Lecture 23 - Principles of Drug Development: Excipients and Additives

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What do Drug Products contain?

Both drug substances / active products and Excipients

Why do we formulate APIs with Excipients?

1. accurate dosage form

2. support organoleptic profile

3. selected based on API physicochemical properties

4. consistency of drug release and bioavailability

5. stability, including protection from degradation

6. ease of administration to the target patient population(s)

7. ensure an efficacious drug product with desired drug properties and a robust manufacturing process

What are ideal characteristics for excipients?

1. Non-toxic

2. Pharmacologically inert

3. Non-reactive

4. Do not interfere with the stability of the API / drug substance

What does GRAS mean?

What is a food additive?

Give some examples of food additives.

GRAS = “Generally Recognized as Safe” according to sections 201(s) and 409 of Federal Food, Drug, and Cosmetic Act

Food additive are any substance intentionally added to food and subject to premarket review and approval by the FDA

• Examples: preservatives, colors, and flavoring agents

What are examples of Organoleptic Properties?

Why are they important in drug production / formulation?

Organoleptic Properties:

• Odor, color, taste, and flavor

• Appearance and palatability

• Important for all age groups, especially pediatrics and geriatrics

Use of pharmaceutical coloring agents to match flavor expectations helps increase patients acceptability

How is flavor selection made when flavoring pharmaceuticals?

Selections made to mask drug bitterness and to make the formulation palatable

Specific selections include:

• Immediate flavor identity

• Acceptable mouthfeel

• Short aftertaste

What does an increase in the number of Hydroxyl Groups result in?

How do Esters, Alcohols, and Aldehydes contribute as flavoring agents?

Increase in Hydroxyl Groups results in an increase in sweetness of the compound (Sucrose = 8 groups, Glycerin = 3 groups, Sucrose is sweeter)

Esters, Alcohols, and Aldehydes are pleasant to the taste due to their volatility; contribute to odor AND flavor

What can flavoring agents consist of?

Give examples of these components.

Oil-Soluble Carriers (Liquids)

• Soybean and other edible oils

Water-Soluble Carriers (Liquids)

• Water

• Ethanol

• Propylene Glycol

• Glycerin

Dry Carriers (Powders)

• Corn Syrup Solids

• Sugars

• Whey Proteins

What needs to be considered when regarding flavoring agents in Capsules or Coated Tablets?

Chewable Tablets?

Drugs in Capsules or prepared as Coated Tablets may be easily swallowed with little to no contact between the drug and taste buds—therefore, no flavoring agents are required

Chewable tablets are usually sweetened and flavored to improve acceptance

What are the five primary tastes?

What chemical property contributes to each one?

1. Sweet — polyhydroxyl compounds, ex. Sucrose

2. Sour — H+, ex. Citric Acid

3. Salty — presence of anions and cations together, ex. NaCl

4. Bitter — high molecular weight salts, ex. Caffeine

5. Umami — category of taste in food, corresponds to flavor of Glutamates

What are the two natural sweeteners most commonly used in drug preparation?

Are they appropriate for use in pediatrics?

1. Sucrose — but cariogenic and calorific (avoid use in pediatrics)

2. Sorbitol — non-cariogenic, non-calorific (appropriate for pediatrics, but can cause diarrhea)

What is the main artificial sweetener we focus on in pharmaceutical preparations?

What does it metabolize into?

What specific population is discouraged from use of this sweetener?

Aspartame

Metabolizes into three components:

• Phenylalanine (AA)

• Aspartic Acid

• Methanol

Use is discouraged in people with phenylketonuria (PKU) due to inability to breakdown the Phenylalanine

What is Phenylketonuria (PKU)?

What does it cause?

How is it treated?

Rare, inherited metabolic disorder in which the body cannot break down the AA Phenylalanine, thereby increasing its levels in the body

Causes a birth defect

Treatment includes a strict diet with limited protein

For Saccharin, what is the:

• Relative Sweetness?

