Pharmaceutics Final Exam (new material)

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solid dosage forms

definition of POWDER

intimate mixutures of DRY FINELY DIVIDED drugs and/or chemicals that may be intended FOR INTERNAL or EXTERNAL USE

powders are used to make what other formulations types

Solid (tablet, capsule, powder inhalations)
liquid (suspensions, solutions)
semisolid (ointments and creams)

advantages of powder dosage forms

easy dose adjustments
greater stability than a liquid
ease of handling
easily modified into other dosage forms (for taste masking, and unit dosage forms)
controlled release is possible with solid dosage forms

efflorescent powder

release water to atmosphere under relatively low humidity

hydroscopic powder

absorbs moisture from air

deliquescent powder

absorb moisture from air to dissolve

eutectic mixtures

mixture of two or more substances that may liquefy, when intimately mixed at room temp

how does particle size affect powder formulations

small particle size -->more surface area
(more soluble, more degradation, PI should be narrow, better suspendability in suspensions, site of deposition in inhalation, texture in ointments

flow properties influenced by shape and surface morphology

glidents can be added to improve flow propterties

inhalation size for deposition

trachea (10-5 micro)
bronchi (6-2 micro)
alveoli (<2 micro)

how does USP-NF define powder fineness

correlation to table where increased mesh size number relates to smaller hole size

trituration

grinding with motor and pestle

levigation

triturating (grinding) as a paste in insoluble liquid (ointment)

levigation agent

low surface tension and less viscous (cannot solubilize in powder) glycerine or mineral oil

pulverization by intervention

re-crystalization as a thin film after dissolving in a volatile solvent (big crystals-->dissolve in solvent grinded evaporated-->film-->crush to finer powder)

milling

"hitting" (need lots of energy) could change polymorphism of the drug or could ad static charge and have absorption of air

spatulation

grinding/mixing with motor and pestel
not good for large amounts or if you have a potent drug
add excess diluent if you want to prevent eutectic mixture
SMALL VOLUME

geometric dilution method

small amount of potent drug has to be mixed wiht a large volume of diluent; LARGE VOLUME

xg of drug + xg of diluent is mix1
mix 1 + 2Xg of diluent is mix2
mix 2 + 4Xg of diluent is mix 3

diffusion

redistribution of particles by RANDOM MOTION
(vertical or axial)
rotational blenders

convection

transfer from one location to another
(motion imparted by impeller as in Ribbon Blender)

Shear

formation of slip planes
high intensity mixers (blade cuts from top to bottom)

disadvantage of blending powders

if different (Size, Density, Porosity) properties can cause STRATIFICATION

stratification

exception

segregation of larger and smaller particles

denser material will move down even if the particle size is smaller

exception: sometime, the fine particles may absorb onto the large particles resulting in better flow and no segregation

topical bulk powders

"dusting powders"
contain diluents (starch or talc)
absorb material and prevent bacterial growth

aerosol powders

for inhalation(1-6 micro in diameter)

oral powders

if dose is large volumes of the powder they can be mixed with liquid or soft food

douche powder

dissolved in warm water by the patient for vaginal use

chartulae

divided powder sachets

definition of granules

prepared agglomerates of powder particles (4-12 sieve size in range) = BIGGER

wet granulation method

granule preparation method where a paste is made and then passed through a sieve and dried

dry granulation method

put in sheets by rollers and then put through punches (SLUGS)
mechanical granulation process

advantage of granules over powders

less segregation- uniform distribution
better flow properties, more stable to moisture because of decreased surface area, less likely to cake during storage and better wettability

what happens to porosity when powders are under compaction

decrease after compaction (air comes out of powder)

or
increase after compaction (DIALATANCY) gets larger

define capsule

solid dosage form in which the drug SUBSTANCE IS ENCLOSED WITHIN either hard or soft SOLUBLE SHELL "container dosage form"

advantages of capsules

odorless and tasteless
easily swallowed (slippery)
elegant (different colors)
fewer manufacturing steps
fewer analytical tests
preferred in clinical trials
CR release granules could be incorporated

disadvantages of capsules

expensive than many other dosage forms. may stick to esophagus

shells are mostly made from

gelatin
also made with starch
Cellulose

gelatin is made from

partial hydrolysis of collagen obtained from the skin, white connective tissue and bones of animals

