DDS Lecture 4 Content

Need for Various Dosage Forms

• to protect drugs from degradation due to humidity or oxygen

• to prevent chemical/enzymatic degradation of drugs in GI

• to make the medicine palatable by masking unpleasant taste or odor

• to provide optimal drug therapy by topical administration

• to provide optimal drug therapy in the form of suppositories and inserts

• to introduce drugs directly into circulation

  • for emergencies

• to provide optimal drug therapy through inhalation therapy

  • nasal passages/airways

• to provide liquid dosage forms for ease of administration

  • for very young , very old patients

General Considerations in Dosage form Design

• nature of illness

• treatment method (local vs systemic)

• age and anticipated condition of patient

When are liquid dosage forms preferred?

• in infants and children younger than 5

  • could choke, spit out tablets

• patients with difficulty swallowing solid dosage forms

Types of liquid dosage forms

1. Solutions (uniform system)

   1. Syrups

   2. Elixirs

   3. Tinctures

2. Dispersed Systems (2 distinct phases, most medications)

   1. Emulsions

   2. Suspensions

Preformulation Studies

• basic study of physical and chemical characteristics of a drug substance before formulating the drug into a proper dosage form

• employ knowledge gained through experience with structurally similar drugs

• collaborative effort of physical, chemical, biological, pharamceutical sciences

Preformulation of Liquid Dosage Forms

1. Active Pharmaceutical Ingredient (API)

   1. Chemical Properties

   2. Physical properties

   3. Stability

2. Excipients

Chemical properties considered in pre-formulation

• structure

• reactivity

• form

Physical properties considered in performulation

• physical description

• particle size

• crystalline structure

• melting point

• solubility

• microscopic examination

• heat of vaporization

• melting point depression

• particle size

• polymorphism

• dissolution

• membrane permeability

• partition coefficient

• pKa/dissociation constants

Microscopic Examination

• physical characteristic

• provides information about particle size range and crystalline structure of drug

Heat of vaporization

• amount of heat required to vaporize 1 g of liquid

• important in volatile drugs

• helps minimize exposure of personnel to hazardous drug vapors

• physical characteristic

Melting point depression

• pure compounds have defined melting points

• impurities can chance (decrease) melting point

• gives information about purity and compatibility with other compounds

• physical characteristic

Particle size

• physical characteristic

• size and distribution affects dissolution rate, bioavailability, content uniformity, texture, taste

• sedimentation rate in liquid dosage forms depends highly on particle size and equal distribution of API throughout formulation

• affects suspendibility in liquid vehicle

• affects texture in ophthalmic preparations and parenterals

Polymorphism

• physical characteristic

• 1/3 organic compounds exist in multiple crystalline form

• polymorphic forms have different melting points, solubility, chemical and physical stability

Solubility

• affected by particle size and pH

• decrease in particle size increases the surface area and solubility

• solubility of weak acids and weak bases are pH dependent

Water Soluble inorganic molecules

• ionic compounds containing monovalent cation and anion

• common salts of alkali metals (Na, K)

• Quaternary ammonium salts

• nitrates, nitrites, acetates, chlorates

• sulfates and sulfites (EXCEPT Ca and Ba sulfates)

• Chlorides, bromides, iodides (EXCEPT silver salts)

Water insoluble inorganic molecules

• hydroxides and oxides of non-alkali metals (EXCEPT alkali metals and ammonium ions)

• sulfides (EXCEPT alkali metal salts)

• Phosphates, carbonates, silicates, borates, hypochlorites (EXCEPT: alkali metal salts, ammonium salts)

