Studied by 8 people
Looks like no one added any tags here yet for you.
what are the types of solid forms
amorphous
crystalline
ionic crystals
covalent crystals
metallic crystals
single component polymorphs
multiple component pseudopolymorphs
what is polymorphism
crystalline forms with the same chemical composition but different internal structures (packing, conformation, etc)
can polymorphs be amorphous or have different physical states
yes
what is a polymorph that can change from one form to another reversibly?
enantiotropic
what is a monotropic polymorph
when transition takes place in only one direction
what impact does changing cis or trans conformation have
can change the state of the substance (ie: solid vs liquid at room temperature)
drug X is available in 2 polymorphs which tend to convert from one form to the other. what can you infer from this
drug X exhibits enantiotropic polymorphism
what are the four most important differences that can occur between polymorphs
solubility
melting point
dissolution rate
bioavailability
what is the difference between stable and meta-stable polymorphs
the stable polymorph is more thermodynamically stable but less soluble whereas the metastable polymorph is more soluble but less thermodynamically stable
are metastable polymorphs developed
yes when an acceptable balance between processability and stability can be found
the stable form is generally preferred for development
what are the factors that can affect polymorphism
temperature and humidity
photostability
solvent
grinding
surfactant
compression
how does temperature/humidity effect polymorphism
physicochemical reactions are accelerated at higher temperatures
humidity acts as a catalyst on the solid surface
how does solvent effect polymorphism
can change growth mechanism and morphology
how does grinding affect polymorphism
during the grinding process solid state polymorphic transformation into non-crystalline or metastable form is caused by mechanical action
how does surfactant affect polymorphism
surfactants affect solution mediated transformation of the drug which depends on the molecular and supramolecular structure of the drug
what is it called when molecular adducts incorporate water into their crystal lattice
hydrates
what is it called when molecular adducts incorporate solvents into their crystal lattice
solvates
what effects do solvates have on drug forms
higher solubility in water
not acceptable as API except for ethanolate solvate
why do organic compounds form hydrates in the presence of water
water has a small molecular size
water has the capability to form multidimensional hydrogen bonds
what is remarkable about hydrates stability
it is the most stable solid form in water and the least soluble form in the GI environment
when are stable hydrates with acceptable bioavailability used
when they have better physicochemical properties
when thay may be the only crystalline form of an API
may be useful for developing suspensions
when is the formation of hydrates undesirable
when hygroscopic drugs or dosage forms are stored improperly (such as high humidity) they may lead to the formation of drug hydrates
are non-hydrous/anhydrous solid forms preffered over hydrates
yes
what is a cocrystal
multicomponent solid state assembly of two or more components held together by intermolecular interactions particularly hydrogen bonds
what is a pharmaceutical cocrystal
API + GRAS (generally regarded as safe substance)
what can salt/cocrystal formation change
dissolution rate
chemical and physical stability
crystallinity
hygroscopy
bulk properties
manufacturability
what are amorphous solids
solids that do not posses a welld efined arrangement and ong-range molecular order
what are the properties of amorphous solids
melt over a wide range of temperatures
meta-stable (aka thermodynamically less stable than the crystalline form of the same drug)
higher solubility and dissolution rate than the crystalline polymorph
how do we get amorphous solids
vapor condensation
precipitation from solution
supercooling of liquid
disruption of crystalline lattice
what are examples of intentional amorphous solid formation
precipitation from solution
solvent evaporation
freeze drying
spray drying
what are examples of unintentional amorphous solid formation
disruption of crystalline lattice
grinding
desolvation
compaction
which of the following pharmaceutical solids will you not prefer for dosage forms
amorphous polymorph will good solubility and acceptable stability
crystalline polymorph with acceptable solubility and good stability
meta-stable polymorph with higher solubility and low stability
hydrate with lower solubility and very good stability
3 because low stability is not preffered
what is a eutectic mixture
two or more components which usually do not interact to form a new chemical compound but, at certain ratios, inhibit the crystallization process of one another resulting in a system having a lower melting point than either of the components
what is an example of a eutectic system
lidocaine-prilocaine 1:1 mixture at 25 c
true or false: amorphous solids have a well define crystal lattice and structure compared to the crystalline solids
false
compressed tableets
most common type of tablet
solid dosage form prepared by compaction
multiple compressed tablets can be used for drugs that require different release profiles or with physical incompatibility
what are the advantages of tablets
easy to handle
