1

Lecture 3: Pharmaceutics.

2

1. Drug Dosage forms:

: sform release Sustained A.

relatively : intended to reduce dosing frequency while maintaining Definition*

consistent blood levels of the drug.

1. Improved patient compliance. :Advantages*

2. Use less total drug. 3. Fewer local or systemic S.E.

4. Less fluctuation in drug level [i.e. avoid toxicity due to high conc. or

lack of efficacy due to low conc.].

Characteristics of drugs intended for formulation into Sustained release drug formula:*

→ WHY?high therapeutic index 1. Have

Because if any failure of the system→ NO toxicity.

so by sustained release allow once or twice daily dosing. 8 hrs -2 1/2with t2. Drugs

<2hrs→can't be made S.R →WHY?1/2*If t

Because we require high drug conc. & high drug release rate which isn't applicable.

> 8 hrs → no need for sustained release drug formula. 1/2*If t

500 mg x 3 times daily so it ise.g. if drug is taken Small total mgs of the drug3.

impossible to make S.R d.f containing 1500 mg.

ic conditions.For ttt of chron4.

*Classification of S.R d.fs:

aqueous solvent -: soln of drug substance in nonbeads or granules the make To 1.

& sugar[e.g. alcohol] → converted to beads or granules by combination with

.starch

N.B. If the drug dose is large→ granules may be composed of drug itself alone.

ated to provide immediate drug release.*Some of granules are left unco Coating: 2.

are cellulose ethylor cellulose material e.g. beeswax*Coats of lipid material e.g.

applied to remaining granules→ some granules receive few coats & some receive

many→ various coat thickness→ S.R effect.

beads 1. Coated

or granules:

e.g. Spansules.

The process by which solids, liquids or gases are encased in → : Definition*

microscopic capsules.

forming substance.-a) Coacervation. b) Film By two methods:*

microencapsulated & mixture of : Drug particles are Encapsulated dissolution*

: microencapsulated KCl→ (adv. as slow K). . Micro Kparticles is placed in D.F e.g

-2. Micro

:encapsulation

*Drug + Matrix material→ compression into tablet.

*The primary dose or portion of the drug to be released immediately is placed on

the tablet as a layer; the rest of dose is slowly released from the matrix.

*Matrix dissolution: drug compressed in tablets with slowly soluble polymer.

KCl embedded in wax matrix. tabs: K SlowN.B.

asteless.: 1) TAdvantages over liquid KCl

ion near GIT. +Minimize high local conc. of K2)

3) Lower incidence of small bowel ulceration.

: AI in plastic matrix→ slow diffusion of AI→ empty tab tablets Nifedipine*

appears in the stool.

-3. Matrix

:tablets

*Composed of tablet core with semi -permeable coat.

*Drug release doesn't depend on pH but depends only on osmotic pressure.

4. Osmotic

e.g. or os :system

system

Drug +resin→ resin-Drug complex→ release due to changes in GIT pH [release is

greater in highly acidic stomach than in less acidic small intestine.

5. Ion exchange

resin:

*By chemical reaction.

*Release depends on GIT pH

6. Complex

formation:

3

:Suppositories B.

Types:*

*weight→2g.

→ ttt of fever.Aspirin & Acetaminophene.g. 1)

→ ttt of insomnia.Chloral hydrate2)

→ for migraine.Ergotamine) 3

emetic.-→ antiProchlorperazine) 4

→ antihistamine.) Promethazine5

.→ ttt of asthmaAminophylline6)

N.B.1) There's no suppositories in the market for epilepsy.

2) Phenazopyridine→ UT anesthetic available only as oral D.F.

Rectal:1.

*Weight → 5g

9 which is spermicidal-→ contain nonoxynolContraceptivee.g. 1)

→ reduce odor producing M.Os.) Benzethonium chloride2

→ azoles.Antifungals3)

WHY? tabs→ vaginal in diluents as used usually is LactoseN.B.

1. Water soluble 2. Inert.

3. Encounters the growth of doderlein's bacilli in vagina.

2. Vaginal:

*60mm long & 5mm diameter.

infective agents.-Antie.g. 1.

→ For ttt of erectile dysfunction [only 6mm long & 1.5mm 1. Alprostadil or PGE2

diameter so called microsuppository].

3. Urethral:

:administration rectal of Characteristics*

1.Neutral pH of colon fluids lessen the possibility of drug inactivation by stomach

acidity.

pass metabolism. st2. Drugs may avoid hepatic 1

:either used for. Drugs 3

a) Local effect. b) Systemic activity.

4. Irritating drugs have less effect on the rectum than on stomach.

5. The release & absorption of drugs is erratic & unpredictable → why?

properties.: 1. Drug Because it depends on

2. Suppository base.

3. Colon condition.

suppositories: of *Preparation

: for cocoa butter.Hand rollinga)

Compression.b)

duction.: *For commercial proFusion in a moldc)

*For all bases.

This method should be used carefully for:N.B.

Thermolabile drugs.1.

→ because in the melt they may settle or float during pouring . Insoluble powders2

depending on their densities → Non uniform drug distribution.

4

bases: Suppository*

:→ fat soluble mixture of TGs.oil] [theobroma butter Cocoa 1.

Characteristics:*

1. Good base for rectal but not vaginal or urethral suppositories.

C.02. Solid up to temperature of 32

C→ it melts.035 -3. At 34

4. During preparation by Fusion method→ it shows polymorphism

[more than one crystalline form] → disadv.

hydrateChloral N.B. Some drugs affect melting point of cocoa butter e.g.

lowers its M.P

Witepsol 2.

No polymorphism. Wecobee 3.

Fattibase 4.

:bases. For these oily 1 N.B.

→ it tends to remain in suppository oil an oil soluble drug is incorporated Ifa)

pool.

→ passes rapidly from oily phase to aqueous phase [adv] ) Water soluble drugb

but how to mix the aqueous drug with oily base?

By Emulsifiers e.g. glycerol monostearate & propylene glycol monostearate.

a. Bases that

melt at body

temperature:

*Also called water-miscible bases.

*For vaginal & rectal suppositories.

e.g. 1) Glycerinated gelatin.

2) Different molecular weight polyethylene glycol [PEG] "Carbowax".

Glycerinated gelatin & Carbowax should be moistened with water before

insertion.

N.B. PEG forms complex with many drugs affect release & absorption.

WHY? →base PEG use ositorysupp vaginal commercial Most Q)

1. Water miscible.

2. Easy to insert.

3. Doesn't require refrigeration.

b. Bases that

dissolve:

5

Powders: C.

solids→ducing particle size of : is the mechanical process of reMilling*

]Comminution[

:Comminution techniques*

The substance is reduced to small particles by rubbing in a mortar with pestle. a. Trituration:

that can be readily removed by agent nd2*Reducing particle size by using

pulverization.

that resist grinding. Gummy substances*Used for

. alcohol→ is reduced by intervention of Camphore.g.

b. Pulverization

by intervention:

solvent [levigating -adding non*The particle size of substance is reduced by

le or using to form a paste→ the paste is then rubbed in a mortar & pest agent]

ointment slab & spatula.

*Suitable for ointment & suspension.

e.g. of levigating agent: Mineral oil.

c. Levigation:

:Mixing powders*

*By spatula on a sheet of paper.

amounts of powders. small1. Mixing :*Useful for

: mixtures that melt at a lower temperature than any of . Eutectic mixtures2

? → bec. Spatulation → very little compression.Whytheir ingredients→

-Thymol-holment -Camphor -: [Phenole.g. of substances that form eutectic mixtures

phenyl Salicylate & phenacetin].

. To diminish contact between agents which tend to form eutectic mixtures:N.B

Kaolin & starch..g. Light Mg oxide, Mg carbonate, Use inert diluents e1.

prevents eutexia with aspirin & phenyl Salicylate. . Silicic acid2

a. Spatulation:

Simple mixing of two or more powders in the mortar. b. Trituration:

*Used when potent substances must be mixed with large amount of diluents→ HOW?

Potent drug + equal amount of diluents in mortar → mix by Trituration → second

portion of diluents equal to volume of powder mix in mortar is added→

Trituration…….& so on.

c. Geometric

dilution:

Fluffy product →نخل d. Sifting:

Mixing powders in large container rotated by motorized process [Industry]. e. Trumbling:

6

Definitions: **Important

it is the study of all aspects of small particles. Micromeritics: 1.

not perceptible to the touch :Impalpable 2.

