Preformulations

Dosage Form Design: Pharmaceutical and Formulation Considerations

Chapter 4

ObjectivesObjectives

After reading this chapter, the student will be able to:

1. List reasons drugs are incorporated into various dosage forms.

2. Compare and contrast the advantages/disadvantages of various drug dosage forms.

3. Describe the information needed in preformulation studies to characterize a drug substance for possible inclusion into a dosage form.

4. Describe the mechanisms of drug degradation and provide examples of each.

5. Describe the five types of drug instability of concern to the practicing pharmacist.

6. Summarize approaches employed to stabilize drugs in pharmaceutical dosage forms.

7. Calculate rate reactions for various liquid dosage forms.

8. Categorize various pharmaceutical ingredients and excipients.

Dosage Form Design: Pharmaceutical and Formulation ConsiderationsDosage Form Design: Pharmaceutical and Formulation Considerations

• The need for dosage forms

• General considerations in dosage form design

• Pharmaceutical ingredients and excipients

General Considerations in Dosage Form DesignGeneral Considerations in Dosage Form Design

• Preformulation Studies

– Physical Description

– Microscopic Examination

– Heat of Vaporization

– Melting Point Depression

– The Phase Rule

– Particle Size

– Polymorphism

General Considerations in Dosage Form Design (cont’d)General Considerations in Dosage Form Design (cont’d)

• Preformulation Studies (cont’d)

– Solubility

– Solubility and Particle Size

– Solubility and pH

– Dissolution

– Membrane Permeability

– Partition Coefficient

– pKa/Dissociation Constants

General Considerations in Dosage Form Design (cont’d)General Considerations in Dosage Form Design (cont’d)

• Drug and Drug Product Stability

– Drug Stability: Mechanisms of Degradation

– Drug and Drug Product Stability: Kinetics and Shelf Life

– Rate Reactions

– Q10 Method of Shelf Life Estimation

– Enhancing Stability of Drug Products

– Stability Testing

Pharmaceutical Ingredients and ExcipientsPharmaceutical Ingredients and Excipients

• Definitions and Types

• Handbook of Pharmaceutical Excipients

• Harmonization of Standards

• Appearance and Palatability

– Flavoring Pharmaceuticals

– Sweetening Pharmaceuticals

– Coloring Pharmaceuticals

Pharmaceutical Ingredients and Excipients (cont’d)Pharmaceutical Ingredients and Excipients (cont’d)

• Preservatives

– Sterilization and Preservation

– Preservative Selection

– General Preservative Considerations

– Mode of Action

– Preservative Utilization

The Need for Dosage Forms

The Need for Dosage FormsThe Need for Dosage Forms

• Mechanism for safe and convenient delivery of accurate dosage

• Protection of drug from atmosphere

• Protection of drug from gastric acid (EC)

• Conceal bitter, salty, or offensive taste or odor

• Provide liquid preparations of insoluble drugs

The Need for Dosage Forms (cont’d)The Need for Dosage Forms (cont’d)

• Provide clear liquid dosage forms (solutions)

• Provide rate-controlled drug action

• Provide topical drug action (ointments, creams, patches, ophthalmic, otic, nasal)

• Provide for insertion into body cavity

• Provide for placement into bloodstream

• Provide for inhalation therapy

General Considerations in Dosage Form Design

Physiological States Altering Response to DrugsPhysiological States Altering Response to Drugs

• Age (infants)

• Age (elderly)

• Diurnal variation

• Pregnancy

• Sex

• Menopause

• Race

• Body weight

• Time of administration

• Tolerance

• Temperature

• Physiological reserve

• Milieu

Factors Affecting Drug Presentation to the BodyFactors Affecting Drug Presentation to the Body

• Portal of drug entry into the body

• Physical form of the drug product

• Design and formulation of the product

• Method of manufacture of the product

• Physicochemical properties of the drug and excipients

Factors Affecting Drug Presentation to the Body (cont’d)Factors Affecting Drug Presentation to the Body (cont’d)

• Physicochemical properties of the drug product

• Control and maintenance of location of drug at the absorption site

• Control of the release rate of the drug from the drug product

Design of Drug ProductsDesign of Drug Products

• Effectiveness

• Safety

• Reliability

• Stability

– Physical

– Chemical

– Microbiological

Design of Drug Products (cont’d)Design of Drug Products (cont’d)

