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Pharmaceutics Final Exam (new material)

solid dosage forms
STUDY
PLAY
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
application of suppositories
coca butter- warmed to room temp and rolled between fingers to soften
glycerinated or PEG- should be moistened with water
pointed end inserted toward orifice
non-laxative ones inserted after defecation
vaginal insertion needs special applicator