Dosage Form Design

Dosage Form Design: Pharmaceutical and Formulation Considerations
Chapter 4
Copyright 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
Objectives
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 Considerations

The need for dosage forms General considerations in dosage form design Pharmaceutical ingredients and excipients
General 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 (contd)

Preformulation Studies (contd) Solubility Solubility and Particle Size
Solubility and pH
Dissolution Membrane Permeability
Partition Coefficient
pKa/Dissociation Constants
General Considerations in Dosage Form Design (contd)

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 Excipients

Definitions and Types Handbook of Pharmaceutical Excipients Harmonization of Standards Appearance and Palatability Flavoring Pharmaceuticals Sweetening Pharmaceuticals Coloring Pharmaceuticals
Pharmaceutical Ingredients and Excipients (contd)

Preservatives Sterilization and Preservation Preservative Selection General Preservative Considerations Mode of Action Preservative Utilization
The Need for Dosage Forms
The 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 (contd)

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
Physiological States Altering Response to Drugs

Age (infants) Age (elderly) Diurnal variation Body weight Time of administration Tolerance
Pregnancy
Sex Menopause
Temperature
Physiological reserve Milieu
Race
Factors 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 (contd)

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 Products

Effectiveness Safety Reliability Stability Physical Chemical Microbiological
Design of Drug Products (contd)

Pharmaceutical elegance Appearance Organoleptic properties Convenience Ease of use Dosing frequency Consumer acceptance

Preformulation Studies Drug and Drug Product Stability
Preformulation Studies
Chemical characterization Physical characterization
Physical 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 Examination
Particle size Particle size range Crystal structure Particle shape
Heat of Vaporization
Vapor pressure Volatile drugs can migrate within a solid dosage form Personnel exposure
Melting Point Depression

Purity determination Identity
The Phase Rule

Phase diagrams Visual picture of presence of solid and liquid phases in binary, ternary, and other mixtures
Particle Size
Dissolution rate Bioavailability Content uniformity Taste Texture Color Stability
Flow characteristics
Sedimentation rates
Polymorphism
Crystalline Amorphous Melting point variation Solubility differences
Solubility
Some aqueous solubility required for therapeutic efficacy Equilibrium solubility Solubility in different solvents
Solubility and Particle Size

Small increases in solubility can be achieved by particle size reduction. Decreases in particle size may enhance dissolution rates.
Solubility and pH
pH:solubility profiles are important. pH can affect solubility.
Dissolution
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 Permeability
pKa, solubility, and dissolution rate data can provide an indication of absorption.
Partition Coefficient
Octanol:water partition coefficient often used in formulation development
pKa/Dissociation Constants
Extent of dissociation or ionization Dependent on pH of medium Can affect absorption, distribution, and elimination
Drug and Drug Product Stability

Physical stability Chemical stability Shelf life of 2-3 years is generally desired
Drug Stability: Mechanisms of Degradation

Hydrolysis, solvolysis Oxidation Other processes
Drug and Drug Product Stability: Kinetics and Shelf Life

Chemical stability Physical stability Microbiological stability Therapeutic stability Toxicologic stability
Rate Reactions
Change of drug concentration with respect to time
Q10 Method of Shelf Life Estimation

Shelf life estimation Q10 = e{(Ea/R)[(1/T + 10) (1/T)]}
Enhancing Stability of Drug Products

Excipients may be added to protect the drug Antioxidants Preservatives Chelating agents Buffering agents
Stability 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.
Kinetics
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 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 (contd)

3. Anticipation of interactions when mixing drugs and dosage forms (incompatibilities) Active drugs
Excipients
4. Dissolution determinations
Importance of Kinetics (contd)

5. ADME Processes in pharmacokinetics A = Absorption D = Distribution M = Metabolism/Biotransformation E = Excretion 6. Drug action at the molecular level
Responsibility 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 (contd)

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?

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? (contd)

Expiration date for refrigerated temperature given; product stored at room temperature and then returned to refrigerator:
What is the new expiration date?
Stability: 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
Definitions
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 (contd)
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
Definitions (contd)
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
Definitions (contd)
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
Definitions (contd)
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 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 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 (contd)

Liquid Dosage Forms Solutions/elixirs/syrups Emulsions Suspensions Tinctures/fluid extracts Sterile liquids Creams Ointments Suppositories
Semisolids
Reaction 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 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 Reaction
An experimental quantity; merely provides information about the way in which the rate depends on concentration
Factors Affecting Reaction Rates

Temperature Dielectric Constant Ionic Strength Solvent Effect Catalysis Light
Chemical Kinetics vs. Chemical Stability

KINETICS Several half-lives STABILITY Down to about 85% of drug remaining Involves complete dosage form Goal is to establish an expiration date.
Pure systems
Goal is to elucidate reaction mechanisms.
First-Order Rate Reaction

dt dC
= kC
Half-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 halflife, t1/2
Zero-Order Rate Reaction

dC\dt = k0
C = k0t + C0
Arrhenius Equation
log = k2\k1 = Ea (t2 T1)\2.3 RT1T2
Arrhenius Equation (contd)