Type A- pig skin
Type B- animal bones

types of capsules

hard gelatin capsules
soft gelatin capsules (soft gels) oily and elastic

comparison hard and soft

hard: not plasticized
soft: plasticized (glycerin, propylene glycol, sorbitol)
SOFT IS MORE ACCURATE

plasticizers give them the rubber band effect and lower glass transition temp

different sizes of hard gelatin capsules

000 Large-->5 (small)
M- smaller than 5 and used in preclinical trials
selection of size depends on dose and density

hard gelatin capsules for animals

7 is large and 13 is small

shells in pharmacy

empty shells are available for pharmacy compounding and clinical trials

capsule shell should have moisture content of 13-15%
dry-brittle; wet- soft and sticky
(hydroscopic)

dipping process of making hard gelatin capsules

dipping, drying, stripping, trimming, joining endes

cap and body

cap is larger and goes around body

in pharmacy (hard gelatin capsules)
method and components (including excipients)

blend ingredients, fill capsule, SEAL AND POLISH

contains:
drug
fillers/diluents
disintegrants
glidents (flow)

should conduct compatibility studies before mixing

types of material forms that can go in capsule

powder or granule (most often), pellets, tablet in capsule, liquid or eutectic mix (make paste with diluent)

hygroscopic substances, highly soluble salts are not perferred for hard gelatin capsules

sealing process

friction by traditional or banding
snap fit
liquid sealing
heat welding

then cleaned and polished

soft gelatin capsule made of

gelatin with plasticizers (glycerin or sorbitol) render the gelatin elastic

high water content may need preservatives (parabens)
hermetically sealed (air tight) (formed filled and sealed in one step

rotary die process of making soft gelatin capsules

2 gelatin sheets are passes through twin rotating dies while filling with medicine
the pockets of fill are sealed by pressure and heat and collected in a refrigerated tank

what are soft gelatin capsules filled with? what shouldn't they be filled with?

water immiscible liquids (oils)
low concentrations of water miscible liquids <5% (glycol or glycerin)
solids, pastes and suspensions

not filled with volatile compounds in high amounts
liquids that easily migrate through the capsule shell (alcohol, ketones, water)

weight variation QC test

weighing by subtraction (10 caps)

content uniformity QC test

tested by specific ASSAY for the drug content in each individual capsule

disintegration QC test

capsules are placed in basket rack and repeatedly immersed 30times/min
capsule should disintegrate completely into a soft mass (No palpably firm core)

dissolution QC test

apparatus (basket or paddle)
samples are collected at regular intervals and assayed to see how much dissolved

goal- reasonable prediction of in-vivo activity
product optimization, quality assurance, and batch to batch variation

stability QC test

drug-excipient interaction, accelerated stability testing and stress testing (temp and humidity)

moisture permeation test

capsule package is stored at different RH(humidity)
look for change in color or weight, pre or post weight of package unit

lozenges

solid preparations intended to dissolve or disintegrate slowly in the mouth
contain one or more medicaments, usually in a flavored sweetened base

prepared by MOLDING or COMPRESSION of sugar based tablets

tablet definition

unit solid dosage forms usually prepared with the aid of suitable pharmaceutical ADJUNCTS

advantages of tablets

unit dose
make special release forms
most stable of all oral preparations

disadvantages of tablets

some drugs resist compression
technological challenge
problems with bioavailability

tablet drug release

tablet disintegrates and goes through dissolution to become in solution and pass biological membrane and get into blood stream

3 types of tablet classes

preparation (molded, compressed, multiple compressed)
coating (sugar, film, enteric)
special (buccal/sublingual, chewable, effervescent, instant disintegrating/dissolving, extended release, vaginal)

molded tablets
also known as
prepared by
advantage
limitation

table triturates
force dampened tablet material into a mold form and then dried

advantage- quickly disintegrates
limitation- small size and low weight (long process to make)

compressed tablets

MOST common
high pressure is used to compact material (punch)

multiple compressed tablet
advantages
limitation

tablet within a tablet/ layered table

advantages:medicinal agents are separated to prevent incompatibility
each layer provides drug release at different stage
limitations:tedious and expensive, requires precision machinery

sugar coated tablets
advantages
disadvantages

coating is sugar-based, water soluble and quickly dissolves after swallowing, may be colored

advantage: protect form air and humidity, masks odor and taste, enhances appearance