*This term is used for powders that either directly applied to the skin or are

incorporated into topical products so they should be extremely fine or impalpable by

Trituration.→ Desired particle size ≤ 50 microns.

[Freez drying] :Lyophilization 3.

are prepared by this method. Sterile powders of water unstable drugs*

?WHYto form a cake… as bulking agentis included in lyophilized products Mannitol*

Because the larger more visible cake is helpful to the pharmacist to make sure that

dissolution is completed.

Conversion of solid to vapor without passing through liquid :Sublimation 4.

phase. a It's an extraction process in which ground drug is soaked in Maceration: 5.

solvent until cellular structure is penetrated & soluble constituents have been dissolved.

mix of 98% zinc oxide + 2% ferric oxide. :powder Calamine 6.

: gives pink color to the mixture which is more cosmetically acceptable than Ferric oxide

white zinc oxide.

It is the ability of substance to attract & retain moisture, also :Hygroscopicity 7.

.deliquescent substances

How to protect these powders from moisture?*

: add inert diluents + double wrapping.a. For divided powders زي اكياس الفوار

use glass jars. bulk powders:b. For زي البروكسيمول

is highly hygroscopic & will absorb moisture even in relatively low GlycerinN.B.

humidity so used so used as humectants to keep creams & other semisolids from drying

out.

7

D. Tablets :

*They are manufactured by: 1. Dry granulation

2. Wet granulation

3. Direct compression.

*Tablet Excipients: 1. Diluents: *used to make up the required bulk of the tablet.

*Common diluents: [starch- mannitol- lactose- dicalcium phosphate-Kaolin &

microcrystalline cellulose].

N.B. Calcium salts can't be used as fillers for tetracycline products→ WHY?

2. Binders &

Adhesives:

*They are added in either dry or liquid form to promote granulation & promote

cohesive compacts during direct compression.

e.g. 1) 10-20% aqueous solution of glucose. 2) Gelatin. 3) Povidone.

4) 25-50% solution of glucose. 5) Cellulose derivatives.

6) Natural gums e.g. Acacia→ disadvantages:

a)contaminated with bacteria. b)Variable in composition.

N.B. Acacia & Gelatin are SAAs.

3. Disintegrants. *they facilitate disintegration when tablet contacts water in GIT.

M.O.A: Draw water into tablet→ swell → tablet burst.

e.g.1. Corn starch & potato starch. 2. Cation exchange resins.

3. Cellulose derivatives. 4. Clays e.g. veegum & bentonite.

4. Lubricant,

Anti-adherents

& Glidants:

[overlapping

function]

a. Lubricant: e.g. Talc, Mg stearate & Ca stearate.

*Improve flow properties of granules.

*Reduce adhesion to dies & punches.

*Reduce punch & die wear.

*Facilitate tablet ejection from the die

b. Glidants: promote the flow of tablet granulation or powder into a die for compression

by reducing friction among particles.

e.g. Potato or Corn starch.

c. Antiadherents: reduce sticking or adhesion of tablet granules or powders to the faces

of punches or die walls.

5. Sweeteners: *For chewable tabs & tabs intended to dissolve in mouth.

*May come from the diluents [Lactose-Mannitol].

e.g. 1)Saccharin: unpleasant bitter after taste [200x more sweet than sucrose].

2) Aspartame: → advantages:1. No bitter after taste.

2. 200x more sweet than sucrose.

3. Provides < 1calorie/ dose.

Disadvantages: disintegrate by heating & moisture.

*C.I: Patients with phenylketonuria→ WHY?

Because Aspartame metabolism phenylalanine.

3) Mannitol: sweetener that is widely employed in chewable tabs→ why?

Bec. although it isn't as sweet as sucrose it leaves a cool taste in the mouth & isn't

hygroscopic.

8

*Tablet types: 1. Enteric coated tabs: *They remain intact in stomach but release ingredients in intestine.

e.g. KCl→ enteric coated→ why?

a) Protect stomach from irritation.

b) Avoid drug decomposition in the stomach.

N.B. 1. Enteric coated tabs shouldn't be taken within 1 hour of ingestion of milk or

antacids→ WHY? → To avoid premature dissolution of the coat.

*Agents used to coat enteric coated tabs:

1-Shellac 2- Cellulose acetate phethalate.

2. Sugar coated: *Steps of coating: a) Seal coating [water proof].

b) Subcoating: e.g. water insoluble shellac.

c) Syrup coating: for smoothing & coloring.

d) Polishing: e.g. Carnauba wax & beeswax.

3. Film-coated tabs: *By alcohol solution of cellulosic polymers & zein.

Notes: 1) Enteric, sugar & film-coated tabs→ mask bitter taste of drugs.

2) Sugar & film coated tabs→ release contents in the stomach.

3) Advantages to manufacturer for using film coated when compared to sugar coating:

a) Less gross weight: sugar coated tabs may be 50% larger than original tabs while film coated tabs

only 2-3% larger.

b) Shorter production time [sugar coat→ many steps].

c) Lower incidence in coat shipping.

4) Wurster process: It is a technique of tablet coating in which:

1)Column of air in which granules & powders suspended.

2) Spray with coating solution.

3) Drying by rotation of solids & introduction of hot air.

*Processing problems: A. Capping & Lamination:

due to entrapment of air

during processing.

*Capping→ is partial or complete separation of top or bottom crown from

main body of the tablet.

*Reasons: 1. too dry granulation.

2. Excessive fine powders.

3. Excessive pressure of compression.

4. Insufficient binder.

*Lamination→ separation of the tablet into two or more layers.

B. Picking & Sticking: due

to excessive moisture or

inclusion of substances

with low melting

temperatures in the

formulae

*Picking→ small pinholes on the surface of tabs.

*Reasons: 1. too damp granulation.

2. Static charges on powders.

3. Scratch punches.

4. Insufficient lubricants.

*Sticking→ adhesion of tablet material to die wall.

C. Mottling: *Unequal color distribution.

9

*Tablets evaluation & control:

1. General appearance.

2. Hardness testers.

3. Friabilators: determine friability by allowing the tablet to roll & fall within a rotating

tumbling apparatus.

a. Tablets are weighed before & after special number of rotations & weight loss is

determined.

b. Resistance to weight loss indicated the ability of the tablet to withstand abrasion

during handling, packing & shipping.

c. Compressed tabs lose 0.5-1% weight→ acceptable.

d. Some chewable tabs & most effervescent tabs are tightly friable & require unit

packaging فوار زانتاك

4. Weight.

5. Content uniformity.

6. Disintegration: evaluated to ensure that the drug is fully available for disintegration

& absorption from GIT.

*Are required for all types to tabs.

*Time for disintegration: a) Coated tabs e.g. sublingual tabs "2 min".

b) Most uncoated tabs "30 mins".

c) Sugar coat "2 hrs".

d) Enteric coated: no evidence of disintegration after 1 hr in

gastric fluid & in intestinal fluid "2 hrs".

e) Buccal tabs: "4 hrs".

7. Dissolution characteristics:

*N.B. 1. Excessive tablet compression→ difficult to disintegrate in the body→ slowing

dissolution.

2. ↑ Drug particle surface area by micronization of drugs e.g. Grisefulvin,

Chloramphenicol & sulfadiazine→ ↑ Dissolution rate so ↓ dissolution time.

3. Formulas that list spermaceti as an ingredient may now be compounded using

a substituent Cetyl ester wax [called synthetic spermaceti → MP 43-46 0C]→ why?

because spermaceti is 1)Expensive 2) Difficult to obtain.

E. Capsules :

*Hard gelatin capsules:

e.g. Prochlorperazine: S.R Spansules in hard gelatin capsules.

*The best choice of diluents for stock powder special in preparing capsules is Lactose→

why? → because it is inert & H2O insoluble.

*Size of capsules: by numbering system

#000 # 5

(largest size) (smallest size)

*Uniformity test→ weight variation test USP

10

F. Ointments :

*Important definitions:

1. Ointments: oleaginous in nature.

2. Creams: generally w/o or o/w emulsions.

3. Pastes: have high content of solids [25%].

4. Gels: semi-solid systems consisting of suspension made up of either small inorganic

particles or large organic molecules interpenetrated by a liquid.

N.B. Carbomers: they are polymers with a number of carboxy gp present → used in

topical products mainly gels as thickening agents.

*↑ pH of the solution containing carbomers→ cross linking of molecules → ↑ viscosity &

vice versa.