Energy of activation calculations
Energy of Activation and Reaction Types

2-3 kcal/mole--------- <10 kcal/mole-------- 10-30 kcal/mole------ Diffusion or photolysis Fast reactions stability problems in development Solvolytic process; most drug degradation
50-70 kcal/mole-------
Pyrolytic reactions
Shelf Life Estimates

Q10 = [K(T+10)]/KT =e[-(Ea/R) ({1/T+10} - {1/T}] Q10 =2 Q10 = 3 Q10 = 4 Lower limit Average, best estimate Upper limit
t90 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 Types

Active pharmaceutical ingredients Pharmaceutical ingredients added to prepare a dosage form
Components 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
Excipients
Coloring agents Sweetening agents Flavoring agents Thickening agents Suspending agents Binding agents
Surfactants
Solubilizing agents Antioxidants
Solvents
Lubricants Perfumes
Preservatives
Fats and oils
Handbook 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 Standards
International harmonization of excipients Pharmaceutical industry is multinational Uniform standards needed
Appearance and Palatability

Compliance issues Odor, color, and taste Important for all age groups, especially pediatrics and geriatrics
Flavoring Pharmaceuticals
Complex area Important for compliance Color and taste should generally match
Flavor
Taste Touch Smell Sight Sound
Four Primary Tastes

Sweet Bitter Sour Salty
Four Primary Tastes (contd)

TASTE Sweet/Sucrose Salty/NaCl Bitter/Caffeine SLIGHT 5% 0.4 0.05 MOD 10% 0.10 0.7 0.10 STRG 15% 0.20 1.0 0.20
Sour/Citric Acid 0.05
Causative Factors for Taste

Hot Astringent Coarseness/Grittiness Coolness Mild, counterirritant Tannins, acids Texture Neg heat of solution
Greater sensitivity to odors than to tastes Females have greater sensitivity to odors than males
Flavor/Odor Correlations with Chemical Structure

Sour taste Saltiness Bitter Sweet H+ Anions & cations High-MW salts Polyhydroxyl cmpds, polyhalogenated cmpds, alpha amino acids
Sharp, biting
Camphoraceous odor
Unsaturation
Tertiary C atom
Flavor/Odor Correlations with Chemical Structure (contd)

Pleasant odor Methylparaben Propyl/butyl paraben Ketones Floral, gauze-pad Numbing mouthfeel
Flavor Selection
Immediate flavor identity Rapid full flavor development Acceptable mouthfeel Short aftertaste No undesirable sensations
Flavoring Techniques
Blending Fruit===========Sour Salty/Sweet/Sour===Bitter Salty===========Decreases sourness Salty===========Increases sweetness Overshadowing Methylsalicylate====Glycyrrhiza
Flavoring Techniques (contd)

Physical Formation of insoluble compounds Emulsification of oils Effervescence High-viscosity fluids Coating tablets
Flavoring Techniques (contd)

Chemical Adsorption-silica gel Complexation Physiological Anesthetic effect====Menthol (mint)
Raspberry Concentrate Imitation

Vanillin Indol Aldehyde C16 0.180 g 0.004 g 0.240 mL
Diacetyl
Phenylethyl alcohol Aldehyde C14
0.060 mL
240 mL 0.015 mL
Aldehyde C18
Aldehyde C20
0.015 mL
0.400 mL
Raspberry Concentrate Imitation (contd)

Orange flower oil Ethyl butyrate Benzyl acetate Alpha novoviol Beta novoviol Lemon oil Propylene glycol qs 0.005 mL 0.120 mL 0.075 mL 0.400 mL 0.200 mL 0.060 mL 100 mL
Flavor Selection Guide

Salty Bitter Acrid/Sour Butterscotch/Maple Wild Cherry/Licorice Chocolate Mint Raspberry/Fruit Berry/Acacia Syrup
Flavor Selection Guide (contd)

Oily Sweet Acid Peppermint/Anise Wintergreen Fruit/Berry/Vanilla Citrus
Sweetening Pharmaceuticals
Complex area Natural vs. synthetic Heat stability
Sweetening Agents
Dextrose Mannitol Saccharin Sorbitol Sucrose
Coloring Pharmaceuticals
Lighter shades preferred
Coloring 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 (contd)

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
Preservatives
Sterilization and Preservation Preservative Selection General Preservative Considerations Mode of Action Preservative Utilization
Sterilization and Preservation

Some products must be sterile Injectables Ophthalmics
Sterilization
Autoclave Filtration
Dry heat
Irradiation
Preservative Selection
Dosage form Route of administration Compatibility with excipients Container and closure compatibility
General Preservative Considerations

Range of activity Concentration required pH requirements Compatibility
Mode 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 Utilization
Benzoic acid/sodium benzoate Alcohol Phenylmercuric nitrate/acetate Phenol Cresol Chlorobutanol Benzalkonium chloride
Methylparaben/propylparaben
Others

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Dosage Form Design: Pharmaceutical and Formulation Considerations

Copyright 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

7. Calculate rate reactions for various liquid dosage forms.