-excipient mixture

with water or other solvents. The three techniques commonly employed in drug-excipient compatibility screening are chromatographic technique using either

HPLC or TLC, differential thermal analysis, and diffused reflectance spectroscopy.

1. Chromatography in drug-excipients compatibility study

2. Differential thermal analysis in drug-excipient compatibility study

3. Diffused reflectance spectroscopy1

An excipient is an inactive substance used as a carrier for the active ingredients of a medication. In many cases, an "active" substance (such as aspirin) may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or mixed with an excipient. Excipients are also sometimes used to bulk up formulations with very potent active ingredients, to allow for convenient and accurate dosage. In addition to their use in the single-dosage quantity, excipients can be used in the manufacturing process to aid in the handling of the active substance concerned. Depending on the route of administration, and form of medication, different excipients may be used. For oral administration tablets and capsules are used. Suppositories are used for rectal administration. Often, once an active ingredient has been purified, it cannot stay in purified form for long. In many cases it will denature, fall out of solution, or stick to the sides of the container. To stabilize the active ingredient, excipients are added, ensuring that the active ingredient stays "active", and, just as importantly, stable for a sufficiently long period of time that the shelf-life of the product makes it competitive with other products. Thus, the formulation of excipients in many cases is considered a trade secret. Pharmaceutical codes require that all ingredients in drugs, as well as their chemical decomposition products are identified and guaranteed to be safe. For this reason, excipients are only used when absolutely necessary and in the smallest amounts possible.9

Classification of excipients in solid dosage forms

Additives are usually classified according to some primary function they perform in the pharmaceutical dosage form. Many additives will also often have secondary functions, which may not be of a beneficial nature in good, solid design of beneficial, while others may impair dissolution .The most effective lubricants are water repellent by their nature, which may retard both disintegration and dissolution.1 The two major classifications of additives by function include those which affect the compressional characteristics of the pharmaceutical dosage form:

► Fillers and Diluents

► Binders and Adhesives

► Glidants

► Lubricants

► Antiadherents

And those which affect the biopharmaceutics, chemical and physical stablity, and marketing consideration of the pharmaceutical dosage form:

► Disintegrants

► Coatings

Changing the dissolution rates of active species

► Colours

► Flavours

► Sweeteners

► Preservatives

► Sorbents1

Fillers and diluents

Fillers fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. By increasing the bulk volume, the fillers make it possible for the final product to have the proper volume for patient handling.A good filler must be inert, compatible with the other components of the formulation, non-hygroscopic, soluble, relatively cheap, compactable, and preferably tasteless or pleasant tasting.Plant cellulose (pure plant filler) is a popular filler in tablets or hard gelatin capsules. Dibasic calcium phosphate is another popular tablet filler. A range of vegetable fats and oils can be used in soft gelatin capsules.Other examples of fillers include: lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.

Binders

Binders hold the ingredients in a tablet together.Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dosis tablets. Binders are usually starches, sugars, cellulose or modified cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, lactose, or sugar alcohols like xylitol, sorbitol or maltitol. Binders are classified according to their application:

· Solution binders are dissolved in a solvent (for example water or alcohol and used in wet granulation processes. Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol.

· Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples include cellulose, methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

Glidants

Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Examples include colloidal silicon dioxide, talc, and etc.

Lubricants

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules.

Antiadherents

Antiadherents are used to reduce the adhesion between the powder (granules) and the punch faces and thus prevent sticking to tablet punches.

Disintegrants

Disintegrants expand and dissolve when wet causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. Disintegrant types include:

· Water uptake facilitators

· Tablet rupture promoters

They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, thereby facilitating dissolution. Examples of disintegrants include: cross linked polyvinyl pyrrolidone, sodium starch glycolate, cross linked sodium carboxymethyl cellulose (crosscarmellose).

Coatings

Tablet coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose (plant fiber) film coating is used which is free of sugar and potential allergens. Occasionally, other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides. Capsules are coated with gelatin.

Colours

Colours are added to improve the appearance of a formulation. Colour consistency is important as it allows easy identification of a medication.

Flavours

Flavours can be used to mask unpleasant tasting active ingredients and improve the likelihood that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial. -a bitter product may use mint, cherry or anise

-a salty product may use peach, apricot or liquorice

-a sour product may use raspberry or liquorice an excessively sweet product may use vanilla

Preservatives

Some typical preservatives used in pharmaceutical formulations are

· antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium

· the amino acids cysteine and methionine

· citric acid and sodium citrate

· ynthetic preservatives like methyl paraben and propyl paraben.

Sorbents

Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by absorption in a dry state.

Sweeteners

Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such as antacid or liquids like cough syrup. Therefore, tooth decay is sometimes associated with cough syrup abuse. Sugar can be used to disguise unpleasant tastes or smells.