*Ointment bases: → is made of hydrocarbons.

1. Oleaginous bases:

*anhydrous *water

insoluble *can't

absorb water.

*aren't washable in

water.

e.g. a) Jelene b) Petrolatum

c) White petrolatum + white wax [called white ointment or simple ointment].

d) Yellow ointment same as white ointment but yellow wax + yellow petrolatum.

N.B. White ointment: very low H2O number.

*H2O number: it is the largest amount of H2O that 100 g of an ointment will hold

at 200C.

*Some characteristics of white petrolatum:

a) Useful for ophthalmic drug→ WHY?

*very low incidence of eye irritation.

*Absence of low susceptibility for microbial growth.

b) For antibiotic with limited solubility→ WHY?

c) Have occlusive characteristics so aids hydrating skin by preventing H2O loss

e.g. ↑ absorption of hydrocortisone.

2. Absorption bases:

*Anhydrous

*H2O insoluble.

*absorb H2O [large

amount].

*Aren't washable in

H2O.

e.g. a)Wool fat [anhydrous lanolin]:→ contains cholesterol as emulsifying agent.

b) Hydrophilic petrolatum: → contains cholesterol as emulsifying agent.

c) Aquaphor: its major ingredient is petrolatum.

N.B. *Absorption bases→ absorb H2O→ w/o emulsion with the aid of their

contents of emulsifying agent.

*Eucerin: similar to aquaphor but it is already w/o emulsion + antimicrobial

preservative→ why?

*Preservative is essential for any topical base containing H2O e.g. w/o, o/w,

aqueous.

*Urea: has good solubility in H2O so solution of it can be made & incorporated

into aquaphor.

3. Emulsion [w/o]:

*H2O insoluble.

*absorb H2O

*aren't washable.

e.g. a) Lanolin [Hydrous wool fat].

b) Cold cream→ [petrolatum bases → H2O ointment].

c) Nivea cream.

4. Emulsion o/w]: H2O

removable bases.

*H2O insoluble.

*Absorb H2O

*washable by H2O

e.g. a) Neobase

b) Vanishing cream

c) Hydrophilic ointment: used for application to a seeping infection as it

absorbs serous fluid readily.

5. Water soluble bases:

*Anhydrous or hydrous.

*Absorbs H2O

*Washable by H2O

e.g. a) Propylene glycol: base + humectants [its uses].

b) PEG ointment.

c) Propylene glycol ethanol.

11

*Incorporation of medical agents in Ointment bases:

a) Levigation:

[see before]

*Stainless steel spatula is used.

*Some substances [e.g. salicylic à- Iodine- mercuric salts] interact with metal

spatula so use rubber spatula.

*Levigation is aided using levigating agent e.g. [Mineral oil, Glycerin].

*Organic solvents e.g. ether, alcohol & chloroform aren't used as levigating

agent→ why? →Because the drug may crystallize when the solvent evaporate.

N.B. Alcohol is common in lotions.

*Incorporating powders or liquids in small amounts of ointment base is best

accomplished on pill tile [ointment tile].

b) Fusion method: N.B. Volatile materials e.g. Iodine, Camphor, Mentol→ added after melted mix

cools to 400C or less.

*Factors that ↑ drug absorption from topically applied

product:

1. covering the area to which topical drug product has been applied.

2. Sweat accumulation → hydration of skin→↑ penetration.

3. Back of hands > palms [thick epidermis].

4. High drug conc.→↑ rate of penetration.

5. Partition coefficient → drugs that are very soluble in vehicle will tend to remain in

vehicle & vice versa.

6. Some substances ↑ skin permeability:

a) Benzene & Chloroform: remove lipids from stratum corneum.

b) Dimethyl Sulphoxide [DMSO]: solvate stratum corneum.

c) Na lauryl sulfate: reversible denaturation of skin protein.

*Examples of Topical products:

1. Allantoin: in topical formulations→ why?

→ used as vulnerary [healing agent] → stimulates tissue repair.

2. Calamine: skin protective to avoid infection.

3. Sulfur: ttt of mild cases of scabies.

N.B. Precipitated sulfur→ is sulfur form that is used by a pharmacist when

extemporaneously preparing ointment→ WHY?

a. Fine particle size b. Large surface area.

4. Cool tar: ttt of mild eczematic conditions "external use only"

*Precautions during ttt with cool tar:

1. it’s a potential carcinogen. 2. Photosensitizer.

a) Cool tar solution:

[also called Liquor

carbonis Detergins

(LCD)].

*Alcohol as a solvent + Polysorbate 80.

*Polysorbate 80: Non ionic surfactant used to disperse H2O insoluble components

of cool tar which will precipitate when highly alcoholic solution is mixed with an

aqueous preparation.

*Solution diluted 1:9 with water or ointment base.

*Sand is used during its manufacture.

*Used for ttt of mild cases of Psoriasis

b) Cool tar ointment: *Cool tar solution is incorporated in Zinc oxide paste.

5. Burrow's solution [Aluminum acetate topical solution]: topical astringent dressing.

6. Compound undecylenic acid ointment:

20 % zinc undecylenate + 5 % free undecylenic acid in PEG ointment base→ ttt of

fungal infections as Athlete's foot.

12

7. Iodine:

a) Iodine solution

USP:

*Iodine (2%) + Sodium iodide (2.4%) → using purified H2O USP as the vehicle.

*I2+Na I→ NaI3 which is H2O soluble.

b) Iodine tincture

USP:

*Iodine (2%) + Sodium Iodide (2.4%) → using diluted alcohol USP as a vehicle.

*Iodine is soluble in alcohol so WHY Na I is included?

Not as hydrotropic agent but rather to allow the tincture to be diluted with H2O with no

ppt.

8. Dakin's solution [Na Hypocrite solution USP]:

*The solution contains 4-6% NaOCl.

*Caution: This solution isn't suitable for application to wounds [not used as antiseptic]

→ why? → because of too strong alkalinity & oxidizing action to be applied to tissue.

*It is similar to commercial household bleach such as Clorox.

*Diluted NaOCl: diluted 10 times [Modified Dakin's solution] → used as germicide &

disinfectant.

9. Hydrogen peroxide topical solution USP (3%): *It is known as 10- volume peroxide→ why?

because 1 ml of solution→ liberates 10 ml of oxygen.

*Use: mild antiseptic for wounds.

*M.O.A: Hydrogen peroxide tissue catalase H2O + O2 Oxidize bacteria.

*1:1 dilution with H2O: Used as mouthwash for treating Vincent's angina.

*6% Hydrogen peroxide solution [20 volume peroxide] → available as a hair & fabric

bleach→ it's too strong for medical use.

10. Chlorohexidine gluconate [4%]: Topical antiseptic # G+ve & G-ve bacteria.

*Skin cleanser. *Hand wash *Surgical scrub (4% solution).

*Oral rinse to prevent oral infection in immunosuppressed pts [M.W].

11. Petrolatum gauze شاش فازلين: It's the 1ry cover used for burns.

*Advantages: a) Exudate flow through gauze.

b) Gauze will not adhere to the wound.

N.B. The best emergency advice for minor burns is Cold H2O.

12. Benzocaine (5%) & Lidocaine: They are effective local anesthetics present in OTC

remedies.

Benzocaine (more common): Lidocaine

*Systemic toxicity is rare due to poor absorption

through skin.

*May cause systemic S.E.

*Hypersensitivity reactions. *Lower incidence of hypersensitivity reactions.

N.B. Benzocaine may be present in some OTC products as Appetite suppressant → HOW?

*It is formulated as lozenges, gum or candies→ ↓ person's ability to detect sweetness →

reduces appetite.

*Put (T) or (F): Benzocaine is suitable as pharmaceutical excipient (F)

13. Phenol (Carbolic acid): possesses both antiseptic & local anesthetic effects but

never used as local anesthetic → WHY?→ It's caustic→ tissue damage.

14. Dextranomer: it is used for ttt of exudating wound only.

*The product consists of spherical beads→ sprinkled onto exudating wound→ the

hydrophilic nature of beads creates strong sucking force→ beads become grayish yellow

when they are saturated with fluids→ so wash away by irrigating with sterile H2O or

saline.

15. Flexible Collodion: contains Camphor +Castor oil.

e.g. Salicylic acid Collodion which is prepared by dissolving salicylic acid in flexible

Collodion.→ keratolytic.

