Pharmaceutical Excipients Notes

Pharmaceutical Excipients

Definition

  • Excipients are substances other than the active medicament(s) included in the manufacturing process or contained in the finished pharmaceutical product dosage form.
  • The word "excipient" is derived from the Latin "excipere," meaning 'to except, which is simply explained as 'other than'.

Purpose of Excipients

  • Modulating the solubility and bioavailability of the active pharmaceutical ingredients.
  • Modulating the immunogenic response of active ingredients.
  • Maintaining the pH and/or osmolality of the liquid dosage form.
  • Improving dosing compliance (to give shape and improve palatability, elegance of the formulation).
  • Increasing the stability of the active ingredient, including protection from degradation/denaturation.
  • Preventing aggregation and dissociation of different molecules (e.g., proteins and polysaccharides).
  • Providing bulk to the formulation.
  • Helping active ingredients to maintain preferable polymorphic form or conformation.
  • Conferring a therapeutic enhancement, such as facilitating drug absorption, reducing viscosity, or enhancing solubility.
  • Aiding in the handling of "API" during manufacturing.
  • Facilitating administration of the drug by the intended route.
  • Facilitating drug absorption or solubility and other pharmacokinetic considerations.
  • Ensuring a robust and reproducible physical product.

Properties of an Ideal Excipient

  • Increase the stability of the product.
  • Must not have any interaction with the active ingredient.
  • Must not adversely affect the product.
  • Should be pharmacologically inert.
  • Should be nontoxic and nonirritant in the concentration administered (FDA approved).
  • Should be nonvolatile.
  • Should be physically and chemically stable throughout the shelf life.
  • Should be effective in low concentration over a wide range of pH.
  • Should be soluble in water as well as oil & fat.
  • Should be colorless, odorless, and tasteless.
  • Should be cheap and readily available.
  • Impurity free
  • Useful in the manufacturing process, to aid in the handling of the active substance.

Importance of Excipients in Drug Products

  • Comprises the product delivery system i.e. transport the active drug at the site in the body where the drug is intended to exert its action.
  • Excipients prevent premature drug release to avoid tissue damage or gastric irritation (e.g., Diclophenac-Na with a coating).
  • Helps the drug to disintegrate into particles small enough to reach the bloodstream more quickly (e.g., Disintegrating agents like Povidone).
  • Protect the stability of the product for maximum effectiveness (e.g., Stabilizers, Antioxidants, Preservatives).
  • Aid in the identification of the product (e.g., Coloring & Flavoring agents).
  • Improve taste and appearance, enhancing patient compliance, especially in children.
  • In many products, excipients make up the total dosage form (e.g., Diluent).

Advantages and Uses of Excipients

  • Used to give a particular size and shape to the medicaments (e.g., Suppositories - Base).
  • To make the medication suitable for administration (e.g., Syrup, Suspension).
  • To protect the medication from the gastric environment (e.g., Coating of a tablet).
  • To mask unpleasant taste and odor (e.g., Sweetening agents & Flavoring agents).
  • To reduce adhesion between powdered granules and punch face (e.g., Glidants).
  • To increase the stability of the product (e.g., Stabilizers).
  • To improve the appearance of the product (e.g., Coloring agents).

Classification of Excipients

  • The most widely used classification is based on their use and objective of their addition in various dosage form.
  • Various types of excipients:
    1. Diluents (Bulking agents, Fillers)
    2. Anti-oxidants
    3. Buffering agents,
    4. Binder
    5. Disintegrant
    6. Chelating agent
    7. Colors, complexing agents
    8. Emulsifying agents.
    9. Flavoring agents and perfumes
    10. Humectants
    11. Ointment base
    12. Lubricants
    13. Glidant
    14. Sweetening agents
    15. Acidifying agents
    16. Air displacement agents
    17. Alkalizing agents
    18. Antifoaming agents
    19. Anti-microbial agents
    20. Preservatives
    21. Solvents & Co-Solvents
    22. Stiffening agents
    23. Wetting and solubilizing agent
    24. Viscosity imparting agent

Diluents (or Fillers)

  • Diluents, also known as fillers or bulking agents, are used to increase the volume or weight of the drug.
  • These are inert substances that can be useful in achieving the desired volume, flow properties, and compressibility for the drug.
  • Tablets normally weigh at least 50 mg.
  • Typically, a diluent such as lactose is needed to bulk up the tablet to a reasonable weight (e.g., 100 – 300 mg).
  • Example: Digoxin tablets contain 0.25 mg of digoxin in a 120 mg tablet
  • Some commonly used diluents are:
    • dibasic calcium phosphate,
    • kaolin,
    • lactose,
    • mannitol,
    • microcrystalline cellulose,
    • powdered cellulose,
    • precipitated calcium carbonate,
    • sorbitol, and starch.
  • For example, a calcium-based salt cannot be used in the manufacturing of tetracycline antibiotics as calcium affects the absorption of the antibiotics from the gastrointestinal tract.

