Chp 4: Dosage Form Design: Pharmaceutical and Formulation Considerations

Dosage Form Design: Pharmaceutical and Formulation Considerations:

1. The Need for Dosage Forms
• Mechanism for safe and convenient delivery • Provide clear liquid dosage forms
of accurate dosage (solutions)
• Protection of drugs from the atmosphere • Provide rate-controlled drug action
• Protection of drug from gastric acid (EC) • Provide topical drug action (ointments,
• Conceal bitter, salty, or offensive taste or creams, patches, ophthalmic, otic, nasal)
odor • Provide for insertion into the body cavity
• Provide liquid preparations of insoluble • Provide for placement into the bloodstream
drugs • Provide for inhalation therapy

2. General considerations in dosage form design

a) Physiological States Altering Response to Drugs
• Age—infants • Race
• Age—elderly • Body weight
• Diurnal variation • Time of administration
• Pregnancy • Tolerance
• Sex • Temperature
• Menopause • Physiological reserve

b) Factors Affecting Drug Presentation to the Body

• Portal of drug entry into the body • Physicochemical properties of the drug
• Physical form of the drug product product
• Design and formulation of the product • Control and maintenance of location of drug
• Method of manufacture of the product at the absorption site
• Physicochemical properties of the drug and • Control of the release rate of the drug from
excipients the drug product

c) Design of Drug Products

• Effectiveness Pharmaceutical elegance
• Safety – Appearance
• Reliability – Organoleptic properties
• Stability Convenience
– Physical – Ease of use
– Chemical – Dosing frequency
– Microbiological – Consumer acceptance

3) General Considerations in Dosage Form Design

i) Preformulation studies
ii) Drug and drug product stability
Preformulation studies
1) Physical Description
• Solids, liquids, gases • Biological properties
• Chemical properties – Ability to get to the site of action and
– Structure, form, reactivity elicit a response
• Physical properties .
– Description, particle size, crystalline
structure, melting point, solubility

2) Microscopic Examination 3) Heat of Vaporization

• Particle size • Vapor pressure.
• Particle size range • Volatile drugs can migrate within a solid
• Crystal structure dosage form.
• Particle shape • Personnel exposure.

4) Melting Point Depression

• Purity determination
• Identity

6) Particle Size
• Dissolution rate • Color
• Bioavailability • Stability
• Content uniformity • Flow characteristics
• Taste • Sedimentation rates
• Texture
7) Polymorphism
• Crystalline • Melting point variation
• Amorphous • Solubility differences

8) Solubility
• Some aqueous solubility is required for • Solubility in different solvents
therapeutic efficacy
• Equilibrium solubility
10) Solubility and pH
9) Solubility and Particle Size • pH can affect solubility
• Small increases in solubility can be achieved
by particle size reduction.
• Decreases in particle size may enhance
dissolution rates

11) Dissolution
• Dissolution may be the 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
12) Membrane Permeability
 pKa, solubility, and dissolution rate data can provide an indication of absorption

13) Partition Coefficient

• Octanol:water partition coefficient often used in formulation development

14) pKa/Dissociation Constants

• Extent of dissociation or ionization • Can affect absorption, distribution, and
• Dependent on pH of the medium elimination

15) Hydrates and Solvates

• Hygroscopic • Efflorescence
• Deliquescent
16) Organic Salt Considerations
• Weak acids • Albuterol sulfate (dosed as the base)
• Weak bases • Diphenhydramine HCl (dosed as the salt)
• Salts

17) Drug and Drug Product Stability

• Physical stability • A shelf-life of 2 to 3 years is generally
• Chemical stability desired

18) Drug Stability: Mechanisms of Degradation

• Hydrolysis, solvolysis • Oxidation

19) Drug and Drug Product Stability: Kinetics and Shelf-Life

• Chemical stability - Each active ingredient retains its chemical integrity and labeled potency within the
specified limits
• Physical stability - The original physical properties, including appearance, palatability, uniformity,
dissolution, and suspendability, are retained.
• Microbiological stability- Sterility or resistance to microbial growth is retained according to the
specified requirements. Antimicrobial agents retain effectiveness within specified limits.
• Therapeutic stability - The therapeutic effect remains unchanged
• Toxicologic stability - No significant increase in toxicity occurs.

20) Enhancing Stability of Drug Products

• Excipients may be added to protect the drug:
– Antioxidants – Chelating agents
– Preservatives – Buffering agents
21) Stability Testing
• Done at each stage of product development. • Product containers and closures must be
considered.
 • Temperature and humidity studies. • Chemical changes of drug degradation.
• Light studies. • The pharmacist is the last professional to
• Changes in physical appearance, color, odor, check for quality and stability prior to
taste, texture. dispensing.