13

16. Ichthammol 10% :مرهم اسود Used for ttt of inflammation & boils.

17. Permethrin: it is a topical Pediculicide & scabicide.

M.O.A: disrupting nerve cell membrane of parasites→ paralysis.

18. Wound debriding agents: "Removes necrotic material from wounds".

1. Collagenase→ [proteolytic].

2. Fibrinolysin→ [Fibrinolytic].

19. Boric acid: isn't used in topical skin preparations for infants→ because it causes

boiled blister rash→ Boron toxicity.

G. Transdermal drug delivery : *Ideal properties of drugs to be formulated into Transdermal delivery systems:

1. High potency with daily dose of 10 mg or less.

2. Lipophilicity.

*Advantage of Transdermal drug delivery systems include:

1. Avoid 1st pass effect.

2. Improves patient compliance.

3. Suitable for drugs with relatively short t1/2.

*e.g. of Transdermal patches:

1. Scopolamine: prophylaxis not ttt of motion sickness.

*applied behind ear 4hrs before antiemetic effect is required. *Effective for 3 days.

2. Fentanyl: ttt of chronic pain→ 72 hrs activity.

3. Nitroglycerin: ttt of angina.

4. Testosterone: ttt of deficiency.

5. 17- estradiol: for postmenopausal women.

6. Nicotine: for smoking cessation (applied 24 h & change location with each

application).

7. Clonidine: Transdermal patch (7 days) → ↓likehood of rebound HTN upon

withdrawal.

*Put (T) or (F): Buspiron is available as Transdermal patch (F).

Available as 100 & 150 mg S.R tabs for smoking cessation.

H. Sublingual tablets : e.g. 1.Isosorbide dinitrate.

2. Nitroglycerin.

3. Hydrogenated ergot alkaloids (Hydergine): mood elevator for ttt of Senile

dementia.

4. Ergotamine tartarate.

N.B. dihydroergotamine is not in form of sublingual tabs.

14

I. Parenterals :

*Needles & Syringes:

1. Hypodermic needles:

a. It is composed of:

a. Hub: *Extension of the needle that fits onto the syringe.

*It's filled onto the syringe body either by a locking system such as luer lock or by

simple friction fit.

b. Bevel: *Portion of needle that is ground for sharpness.

*The back portion (heel) of the bevel is left dull→ a dull heel has been shown to

decrease the incidence of coring of rubber closure & the skin.

c. Cannula: *Shaft portion of the needle.

*Both shaft strength & flexibility are needed

d. Lumen [Bore]: *The hole in the shaft.

b. Hypodermic needle size is expressed by: → gauge numbers.

*Gauge number: it refers to the external diameter of the Cannula.

*The larger the number→ the smaller the diameter.

e.g. 21 gauge needle is smaller in diameter than 19- gauge needle.

*Length of cannula is also specified in inches: it is the distance from needle tip to the

junction with the hub.

c. The bevel length of a hypodermic needle may vary from very short to long.

*Short bevel is preferred for injection→ I.V→ WHY?

To reduce the possibility of perforating the back wall of the vein.

N.B. For Intradermal injection: a very short bevel is preferred.

2. Other needles:

a. Winged needles:

for I.V injection.

e.g. Scalp- scalp vein or butterfly: composed of 2 flexible wing like projections

(plastic) + stainless steel needle.

*Action of wings: 1) Ease manipulation of the needle during insertion.

2) allow the needle to be anchored with tape to the skin.

b. Needle for insulin

injection:

*Only small volumes are injected so: 1) small bore needle [25G-30G].

2) Short [3/8" to 5/8"].

c. Propylene syringes. Can withstand autoclaving.

d. Other plastic syringes. Gas sterilized.

e. Filter needle:

*Used for removal of large particulate matter.

e.g. glass fragments but not suitable to remove pyrogen or bacteria→ why?

because pore size is 5 micron (too coarse).

15

*Some parentral routes: a. I.M: *The I.M injection site that is suitable for child < 3 years of age is Vastus Lateralis→why?

Because it is 1) Largest developed muscle in young children.

2) Free from major nerves & veins.

N.B. Volume limitation should be 1 ml.

b. Intradermal: *The smallest volume of injection.

*This route is usually limited to diagnostic determinations, desensitization or

immunization into forearm.

*Usually only 0.1 ml volumes are used.

c. I.V bolus *= IVP: Intravenous push [bolus].

*Even distribution of drug into the blood after IV bolus takes 4 minutes.

d. S.C: *Q) Although isotonicity is desirable for almost all Parenterals, it is critical for S.C

injection→ why?

Because S.C injection: 1) comes into contact with large number of nerve endings.

2) May remain at injection site for long period.

*If the solution isn't isotonic→ pain.

*Solution injected S.C shouldn't exceed 1 ml.

N.B: T he potential effects of hypotonic or hypertonic I.V injection are offset by their

dilutions in large volume of blood into which they are injected but the volume injected

shouldn't be large & rate of injection must be slow..

e. IV infusion: *The term Venoclysis is most closely associated with I.V infusion

*Hypodermoclysis: it is the intentional administration of IV fluids into S.C tissue→ why?

For patients whose veins are inaccessible e.g. infants or obese patients.

*Maximum volume of fluid that should be administered daily by I.V infusion is 4 L.

f. IV injection:

(infusion &

bolus):

*Suspension isn't suitable for this route→ why?

1. Suspension particles may block blood vessels.

2. Insoluble suspension particles may dissolve faster than desired in blood→ immediate

therapeutic activity when S.R activity is desired.

*Only insulin (regular insulin "soluble zinc insulin crystals) may be taken I.V while

other suspensions are taken S.C.

*Other special routes for injection: 1. Intra-articular: in joint.

2. Intra-synovial: in joint fluid.

3. Intrathecal: in spinal cord fluid.

*Parentral Labels:

Include by Name:1)Antimicrobial preservatives.

2) Isotonicity adjustors.

3) pH adjustors.

4) Antioxidants.

N.B. a) Head space gases aren't written on the label→ they are inert gases that displace

oxygen to ↑ stability.

b) The quantity of pH adjustors isn't written.

**Expiration date that should be placed on the label of parentral admixture prepared in

hospital pharmacy is 24 hours.

16

*Some parentral products: 1. Potassium

injection:

1. Never taken by I.V bolus→ why? → Because it may cause cardiac arrest.

2. May be taken by slow I.V infusion to allow dilution of K+ by blood.

2. Fluorouracil: 1. Routes of administration (Injection & topical).

2. I.V injection [most common].

3. No oral D.F→ Why? Because of irregular absorption from GIT.

3. Heparin Na: 1. May be taken I.V (Bolus→ loading dose/ infusion→ maintenance dose), S.C

2. Never taken I.M→ Why? To avoid local hematoma.

4. Gentamycin

sulfate

[garamycin]:

*Is most stable in aqueous solution.

بودرة ليست و ماء

5. KCl:

الموت الاسود

1. Parentral containers of KCl must be packaged with BLACK-FLIP OFF button→

why? → Because it is very dangerous if infused undiluted & reports say that it caused

many fatalities in hospitals.

N.B. There is no color code for other Parenterals that are packaged in vials.

2. Given by slow I.V infusion.

6. Iron dextran

injection USP:

1. Most iron salts are taken orally except iron dextran.

2. It is a colloidal solution of ferric hydroxide complexed with dextran.

3. Uses: ttt of iron- deficiency anemia that doesn't respond to oral therapy.

7. Diazepam: *It shouldn't be added to any infusion bottle→ why?

Because it will ppt even when added to normal saline or 5% dextrose solution.

8. Ampicillin: 1. The most stable vehicle for Ampicillin is 0.9% NaCl → 8 hrs stability.

N.B. Dextrose 5% → less than 4 hrs stability.

9. Erythromycin

lactobionate:

*If reconstituted with normal saline or other vehicles containing inorganic salts→

ppt→ how to overcome?

Reconstitution by sterile H2O for injection→ once reconstituted, the solution can be

diluted with normal saline or lactated Ringer's solution provided that pH remains in

the range of 6-7.5.

10. Ascorbic

acid:

*Solution of ascorbic acid would be too acidic for injection→ How to overcome?

Add alkali such as NaOH, NaHCO3, Na2CO3→So adjusts H between 5.5 & 7.

11. Anesthetics: *anesthetics & routes of administration: 1) Cocaine→ topical.

2) Dimethisquin→ topical. 3) Mepivacaine→ local injection.