New pharmaceutical excipients

Direct compressible diluents

Crystalline lactose 100% monohydrate

Brand name: Tablettose® 80

It is an agglomerate crystalline lactose 100% monohydrated (USP/NF-Ph.Eur. – JP) that was designed in the Seventies for direct compression. It combines the good fluidity of heavy particle lactose and the good compressibility of a fine worn out lactose. It is white, smooth to tact, very stable and nonhygroscopic dust. Its great specific area facilitates a fast dissolution. The irregular surface of the agglomerate one is structured so that it facilitates a good adhesion of the assets providing stable uniformity of assets and mixtures.

Applications

1. Conventional Tablets

2. Effervescence Tablets

Property

Fluidity: it demonstrates very good properties of flow, even mixing it with active principles of bad fluidity.4

Crystalline lactose monohydrate & amorphous

lactose

Brand name: FlowLac® 100 Spray is a monohydrated lactose dried (USP/NF - Ph. Eur. – JP) designed for direct compression. It is compound of a 85% of crystalline lactose monohydrated and a 15% of amorphous lactose that confers very good properties to him of compressibility. Due to the process of spray dried, the grains are spherical which confers excellent properties of fluidity. They are recommended for tablets of low doses, masticables tablets, effervescence tablets and filling of capsules.

Applications

1. Formulations of with low doses of assets

2. Masticable tablets

3. Effervescences Tablets

4. Filling of capsules

Property

1) Fulidity: it demonstrates very good proiperties of flow, even mixing it with active principles of bad fluidity.

2) Compressibility: FlowLac-100 does provide equivalent or better.

Spray dried maltose powder

Brand name: Advantose™ 100

Advantose™ 100 maltose powder is a spray dried disaccharide carbohydrate. The safety and mouth feel qualities of maltose are well known. Now, by spray drying, the flow and tableting properties are greatly improved. It could be said that maltose has the flow propetis of Dicalcium phosphate, the compressibility of MCC, and a better solubility than lactose. As can be seen in the microphotographs below of Advantose™ 100 maltose powder, these spray dried particles are spherical and the combination of fine and coarse particles contribute to superior flow.

Applications

1. It can be used with low bulk density

materials.

2. It tolerates variability in lubricant levels.

3. It produces stable tablets.

4. It has low hygroscopicity.

5. It is stable at various mix times.

6. It has good dilution potential.

Silicified microcrystalline cellulose

Brand name: PROSOLV SMCC®

PROSOLV® is a high functionality ingredient that offers significant benefits in terms of tablet size, production yield and overall cost. Early use in formulation development can result in early market entry, direct compression formulas, and smaller tablets that consumers prefer.

PROSOLV® Characteristics

· High Compactibility

· High Intrinsic Flow

· Enhanced Lubrication Efficiency

· Improved Blending Properties

PROSOLV® Benefits

PROSOLV® provides tremendous benefits throughout the product lifecycle in:

· Formulation

· Manufacturing

· Marketing

Silicified Microcrystalline

Cellulose (Microcrystalline Cellulose, Ph.Eur., NF, JP & Silica, Colloidal Anhydrous, Ph.Eur. & Colloidal Silicon Dioxide NF & Light Anhydrous Silicic Acid JP) High functionality excipients are inactive ingredients that meet four criteria:

1. They are multifunctional. They contribute two or more functions to a formulation through a single ingredient.

2. They have high inherent functional performance, even at low use levels, allowing for increased batch sizes and higher drug loading.

3. They require no complex processing, making them ideal for cost effective direct compression processes.

4. They impart their high inherent functional performance to the overall formulation. This last criterion is critical since it separates high functionality excipients from other multi-functional excipients or conventional specialty grade excipients.

Binders are ingredients that can be used in a wet or dry state and help to bind all of the ingredients in a formulation together to achieve a robust dosage form. Microcrystalline cellulose is one example that enables formulators to develop effective direct compression and wet granulation processes.8

Poly Vinyl Pyrrolidone + Vinyl acetate

Brand name: PLASDONE S-630

Physical & chemical properties

Hydrophilicity/ hydrophobicity

Addition of vinyl acetate groups to the vinylpyrrolidone polymer chainreduces its hydrophilicity relative to PVP homopolymer.

Compressibility

It has higher compressibility making it an excellent choice as a tablet binder aid for direct compression and dry granulation.

Compatibility

PLASDONE S-630 polymer is compatible with a wide range of active and in active ingredients used in pharmaceutical products.

Solubility

It is soluble in water and a wide variety of pharmaceutically acceptable solvents, including alcohols, esters and ketones.