light and compact
greater dose precision and least variation in content uniformity
enable fractional dosing
lowest cost large scale manufacturing
high stability and durability
what are the limitations of tablets
not all drugs can be compressed into a tablet
consider powder, granules, capsules
some drugs may undergo polymorphic transitions during tableting
can be difficult to swallow
large doses are difficult to formulate
taste masking can be difficult
poor physically and chemically stable drugs may not be compatible
what are the ingredients/excipients used for developing tablets
diluents
binders
glidants
lubricants
disintegrants
flavors, sweeteners, colorants
what are diluents used for in tablets and what are some common examples
increase bulk, provide cohesion/compressibility
microcrystalline cellulose, lactose, sucrose, mannitol
what are binders used for in tablets and what are some common examples
promote particle adhesion to maintain tablet integrity
pregelatinized starch, hydroxyproylmethyl cellulose, polyvinyl pyrrolidone
what are glidants used for in tablets and what are some common examples
ensure free flowing and uniform powder
talc, colloidal silicon dioxide
what are lubricants used for in tablets and what are some common examples
decrease the cohesion between the powder and machinery
magnesium stearate
what are disintegrants used for in tablets and what are some common examples
promote breakdown of the tablet during drug release
sodium starch glycolate, crosspovidone
what are flavors, sweeteners, colorants used for in tablets and what are some examples
menthol, vanillin, aspartame, dextrose, sucrose, dyes
direct compression in manufacturing
do not need granulation, useful in highly compressible materials, requires directly compressible excipients, can be used in drugs that are susceptible to hydrolysis
what are the portions of the tablet compression process
upper punch and die cavity influence tablet shape, size, and markings
the amount of powder filled into the die cavity influences tablet thickness-weight
punches compress to influence tablet thickness
lubricants are used to expel the die cavity with the force of the lower punch
what does plastic deformation do in the tablet compression process
allows the powder particles to deform around each other which increases tablet integrity
which of the following do you definitely need to develop directly compressible tablets
directly compressible excipients
glidants
coloring agent
1 +2
all of the above
4
why do we need tablet coating
decreased damage
improved stability
protects people handling drugs
better patient experience
modified drug release mechanisms
sugar coated tablet
multi-step process to do
improves taste but is time consuming
cannot be used with water sensitive ingredients
big increase in tablet size
gelatin coated tablets
tablets are dipped into a melted gelatin mixture (often presented as caplets)
tamper-proof
cannot be used with water sensitive ingredients
film coated tablets
most common
thin and smooth polymer material
resistant to damage and enables alterations in dissolution characteristics
what are the excipients used for film coating
film former (base) = hydroxypropyl methylcellulose
plasticizer (flexibility) = castor oil, glycerin, polyethylene glycol
surfactants (decrease surface tension for uniform spreadability) = polysorbate 80
anti-foaming agents (ensure smooth coating) = simethicone emulsion
solvents (allow for application) = water and alcohol acetone mixture
enteric coated tablets
gastro-resistant
coated in polymers like cellulose acetate phthalate, polymethyl methacrylates
which of the following tablets does not make sense as a final product
tablets with sugar coating for taste masking
gelatin coated tablets
tablet to treat vaginal infections
enteric coated chewable tablet
4
how is hardness used in tablet evaluation
used as internal quality control parameter
depends on powder compressibility, compression pressure, and amount of binder
how is friability used in tablet evaluation
measure of the tendency for a tablet to powder, chip, and fragment
tablets should not lose more than 0.5=1% of their weight during friability testing
how is tablet disintegration used in tablet evaluation
tablets are tested in water, simulated gastric fluid, or simulated intestinal fluid
ordinary tablets should disintegrate within 5-30 min
enteric coated tablets should not disintegrate within 1 hr in simulated gastric fluid and should in 2 + hours in intestinal fluid
how is tablet dissolution used in tablet evaluation
in vitro testing is done as a quality control measure
sublingual tablets are supposed to rapidly release the drug under the tongue. Using this information identify the FALSE statement from below
sublingual tablets would not disintegrate quickly in the mouth
sublingual tablets will have very high hardness
sublingual tablets will never require flavoring agents
1 + 2
all of the above
5
what are the types of modified release dosage forms
extended release (slowly release to control rate of dissolution, release and absorption)
delayed release (delay dissolution.. enteric is example)
repeat action (two layers to do immediate and delayed)
target release (particular organ or tissue)
what are the drug properties that generally need modified release dosage forms
instability of drugs in the stomach or intestine
drugs that irritate the stomach
drugs with site specific absorption window
drugs with pH dependent solubility