• Bitterness Level?

• Aftertaste Level?

• Calories?

• Acid Stability?

• Heat Stability?

Relative Sweetness — 300

Bitterness Level — moderate to strong

Aftertaste Level — moderate to strong; sometimes metallic or bitter

Calories — 0 calories (awesome)

Acid Stability — excellent

Heat Stability — excellent

What is the Bitterness Level of Sucrose and Aspartame?

Aftertaste Level?

Sucrose:

• Bitterness Level — None

• Aftertaste Level — None

Aspartame:

• Bitterness Level — None

• Aftertaste Level — None

Where are most pharmaceutical colorants obtained from?

Give an example of a common product that is colored.

Most colorants are synthetic, but some are obtained from Natural Mineral and Plant sources

Example:

• Red Ferric Oxide is mixed with some Zinc Oxide powder to give Calamine its pink color

What dosage forms do NOT contain color additive?

Ointments, Ophthalmics, and Parenteral products

What are the three classifications of color additives?

What are they classified according to?

Classified according to their approved uses

1. FD&C — used in foods, drugs, and cosmetics

2. D&C — used in drugs, some in cosmetics, and some in medical devices

3. External D&C — restricted to external parts of the body and not including the body surface covered by mucous membrane

What must be considered when looking at sterilization preparation of Ophthalmic and Injectable Preparations?

They are sterilized during manufacture; many require an antimicrobial preservative to maintain their aseptic condition throughout storage and use

Certain IV Preparations give in large volumes as blood replenisher or as nutrients must NOT contain bacteriostatic additives

What must be considered when looking at sterilization preparation of Aqueous Preparations?

Aqueous Preparations do not need to be sterilized when prepared (despite susceptibility to microbial growth)

What specific hydroalcoholic and alcoholic preparations do NOT required the addition of a chemical preservative?

Elixirs, Spirits, and Tinctures

What is the mode of action of preservatives?

Interfere with microbial growth, multiplication, and metabolism

What is the function of Diluents in Formulation?

What is its working principle?

Function:

• fillers

Working Principle:

• Make up the bulk of the solid unit dosage forms when the drug itself is inadequate to produce the bulk

What is the function of Binders and Adhesives in Formulation?

What is its working principle?

Function:

• Impart cohesive qualities to powdered material

Working Principle:

• improves free flow qualities by formulation of granules to desired hardness and size

What is the function of Lubricants in Formulation?

What is its working principle?

Function:

• reduce interparticular friction, prevent adhesion of tablet material to surfaces of dies, punches facilitate easy ejection of table from die cavity, and improve rate of flow tablet granulation

Working Principle:

• interpose a film of low shear strength, which interfaces between the tabletting mass and die wall

What is the function of Glidants in Formulation?

What is its working principle?

Function:

• improve flow characteristics of powder mixture

Working Principle:

• added in dry state prior to compression to reduce friction between particles

What is the function of Disintegrants in Formulation?

What is its working principle?

Function:

• facilitate breakup or disintegration after administration

Working Principle:

• function by drawing water into the tablet, swelling it and causing the tablet to burst apart

What is the function of Superdisintegrants in Formulation?

What is its working principle?

Function:

• improved disintegrant efficacy, resulting in decreased use levels when compared to traditional disintegrants

Working Principle:

• function by drawing water into the tablet, swelling it and causing the tablet to burst apart

What is the function of Coloring Agents in Formulation?

What is its working principle?

Function:

• impart aesthetic appearance to dosage form, disguising off color drugs, and allowing for product identification

Working Principle:

• N/A

What is the function of Flavors in Formulation?

What is its working principle?

Function:

• Limited to chewable tablets / tablets intended to dissolve in mouth

Working Principle:

• mask unpleasant taste

What is the function of Sweeteners in Formulation?

What is its working principle?

