FunSci 2 Exam #2

Disperse systems

preparation containing un-dissolved drug distributed through a vehicle

• undissolved = dispersed phase solid, liquid, or gas

• vehicle = dispersion medium = continuous phase

Coarse particles

10-50 micromoles

• eX) suspensions and emulsions

Fine particles

0.5-10 micromoles

EX) magmas and gel

Suspensions

finely divided drug solid particles distributed somewhat uniformly in a vehicle exhibits minimum degree of solubility

• not fully insoluble only small amounts dissolves

• contains coarse particles

• can be a dry powder to reconstitute or ready to use

Benefits of suspensions

• drug is insoluble in water

• drug is unstable in aqueous media (antibiotics)

• Bad taste

• difficulty swallowing solid dosage form

• improved compliance (flavored and sweetened)

Features of suspensions

• settle slowly and is easily re-disperse uniformly upon shaking

• particle size should remain fairly constant upon long standing

• pour readily and evenly (good viscosity)

• Maintains therapeutic efficacy, chemical stability, and esthetic appeal

Theory of sedimentation (Stokes’s law)

V = d² (particle density - medium density) g / 18 n

To decrease rate of sedimentation: (slower the rate the better)

• decrease particle diameter

• increase viscosity

• decrease differences in density of particle and medium

as particle size decreases

increase SA → increase surface free energy → more thermodynamically unstable → flocculation

To ensure particles don’t flocculate too much and need to approach a stable state

add surfactants to ensure caking doesn’t occur

Deflocculated system:

small particles with strong forces, settles slowly, irreversible (caking)

Flocculated system

loose fluffy aggregates (weak van der waal forces), settles quickly, reversible upon shaking

A good particle size

size must be able to form flocs or floccules

To increase flocculation you can use

• electrolytes

• surfactants

• polymers

• suspending agents

Electrolytes increase flocculation by

reducing the electrical barrier and repulsion between charged drug particles

• creates weak bonds to the drug so that it is easily broken by shaking

• zeta potential = surface electrical charge

  • want a low zeta potential

Polymers increase flocculation by

having affinity to drug particles, by building inter-particle bridges

• don’t add too much or polymer coats each particle individually

• EX) spans (tween 80), polysorbets, Na caryl SO4

Surfactants increase flocculation by

reducing interfacial tension between particles

• aids in wetting so powder doesn’t float to surface instead is dispersed in medium

• HLB = 7-9

  • want small contact angle to have complete wetting

  • Ex) alcohol, glycerin, propylene glycol

Suspending agents increase flocculation by

increase the viscosity of the dispersion media

• increasing viscosity → decreases rate of sedimentation

• Ex) carboxymethylcellulose (CMC), xanthan, bentonite

  • Don’t use too much, or it increases viscosity too much, leading to complexation with the drug

Preparation of suspensions

1. reduce particle size

2. add wetting agent

3. dissolve water-soluble ingredients

4. Add dispersion medium to wetted particles

Packaging and storage of suspensions

containers should contain adequate air space for shaking

• protect suspensions from light (if light sensitive), freezing, and excessive heat

• labels always include shake well before use

Suppositories

insertion into body orificies, to melt/soften or dissolve and releases its active drug to exert local or systemic effects

• EX) rectal, vaginal, urethral

• has different shapes and weights

Rectal administration

suppositories, tablets, capsules, ointments, and enemas

• local effect (laxatives) - glycerin, hemorrhoids (reduced systemic adverse effects)

• systemic effect: anti-inflammatory, analgesic

  • needs to be absorbed into the blood to have effect

Shape: bullet, finger shape

Weight: adult 2g, child 1g

Vaginal administration

insertion with aid of appliance, such as suppositories, tablets, capsules, solutions, sprays, creams, ointments, and foams (aerosols)

• local effect: fungal infection

• systemic effect: estrogen hormones

Shape: globular or oviform

Weight: 5g

• mostly prepared with hydrophilic bases (provides extended release)