4) 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

1) Importance of Kinetics
a) Selection of proper storage temperature b) Selection of proper container for dispensing
– Temperature – Glass versus plastic
– Light – Clear versus amber versus opaque
– Advising the patient on storage – Cap liner selection
conditions

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

– Active drugs
– Excipients

e) ADME processes in pharmacokinetics

– A = Absorption – M = Metabolism/biotransformation
– D = Distribution – E = Excretion

2) Responsibility of the Pharmacist

• Dispense the oldest stock first and observe • Dispensing in a proper container with proper
expiration dates. closure
• Store products under conditions stated in • Informing/educating patients concerning
USP monographs and/or labeling. proper storage and use of products,
• Observe products for evidence of instability. including the disposition of outdated or
• Properly treat/label products that are excessively aged prescriptions
repackaged, diluted, or mixed with other
products.

3) Why Do We Need Shelf Life Estimates?

 Expiration date given at room temperature:  Expiration date for room temperature given
o What is the expiration extension if and it is desired to heat (autoclave):
refrigerated? o What is the % decomposition?
 Expiration date for refrigerator temperature  Expiration date for refrigerated temperature
given: given; product stored at room temperature
o How long if left at room and then returned to refrigerator:
temperature? o What is the new expiration date?
4) 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

5) Definitions
 Accelerated testing
o Studies designed to increase the rate of chemical or physical degradation by using exaggerated
storage conditions
 Bulk drug substance
o Active drug before formulation
 Drug product
o Finished dosage form
 Expiration date
o 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
o The interval that a drug product is expected to remain within the approved specifications after
manufacture
 Primary stability data
o 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
o 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
o The capacity of a drug product to remain within specifications established to ensure its identity,
strength, quality, and purity
 Strength
o A quantitative measure of the active ingredient, as well as other ingredients requiring
quantitation
 Supportive stability data
o Data other than primary stability data

6) Observing Products for Evidence of Instability

• Solid dosage forms
– Hard/soft gelatin capsules: Hardening, softening, expansion, distortion of the shell
– Uncoated tablets: Crushed, broken, cracks, swelling, fusion of tablets, appearance of crystals
– Coated tablets: cracks, mottling, or tackiness in the coating and the clumping
– Dry powders and granules: Discoloration, caking instead of free flow, bacterial growth, release
of pressure upon opening
• Liquid dosage forms
 – Solutions/elixirs/syrups: precipitation, discoloration, haziness gas formation (microbial growth)
– Emulsions: Breaking, Creaming
– Suspensions: Caking, crystal growth, difficulty in resuspending
– Tinctures/fluid extracts:
– Sterile liquids: Discoloration, haziness, precipitation
• Semisolids
– Creams: Emulsion breakage, crystal growth, shrinkage due to evaporation of water, microbial
growth
– Ointments: Change in consistency, separation of liquid, drying
– Suppositories: Excessive softening, drying, hardening, evidence of oil stains on packaging
–
7) Factors Affecting Reaction Rates
• Temperature
• Dielectric constant
• Ionic strength
• Solvent effect
• Catalysis
• Light
•
8) Chemical Kinetics versus Chemical Stability
Kinetics Stability
• Several half-lives. • Down to about 85% of the drug
• Pure systems. remaining.
• Goal is to elucidate reaction • Involves the complete dosage form.
mechanisms. • Goal is to establish an expiration date.

9) Half-Life
• Is meaningless to attempt to describe the time required for all material to decompose (i.e., infinity).
• Therefore, the reaction rate can be described by K or half-life, t .
1/2
Zero-Order Rate Reaction
If the loss of drug is independent of the concentration of the reactants and constant with respect to time (i.e., 1
mg/mL/h), the rate is called zero order. The mathematical expression is
C = −k0t + C0
where C0 is the initial concentration of the drug. The unit for a zero rate constant k0 is concentration per unit
time, such as moles per liter per second or milligrams per milliliter per minute.
t1/2 =(0.5* C0)/k0

Example 1
A drug suspension (125 mg/mL) decays by zero-order kinetics with a reaction rate constant of 0.5 mg/mL/h.
What is the concentration of intact drug remaining after 3 days (72 hours), and what is its t1/2?

Example 2
How long will it take for the suspension to reach 90% of its original concentration?
Drug suspensions are examples of pharmaceuticals that ordinarily follow zero-order kinetics for degradation.

First-Order Rate Reactions

If the loss of drug is directly proportional to the concentration remaining with respect to time, it is called a first-
order reaction and has the units of reciprocal time, that is, time−1. The mathematical expression is

C is the concentration of intact drug remaining, t is time, and k is the specific reaction rate constant, Where C 0 is
the initial concentration of the drug.