• Pharmaceutical elegance

– Appearance

– Organoleptic properties

• Convenience

– Ease of use

– Dosing frequency

– Consumer acceptance

General Considerations in Dosage Form DesignGeneral Considerations in Dosage Form Design

• Preformulation Studies

• Drug and Drug Product Stability

Preformulation StudiesPreformulation Studies

• Chemical characterization

• Physical characterization

Physical DescriptionPhysical Description

• Solids, liquids, gases

• Chemical Properties

– Structure, form, reactivity

• Physical Properties

– Description, particle size, crystalline structure, melting point, solubility

• Biological Properties

– Ability to get to site of action and elicit a response

Microscopic ExaminationMicroscopic Examination

• Particle size

• Particle size range

• Crystal structure

• Particle shape

Heat of VaporizationHeat of Vaporization

• Vapor pressure

• Volatile drugs can migrate within a solid dosage form

• Personnel exposure

Melting Point DepressionMelting Point Depression

• Purity determination

• Identity

The Phase RuleThe Phase Rule

• Phase diagrams

• Visual picture of presence of solid and liquid phases in binary, ternary, and other mixtures

Particle SizeParticle Size

• Dissolution rate

• Bioavailability

• Content uniformity

• Taste

• Texture

• Color

• Stability

• Flow characteristics

• Sedimentation rates

PolymorphismPolymorphism

• Crystalline

• Amorphous

• Melting point variation

• Solubility differences

SolubilitySolubility

• Some aqueous solubility required for therapeutic efficacy

• Equilibrium solubility

• Solubility in different solvents

Solubility and Particle SizeSolubility and Particle Size

• Small increases in solubility can be achieved by particle size reduction.

• Decreases in particle size may enhance dissolution rates.

Solubility and pHSolubility and pH

• pH:solubility profiles are important.

• pH can affect solubility.

DissolutionDissolution

• Dissolution may be rate-limiting step in the absorption of poorly soluble drugs.

• Can affect onset, intensity, and duration of response and control overall bioavailability of the drug from the dosage form

Membrane PermeabilityMembrane Permeability

• pKa, solubility, and dissolution rate data can provide an indication of absorption.

Partition CoefficientPartition Coefficient

• Octanol:water partition coefficient often used in formulation development

pKa/Dissociation ConstantspKa/Dissociation Constants

• Extent of dissociation or ionization

• Dependent on pH of medium

• Can affect absorption, distribution, and elimination

Drug and Drug Product StabilityDrug and Drug Product Stability

• Physical stability

• Chemical stability

• Shelf life of 2-3 years is generally desired

Drug Stability: Mechanisms of DegradationDrug Stability: Mechanisms of Degradation

• Hydrolysis, solvolysis

• Oxidation

• Other processes

Drug and Drug Product Stability: Kinetics and Shelf LifeDrug and Drug Product Stability: Kinetics and Shelf Life

• Chemical stability

• Physical stability

• Microbiological stability

• Therapeutic stability

• Toxicologic stability

Rate ReactionsRate Reactions

• Change of drug concentration with respect to time

Q10 Method of Shelf Life EstimationQ10 Method of Shelf Life Estimation

• Shelf life estimation

• Q10 = e{(Ea/R)[(1/T + 10) – (1/T)]}

Enhancing Stability of Drug ProductsEnhancing Stability of Drug Products

• Excipients may be added to protect the drug

– Antioxidants

– Preservatives

– Chelating agents

– Buffering agents

Stability TestingStability Testing

• Done at each stage of product development

• Product containers and closures must be considered

• Temperature and humidity studies

• Light studies

• Changes in physical appearance, color, odor, taste, texture

• Chemical changes of drug degradation

• Pharmacist is last professional to check for quality and stability prior to dispensing

Kinetics and Drug Stability

Kinetics is important in all phases of the drug development process as well as in quality control,

stability, bioavailability, and therapeutic drug monitoring.

KineticsKinetics

• The study of the rate of chemical change and the way this rate is influenced by conditions of concentration of reactants, products, and other chemical species that may be present and by factors such as solvent, pressure, and temperature

Importance of KineticsImportance of Kinetics

1. Selection of proper storage temperature

– Temperature

– Light

– Advising patient on storage conditions

2. Selection of proper container for dispensing

– Glass vs. plastic

– Clear vs. amber vs. opaque

– Cap liner selection

Importance of Kinetics (cont’d)Importance of Kinetics (cont’d)

3. Anticipation of interactions when mixing drugs and dosage forms (incompatibilities)

– Active drugs

– Excipients

4. Dissolution determinations

Importance of Kinetics (cont’d)Importance of Kinetics (cont’d)

5. ADME Processes in pharmacokinetics

– A = Absorption

– D = Distribution

– M = Metabolism/Biotransformation

– E = Excretion

6. Drug action at the molecular level

Responsibility of the PharmacistResponsibility of the Pharmacist

• Dispense oldest stock first and observe expiration dates.