Suppositories shape and weight

shape allows for easy insertion, retention for appropriate period

Weight:

• adult suppository weight is about 2 g

• child suppository weight is about 1 g

Urethral suppositories

less common

Shape: pencil shaped bougies, 3-6 mm diameter and 140 mm long

weight: 4 g for males, and 2 g for females

Advantages of suppositories

1. The patient can not use the oral route: problem with the GIT, lots of vomiting, and individuals are unable/unwilling to swallow

2. Drug is less suited for oral administration: irritates the stomach ( NSAIDs), unstable pH of GIT, if the drug is susceptible to enzymatic attack or the first pass effect, or the drug has a bad taste

• 60% of the drug is saved from first-pass metabolism by traveling through the lower and middle hemorrhoidal vein

Disadvantages of Suppositories

• incomplete absorption

• development of proctitis and irritation of mucus membrane

• shelf life due to melting issues

Physiological factors that affect drug absorption of suppositories

1. Colonic content: want an empty rectum for better absorption/bioavailability

2. Circulation route: absorbed rectally, bypasses the liver through the lower hemorrhoidal veins, and lymphatic circulation also increases drug absorption

3. pH of rectal fluids: limited fluids in rectum (2-3 mL), typically neutral in nature, want to administer drug in the way you want it to be absorbed

Drug factors that affect drug absorption of suppositories

1. Lipid water solubility: base influences drug release

• hydrophilic drug + hydrophilic base = efficient release (sink condition)

• hydrophilic drug + lipophilic base = efficient release (no escape to surroundings, drug partitions into rectal fluids)

• Lipophilic drug + hydrophilic base = efficient release

• lipophilic drug + lipophilic base = not efficient release

  • lipophilic base = cocoa butter

  • hydrophilic base = atropine sulfate (salt)

2. particle size: decreased particle size → increases dissolution rates

• If the concentration of the drug exceeds a certain amount, no further increase in absorption rate

3. Nature of base: if base interacts with drug = impaired absorption, if base irritates the mucous membrane of the rectum = initiates bowel movement to minimize drug absorption

Ideal base for suppositories

• must melt at body temp

• non-toxic/non-irritant

Cocoa butter

• melting point range 30-36 degree C, so it readily melts in the body

• ideal suppository base

• has polymorphism = different radicals of base resulting in different effects due to melting at different temperatures

  • Disadvantages:

    • Due to m.p., it can melt in hot climates: to fix this problem, add a volatile oil (beeswax 4%, camphor, chloral hydrate, and phenol)

    • prone to oxidation, which can lead to a significant smell

    • tends to stick to molds, so it must be lubricated before use

Synthetic fat bases for suppositories

prepared by hydrogenating suitable vegetable oils (novata, suppocire, and witepsol)

• disadvantages:

  • Melted fats are less viscous: increased risk of sedimentation, lack of uniform drug distribution, localized irritancy

  • becomes brittle if cooled too rapidly

Water soluble and water miscible bases of suppositories

they don’t melt around body temp, slowly dissolves, results in extended release of drug

• glycerol-gelatin bases: 10% water

  • glycerol suppositories base: 16% water

Disadvantages of glycerol-gelatin base:

• causes a laxative effect by drawing water into the mucosa

• can cause rectal irritation due to only 2-3 ml of fluid in the rectum

• hygroscopic so requires careful storages

• more likely to have microbial contamination due to water in base (need preservative)

macrogels as suppository bases:

polyethylene glycol (PEG): polymers of repeating ethylene oxide, works by dissolving in body fluid

• exists as liquids (200-600g), semisolids (600-1000g), and solids (>1000) according to wt

  • increase mwt → increases hardness, which will decrease drug release (also increases brittleness)

  • Release depends on base dissolving rather than melting (50 degree C)

Advantages of macrogels as suppository bases:

• no physiological effect (no lax effect)