General Rules of Solubility for Organic Molecules

• most drug molecules are organic

• one polar functional group can solubilize 5 carbonds

• molecules having branched chains are more soluble than straight chains

• water solubility decreases with increases in molecular weight

• structural similarity with solute and solvent = increased solubility

Very soluble

<1 parts solvent for 1 part solute

Freely soluble

1-10 parts solvent required for 1 part solute

Soluble

10-30 parts solvent required for 1 part solute

Sparingly soluble

30-100 parts solvent for 1 part solute`

Slightly Soluble

100-1000 parts solvent for 1 part solute

Very Slightly Soluble

1000-10,000 parts solvent for 1 part solute

Practically insoluble or insoluble

>10,000 parts solvent for 1 part solute

Membrane permeability

• physical characteristic

• depends on pKa, solubility, dissolution rate, lipid solubility of drug molecule

• evaluated in pre-formulation by studying drug transport rate in everted intestinal sac model

Partition Coefficient

• physical characteristic

• measure of molecule’s lipophilic character

• lower log P = hydrophilic

• higher log p = lipophilic

• ideal range: positive, less than 5

• octanol chosen for formula because 8C chain mimics lipid bilayer

pKa/Dissociation constant

• physical characteristic

• degree of ionization is dependent on pH

• degree of ionization affects solubility, absorption, distribution, elimination

• pKa important when forming admixtures of drugs

  • should not mix drugs with very different pKa, can cause precipitation

Physical Stability

• can see without testing

• not always permanent

Chemical stability

• cannot see without testing

• can sometimes be smelled

• can be permanent

Most common drug instability

chemical degradation by hydrolysis or oxidation

Hydrolysis

• affects esters, amides, lactones, lactams

• drug molecules interact with water molecules to yield breakdown products

• ex. aspirin + water → salicylic acid + acetic acid

  • if it smells like vinegar, aspirin has degraded by hydrolysis

Oxidation

• affects alcohols, aldehydes, alkaloids, phenols, sugars, unsaturated fats and oils

• loss of electron

• many are auto-oxidation: occur spontaneously under the initial influence of atmospheric oxygen and proceed slowly at first and then more rapidly

• triggered by light exposure

Protection against hydrolysis

• using water substitute (glycerin, propylene glycol, alcohol)

  • vegetable oils used for some injections

• making suspension in non-aqueous vehicle than making an aqueous solution

• making drug formulation in dry form ready for reconstitution in pure water prior to use

  • most commonly used

• refrigerating

  • prevent microbial growth

  • reduce temperature catalyzed hydrolysis

• maintain pH between 5-6

  • hydrolysis more stable at acidic pH

Protection against oxidation

• including antioxidants in formulation

• replacing oxygen with nitrogen in formulation bottles

• chelating trace metals in the formulation

• packaging in light resistant containers

• store in cool, dark place

Sodium sulfite

antioxidant for high pH

Sodium bisulfite

antioxidant for intermediate pH

sodium metabisulfite

antioxidant for low pH

Common excipients in liquid formulations

• flavoring agents

• sweetening agents

• coloring agents

• preservatives

Electronic Tongue

• provides information on bitterness levels and the stability of flavors in terms of taste

• “taste fingerprint”

Flavoring Agents

• excipients

• used for imparting new flavor or masking undesirable flavor

• 3 types: natural, artificial, spice

• added to liquid formulations to mask bad taste

• color, odor, texture, and taste should match

• milder flavors used for long-term medications

  • to avoid flavor fatigue

• not recommended for infants under 3-6 months

Natural AA flavor

• all components derived from AA

• exact composition not known

AA flavor - natural and artificial

• at least one component derived from AA

• no definition of natural-to-artififcial ratio

AA flavor with other natural flavors (WONF)