• Store products under conditions stated in USP monographs and/or labeling.

• Observe products for evidence of instability.

• Properly treat/label products that are repackaged, diluted, or mixed with other products.

Responsibility of the Pharmacist (cont’d)Responsibility of the Pharmacist (cont’d)

• Dispensing in proper container with proper closure

• Informing/educating patients concerning proper storage and use of products, including the disposition of outdated or excessively aged prescriptions

Why Do We Need Shelf Life Estimates?Why Do We Need Shelf Life Estimates?

• Expiration date given at room temperature:

– What is the expiration extension if refrigerated?

• Expiration date for refrig temperature given:

– How long if left at room temperature?

• Expiration date for room temperature given and it is desired to heat (autoclave):

– What is the % decomposition?

Why Do We Need Shelf Life Estimates? (cont’d)Why Do We Need Shelf Life Estimates? (cont’d)

• Expiration date for refrigerated temperature given; product stored at room temperature and then returned to refrigerator:

– What is the new expiration date?

Stability: USPStability: USP

• The extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., its shelf life), the same properties and characteristics that it possessed at the time of manufacture

DefinitionsDefinitions

• Accelerated Testing

– Studies designed to increase the rate of chemical or physical degradation by using exaggerated storage conditions

• Bulk Drug Substance

– Active drug before formulation

• Drug Product

– Finished dosage form

Definitions (cont’d)Definitions (cont’d)

• Expiration Date

– The date placed on the immediate container label of a drug product that designates the date through which the product is expected to remain within specifications

• Expiration Dating Period

– The interval that a drug product is expected to remain within the approved specifications after manufacture

• Primary Stability Data

– Data on the drug product stored in the proposed container-closure for marketing under storage conditions that support the proposed expiration date

• Stability-Indicating Methodology

– Quantitative analytical methods based on the characteristic structural, chemical, or biological properties of each active ingredient of a drug product, and that will distinguish each active ingredient from its degradation products so that the active ingredient content can be accurately measured

• Stability

– The capacity of a drug product to remain within specifications established to ensure its identity, strength, quality, and purity

• Strength

– A quantitative measure of active ingredient, as well as other ingredients requiring quantitation

• Supportive Stability Data

– Data other than primary stability data

Physical Paths of InstabilityPhysical Paths of Instability

• 1. Polymorphs

– Cocoa butter, Cortisone Acetate

• 2. Crystallization

– Solutions, suspensions

• 3. Vaporization

– Flavoring agents, cosolvents, nitroglycerin

• 4. Particle sedimentation

– Suspensions

Observing Products for Evidence of InstabilityObserving Products for Evidence of Instability

• Solid Dosage Forms

– Hard/soft gelatin capsules

– Uncoated tablets

– Coated tablets

– Dry powders and granules

– Powders/granules for solution/suspension

– Effervescent tablets/granules/powders

Observing Products for Evidence of Instability (cont’d)Observing Products for Evidence of Instability (cont’d)• Liquid Dosage Forms

– Solutions/elixirs/syrups

– Emulsions

– Suspensions

– Tinctures/fluid extracts

– Sterile liquids

• Semisolids

– Creams

– Ointments

– Suppositories

Reaction KineticsReaction Kinetics

• Want two things from kinetic data:

– Reaction order

– Reaction rate

• In considering the chemical stability of a pharmaceutical, we need to know the REACTION ORDER, which is obtained experimentally by measuring the REACTION RATE as a function of concentration of the degrading drug.

Reaction KineticsReaction Kinetics

• The overall ORDER of a reaction is the SUM of the EXPONENTS of the CONCENTRATION terms of the RATE EXPRESSION.

• The ORDER with respect to EACH REACTANT is the EXPONENT of the INDIVIDUAL CONCENTRATION terms in the RATE EXPRESSION.