Different types of Diluents

  • Water-soluble – sugars (glucose, sucrose) and sugar alcohols (sorbitol, mannitol) can contribute to tablet solubility and also assist when dissolving a tablet in the mouth
  • Water-insoluble - Those typically used are lactose, microcrystalline cellulose, calcium hydrogen phosphate (CaHPO<em>4.2H</em>2O)(CaHPO<em>4 .2H</em>2O). Some others used are CaCO<em>3CaCO<em>3, CaSO</em>4CaSO</em>4, and kaolin.
  • Microcrystalline cellulose (e.g., Avicel PH) is a partially depolymerized form of cellulose consisting of porous particles.
  • Comes in a number of grades.
  • Also has some lubricant and disintegrant properties
  • Diluent/drug incompatibilities - may be a problem.
  • Example: Do not use calcium sulfate with tetracyclines

Chemical Nature of Diluents

  • Diluents are further divided into three subtypes on the basis of their chemical structure: as organic, inorganic and co-processed.
    • Organic materials: Carbohydrates and modified carbohydrates are the major examples of this category i.e.lactose, starch and pre-gelatinized starch, sucrose, mannitol, sorbitol, powdered and microcrystalline cellulose(MCC).
    • Inorganic materials: These materials are also used commonly in pharmaceutical industries nowadays. Calcium phosphates i.e. anhydrous Dibasic Calcium pho-sphate, dibasic calcium phosphate and tribasic calcium phosphate are main examples of this category.
    • Co-processed diluents: Co-processed diluents are prepared from the combination of two or more diluents by an appropriate process. The product thus formed are physically modified in such a way that product do not lose their stability and chemical nature. e.g. SugartabR,

Water soluble and insoluble diluents

  • Diluents are also divided into water insoluble and water soluble:

    • Water-insoluble diluents: Examples of water-insoluble diluents are starch, powdered cellulose, microcrystalline cellulose, and calcium phosphate, etc.
    • Water-soluble diluents: Lactose, sucrose, mannitol, sorbitol, etc.

  • Sucrose is a disaccharide in nature and used as a sweetening agent. It is used even in larger amounts as a diluent/sweetener in tablets and liquids. Sucrose is absorbed when it gets hydrolyzed into glucose and fructose in the small intestine. Sucrose is excreted unchanged in urine when given by IV route.

  • Lactose is widely used as an excipient in pharmaceutical manufacturing as a filler or diluent in tablets, capsules, and to give bulk to powders. Lactose has no reaction with most drugs, whether it is used in hydrous or anhydrous form.

  • Methylcellulose is the organic material used as a diluent in the pharmaceutical formulation. It is the cellulose derivative.

  • Dicalcium phosphate (DCP) is a combination of positively charged particles of calcium and negatively charged particles of hydrogen phosphate which is interchangeable with the phosphate in the body. Long-term use of DCP results in upset in the balance of phosphates and other chemicals in the body.

  • Calcium carbonate: It is the principal form of calcium found in bovine milk and blood. It is used in a variety of dental products for remineralization and as a diluent in some medications where it gives the tablet a grey color in the absence of coloring agents.

  • Polyethylene glycol used as an inactive ingredient in the pharmaceutical industry. At high doses, it causes teratogenic activity, which increases fetal loss, decreases body weight, and malformation.

Issues with Diluents

  • Absorption of drugs onto diluent.
  • Do not use lactose with amine drugs, as this can lead to discoloration (Maillard reaction).
  • Can have combined diluent and binder properties
    • starch, hydroxypropyl methylcellulose (HPMC) - hypromellose
    • Celluloses are used as “dry binders”
    • most commonly used is microcrystalline cellulose.

Buffering Agents (pH adjusting agents)

  • Buffers are aqueous solutions containing partly neutralized weak acids or bases that show little change in pH [H+ concentration] whatever ions are added.

  • To resist the change in pH upon dilution or on the addition of an acid or alkali.