Function:

• impart sweet taste to the formulation; use is limited to chewable tablets

Working Principle:

• N/A

What is the function of Sorbents in Formulation?

What is its working principle?

Function:

• moisture proofing

Working Principle:

• limits the fluid sorbing, taking up liquid or gas by adsorption or absorption in dry state

What is the function of Coating Materials in Formulation?

What is its working principle?

Function:

• protect tablet ingredients from deterioration by moisture, help swallowing unpleasant tasting tablets

Working Principle:

• N/A

What is the function of Plasticizers in Formulation?

What is its working principle?

Function:

• for soft gelatin capsule preparation, gelatin based suppositories, film coated tablets, etc.

Working Principle:

• product elasticity and flexibility to the coating materials in case of tablets, determine hardness of capsule shell in case of soft gelatin capsule, and impart softness and resilience to suppositories

What ingredients are used to compound Calamine (Dusting Powder)?

Include Therapeutic Activity.

Calamine:

• protectant, astringent

Magnesium Stearate:

• lubricating agent

Talc:

• vehicle

What ingredients are used to compound Tri-Estrogen Capsules?

Include Therapeutic Activity.

Estriol:

• endogenous estrogen

Estrone:

• endogenous estrogen

Estradiol:

• endogenous estrogen

Lactose, hydrous:

• bulk diluent

What are ODT?

Orodispersible Tablets (or Orally Disintegrating Tablets)

Dispersible tablets that rapidly disintegrate without chewing when placed on top of the tongue; do NOT require water for administration

What are the two main types of ODT?

Describe them.

Lyophilised Units:

• carrier excipient is predominantly Sucrose

• disintegrate in <5 seconds

• only low drug loading possible (~5-10mg)

• prone to friability (packed into blisters)

Conventional Tablets:

• can involve novel/conventional and or combination excipients

• disintegration time varies

• larger drug loading is possible (up to ~500mg)

• more robust; can be packed into bottles and blisters

What is the function of Solvents in Formulation?

What is its working principle?

Function:

• dissolve solute / API

Working Principle:

• break bonds and reduce effective charge on ions, thus increasing solute-solvent forces of attraction

What is the function of Co-Solvents in Formulation?

What is its working principle?

Function:

• increase solubility of solute in solvents

Working Principle:

• co-solvent system works by reducing interfacial tension between predominantly aqueous solutions and hydrophobic solutes

What is the function of Buffers in Formulation?

What is its working principle?

Function:

• maintain pH of the formulation

Working Principle:

• binding hydrogen ions in acids and donating hydrogen ions in bases

What is the function of Antimicrobial Preservatives in Formulation?

What is its working principle?

Function:

• prevent microbial growth in formulations

Working Principle:

• bacteriostatic action

What is the function of Antioxidants in Formulation?

What is its working principle?

Function:

• control oxidation

Working Principle:

• get preferentially oxidized or block an oxidative chain reaction

What is the function of Wetting Agents in Formulation?

What is its working principle?

Function:

• aid wetting and dispersion of hydrophobic APIs

Working Principle:

• reduce interfacial tension between solids and liquids in suspensions

What is the function of Antifoaming Agents in Formulation?

What is its working principle?

Function:

• discourage formation of stable foam

Working Principle:

• lower surface tension and cohesive binding of liquid phase

What is the function of Thickening Agents in Formulation?

What is its working principle?

Function:

• prevent settling / sedimentation, modify viscosity

Working Principle:

• work by entrapment of solid particles

What is the function of Humectants in Formulation?

What is its working principle?

Function:

• slows evaporation of aqueous vehicles from dosage forms

Working Principle:

• hygroscopic in nature, which helps in preventing evaporation of solvent

What is the function of Chelating Agents in Formulation?

What is its working principle?

Function:

• protect drug from catalysts that accelerate the oxidative reaction

Working Principle:

• form complexes with metal ions, inactivating their catalytic activity in oxidation of medicaments

What is the function of Emulsifying Agents in Formulation?