• not prone to microbial contamination

• less likelihood of leakage from the body

• significant contracts upon cooling so no lubricant needed

Disadvantages of macrogels:

• hygroscopic so store carefully

• high water absorbing capacity leads to irritation of mucosa

• becomes brittle if cooled quickly

• incompatibile with several drugs

molding of suppositories

use of metal or plastic molds to ensure smooth surface of suppositories

• use a clean lubricated mold, then pour mixture of base and active ingredients, cool suppositories

High humidity of supposiories

absorb moisture and becoming spongy

Extreme dryness

lose moisture and becomes brittle

Storage of suppositories

Cocoa butter: preferably refrigerated (2-8 degree C)

glycerinated gelatin: controlled room temp 20-25 degree C

PRG: stored at usal room temp

Quality control of suppositories

• melting (specific for fatty bases)

• drug release

• content uniformity

• mechanical strength

• appearance

Emulsions

a system of two immiscible liquid phases, composed of small globules of liquid dispersed through a vehicle

• requires the addition of SAA

• droplet size = 0.1-100 micromoles

• advantages: mask bad tastes, realtivly stable mixture of 2 immiscible liquids, easily absorded due to small particle sizes, irritant substance can be coated by SAA in the internal phase to lessen irriation

Dispersed phase

internal phase, discontinuous phase

Dispersion phase

external phase, continuous, dispersion

o/w emulsion

internal phase: oil

external phase: water

• hydrophilic

• diluted with water

• conducts electricity

w/o emulsion

internal phase: water

external phase: oil

• hydrophobic

• oil miscible liquids

Phase volume:

• The emulsion type is determined by the larger phase

• If the dispersed phase is >50%, then the emulsion can be unstable

Type of emulsifying agent

high HLB = O/W emulsion

Low HLB = W/O emulsion

• selection of SAA depends on type of emulsion

Theories of emulsification

1. surface tension theory

2. oriented wedge theory

3. plastic or interfacial film theory

All relies on SAA to reduce interfacial tension between the two liquids

• Water-soluble agents encourage o/w, and oil-soluble agents encourage w/o emulsions

Preparations of emulsions

1. emulsifier capable of promoting emulsification

2. be compatible with other ingredients

3. not interfere with stability/efficiacy

4. be stable and does not deteriorate

5. be non-toxic

6. little oder or taste

Emulsifying agent

contains both hydrophilic and hydrophobic portions

• determined by HLB values

antifoaming HLB

1-3

W/O emulsifiers HLB value

3-6

wetting agents HLB values

7-9

O/W emulsifies HLB values

8-18

solution HLB values

15-20

Emulsifying and stabilizing agents

1. carbohydrate materials: o/w emulsions (e.g., gums acacia, agar, cellulose (stabilizes liquids)

2. Proteins: o/w emulsions, ex) gelatin, egg yolk, casein, amino acids = polar, disadvantage = too fluid and becomes more fluid upon standing (stabilizes liquids)

3. High MW alcohols: o/w emulsions, ex) stearyl alcohol, cetyl alcohol, glyceryl monostearate (for thickening and stabilizing liquids)

4. Wetting agents: contain both hydrophilic and lipophilic groups, depending on agent can cause o/w or w/o emulsions Ex) anionic - sodium lauryl sulfate and non-ionic - tweens, spans

5. Finely divided solids: forms o/w emulsions, ex) bentonite, MgOH, AlOH, CMC to increase viscosity

Emulsion preparations

• dry gum method (continental)

• Wet gum method (english)

4 stages of stability for emulsions

1. flocculation

2. aggregation and coalescence

3. creaming

4. breaking

Creaming of emulsions:

• aggregation of internal phase globules have greater tendency than rise or fall to bottom of solution

  • reversible: upon shaking

Breaking emulsions

flocculation → coalescence of the globules of the internal phase, and separate that phase into a layer → breaking

• irreversible process (protective sheath where globules no longer exist)