  • Requirements:

    • the pH should be determined at the final temperature, in presence of salts.
    • The buffering compound should not absorb at wavelengths
    • Optimum buffering range,
    • solubility,
    • compatibility with spectrometric or immunometric or cell assays

  • Examples of Buffering Agents:

    • mineral buffers
      • Phosphate, Borate, Citrate
    • organic buffers
      • Glycine

  • Application

    • For solubilizing, many reagents require a more polar [i.e. Ethanol] or a polar solvent [DMSO- Dimethyl sulfoxide, DMF- Dimethylformamide]
    • preservatives, e.g. Bacteriostatics , Protease or phosphatase inhibitors,
    • compounds to block undesired reactions, i.e. detergents, saturating agents, chelatant

Binders

  • Binders are added to tablet formulations to ensure the tablet remains intact after compaction has taken place (adhesive nature).

  • They are also important in ensuring granules have the appropriate cohesive properties prior to compaction

  • Binders may be added to a dry powder mix that is then compacted into tablets or into a mix that is then granulated before compaction (mechanical strength).

  • The type of solvent required for use in the granulation process is important in determining whether a particular binder is suitable or not.

  • The amount of binder used is important:

    • if too much binder is used the tablet formed will be too hard resulting in excessive wear on punches and dies
    • if too little binder is used the tablet formed will be too soft

  • The amount of binder generally used in a tablet formulation is about 2% - 10% by weight

  • Commonly used binders include:

    • Pregelatinized starch (direct compression 5-20%; wet granulation 5-10%)
    • Cellulose binders (water soluble) - methylcellulose (MC) (1-5%), carboxymethylcellulose(CMC) (1-6%), hypromellose (hydroxypropylmethylcellulose) (2-5%)
    • Povidone (polyvinyl pyrrolidone - PVP) (0.5-5%) - soluble in both water and aqueous ethanol. It is available in a range of different molar mass grades each of which have varying properties.

Solution & Dry Binders

  • Solution binders (to bind powder particles together during wet granulation, improving tablet cohesion, flowability, and compactibility, while also potentially influencing drug release.)
    • Gelatin
    • Polyvinyl pyrrolidone (PVP) - povidone
    • Cellulose derivatives
    • Polyethylene glycol (PEG) – macrogol, carbowax.
    • Sucrose
    • Starch
  • Dry binders (direct compression and dry granulation, enhancing tablet strength, reducing fines, and improving granule properties)
    • Cellulose
    • Methyl cellulose
    • PVP
    • PEG

Lubricant

  • Tablet formulations need lubricants in order for high-speed tablet machines to function effectively

  • Compression of granules produces heat as particles slide over each other during the compaction process

  • The tablets produced need to be easily ejected so they don’t chip/fragment

  • It is therefore important to reduce friction between

    • the particles during as they flow into die and during compression
    • the tablet and punches during compression
    • the tablet and die during and after compression for ease of ejection

  • Lubricants are used in solid dosage forms (tablets and capsules) to prevent the adhesion of granules to dies and punches during their compression in the granulation process, which promotes the smooth ejection of powder granules.

  • Lubricants may also have a role in improving the rate of flow (glidant function) of granules entering the tableting machine.

  • Lubricants are generally mixed with the granules just before compression.

  • The concentration for lubricants used in tablet formulations generally range from around 0.1% to 5%.

  • Magnesium stearate, stearic acid, and talc are typically used.

  • Note that:

    • the rate of tablet disintegration may be affected by the presence of these substances as they are hydrophobic in nature
    • too much lubricant may lead to the “water-proofing” of tablets
    • lubricants may also reduce the bonding strength between particles in tablets

Flow Modifier Agents

  • Some Commonly Used Antifrictional Agents
    • Soluble lubricants
      • Adipic acid
      • d,l-Leucine
      • Glyceryl triacetate
      • Magnesium lauryl sulfate
      • PEG 4000, 6000, and 8000
      • Polyoxyethylene monostearates
      • Sodium benzoate
      • Sodium lauryl sulfate
    • Insoluble lubricants
      • Calcium, magnesium, and zinc salts of stearic acid
      • Glyceryl behenate
      • Glyceryl palmitostearate
      • Hydrogenated vegetable oils
      • Light mineral oil
      • Paraffins
      • Polytetrafluoroethylene
      • Stearic acid
      • Sucrose monolaurate
    • Glidants
      • Calcium silicate
      • Fumed silicon dioxide
      • Magnesium carbonate
      • Magnesium oxide
      • Starch
      • Talc
      • Polyethylene glycol.
      • Talc
      • Waxes
    • Antiadherants
      • Most lubricants
      • Starch
      • Talc