• all components are natural

• at least one component is derived from AA

Natural flavor-AA type

• all components are natural

• no component is derived from AA

AA flavor- artificial

all components are artificial

Conceptual flavor

• may contain artificial flavors

• no reference point

• may only have to declare in ingredient declaration

Suggested flavors to mask salty tastes

cinnamon, raspberry, orange, maple, butterscotch, licorice

Suggested flavor to mask sweet taste

fruit, berry, vanilla

suggested flavor to mask bitter taste

cocoa, chocolate, mint, cherry, walnut, licorice, raspberry

suggested flavor to mask sour/acid taste

fruit, citrus, cherry

suggested flavor to mask oily taste

wintergreen, peppermint oil, lemon, anise

suggested flavor to mask metallic taste

mint, marshmallow

Flavors to mask antibiotics

• cherry

• maple

• pineapple

• orange

• strawberry

• vanilla

• banana-pineapple

Flavors to mask antihistamines

• apricot

• cherry

• cinnamon

• grape

• honey-lime

• peach-orange

Flavors to mask barbiturates

• banana-pineapple

• banana-vanilla

• cinnamon-peppermint

• lime

• grenadine strawberry

Flavors to mask decongestants

• apricot

• cherry

• buterscotch

• strawberry

• lemon

• maple

• orange

• tangerine

• coriander

Flavors to mask Electrolyte and geriatric solutions

• cherry

• lemon-lime

• grape

• strawberry

• lime

• raspberry

• root beer

Sweetening Agents

• colorless and odorless

• soluble in water

• pleasant tasting

• free from after taste

• stable over wide pH range

Sweetner examples

• acesulfame potassium (200x sweeter than sucrose)

• aspartame (200x sweeter than sucrose)

• sodium saccharin (600x sweeter than sucrose)

• saccharin (300x sweeter than sucrose)

Coloring Agents

• impart color

• contraindicated in sterile solutions

• dark colors generally not used (dark purple, navy, black, brown)

• natural colors (red ferric oxide, titanium oxides) and FDA approved synthetic dyes (D&C and FD&C)

Preservatives

Should…

• prevent microbial growth

• prevent growth of most likely contaminants

• soluble in aqueous phase of preparation in adequate concentration

• percentage of undissociated preservative at pH should be capable of permeating microbial cell wall

• non-irritating, non-sensitizing, non-toxic

• chemically stable during shelf-life

• compatible with other ingredients

Mechanisms of Preservatives

• partial lysis of cell wall

• lysis and cytoplasmic leakage

• protein denaturation

• inhibition of cell wall synthesis or enzyme systems

• oxidation/hydrolysis of cellular contents

Preservatives that partially lyse cell wall

• phenols

• alcohols

• quaternary compounds

Preservatives that act by lysis and cytoplasmic leakage

• phenols

• alcohols

• quaternary compounds

Preservatives that act by protein denaturation

• benzoic acid

• alcohols

• boric acids

• p-hydroxybenzoates

Preservatives that act by inhibition of cell wall synthesis or enzyme systems

mercurials

General Formulation Considerations

• formulation prototypes developed after pre-formulation evaluation of API

• liquid dosage form primarily consists of API, solvent/diluent, co-solvents, preservatives

• oral liquid dosage forms may have coloring and flavoring agents in addition to sweetening agents

• viscosity of product is important for palatability and suspending properties

  • also for ease of pour

Types of liquid dosage forms

• oral

• parenteral

• topical

• other

Oral liquid dosage forms

• solutions

• suspensions

• emulsions

• liquid-filled soft and hard gel capsules

Parenteral liquid dosage forms

• solutions

• suspensions

• emulsions

Topical liquid dosage forms

• solutions

• suspensions

• emulsions

Other liquid dosage forms

• otic products

• nasal sprays

• ophthalmic

Solubility

• important to determine if formulation will stay in solution for life of product

• affected by temperature, electrolytes, complexation with other components

• solubility studies carried out at formulation stage

• solubility can be increased by salt formation

Viscosity

• measure of resistance of fluid deformed by either sheer stress or tensile stress

• viscosity will affect flow properties and dispensing

• viscosity enhancers can be used to allow dosing control

Packaging liquid dosage forms

• viscosity and dosage form determines type of container

• high temperature enhances flow properties

• in most cases, pump system utilized to deliver product to container through filter (sterile or non-sterile)

Process Validation

• identifies critical steps in manufacturing process

• limits specified for mixing times, heating ranges, room conditions

• effect of above factors on incorporation of API, preservatives, excipients

Stability (USP)