Order of a ReactionOrder of a Reaction

• An experimental quantity; merely provides information about the way in which the rate depends on concentration

Factors Affecting Reaction RatesFactors Affecting Reaction Rates

• Temperature

• Dielectric Constant

• Ionic Strength

• Solvent Effect

• Catalysis

• Light

Chemical Kinetics vs. Chemical StabilityChemical Kinetics vs. Chemical Stability

• KINETICS

• Several half-lives

• Pure systems

• Goal is to elucidate reaction mechanisms.

• STABILITY

• Down to about 85% of drug remaining

• Involves complete dosage form

• Goal is to establish an expiration date.

First-Order Rate ReactionFirst-Order Rate Reaction

dC= kC

Half-LifeHalf-Life

• Is meaningless to attempt to describe the time required for ALL material to decompose (i.e., infinity)

• Therefore, reaction rate can be described by K or half-life, t1/2

Zero-Order Rate ReactionZero-Order Rate Reaction

–dC\dt = k0

C = –k0t + C0

Arrhenius EquationArrhenius Equation

log = k2\k1 = Ea (t2 – T1)\2.3 RT1T2

Arrhenius Equation (cont’d)Arrhenius Equation (cont’d)

• Energy of activation calculations

Energy of Activation and Reaction TypesEnergy of Activation and Reaction Types

• 2-3 kcal/mole----------

• <10 kcal/mole---------

• 10-30 kcal/mole-------

• 50-70 kcal/mole-------

• Diffusion or photolysis

• Fast reactions stability problems in development

• Solvolytic process; most drug degradation

• Pyrolytic reactions

Shelf Life EstimatesShelf Life Estimates

• Q10 = [K(T+10)]/KT

• =e[-(Ea/R) ({1/T+10} - {1/T}]

• Q10 =2 Lower limit

• Q10 = 3 Average, best estimate

• Q10 = 4 Upper limit

t90 Equation for Shelf Life Estimatest90 Equation for Shelf Life Estimates

• t90(T2) = t90(T1)/Q10(Delta T/10)

• Note: A “+” Delta T decreases shelf life and a “-” Delta T increases shelf life

Pharmaceutical Ingredients and Excipients

Definitions and TypesDefinitions and Types

• Active pharmaceutical ingredients

• Pharmaceutical ingredients added to prepare a dosage form

Components of Drug Delivery SystemsComponents of Drug Delivery Systems

• Drug

• Route of administration

• Suitable physical dosage form

• Use of chemical derivatives of the drug

• Control of certain physicochemical and/or biochemical processes that alter the rate and extent of response

ExcipientsExcipients

• Coloring agents

• Sweetening agents

• Flavoring agents

• Surfactants

• Solubilizing agents

• Antioxidants

• Preservatives

• Thickening agents

• Suspending agents

• Binding agents

• Solvents

• Lubricants

• Perfumes

• Fats and oils

Handbook of Pharmaceutical ExcipientsHandbook of Pharmaceutical Excipients

• Monographs on more than 250 excipients used in dosage form preparation

• Additional excipients listed in Food Chemicals Codex and National Formulary

Harmonization of StandardsHarmonization of Standards

• International harmonization of excipients

• Pharmaceutical industry is multinational

• Uniform standards needed

Appearance and PalatabilityAppearance and Palatability

• Compliance issues

• Odor, color, and taste

• Important for all age groups, especially pediatrics and geriatrics

Flavoring PharmaceuticalsFlavoring Pharmaceuticals

• Complex area

• Important for compliance

• Color and taste should generally match

FlavorFlavor

• Taste

• Touch

• Smell

• Sight

• Sound

Four Primary TastesFour Primary Tastes

• Sweet

• Bitter

• Sour

• Salty

Four Primary Tastes (cont’d)Four Primary Tastes (cont’d)

• TASTE SLIGHT MOD STRG

• Sweet/Sucrose 5% 10% 15%

• Sour/Citric Acid 0.05 0.10 0.20

• Salty/NaCl 0.4 0.7 1.0

• Bitter/Caffeine 0.05 0.10 0.20

Causative Factors for TasteCausative Factors for Taste

• Hot Mild, counterirritant

• Astringent Tannins, acids

• Coarseness/Grittiness Texture

• Coolness Neg heat of solution

• Greater sensitivity to odors than to tastes

• Females have greater sensitivity to odors than males

Flavor/Odor Correlations with Chemical StructureFlavor/Odor Correlations with Chemical Structure