Glidants and Antiadherents

  • Glidants are the excipients used in solid dosage forms to reduce the friction between the particles/granules, promoting the smooth flow of powder particles.
    • This is especially important during high-speed tablet manufacture.
  • They are also known as anti-caking agents, according to USP (United States Pharmacopoeia), which prevent caking or clumping of granules when stored in bulk.
    • Examples – Talc, corn starch, aerosil, and syloid.
  • Talcum powder (talc) traditionally used (1-2% w/w), also colloidal silica, magnesium stearate (only at concentrations <1% w/w), and starch are used as glidants.
  • Talcum powder (talc), magnesium stearate, starch, and cellulose are used as anti-adherents.
  • Most common in use is colloidal silica (0.2% w/w). This can also absorb problem oily ingredients.
  • Glidants and antiadherents - reduce “sticking and picking” problems.

Disintegrants

  • Disintegrants are added to a tablet formulation to facilitate its break-up or disintegration in the gut

  • Disintegrants work via a variety of different mechanisms.

    • increase water uptake into the tablet by enhanced capillary action.
    • have great affinity for water and swell when moistened.
    • release gases that break down tablet structure

  • Disintegrant use includes starches (∼10% added), cellulose, cross-linked PVP, sodium starch glycolate, sodium carboxymethyl cellulose (Note: sodium starch glycolate can swell very quickly; around 4-8x in around 10 s.)

  • Occurs in two steps

    1. GI fluids wet solids and penetrate pores of tablet – so need agents that facilitate water uptake – soluble e.g. surface active agents.
    2. The swelling up of disintegrant produces aggregates of primary particles. Subsequent deaggregation into primary drug particles may be due ALSO to “repulsion of particles” in contact with water.

  • Disintegration is affected by:

    • The amount of binder used. If too much binder, then the tablet will not disintegrate
    • Hardness of the tablet.
      • Too hard and it fails the Disintegration Time test.
      • Too soft and the tablet fails the friability test.
    • Less “wicking” and capillary wetting.
    • Can also make “effervescent tablets” (rapidly disintegrating tablets).
      • Mix sodium bicarbonate with tartaric/citric acid.
      • The tablets must be stored dry though and not be exposed to moisture during production (unless a small amount of silicones are added to one ingredient).
    • Ideally, the tablet should break up into individual drug particles.

Acidifying Agents

  • Acidifying agents are the substances that are used in liquid preparation to provide acidic media for product stability.
    • E.g… Citric acid, Acetic acid, Fumaric acid, Hydrochloric acid, Nitric acid.
  • The pH of the stomach is 1.5 -2 when empty and rises to pH 5-6 when food is ingested.
  • The pH of the stomach is so low because of the secretion of HCl.
  • Gastric HCl acts by destroying the bacteria in the ingested food and drinks. It softens the fibrous food and promotes the formation of the proteolytic enzyme pepsin.
  • This enzyme is formed from pepsinogen at acidic pH (<6).
  • Pepsin helps in the metabolism of proteins in the ingested food.
  • Therefore, lack of HCl in the stomach can cause Achlorhydria.

Air Displacement Agents

  • Air displacement agents are the substances employed to displace air in a hermetically sealed container to enhance product stability.
    • e.g..
      1. Nitrogen and
      2. Carbon dioxide

Alkalizing Agents

  • Alkalinizing agents are the substances which provide an alkaline medium for product stability in liquid preparations.
  • Alkalinizing agent excipients are important in pharmaceutical formulations where the active pharmaceutical ingredient requires an alkaline environment for stability or therapeutic effectiveness.
  • E.g…
    • Ammonia solution, Ammonium carbonate, Diethanolamine, Monoethanolamine,
    • Potassium hydroxide, Sodium bicarbonate, Sodium borate, Sodium carbonate,
    • Sodium hydroxide
    • Sodium citrate/citric acid, Sodium lactate

Anti-Foaming Agent

  • A defoamer or an anti-foaming agent is a chemical additive that breaks up and inhibits the formation of foams in liquids by reducing interfacial tension between two phases.
  • A familiar example is the drug is Simethicone which is the active ingredient in drugs such as Entacyd plus.
  • Others include:
    • Lauric acid NF32
    • Myristic acid
    • Palmitic acid.

Adsorbents

  • It is an ability of an agent to adhere other molecules onto its surface by physical or chemical means.
  • Powdered cellulose and activated charcoal are examples of such agents.