3) Tetracaine→ topical& local injection. 4) Lidocaine→ topical ,local&IV infusion.

5) Procaine→ Intravenous & local injection (not topically due to poor absorption).

Q) Local anesthetic that isn't administered topically is: Procaine.

12. Insulin: 1. Insulin metabolism occurs both in liver & kidney.

2. Drug has a short plasma t1/2→ if injected IV→t1/2: 5-6 mins.

3. Product is available without a prescription e.g. U 100.

4. Single peak insulin is more pure than the former insulin→ Explain!

Single peak: means that it displays a single peak when assayed by chromatography

[this means nearly 99% purity]>>> older insulin products but it still has some

antigenic properties.

5. Single component insulin: refers to insulin that is obtained from single source

usually either pork or beef.

6. Onset of insulin action: a) Fast acting insulin→ 1 hour.

b) Intermediate acting insulin→2 hrs. c) Long acting insulin→ 7 hrs.

7. Characteristics of Insulin syringes: 1) 40U & 100U.

2) Color coded & calibrated. 3) Available as 1ml & o.5 ml

*100U insulin syringe: →0.5ml: it is calibrated in1unit increments to a max. of 50U.

1ml: it is calibrated in 1 unit increments to a max of 100 U.

17

*So for measurement of 25U we use 100U syringe that has a maximum capacity of

50U to↑ accuracy.

*Best needle for insulin injection 25G 5/8".

*N.B. All insulin products currently available are stable at room temp.

So travelling diabetics should be advised to avoid exposure of their insulin to very

high temperature & told that it isn't necessary to refrigerate the vial in use.

*Insulin vials stored in pharmacies are required to be refrigerated because they may

be kept in stock for long period of time.

13.

Amphotercin B:

I.V& Topical.

*Available in vials containing 50 mg of drug as powder.

*Because of Colloidal nature of the product→ only sterile water for injection without

preservative is used for reconstitution.

*It is administered by Slow I.V infusion over 2-6 hrs period.

*Never use electrolytes for reconstitution → why?

Because they will ppt [salt out] the drug.

14. Liposomal

powders:

*They are reconstituted using sterile H2O for injection.

*Don't reconstitute using NaCl→ why? →to avoid breakage of liposomal system.

*Dose< conventional dose→ why? → Because they are formulated as targeted drug

delivery systems→ drug will concentrate in areas of the body in which they are most

active so dose must be decreased otherwise toxicity occurs & vice versa.

(If conventional drug is required & liposomal dose is given→ the dose may be

subtherapeutic.

15. Ampicillin:

(syrup)

*Stored in refrigerator at cold temperature 2-80C But not freezed

**I.V fluids & water:

1. Dextrose & NaCl:

a. 5% Dextrose injection (D5W), Normal saline 0.9%(0.9NS)→ both has osmolarity that is

approximately 300 mosm/L→ so they are iso-osmotic &isotonic with the blood.

Q) A. The osmotic pressure of 0.1 molar dextrose will be approximately how many times

that of 0.1 molar NaCl?→ answer: is (1/2)→ why?

because: Osmotic pressure is one of the colligative properties (colligative properties

depend on no of particles) ∵NaCl is electrolyte that ionized to Na+ & Cl- & dextrose

doesn't ionize ∴no of particles of NaCl is twice that of dextrose so osmotic pressure of

NaCl is twice that of dextrose.

B. Put (T) or (F):

1. D5W/0.9 NS is isotonic (F).

Its osmolality is 600 mosm/L so it is hypertonic.

2. D5W/0.9 NS is very harmful if infused. (F)

Because it is rapidly diluted by blood so it is safe.

3. D2.5 W/0.45 NS is isotonic. (T).

2. Ringer's solution: they are suitable for fluid & electrolyte replacement particularly for post-surgical

patients.

a. Ringer's injection: It's an electrolyte solution which consists of isotonic solution of NaCl, KCl & CaCl2

b. Lactated Ringer: *Similar to Ringer's + Na lactate.

*It is considered to be approximately as extracellular fluid of human body.

*The injection has pH 6-7.5 BUT has an alkalinizing effect→ why?

Because lactate is metabolized to bicarbonate.

18

3. Water for injection:

Water type: Comment:

A. Bacteriostatic

water for

injection USP:

(BSWfI)

*It is sterile H2O for injection that contains one or more suitable antimicrobial agents

*e.g. of antimicrobial agents is Benzyl alcohol→ C.I in premature infants due to fetal

toxic syndrome.

*The maximum volume allowed as a parentral package for bacteriostatic water for

injection is 30 ml→ why?

Because if large volume is infused→ toxicity due to presence of preservative.

*The use of BSWfI is appropriate as reconstituting agent for multi-dose vial

preservative→ فلازم مره كزا على بتتاخد

N.B. It isn't used for single dose vial→ why?

B. Sterile water

for injection

USP:

prepared by

distillation then

autoclaving.

* Water sterilized & packaged in single dose containers of type I & II glass.

*Containers don't exceed 1L.

*The limitation of total solids depends on the size of the container→ Explain!

It is 40 ppm for 30ml vials & 20 ppm for 1L vial because of relatively smaller surface

area.

C. Water for

injection USP:

*It is the form of water that is most commonly used as solvent for Parenterals during

manufacture.

*Prepared by distillation or reverse osmosis.

*It conforms to the standards of purified H2O but it is also Pyrogen free.

N.B Pyrogens: → are bacterial byproducts which cause febrile reaction.

Test:

D. Purified

water USP:

Not used for

injection.

*Obtained by distillation, ion exchange & reverse osmosis……….

*The method of preparation must be indicated on its label.

*Limit of dissolved solid not more than 10 ppm (i.e. it has the lowest permissible level of

dissolved solids).

*It is also not suitable for ophthalmic preparations because it is hypotonic→ irritation.

N.B Purified water (hypotonic) + RBCs→ burst occurs.

N.B.: What happen if we mix NaHCO3 with 5% glucose?

Nothing will happen (but give hypertonic solution).

N.B: *Use of Edeta as chelating agent in parentral solutions & other uses:

EDETA: Ethylene diamine tetra acetic acid

*M.O.A: chelating agent or ligand e.g. edeta (electron donor)+ divalent or more metal

ion→ ring structure complex.

e.g. 1. EDETA is commonly used in parentral solutions to bind trace metals e.g. copper

& iron.

2. EDETA is taken IM to reduce blood levels & depot stores of lead in acute & chronic

lead poisoning & lead encephalopathy→ chelate form with lead is stable, H2O soluble &

readily excreted by the kidney.

*Put (T) or (F): EDETA is the best chelating agent for lithium & sodium (F).

Because they are monovalent ions.

*Storage of parentral solutions:

Q) What is the meaning of " Store in Cool place"?

Cool place temp: 8-150C (46-590 F) so may be stored in refrigerator or cooler set at 590

F.

19

*Packaging of Parentral products:

1. Mini-bottles:

1) They are partially filled glass containers usually consist of 250 ml bottles

containing 50, 100 or 150 ml of either DSW or NS.

2) To these bottles one can easily add drug solutions, taking advantage of the

vacuum present in the mini-bottle.

*Notes: a) Plastic bags are also employed for preparing parentral admixture but

the plastic units don't have vacuum but are flexible enough to accommodate

additional liquids.

b) Glass bottles may be divided into 2 types:

1. Presence of airway tube: extend from rubber stopper to above fluid surface.

2. Absence of airway tube: airway is an integral part of the administration set.

c) Plastic parentral bottles & bags differ from glass units in that the plastic units

have two entry ports→ Explain!

1. One port: covered with latex cap through which pharmacist or nurse can

inject solutions into the unit.

2. 2nd port: IV set is inserted inside it.

2. Piggyback:

1. The term piggyback is most commonly associated with intermittent therapy.

*Intermittent therapy: administration of parentral drugs at space intervals→

how? Pharmacist prepare mini-bottle of drug solution (called piggyback) → this

unit is attached to the tubing of a large volume parentral bottle (LVP) already

hanging on the patient.

*Advantages of this system: 1) saves the patient from multiple injection (reduces

potential for thrombophlebitis = inflammation of vein).

2) Assures high blood levels of the additive drug because minibottle solution is

infused in a short period of time (greater conc. gradient).

3) Avoids stability or compatibility problems.

3. ADD-Vantage system:

*It is a vial attached to a mini-bag of diluents.