disadvantage: time and expertise, increases size and weight

film-coated tablets
advantage

covered by a thin film of a polymer

advantage: durable, less bulky, less time consuming than sugar

enteric coated tablets
advantage

resists dissolution or disruption in the stomach but not the intestine

advantage: protect drugs that are destroyed in acid, protect stomach from drugs that cause irritation to the gastric mucosa

buccal or sublingual tablets (flat or oval)

intended to dissolve in the buccal pouch or beneath the tongue

buccal- dissolves slowly for sustained release
sublingual- dissolves rapidly for quick release

both avoid presystemic elimintation

chewable tablets
common diluent

chewed and allowed to dissolve in mouth
mannitol-common diluent (negative heat of solution (endothermic))-cooling
and flavor

(dental gums for local action)

effervescent tablets

tablets made by effervescent salts
fast acting
acid + bicarb--> drug + water and CO2 released
endothermic-takes energy

instant dissolving tablets

dissolve in mouth within one minute
prepared with water soluble excipients
SOFT DIRECT COMPRESSION or LYPHILIZATION

fast disintegrants, no strong binders (fall apart)

vaginal tablets

uncoated and bullet shaped which are inserted into vagina for localized effect antibacterial

dental cones

after extraction of teeth
packed in socket for antibacterial, astringent, coagulant effects

diluents in compressed tablets

used to add bulk to the volume "fillers"
insoluble or soluble

binders in compressed tablets

hold the ingredients in tablet together (important to get the required mechanical strength) "Sticky"

disintegrating agents

help breat tablet apart in the GIT (release drug for absorption) "breaker"

glidants

improve flow properties (talc, Mg stearate)

lubricants

reduces friction between tablet and the walls of the die cavity or punch "prevent sticking in production"

colorants

have to be FDA approved colors

wet granulation method for compressed tablets

process of using a SOLUTION BINDER to the powder mixture
manage amount of liquid because overwetting-->too hard and underwetting--> too soft and friable

steps in wet granulation and which excipients are added at each step

weigh and blend (drug + diluents and disintegrants), prepare wet mass (binders, adhesives) screen into pellets or granules, dry, dry screen (smaller to get uniform granules), lubrication and blending(add glidant for flow, lubricant for friction and antiadherent for stickyness to die or punch), tablet by compression( granule size depends on the tablet size)

wet screen then dry screen

fluid bed granulation method for compressed tablets

all-in-one granulation
blending (drugs, diluents, and disintigrants (not glidants)), granulation, drying in "blender"
ONE step

dry granulation for compressed tablets

blending (fine powder), roller compaction(flakes), size reduction(granules-hammer), lubrication, compaction into tablets (passed through screen)

rationale behind granulation

prevent segregation
improve flowability
improve compaction due to better distribution of the binder within the granules
improve homogeneity

direct compression method
advantage
disadvantage

compressing directly from a powder blend
advantage-fewer steps, no heat or liquid (for heat labile or water sensitive drugs), faster dissolution
disadvantages- only for free flowing and compressible powders, could be expensive (diluents and disintegrants)

tablet punch

single punch (fill, remove excess, pressure, push out)- top and bottom punch

capping

partial or complete separation of the top and bottom crown
cause- dirty punches, too dry granules, improper lubricant

lamination

the separation of tablet into two or more layers
cause-air entrapment, too hydrophobic lubricant, rapid decompression

chipping

breaking off tablet edge
cause- too dry, too little binder, incorrect machine setting

picking

removal of a tablet's surface material by punch
cause- too moist, too little lubricant, too warm or too much binder

sticking

adhesion of the table material to the die wall
cause- too moist, too little lubricant

cracking

fine cracks on the upper and lower central surface of table (very rarely on the side walls)
cause- too dry too cold too large of granules

mottling

unequal distribution of color
cause- dye migrates to surface while drying or improper mixing

advantages to tablet coatins

improve stability,
mask taste or odor
drug release (enteric or delayed)
aesthetics or distinction

prevent inadvertent contact with drug
increase strength
cover imperfections

types of coating

sugar (syrup)
film (polymer)
gelatin
compression coating (tab in tab)

sugar coating

involves successive application of sucrose-based coating formulations to tablet cores

sealing, subcoat, smooth, color, polish, imprint

sealing of tablet core in sugar coating

prevent moisture penetration (if hygroscopic present)