  • be careful with extreme cooling and heating

Microemulsions

inherently stable emulsion

• transparent

• 10-100 nm

• surfactant HLB = 15-18

  • Advantages: rapid oral absorption, enhanced transdermal absorption

  • SAA = 10-50

self micro emulsifying drug delivery system (SMEDDS)

• not a microemulsion yet

• closely related system

• rapid dispersion

• auto emulsification:

  • spontaneous formation of ME

  • one step preparation

  • order of mixing is not critical

semisolids are prepared for what body parts

• skin/mucus membranes

• eye

• nose

• vagina

• rectum

Semisolids include what dosage forms

ointments, creams, gels, and pastes

Ointments

can be medicated or unmedicated

• can have one of 4 types of bases:

  • oleaginous

  • absorption base (anhydrous absorption base or W/O emulsions)

  • water removable base

  • water-soluble base

choice of base depends on desired properties

Oleaginous base for ointments

100% lipophilic

• protects escape of moisture (high occlusive effect)

• remains on skin for long time and is difficult to wash off

• no preservative

  • EX) petrolatum, white petrolatum, white ointment, and yellow ointment

absorption bases

ability to absorb water divided into two types

• anhydrous absorption bases

• W/O emulsions

anhydrous absorption base

consists of hydrocarbon bases

• primarily lipophilic → good occlusive properties

• can absorb water due to surfactants (stearyl alcohol)

  • hydrophilic petrolatum, lanolin, Aquaphor

W/O emulsions in ointments

moderate protective, occlusive and emollient properties

• still greasy and not water washable

• water is 20% of total amount of ointment

  • ex) cold cream, eucerin, rose water ointment

Water removable bases for ointments

O/W emulsions (water is the dominant phase)

• easily washed from the skin

• nonocclusive, non-greasy

• absorbs serious discharge

• need parabens (preservatives)

  • hydrophilic ointment, vanishing cream

Water soluble bases for ointments

does not contain any oleaginous components

• completely water-washable

• mostly used for the incorporation of solids

  • EX) PEG ointment

How to choose an appropriate base for ointments

1. desired release rate: lipophilic drug - treats local infection, if you want a hydrophilic base = drug prefers to partition out of base, if lipophilic base = minimal or no drug release

2. desirability of occlusive base

3. stability of the drug in an ointment base

4. drug effects on ointment base

5. ease of removal (washability)

6. Degree of greasiness

Preparation of ointments

1) incorporation method:

• mortar and pestle

• spatula and ointment slab

  • Geometric dilution: ensure uniform distribution of the drug within the base

  • ointment or roller mills: allows uniform composition and smooth texture

2) fusion method:

• melting of components of the ointment and then cooled with constant stirring

  • volatile components are added last when the temperature is low enough

Microbial content of ointments

topical applications are not required to be sterile except for ophthalmic preparations

• must meet standards of microbial growth

  • preservatives may be added

Minimum fill test for ointments

determination of the net weight or volume of the contents of filled container

• tests for air bubbles → decreases amount of ointment

  • test ensure proper contents as per label claim

Packaging, storage, and labeling of ointment

• large mouth ointment jars: a highly viscous preparation allows for easy application

• metal/plastic tubes: squeezing of product and screw top minimizes microbial contamination

  • must be a well-closed container and stored in a cool temperature

Gels

semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid vehicle

• jelly-like by the addition of: carbomers, CMC, hydroxypropyl methylcellulose

• 0.5-2% in water

  • can be administered via: skin, eye, nose, or vaginal/rectum

Single phase gels

macomolecules are distributed so that no apparent boundaries exist (clear media)

• homologous - vast majority

Two phase gel

consists of distict particles, mostly inorangic and opaque

• antibacterial soap

Pastes

semisolid preparations intended for application to skin

• 25% solid which allows it to be more viscous and thick

• good at absorbing discharge/water from diapers

  • Zinc oxide paste