*Health professional simply engage the vial into the bag so allowing

reconstitution of the powder.

4. Pharmacy-bulk

packages:

1) Units intended for preparation of sterile Parenterals. These units are ideal

when reconstituting an antibiotic powder for transfer into several mini-bottles so

they aren't used for direct infusion of drugs.

2) They don't have antimicrobial preservative (they are pierced only once & used

in a short period of time).

5. Busher-injector: *It is an automatic device for self administrating (injecting).

*The patient fills it with filled syringe.

*Used mainly by patients using Insulin.

6. Elastomeric containers *Contain elastic balloon that is filled with sterile solution→ slowly but constantly

collapse→ provide steady volume of drug solution (zero order) → pass through

small diameter infusion line.

7. PCA units (patient

controlled analgesia):

a) Originally used for slow infusion of analgesics e.g. Morphine sulfate.

b) Currently used for many other infusion solutions

N.B. Some Abbreviations:

1. KVO: keep vein open by setting up LVP of 5% dextrose or 0.9% NaCl injection for

20

very slow infusion.

2. IVPB: IV push bottle (piggyback).

2. Homogenous & Heterogeneous Systems:

1. Homogenous Systems:

some definitions:

* Solutions: homogenous system of a solute in a solvent.

*Saturated solutions: are solutions that at a given temperature & pressure, contain the

maximum amount of solute that can be accommodated by the solvent.

*Solutes can be: Gases, liquids or solids & electrolytes or non electrolytes.

**Electrolytes: → substances that form ions in solutions e.g. NaCl, HCl & atropine

SO4.

**Strong electrolytes: e.g. NaCl & HCl→ are completely ionized in H2O.

**Weak electrolytes: e.g. aspirin & atropine→ are partially ionized in H2O.

Their aqueous solutions conduct electric current.

N.B. Conductivity: the ability to conduct current in an electric solution by movement of

ions.

**Non electrolytes: substances that don't form ions when dissolved in H2O e.g. Glycerin,

sucrose, urea…..etc.

Their aqueous solutions don't form ions when dissolved in H2O.

2. Colligative properties:

*Colligative properties of solution: are related to total number of solute particles in the

solution but independent of other chemical properties.

*Any of the colligative properties can be used to: → determine tonicity of solutions.

**Colligative properties include the following:

1. Lowering of Vapor pressure:

*Definition of Vapor pressure(Vp) of liquid:

it equals atmospheric pressure 760 mmHg at liquid boiling

point.

*↑ Temperature→ ↑ vapor pressure.

*↑ no. of solute particles in solution→ ↑ B.P &↓ Vp (lowering vapor pressure).

Raoult's law: PA= XA P0A

PA: Partial vapor pressure P0A: vapor pressure of pure A.

XA: mol fraction of the solute A.

2. Elevation of boiling point: it is the point at which the vapor pressure of a liquid

equals atmospheric pressure 760 mmHg.

↑ Number of solute particles in solution→ ↑ B.P (elevation of B.P).

3. Depression of freezing point:

*Definition of freezing point or melting point: it is the temperature at which solid &

liquid phases are in equilibrium under pressure of 1 atmosphere.

↑ Number of solute particles in solution→ ↑ depression of freezing point.

4. Osmotic pressure:

Vant Hoff equation→ defines osmotic pressure.

21

**Methods of calculating isotonicity adjustment (in

practice):

A. NaCl equivalents: → also called E values

*definition: it is the weight of NaCl that will produce the same osmotic effect as 1 gram

of the specified chemical.

e.g. Morphine HCl has E value of 0.15: this means that 1 gm of morphine HCl produces

the same osmotic pressure in solutions as 0.15 g of NaCl.

B. Freezing point depression:

*Blood freezes at (-o.520C) so any solution that freezes at this temperature will be iso-

osmotic with blood.

*It is used for isotonicity adjustment for both ophthalmic & parentral solution in

pharmaceutical industry→ why? → because freezing point can be easily measured.

**Disadvantages of above two methods:

The adjusted solution will be iso-osmotic but may not be isotonic → how to overcome?

For parentral solution to be isotonic:

1) adjust solution to correct iso-osmotic pressure with blood by E value or freezing point

depression.

2) Mix solution with RBCs to observe whether hemolysis occurs, if no hemolysis so

isotonic.

Q) Put (T) or (F):

1) All aqueous solutions that freeze at (-0.520C) are isotonic with RBCs (F).

They are iso-osmotic but not necessarily isotonic.

2) All aqueous solutions that freeze at (-0.520C) are iso-osmotic with each other & with

blood (T).

3) An isotonic solution has the osmotic pressure as blood (T).

*Notes:

1) Solutions that are hypertonic (higher osmotic pressure)→ causes crenation of RBCs→

why? → because H2O passes out of RBCs → crenation (shrink or wrinkled appearance).

2) Solutions that are hypotonic (lower osmotic pressure) → H2O passes into RBCs→ cell

swell & rupture with release of contents of Hb (hemolysis).

3) Some products

e.g. Boric acid- Glycerin – urea & propylene glycol→ cause hemolysis of RBCs even

when they are iso-osmotic with RBCs.

while Glucose→ no hemolysis & it is used in large volume parentrals for infusion.

4) Freezing point of 0.9% NaCl aqueous solution is (-0.520C) → same as human blood&

tears.

C. Henderson- Hasselbalch equation: 1. For weak bases: pH= pka +log (base)/ (salt).

2. For weak acids: pH= pka+ log (salt)/ (acid).

pH: It is the negative log hydronium ion conc.

pka: It is the negative log of ionization constant (dissociation constant).

22

↑pka→ means↓ ability to ionize,

&↓ pka→ ionization→ so strong acids e.g. HCl→ ionize completely into H+ &Cl-so pka

is close to zero (0).

N.B. Salt & acid conc. is expressed in moles.

*Buffer: can be a combination of weak acid & its salt or combination of weak bases &

its salt.

*Buffer action: resistance to change in pH

*Buffer capacity: a) It is the ability of buffer solution to resist change in pH caused by

addition of given amount of à or base.

b) It is the number of gram equivalents of an acid or base that

changes the pH of 1 L of buffer by 1 unit.

*Half neutralization point→ pH = pka→ this means:

log salt/acid= zero→ so salt/acid=1 coz log 1=0 which means salt conc.=acid conc.

At this point the buffer has best buffering capacity.

Q) Complete: Data required to measure pH of buffer system ………. & ……………

Answer: a) pka of the weak acid b) Molar conc. of weak acid (salt/acid).

Q) Drug has pka=6.2, what is the % of ionized to unionized form of this drug in

small intestine i.e. pH =6.2?

Answer: pH= pka→ half neutralization point.

Ionized: unionized

50% : 50%.

Examples of weak bases:

1. Alkaloids:

*Characteristics: 1) poor H2O solubility but are soluble in alcohol.

How to ↑↑ H2O solubility? → by salt formation with strong acid

e.g. Morphine HCl , Morphine SO4 , Cocaine HCl, Atropine SO4 & Pilocarpine HCl.

2) pka>7 3) contains nitrogen in their structure.

4) Stereoisomers with large difference in therapeutic activity is common.

Q) What do you expect upon mixing of?

1. Morphine SO4+ Hydroxyzine HCl→ Compatible……why? → because both have acidic pH

2) Morphine SO4 + Heparin Na→ precipitate……..why?→ because Heparin Na has basic pH while

Morphine SO4 has acidic pH

3) Aminophylline (basic) + Heparin Na→ compatible.

4) Aminophylline (basic) + KCl (neutral pH) → compatible.

5) Morphine SO4 + Dobutamine HCl→ compatible.

6) Tobramycin SO4 + Acetazolamide/phenytoin Na→ incompatible.

2. Haloperidol: *Base with very poor H2O solubility→ how to ↑↑ solubility?

by salt formation e.g. Haloperidol HCl & Haloperidol lactate.

N.B. Haloperidol decanoate: it isn't salt but ester form that dissolves in oil

vehicle →taken I.M & t1/2 is 3 weeks.

*Examples of week acids: → case study.

Acid: Acetic Acetyl salicylic Boric Lactic Salicylic HCl Sulfuric Nitric

Pka: 4.76 3.49 9.29 3.86 2.97 Close to zero

Q)Complete:

1) Boric acid is the weakest acid.

23

2) Salicylic acid is the strongest acid between weak acids.

3) Lactic acid is the best to prepare a buffer with greatest buffer capacity at pH=4.