subcoating

3-5 cots
applied to round the edges and build up the size
add thick syrup binder and gelatin and then dust with sugar or starch. drying rate is critical

smoothing

fill the imperfection caused by subcaoting (5-10 coats- heavy syrup)

finishing and coloring
polishing
imprinting

roll tablets in LIGHT syrup (may be colored) in a clean pan
polishing (carnauba wax)
imprint

disadvantages of sugar coating

tedious and time consuming
expertise and trained technicians
size and weight doubled
batch to batch variability (even within same batch)
large mass may all stick together

film coating

involved the deposition of thin uniform film of a polymer layer surrounding a tablet
polymer may be aqueous (evaporate in water) or non-aqueous(evaporate, toxic, expensive)

other ingredients in filmcoating

platicizer for increased flexibility and decrease glass transition temp
alloying substance (water sol that lets water get to disintegrant if coated with water insol)
surfactant- spans or spreads
opaquants /colorants
gloss providers (bees wax)

enteric coating

type of film
that includes polymers like (methyacrylic acid co-polymer C
that are not soluble in acidic pH

advantage- more durable, less bulky, easy and less time consuming

gelatin coated tablets

geltabs
soft smooth easy to swallow with water
coating (gelatin of capsule shaped tablet)

problems with coating

picking/chipping, roughness, sticking, film cracking/peeling

packing and storage of tablets

air tight containers with low humidity (no extreme temps)
store with desiccant (silica gel) or blister pack (if sensitive to moisture)
store in light resistant container if light sensitive

storage of nitroglycerin tab

evaporates or explosive
glass container with metal screw cap
no more than 100/container
warning-keep in original container and closed
room temp storage

quality control tests for tablets

set up in us pharmacopeia
bulk density/tapped, particle size, loss on drying (before)

weight variation, tablet friability, disintegration, dissolution, container permeation tests, and labeling of inactive ingredients

buccal do not have

disintegrants
want to stick to cheek and slowly release

hardness test for quality control for tablets (USP DOES NOT REQUIRE)

applied compression with greater pressure for harder tablet
should resist breakage during packaging, shipping and storage
disintegrate when needed

apply increasing pressure on the tablet until the tablet breaks

friability testing (for UNCOATED TABLETS)

abrasion and shock (friabilator)
pre weigh and drops tablets as it turns
<1% weight loss is acceptable

weight variation and content uniformity

weight 10 or more
content- check homogeneity of batch through assay in each individual tablet

tablet disintegration

placed in basket/rack, immersed 30times /min and passed through screen
(no palpable mass)

dissolution

basket or paddle apparatus
sample at intervals and assay

definition of suppository

solid dosage forms intended for administration into body orifices where they melt, soften, or dissolve and exert local or systemic effects

use and types

mainly rectal (suppository)

occasionally- vaginal (pessaries) or urethral (bougies)

sizes and shapes

rectal 4gm adult and 2 gm child (big bullet)
vaginal 3-5gm with oval applicator (pessaries)
urethral - long and thin (bougies)

rectal- local effect

pain, itching, and hemorrhoids**
astringents, antiseptics, local anesthetics
vasoconstrictors (prevent bleeding), anti inflammatory and some laxatives**

vaginal-local effect

contraceptives, antiseptics, antimicrobials

urethral-local effect

antibacterial or local anesthesia, erectile dysfunction

systemic effect- rectal

only route used for systemic medication using suppositories
-those who can't take meds orally
-ideal for unstable drugs in upper GIT or irritating
-lower rectum-no first pass metabolism
-colon has less enzymatic activity against proteins

advantages of suppositories

self admin
avoid oral and parenteral
avoid first pass
protect from harsh stomach
alternative if it causes nausea or vomiting
if oral intake is restricted before surgery
patients with severe vomiting

targeted delivery system (localized action and reduced systemic distribution)

disadvantages of suppositories

patient compliance
mucosal irritation
erratic and undesired absorption (too high-->first pass) and installation may cause defecation
state of GIT affects absorption (diarrhea and disease states)
can melt at ambient temperatures

ideal base for suppository

put drug in base (melt it and pour in into a mold)

nontoxic or nonirritating to mucous membrane
compatible with drug and other ingredients
remain molten for enough time to pour into molds but solidifies rapidly to minimize sedimentation of dispersed solids, contracts on cooling to allow easy removal from mold, melt at or below body temp or dissolve in body fluids to release med