What is its working principle?

Function:

• prevent coalescence of the dispersed globules

Working Principle:

• forms barriers at interface and reducts interfacial tension

What is the function of Flocculating Agents in Formulation?

What is its working principle?

Function:

• prevent caking

Working Principle:

• addition of an electrolytes reduces the magnitude of zeta potential of dispersed particles

What is the function of Sweetening Agents in Formulation?

What is its working principle?

Function:

• imparts sweetness

Working Principle:

• N/A

What is the function of Colors in Formulation?

What is its working principle?

Function:

• impart color

Working Principle:

• N/A

What is the function of Flavors in Formulation?

What is its working principle?

Function:

• impart flavor

Working Principle:

• N/A

What is the function of the Excipient used in aerosol propellant in Formulation?

What is its working principle?

Function:

• develops pressure in the container, which expels the product

Working Principle:

• N/A

What ingredients are used to compound Diphenhydramine HCL Solution?

Include Therapeutic Activity.

Diphenhydramine HCl

• antihistamine

Glycerin

• sweetener, solvent

Simple Syrup

• sweetening agent

Vanillin Alcoholic Solution (67 mg%)

• flavoring agent

Distilled Water

• solvent

What ingredients are used to compound Niacin Suspension?

Include Therapeutic Activity.

Niacin

• antilipidemic agent

Cetylpyridinium Chloride

• preservative

Xanthan Gum

• suspending agent

Purified Water

• solvent

Suspension Structured Vehicle NF

• suspending and sweetening vehicle

What ingredients are used to compound Artificial Tears Solution?

Include Therapeutic Activity.

Polyvinyl Alcohol

• viscosity, lubrication

Povidone

• viscosity, dispersion

Cetylpyridinium Chloride

• preservative

Sterile Sodium Chloride for Injection

• solvent

What ingredients are used to compound PCL Stomatitis Mouthwash?

Include Therapeutic Activity.

Tetracycline USP

• antibiotic

Diphenhydramine HCl USP

• local anesthetic

Nystatin USP

• antifungal antibiotic

Glycerin USP

• sweetening agent

Ora-Plus

• suspending vehicle

Ora-Sweet

• sweetening vehicle

What is the function of Structure Forming Excipients in Formulation?

form gel like structure

What is the function of Solubilizers in Formulation?

enhance solubility of the API in ointments

What is the function of Gelling Agents in Formulation?

form gels

What is the function of Emollients in Formulation?

modify vehicle/skin characteristics to assist penetration of API through skin

What is the function of Suppository Bases in Formulation?

used to form base for dissolving API

What ingredients are used to compound Cold Cream?

Include Therapeutic Activity.

Cetyl Esters Wax

• texturing agent

White Wax

• stiffening agent

Mineral Oil

• internal-laxative; external-emollient, texturing agent

Sodium Borate

• preservative, alkalizing agent

Purified Water

• vehicle

What excipient-excipient reaction occurs when Gelatin interacts with Placticizer?

Produces soft gelatin capsule

What Package-Excipient interactions can occur with glass?

Leaching of Alkali

• causes change in pH of formulation

Oxides of Boron, Sodium, Potassium, Calcium, Iron, and Magnesium in glass containers

• alter physical and chemical stability of formulation

Oxidative reactions due to glass container

• Iron and Manganese oxide cations catalyze oxidation reactions; extracted from glass and cause decomposition

What Package-Excipient interactions can occur with Plastic?

Moisture Uptake

• capsule becomes soft and sticky, which affects dissolution behavior

Sorption

• preservatives are sorbed into the containers, leading to the loss of its activity

What Package-Excipient interactions can occur with metal?

Corrosion

• tin tube can be corroded by acidic conditions

What Package-Excipient interactions can occur with rubber?

Leaching

0 presence of rubber closure extractives in the vial solutions could affect pyrogenicity of injectable preparations and cause toxicity