WHY? because pka of lactic acid nearly= required pH→ this is neutralization point

(greatest buffer capacity).

Notes: 1. All antacid preparations except Al (OH)3→ ↑ pH of urine so ↑ excretion of acidic

drugs & ↓ excretion of basic drugs.

2. Boric acid is an effective buffer in ophthalmic solutions→ why?

because it will make slightly acidic pH when placed in eye→ quickly neutralized by

buffer of lacrimal fluids, it also has weak antimicrobial activity.

3. Nasal & ophthalmic solutions should have the following characteristics:

a. Acidic pH b. Isotonicity c. Ability to resist growth of M.O

d. Only moderate buffer capacity→ why? → to allow the organ's natural buffer system

to overcome any pH difference otherwise irritation results.

4. Phosphate buffers are often used for nasal preparations.

5. Nasal solutions have pH 5.5-7.5 → why?

To prevent interference with normal cilia motion.

*pH of different body areas:

Body area pH Comment:

1. Blood→ pH= 7.4 * Acid base balance maintained by 3 homeostatic mechanisms:

1. Endogenous chemical buffers: e.g. bicarbonate & carbonic à

2. Respiratory control.

3. Renal function.

* Impairment of these mechanisms→ alkalosis or acidosis.

2. Lacrimal fluids→

pH=7.4

*Can tolerate pH 6-8 with minimum discomfort.

*Buffering system of lacrimal fluid is efficient enough to adjust pH of most

ophthalmic solutions.

*However some solutions particularly those that are strongly acidic

drugs→ discomfort.

3. Skin→ pH= 5.5 *Based on measurement of lipid film that covers epidermis.

*Vary greatly between body areas (pH 4→ 6.5)

4. Vagina→ pH=4-4.5 *Acidic→ WHY? → To discourage growth of pathogenic M.O & provide

suitable environment for growth of acid- producing bacilli.

2. Heterogeneous Systems→ Suspensions & Emulsions.

*Stoke's law:

d: particle (or droplet diameter).

g: acceleration due to gravity.

(pp-p f): difference between density of particles (pp) & density of dispersion medium (pf).

Viscosity of dispersion medium.

24

Stoke's law is used for:1. measuring sedimentation rate in suspension

2. measuring rate of creaming in emulsions.

A. Suspensions:

* Lotions, magmas: → they are suspension of finely divided material in small

amount of H2O.

1) Characteristics of suspensions:

a. The ideal suspension consists of: small, uniform sized particles of dispersed phase

suspended uniformly without any tendency to settle.

b. The particle size of suspended particles normally ranges from 0.5- 5.0 microns.

c. It can be used for oral, external or parentral use.

d. Although most drugs decompose following 1st order kinetics, Oral suspension follow

→ Zero Order Kinetics→ WHY? → Because the limiting factor is the amount of drug

actually in solution.

e. Thickening of a suspension will slow its sedimentation, but it is still necessary to get

the product out of the bottle→ How to overcome this problem?

By: 1. Thixotropy: reversible solution- gel system→ this means that it is gel that forms

flowable solution when shaken, on standing, reformation of gel will slow particle setting.

2. Pseudoplastic flow→ greater flow rate after system has been agitated.

N.B. The sedimentation property is best described by Stoke's law.

f. The powders used in suspension are→ H2O insoluble e.g. Calamine, zinc oxide&

propoxyphene napsylate (analgesic).

g. The formulation of suspension requires the following agents: → SPWDF

1. Suspending agent: Acacia, tragacanth, methyl cellulose, carboxymethyl cellulose &

clays e.g. Veegum & bentonite.

2. Flocculating agent. 3. Wetting agent

4. Dispersant. 5. Preservative.

h. A suspended system can be classified into: 1. Flocculated suspension 2. Deflocculated suspension 1. Sedimentation rate: High Very low

2. Particles in dispersed

phase:

In contact with one another→ forms

network like structure.

Exist as a separate entity

3. Sediment: Loosely packed. Forms a hard cake.

4. Redispersion: The suspension can be easily redispersed

by shaking

Cannot be easily redispersed

5. The supernatant

liquid:

Clear Cloudy

i. Problems that may arise in poorly manufactured suspensions:

Caking: → particle settling→ formation of dense pack in the bottom of the container→

it's difficult to break this cake to reconstitute original suspension.

25

B. Emulsion:

1. Definition: it is a heterogeneous system of two immiscible phases, one of which is

water & the other is oil→ Liquid/liquid dispersion system.

*The particle size of an emulsion droplet is 0.1-100 microns.

2. Emulsions are divided into following categories:

1) O/W emulsion: *Water → continuous phase & oil→ dispersed phase

*e.g. Emulsions for oral administration →to hide taste &↑ palatability.

2) W/O emulsion: Oil→ continuous phase & water→ dispersed phase.

3) O/W/O or

W/O/W emulsions:

Also known as multiple emulsion.

4) Microemulsions: *it is W/O or O/E emulsion with particle size 100 A0-600 A0

*Unlike emulsions, they are clear & thermodynamically stable.

*Na lauryl SO4 or Potassium oleate → used as emulsifying agent.

* They are generally used to solubilize drugs in pharmaceutical industry.

5) Nanoparticle

emulsions:

*Similar in size & shape to the globule of microemulsion.

*It is prepared by polymerization process.

* It is used to solubilize drugs, globulins & toxoids.

3. The formulation of emulsion requires the following agents: → PAVE

1. Emulsifying agent

a. Natural: Acacia, Agar, Tragacanth, pectin, gelatin (gelatin is protein), methyl cellulose &

carboxymethyl cellulose.

b. Synthetic→ called surfactants

1. Anionic: *The large active portion of the surfactant bears a –ve charge & would migrate to

anode in an electric field.

e.g. Soaps

Na lauryl sulfate →o/w → is compatible with Icthammol & Econazole NO3.

Dioctyl Na sulfosuccinate→ O/W

Triethanolamine stearate

Ammonium laurate

Docusate Na: stool softener.

2. Cationic: *Active portion (+ve charge) & migrates to Cathode

e.g. Benzalkonium chloride

Cetyl pyridinium chloride.

Cetrimide

*They are incompatible with anionic surfactants.

e.g. Benzalkonium chloride + Soaps→ inactivation.

3. Non-ionic: *No tendency to migrate to either pole in an electric field

e.g.

A. Sorbitan esters (spans): B. Polysorbates (tweens):

W/O emulsifying agents O/W emulsifying agents

Used as wetting agents Used as detergents & solubilizing

agents

e.g. Sorbitan monopalmitate &

Sorbitan monostearate

c. Cetomacrogel: it is incompatible with Tannic acid, ammonium salts & phenol.

26

N.B 1. Cetocteryl alcohol + Na lauryl sulfate→ Anionic

Cetrimide→ Cationic O/W emulsion.

Cetomacrogel 1000→ non ionic

2. Preservatives 3. Antioxidants. 4. Viscosity enhancer

*Important Notes:

1.HLB (Hydrophilic lipophilic balance)→ for classification of Non-ionic surfactants.

*Emulsifiers are given numbers 1-20.

*↓ HLB value→ lipophilic. * ↑HLB value→ hydrophilic

*Mix 2 emulsifiers of different HLB values→ can give best HLB value for certain

emulsion formulae.

*HLB < 9→ W/O emulsion→ spans.

*9-11→ W/O or O/W

*HLB > 11→ O/W

N.B. Some anionic & cationic surfactants have HLB value

*To prepare W/O emulsion: we use W/O emulsifier e.g. spans.

*Nonoxynol: is SAA with spermicidal action.

*Rose oil + Cetrimide 20%→ stabilization by agitation.

*SAA is added to tablets→ to improve dissolution & bioavailability.

*Uses of Surfactants in pharmaceutical products:

1. percutaneous absorption enhancers e.g. Na lauryl sulfate.

2. Cleansing agents e.g. in contact lenses solution.

3. Therapeutic activity e.g. Dioctyl Na sulfosuccinate (Docusate) → it is non-toxic & non-

irritating so used as emollient laxative to soften stools.

Q) How to prepare O/W emulsion of chlorhexidine?

Chlorhexidine is cationic so we use cetrimide (compatible with chlorhexidine as it is

cationic surfactant) to prepare O/W emulsion.

Q) Complete: Wool alcohol is used as emulsifier during salicylic acid preparation.