what does the suppository base effect

rate and extent of release of medications

types of bases

fatty acid or oleaginous bases
water sol bases (hydrophilic)
mix of fatty and water soluble bases

drug release in oleaginous bases

melts at body temp and spreads quickly

drug release in hydrophilic bases

dissolves in body fluids slowly and diffuses from fluids

example of fatty acid or oleaginous base

theobroma oil (coca butter)

theobroma oil

TAG
yellowish-white, solid, brittle fat, unsaturated

melts non irritating oil at body temp
need refrigerated for storing**

little contraction after cooling so LUBRICANT is required
prone to oxidation (store in cold, dark place)

exists in 4 polymorphic forms (different MP)
heat for short time to minimize formation of unstable low MP forms

cetyl steryl wax can be used to increase melting point

warnings with theobroma oil

do not raise temp to high, do not heat for too long, do not rapidly cool : nucleation theory

nucleation theory

do not heat above 34.5 for long time cause need seed crystals to get lowest form and then heat enough to remove higher but keep lowest
heat enough so some of lowest is still present and acts as seed
prolonged--> no seed
tricks- add see from stock

using hydrogenated fatty acids

no polymorphism (unaffected by overheating)
solid at room temp
mostly saturated (low iodine number)
small temp difference between melting and solidification so soldify quickly
show marked contraction so no lubricant necessary
MORE EXPENSIVE-disadvantage
immediate release

water soluble bases

more of extended release
dissolve in body fluids rather than melting at body temp
make with high MP substances, drug release is slow, safe storage at room temp, ease and slow insertion

examples: glycerinated gelatin, polyethylene glycol

glycerinated gelatin

dissolves slowly for prolonged release

most frequently used for vaginal suppositories
where prolonged action is required
20% gelatin, 80%glycerin 10% water

urethral suppositories are prepared with higher concentration of gelatin (80%)

can absorb moisture (because of gelatin)
protect form atm moisture and may have dehydrating effect upon insertion (cause irritation) wet with water before insertion

poyethylene glycol (PEG)

water soluble base that vary in length, MW and physical state

dissovles slowly for prolonged release
imcompatible with drugs prone to oxidation
interact with polyethylene (do not dispense in these types of plastic containers)

mixtures of bases

emulsion (mix cocoa butter with emulsifying agents)
soap may be used as base as simple laxative

3 ways to prepare a suppository

fusion or molding (most common)
compression
hand rolling

steps in molding

calibrate mold and determine amount of base
melt base in water bath
add medicaments
lubricate mold (for cocoa butter and gelatin)
pouring with little excess
allow mold to cool
scrape off excess and remove from mold
trimming packaging, labeling

how do you calibrate the mold and determine amount of base

volume of suppository base melt per mold cavity, make 10 with base, measure average weight, and volume after melting D=W/V
amount of base=displacement value(density factor)

density factor

used to determine how much of a base will be displace by a drug (depends on density of drug and base)
=density of drug/density of base
=weight of drug/weigh of base displaced
weight of drug/ D factor= weight of base displace
if factor is not available use double casting method (Paddock)

double casting method

determine average weight of 10 blank suppos=A
grams of drug/ suppository x 10
melt half of base (5xA)
incorporate drug and partially fill cavity
fill remaining of cavity with a melt of the blank base
determine the average weight of drug loaded suppositories (C)
B/ (A+B-C)=density factor
or total added to supp - weight of supp=weight displaced

preparation with molding

incorporated in melted base portion
hard crystalline material are dissolved in min amount of solvent**
lubricate mold
pour excess melt

compression method of preparation

uniformly mixed material compressed like tablets inside a mold

used in large scale
for heat labile and insol drug subs

hand rolling method of preparation

used with coca butter (easy to manipulate at room temp)

mixed with grated butter and rolled into uniform cylinder witha spatula
rolled mass is cut into appropriate sizes
no heat, equipment, or special calculations (not elegant)

stability and storage of each type
glycerin
coca butter
light sensitive

glycerin- tightly closed container (hygroscopic)
coca butter- stored in refrig (individually wrapped (adhere to each other)

light sen- in opaque container

quality control for suppositories

appearance, texture, weight variation, content uniformity, fragility, melting range test, disintegration test, drug release test

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