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

Shelf-life

• time for original potency of the API to be reduced to 90%

Kinetics and Shelf-life

• chemical stability affected by temperature, light, humidity

• chemical stability of API determines shelf-life of dosage forms

  • kinetics = just drug

  • shelf life = whole formulation stability

• stability and expiration date based on kinetics of degradation reactions

  • zero-order rate reactions

  • first-order rate reactions

Shelf-life estimation

Kinetic studies

• measure concentration of drug at given intervals under specific pH, temperature, ionic strength, light intensity, and drug concentration

Importance of Kinetics

• selection of proper storage temperature

• selection of proper container for dispensing

• anticipation of interactions when mixing drugs and dosage forms

• dissolution determinations

Estimating shelf life at given temperatures

• increase in change in temperature will decrease shelf-life

• decrease in change in temperature will increase shelf-life

• Average, best estimate for Q10 = 3

  • lower limit = 2

  • upper limit = 4

Drug X has a shelf life 240 hours when stored in a refrigerator (5⁰C). The estimated shelf life of Drug X at room temperature (25⁰C) will be ___________ 

( t₉₀(T₂) = t₉₀(T₁)/Q₁₀^(ΔT/10))

t₉₀(T₂) = 240/3^20/10

^{= 26.66 ~ 27 hours}

What Stability testing considers

• before approval and marketing, stability must be assessed

• influence of pharmaceutical ingredients

• influence of container and closure

• manufacturing processes

• packaging components

• conditions of storage

• anticipated conditions of shipping, temperature, light, humidity

• anticipated durations and conditions of pharmacy shelf-life and patient use

Stability Testing

• accelerated (6 months at 400C and 75% RH)

• long term stability under usual conditions of transport and storage

• sometimes samples are maintained at the long-term stability conditions for up to 5 years (250C ± 20C and RH of 60% ±5%)

• gives information on drug product stability and actual shelf-life

Kinetic data tells you

• reaction order

• reaction rate

• reaction order obtained experimentally by measuring reaction rate as function of concentration of degrading drug

• chemical stability determined by reaction order

Factors affecting reaction kinetics

• temperature

• dielectric constant

• ionic strength

• solvent effect

• catalysis

• light

Physical paths of instability

• polymorphs

  • cocoa butter, cortisone acetate

• crystallization

  • solution, suspension

• vaporization

  • flavoring agents, co-solvents

  • nitroglycerin

• particle sedimentation

  • suspensions

Tablet visible signs of instability

• appearance (cracking, chipping, mottling)

• friability

• hardness

• color

• odor

• moisture content

• clumping

• disintegration

• dissolution

Visible signs of capsule instability

• moisture

• tackiness

• color

• appearance

• shape

• brittleness

• dissolution

Visible signs of powder/granule instability

• appearance

• color

• odor

• moisture

Visible Signs of Instability Coated tablets

• integrity of coating

• chipping

• appearance (cracking, chipping, mottling)

• friability

• hardness

• color

• odor

• moisture

• content

• clumping

• disintegration

• dissolution

Kinetics vs Stability

1. Kinetics:

   1. Many half-lives

   2. Pure systems (pure drugs)

   3. to understand reaction mechanisms

2. Stability

   1. 85% drug remaining at endpoint

   2. involves entire dosage form

   3. purpose: establish expiration date

Drug Stability Assessment

• chemically analyzed by HLPC with UV detection

• HPLC: mobile phase, column, detector, pump, auto-sampler, data processing software (or integrator)

USP Stability Guidelines for Extemporaneous Formulation in Absence of Stability Information

• non-aqueous and solid formulations in which manufactured drug is API = no later than 25% of time remaining for product’s expiration or 6 months (whichever is earlier)

• non-aqueous liquid and solid formulations containing USP or NF substance as API = BUD of 6 months

• Water-containing formulations prepared from solid form = BUD not later than 14 days in storage at refrigerated conditions

• Other preparations = BUD 30 days or end of therapy (whichever is earlier)