Viscosity

It is good viscous enough to be used as a wet granulating binder. In tablet coating, the low solution viscosity of PLASDONE S-630 copolymer results in higher solids coating formulations which can reduce application time and increase productivity.6

Fillers and binders property togethers

Functional Filler

ARBOCEL®

Powdered Cellulose, Ph.Eur., NF, JP

Powdered cellulose is used as an economic and inert diluent in tableting and capsule filling. Especially in wet granulation it works synergistically with other economic excipients such as starch or lactose. Combined with these, ARBOCEL® improves tablet hardness and disintegration time.

Cellulose + lactose

Brand name: CELLACTOSE 80

Cellactose 80 is spray-dried compound consisting of 75% alpha-lactose monohydrate (Ph. Eur./USP-NF/JP) and 25% cellulose powder (Ph.Eur.) dry matter. Cellactose 80 , designed especially for direct tableting, combines filling & binding properties of two excipients which have been synergistically combined to an one-body excipients providing better tableting performance at lower cost.

<32micro<=20% Angle of repose: 32-35º

<160micro 35-65% Density poured :380(g/l) <200micro>=80% Density tapped : 500(g/l)

(Air jet sieve) Hausner ratio : 1.2

Applicatons

1. Herbal extract tablets

2. Chewable tablets

3. Mineral salt tablets

4. Cores for coating

5. Oblong tablets4

Microcrystalline cellulose+lactose

Brand name: MICROCELAC 100

Particle size distributon

MICROCELAC 100 is spray dried compound

consisting of 75% alpha-lactose monohydrate & 25%

Microcrystalline cellulose DRY MATTER. Both filling

& binding propetrties of two excipients which have

been synergistically combined to an one-body

excipients providing better tableting performance at

lower cost.

<32micro<=15% Angle of repose: 34º

<160micro 70% Density poured :500(g/l)

<250micro>=90% Density tapped : 610(g/l)

(Air jet sieve) Hausner ratio : 1.16

EMDEX®

Dextrates, NF Ideal for chewable and soluble tablets, EMDEX® is the only compendial (NF) dextrate that delivers the required flow, compaction, taste masking and flavor carrying capacity. It is highly water-soluble and gives a cool smooth mouth feel. EMDEX® is also available GMO free.

Disintegrants

Starch + Lactose

Brand Name: StarLac

It is directly compressible grade material. It is made of crystalline lactose monohydrate & maize starch in a portion of 85:15 respectively. It has good fluidity & in their main application the tablet with low doses ,elobration of nuclei of coverings.4 Property

(a) DISINTEGRANTION: use as additional super disintegrant can be reduced or avoided.

(b) COMPRESSIBILITY: It is used as direct compression & offer excellent compressibility.

(c) FLUIDITY: It ensure uniformity of weight ,greater capacity of pick particle ,greater rank of speed of compression.4

Soy Polysaccharide

Brand name: emcosoy

Soy polysaccarides, is an all-natural, soft while to light-tan power, which Dose not contain starch or sugar. It is derived from dehulled and defatted soybean fiakes by a special process.

Emcosoy is a kosher product and is manufacture without the use of bleaching agents.

Emcosoy typically has 75% dietary fiber with the main components including five type of higher polysaccarides: cellulose, hemicellulose, protein, gum and mucilage. It is ideally suited for low calorie(2 kcal/g) and diabetic applications.Emcosoy sts ip excellent disintegration and improved dissolution characteristics when tablets are prepared by direct compression. Its use in soluble system has evidenced fast and efficient disintion of tablets prepared with a broad range of hardness values.

Superdisintegrants

Despite a rising interest in controlled –release drugs delivery system ,the most common tablets are those intended to be swallowed whole, disintegrating and releasing their medicaments rapidly in the gastrointestinal tract. A Disintegrant is substance in a tablet formulation that enables the tablets to break up into smaller fragments upon contact with gastrointestinal fluids .Such a rapid rupture of tablet matrix increase the surface area of the tablet particles ,there by increasing the rate of absorption of the active ingredient and producing the desired therapeutic action.The proper choice of disintegration and its consistency of performance are critical to formulation development of such tablets. In the past starch was one of the most widely used inexpensive and effective tablets disintegrants. A high concentration of starch is required to bring about effective disintegration. Examples of Superdisintegrants are crosscarmellose ,crospovidone and sodium glycolate which are cross linked cellulose crosslinked polymer and a crosslinked

starch, respectively. Viscous grades which form a gel in water and chloride reduced types (PCF) complying with Japanes food regulations are available on request

Sodium Starch Glycolate

Brand name: VIVASTAR

VIVASTAR (Sodium Starch Glycolate)-Super Disintegrant having great disintergration power and cost savings.VIVASTAR PSF (Pharmaceutical Solven Free) is innovative in that it can improve stability of certain drugs by removing residual solvents. Viscous grades which form a gel in water and chloride reduced  types (PCF) complying with Japanes food regulations are available on request.