4. Methods of emulsion preparations:

1. Dry gum method.

2. Wet gum method. Using natural emulsifying agents.

3. Bottle method.

4. Nascent soap method→ use synthetic agents.

5. Problems with the stability of emulsion: A. Creaming: 1. Definition: the concentrated layer of dispersed phase particles in the form of loosely

attached floccules.

2. The emulsion can be redispersed by vigorously shaking the bottle.

3. The rate of creaming can be calculated by Stoke's law.

B. Cracking: 1. It is more severe problem compared to creaming.

2. In cracking, emulsion is destroyed & separated into two phases.

3. Causes of cracking: a) high temperature. b) Addition of electrolytes

c) M.O d) opposite type of emulsifying agent.

C. Coalescence: 1. Particles of dispersed phase merge to form large particles.

* Surfactants usually overcome this problem.

6. Stability of emulsion: → it can be evaluated by :

a) Phase separation: can be calculated by measuring the volume of separated phase after

27

definite time interval.

b) Globule size.

c) Flow properties.

d) The effect of stress on emulsion.

3. Chemical kinetics & Drug stability:

1. Antioxidants: react with free radicals.

A. Oil soluble: B. Water soluble:

e.g. Ascorbyl palmitate

Vitamin E

e.g. Ascorbic acid

Sodium sulfite

sodium bisulfate: it is a mixture of

ingredients (sodium bisulfate + sodium

metabisulfite)→ when dissolved in H2O,

sodium thisulfite is converted to sodium

bisulfate.

S.E: Sensitivity reaction causing difficulty in

breathing.

*Examples of substances liable to oxidation:

1. Epinephrine: *very sensitive to oxidation giving toxic byproducts.

*Early sign of oxidation is the presence of pink color.

*by time it darkens & forms brown ppt.

2. Aminophylline: *by exposure to air, it may change to more toxic form→ how?

*Aminophylline (Theophylline + Ethylene diamine) ↑ water solubility

of Theophylline exposure to air CO2 absorbed

free Theophylline crystals

*USP states: don't use the injection if crystals separated.

2. Denaturation: → occurs for proteins.

*Occurs by changes in temperature, solvent system……etc.

*Even vigorous shaking may cause denaturation so many brochures specify that

reconstitution should be accomplished by gentle rolling of containers between palms.

3. Preservatives:

e.g. Methyl-paraben: it is ester of p-hydroxybenzoic acid.

4. Expiry date & beyond use date:

Q) What does the following means?

1. Expires July 2005→ *the pharmacist may continue to dispense the product till July 31

2005. *The product has lost sufficient activity to meet USP requirements.

2. Beyond use date→

28

4. Sterilization :

A) Sterile areas: HEPA Filters (high efficiency particulate air filters).

Types of laminar flow through hepa filters:

1. Horizontal laminar flow:

* It provides maximum protection for parentral admixture.

*Disadvantages: it offers no protection for the operator when

anticancer agents are being prepared.

2. Vertical laminar flow:

Advantages: it protects the operator when preparing anticancer

agents.

*Disadvantages: ↑ risk of product contamination.

3. Convergent flow

(newest hood design)

*Combines both vertical & horizontal flow

Notes: 1. Alcohol 70% & isopropyl alcohol 70% are two disinfectant solutions used to

disinfect laminar flow hoods before compounding admixtures.

2. Dioctyl phthalate (DOP) Smoke test: ensures that no particle layer that 0.3mm passes through

HEPA filter.

3. When preparing most parentral admixtures, the pharmacist will work in an area at least 6

inches from the edge of benchtop turbulence for flow.

B. Sterilization methods & Equipments:

1. Thermal sterilization:

a. Moist heat sterilization:

(most widely used)

*M.O.A: Objects to be sterilized are exposed to saturated steam

under pressure at temperature of 1210C for at least 15 min→

M.O destroyed by cellular protein coagulation.

* N.B. Autoclave: usually used for moist heat sterilization.

Advantages: less product & equipment damage compared to dry

heat sterilization.

b. Dry heat sterilization: *For materials that can't withstand moist-heat (temperature at

least 1600C for 2 hrs) e.g. for oil, fats & powders.

2. Chemical (gas) sterilization: *Used to sterilize surface & porous materials e.g. surgical

dressings) e.g. Ethylene oxide in combination of heat & moisture.

*N.B. Ethylene oxide gas isn't practical for solutions→ why?

because it leaves residues.

3. Radioactive sterilization: *Electromagnetic or particulate radiation.

e.g. Some ophthalmic ointments

4. Mechanical sterilization

(filtration):

*For solutions.

*It includes: a) Depth filters.

b) Screen (membrane) filters→ types:

1) Particulate filters.

2) Microbial filters.

3) Final filters (either particulate or microbial→

referred to as in line filters→ why?→ because

they are used to remove particulate or M.O from

I.V solutions during infusion.

29

→Characteristics of membrane filtration:

1. Suitable for heat labile solutions.

2.. Convenient for sterilizing small volumes (for

extemporaneously prepared solution)

N.B. Important agents & their method of sterilization:

Agent: Method of sterilization:

1. Dusting powder: By dry heat 1200C for 60 min.

2. PVC (plastic): By autoclaving.

3. Lignocaine, adrenaline,

digoxin & atropine:

By heating at 1150C

4. Benzyl penicillin,

Nystatin & streptomycin:

Thermolabile.

*Most practical method for sterilizing ophthalmic solution is membrane

filtration through 0.2 micron filter.

*American society of health system (AsHp) has developed risk

level classification:

3 levels & level 3 is the strictest.

30

5. Nuclear Pharmacy :

1. Definitions:

A) Isotopes: they are atomic species that have same atomic number (number of

protons), but different number of neutrons (i.e. different mass number).

Mass number= no of protons+ no of neutrons

*Same chemical element with same chemical properties.

B) Rad: it is the amount of radiation energy that has been absorbed by living tissue

(Quantitative measurement of radioactivity).

C) Decay rate: it is the rate at which radioactive atoms undergo radioactive

disintegration.

*It follows 1st order reaction.

*Units for expressing radioisotope decay include Curie (Ci) & Becquerel.

2. Types of radiation:

Electromagnetic radiation: Particulate radiation

e.g. Gamma radiation, X-ray & UV.

*They emit photons.

*High penetration power.

*Gamma radiation: has greatest penetrating power

→ easily penetrate a foot of tissue & several inches of

lead.

e.g. Alpha & Beta radiation.

*Alpha: consists of 2 protons & 2 neutrons.

*Beta: exists in two types negative electrons

(negatron) & positive electrons (positron).

*Low penetration power.

- radiation: has the least penetrating power.

3. Radiopharmaceuticals may be: Diagnostic

Therapeutic

I. Diagnostic radiopharmaceuticals:

*Characteristics: 1. they should contain a radionuclide with a half life short enough to

minimize radiation exposure to the patient yet long enough to allow for collection of

imaging information.

2. The radionuclide should emit Gamma radiation (Gamma camera).

N.B. The dose rate (retrogens/h) from a point source of Gamma emitter varies inversely

with the square of distance

I 1/R2 (I: Gamma intensity & R2: Distance2).

3. Examples:

a) Technetium99m TC: is ideal isotope for diagnosis→ why?

Because t1/2→ 6 hours & emits Gamma radiation.

*It is commercially available as radioisotope generator→ Explain!

→99m TC is produced by radioactive decay of Molybdenum99 (99Mo).

→This 99Mo (parent nuclide) is adsorbed on ion-exchange column made of alumina→ by

decay99Tc is formed & exchanged with Cl- available in 0.9% saline eluate solution

washed through the column.

To separate the long half life parent nuclide (99Mo) from the short half life daughter

nuclide (99Tc).

b) Sodium Iodide 123I:→ Thyroid scan.

II. Therapeutic radiopharmaceuticals:

a) Sodium phosphate 32P: → antineoplastic for ttt of polycythemia (↑RBCs).

M.O.A: causes cell damage by - particulate emission.

b) Sodium Iodide 131I:→ Used for both diagnostic & therapeutic purposes.

*Sodium iodide capsules is carrier free (No diluent used) & capsule is sealed.

1. Diagnostic: → taken in low doses to evaluate nodules:

31

Nodules that don't take Iodine (cold nodules) are usually cancerous→

removed surgically.

Nodules that take Iodine (hot nodules) are usually benign.

2. Therapeutic: → in higher doses for ttt of thyrotoxicosis.