The half-life equation for a first-order reaction is:

Example 3
An ophthalmic solution of a mydriatic drug at 5 mg/mL exhibits first-order degradation with a rate of 0.0005/d
How much drug will remain after 120 days, and what is its half-life?

Example 4
In Example 3, how long will it take for the drug to degrade to 90% of its original concentration?

Energy of Activation: Arrhenius Equation

Stability projections for shelf life (t90 or the time required for 10% of the drug to degrade with 90% of the intact
drug remaining) are commonly based on the Arrhenius equation:
which relates the reaction rate constants (k) to temperatures (T) with the gas constant (R) and the energy of
activation (Ea).
The relationship of the reaction rate constants at two different temperatures provides the energy of activation for
the degradation. By performing the reactions at elevated temperatures instead of allowing the process to proceed
slowly at room temperature, the Ea can be calculated and a k value for room temperature determined with the
Arrhenius equation.

Example 5
The degradation of a new cancer drug follows first-order kinetics and has first-order degradation rate constants
of 0.0001/h at 60°C and 0.0009/h at 80°C. What is its Ea?

10) Shelf Life Estimates

• Q10 = e{(Ea/R) [(1/T+10) − (1/T)} • Q10 = 3 Average, best estimate
• Q10 = 2 Lower limit • Q10 = 4 Upper limit
The Q10 method of shelf-life estimation lets the pharmacist estimate the shelf life for a product that has been
stored or is going to be stored under a different set of conditions.
Q10 is, therefore, the factor by which the rate of spoilage increases when the temperature is raised by 10C.
Q10 allows for the prediction of a product's shelf life under real-life conditions based on the results of testing
conducted at high temperatures.
Where, Ea is the energy of activation, R is the gas constant, and T is the absolute temperature.
The commonly used Q values of 2, 3, and 4 relate to the energies of activations of the reactions for temperatures
around room temperature (25°C).
For example, a Q value of 2 corresponds to an Ea (kcal/mol) of 12.2, a Q10 value of 3 corresponds to an Ea of
19.4, and a Q value of 4 corresponds to an Ea of 24.5.
Reasonable estimates can often be made using the value of 3.

11) t Equation for Shelf-Life Estimates

90
(T/10)
• t
(T ) = t (T )/Q
90 2 90 1 10
• Note: A “+” T decreases shelf life and a “−” T increases shelf life
Where t90T2 is the estimated shelf life, t90T1 is the given shelf life at a given temperature, and ΔT is the
difference in the temperatures T1 and T2.

OR

ts(T1) and ts(T2) are the shelf-lives at temperature T1 and T2

Example 1
An antibiotic solution has a shelf life of 48 hours in the refrigerator (5°C). What is its estimated shelf life at
room temperature (25°C)?
Using a Q value of 3, we set up the relationship as follows:

Example 2
An ophthalmic solution has a shelf life of 6 hours at room temperature (25°C). What is the estimated shelf life
in a refrigerator at 5°C? (Note: Because the temperature is decreasing, ΔT will be negative.)

5) Pharmaceutical Ingredients and Excipients

• Active pharmaceutical ingredients
• Pharmaceutical ingredients added to prepare a dosage form

1) Excipients
• Coloring agents • Thickening agents
• Sweetening agents • Suspending agents
• Flavoring agents • Binding agents
• Surfactants • Solvents
• Solubilizing agents • Lubricants
• Antioxidants • Perfumes
• Preservatives • Fats and oils

2) Harmonization of Standards
• International harmonization of excipients. • Uniform standards needed.
• Pharmaceutical industry is multinational.
3) Appearance and Palatability
• Compliance issues • Important for all age groups, especially
• Odor, color, and taste pediatrics and geriatrics
4) Four Primary Tastes
• Sweet • Sour
• Bitter • Salty

5) Sweetening Agents
• Dextrose • Sorbitol
• Mannitol • Sucrose
• Saccharin

6) Preservatives
• Sterilization and preservation • Mode of action
• Preservative selection • Preservative utilization
• General preservative considerations
7) Sterilization and Preservation

Some products must be sterile:

Injectables Filtration

Ophthalmics Dry heat

Irradiation

Sterilization

Autoclave

8) Preservative Selection

Dosage form Compatibility with excipients

Route of administration Container and closure compatibility

9) General Preservative Considerations

Range of activity pH requirements

Concentration required Compatibility

10) Mode of Action of Preservatives

Modification of cell membrane permeability Inhibition of cellular metabolism
Lysis and cytoplasmic leakage Oxidation of cellular constituents
Irreversible coagulation of cytoplasmic constituents Hydrolysis

11) Preservative Utilization

Benzoic acid/sodium benzoate Cresol
Alcohol Chlorobutanol
Phenylmercuric nitrate/acetate Benzalkonium chloride
Phenol Methylparaben/propylparaben