• Sour taste H+

• Saltiness Anions & cations

• Bitter High-MW salts

• Sweet Polyhydroxyl cmpds, polyhalogenated cmpds,

alpha amino acids

• Sharp, biting Unsaturation

• Camphoraceous odor Tertiary “C” atom

Flavor/Odor Correlations with Chemical Structure (cont’d)Flavor/Odor Correlations with Chemical Structure (cont’d)

• Pleasant odor Ketones

• Methylparaben Floral, gauze-pad

• Propyl/butyl paraben Numbing mouthfeel

Flavor SelectionFlavor Selection

• Immediate flavor identity

• Rapid full flavor development

• Acceptable mouthfeel

• Short aftertaste

• No undesirable sensations

Flavoring TechniquesFlavoring Techniques

• Blending

– Fruit===========Sour

– Salty/Sweet/Sour===Bitter

– Salty===========Decreases sourness

– Salty===========Increases sweetness

• Overshadowing

– Methylsalicylate====Glycyrrhiza

Flavoring Techniques (cont’d)Flavoring Techniques (cont’d)

• Physical

– Formation of insoluble compounds

– Emulsification of oils

– Effervescence

– High-viscosity fluids

– Coating tablets

Flavoring Techniques (cont’d)Flavoring Techniques (cont’d)

• Chemical

– Adsorption-silica gel

– Complexation

• Physiological

– Anesthetic effect====Menthol (mint)

Raspberry Concentrate ImitationRaspberry Concentrate Imitation

• Vanillin 0.180 g

• Indol 0.004 g

• Aldehyde C16 0.240 mL

• Diacetyl 0.060 mL

• Phenylethyl alcohol 240 mL

Raspberry Concentrate Imitation (cont’d)Raspberry Concentrate Imitation (cont’d)

• Orange flower oil 0.005 mL

• Ethyl butyrate 0.120 mL

• Benzyl acetate 0.075 mL

• Alpha novoviol 0.400 mL

• Beta novoviol 0.200 mL

• Lemon oil 0.060 mL

• Propylene glycol qs100 mL

Flavor Selection GuideFlavor Selection Guide

• Salty Butterscotch/Maple

• Bitter Wild Cherry/Licorice

Chocolate Mint

• Acrid/Sour Raspberry/Fruit

Berry/Acacia Syrup

Flavor Selection Guide (cont’d)Flavor Selection Guide (cont’d)

• Oily Peppermint/Anise

Wintergreen

• Sweet Fruit/Berry/Vanilla

• Acid Citrus

Sweetening PharmaceuticalsSweetening Pharmaceuticals

• Complex area

• Natural vs. synthetic

• Heat stability

Sweetening AgentsSweetening Agents

• Dextrose

• Mannitol

• Saccharin

• Sorbitol

• Sucrose

Coloring PharmaceuticalsColoring Pharmaceuticals

• Lighter shades preferred

Coloring AgentsColoring Agents

• Dyes: FD&C, D&C, Ext D&C

• Lakes: Calcium and aluminum salts

• Liquids: 0.001% to 0.0005%

• Powders: 0.1%

• Caramel

• Ferric oxide: Red/yellow

Coloring Agents (cont’d)Coloring Agents (cont’d)

• Red No. 1, Ponceau 3R, Cherry Red

– 9.8/5

• Blue No. 1, Brilliant Blue, Blue-Green

– 20/20

• Yellow No. 5, Tartrazine, Lemon Yellow

– 20/18

PreservativesPreservatives

• Sterilization and Preservation

• Preservative Selection

• General Preservative Considerations

• Mode of Action

• Preservative Utilization

Sterilization and PreservationSterilization and Preservation

• Some products must be sterile

– Injectables

– Ophthalmics

• Sterilization

– Autoclave

– Filtration

– Dry heat

– Irradiation

Preservative SelectionPreservative Selection

• Dosage form

• Route of administration

• Compatibility with excipients

• Container and closure compatibility

General Preservative ConsiderationsGeneral Preservative Considerations

• Range of activity

• Concentration required

• pH requirements

• Compatibility

Mode of ActionMode of Action

• Modification of cell membrane permeability

• Lysis and cytoplasmic leakage

• Irreversible coagulation of cytoplasmic constituents

• Inhibition of cellular metabolism

• Oxidation of cellular constituents

• Hydrolysis

Preservative UtilizationPreservative Utilization

• Benzoic acid/sodium benzoate

• Alcohol

• Phenylmercuric nitrate/acetate

• Phenol

• Cresol

• Chlorobutanol

• Benzalkonium chloride

• Methylparaben/propylparaben

• Others

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