drugs that require multiple admin in a day
what are the physiological/disease specific factors that generally need modified release dosage forms
different pH ranges through the GI tract
diseases that need site specific delivery
disease that need long term treatment
what are the advantages of extended release formulations
less fluctuations in drug blood levels
reduction in drug dosing frequency
enhances convenience and compliance
reduction in adverse side effects
reduce in overall healthcare costs
uniform absorption
what are the drug characteristics for drug used in ER formulations
administered in relatively small doses
possess good margin of safety (aka not a narrow therapeutic index)
they are used in the treatment of chronic not acute disease states
a drug belonging to which of the following BCP class will be the most suitable candidate for the ER formulations
class 1
how can you obtain ER formulations
modifying drug dissolution
controlling drug diffusion rates
extend the GI transit time
coated beads, granules, or microspheres
use of coated agents to delay drug release
can be a mix of IR and ER granules so some may be uncoated
changing the thickness of the coat will provide varying levels of drug dissolution/release
different coats have different release times
microencapsulation
microscopic particles with a thin coating surrounding the drug
thickness tailors drug release
allows the drug to be dispersed across a large section of the intestinal tract
embedding drug in slowly eroding system
allows for er and ir by mixing the drug with an excipient and compressing it into granules, some are not coated in order to achieve immediate release
embedding drug in hydrophilic matrix system
drug release is controlled by diffusion and dosage form erosion
done by mixing drug with hydrophilic matrix (hydroxypropyl methylcellulose), once this encounters the GI fluids it begins to hydrate and form a gel where the drug is release through to allow for the delayed release
embedding drug in inert plastic matrix
drug is granulated with an inert plastic material (polyethylene, polyvinyl acetate, polymethacrylate) to allow the drug to slowly relase from the plastic matrix via diffusion, the plastic matrix may then be covered by IR form to allow for both IR and ER
mechanisms are leaching and fiffusion
ion exchange resins
ionic drugs are passed through an ion-exchange column where a resin drug complex forms and drug release is based on the GI pH and electrolyte concentrations
osmotic pumps
in osmosis controlled drug release
osmotic transport of liquid in to release unit
dissolution of drug within the release unit
transport of a saturated drug solution by pumping of the solution through a single orifice through pores in the semi-permeable membrane
this membrane is usually cellulose acetate
which of the following physicochemical properties must a drug possess to be delivered via ion-exchange resin?
tendency to ionize in physiological environment
small particle size
acceptable taste
low solubility
1
in vitro in vivo correlation
critical to oral extended release dosage forms
three categories A,B,C
A most common
[predictive mathematical model for the relationship between the entire in vitro dissolution and release time course and entire in vivo response time course
Identify the drug property that is NOT preferred to develop ER formulation
high solubility
high permeability
good safety margin
very short half life
4
what can drug ionization effect?
solubility lipophilicity permeability
what is a non-electrolyte
a compound that does not ionize in water
what are examples of non-electrolytes
sugars
alcohols
ethers
esters
ketones
aldehydes
most amides
what is an electrolyte
compound that ionizes in water or an aqueous environment
what is the difference between a strong electrolyte and a weak electrolyte
strong electrolytes completely ionize in water (ie NaCl) while weak electrolytes only partially ionize (ie acetic acid, ammonia)
what are examples of weak acids
carboxylic acids
sulphonic acids
phenols
thioa
imides
what are examples of weak bases
aliphatic amines
aromatic amines
n-heterocycles
define pKa
the measure of strengths of weak acids and bases
remember that pKa only tells the measure of strength not if the compound is an acid or base
lower is stronger
what are the factors affecting pKa
ionizing group
molecular size
medium effects
substituent effects
what are medium effects
solution
pH
solvent
what are substituent effects
type (leaving)
position
which of the following is true
phenols are weakly acidic substances
sodium hydroxide is a strong base
aromatic amines are weakly acidic substances
1+2
all of the above
1+2
understand that aromitic amines are weakly basic and not acidic
what is a polyprotic system
acids or bases that can donate or accept more than one proton
examples include amino acids and proteins
which is the following is the strongest acid
1: APAP (pKa 9.5)
2: Ibuprofen (pKa 4.8)
3: salicylic acid (pka 2.98)
salicylic acid
describe what the henderson hasselbach equation tells us
the relationship between pH and pKa
it determines how much of a compound is ionized to an acid or a base
what occurs when pH = pKa
50% of the drug exists in ionized form and the remaining is in non-ionized form
describe buffer capacity
a measure of the efficiency of a buffer in resisting changes in the pH value
a higher buffer capacity is a more resistant buffer
what is buffer capacity dependant on
ratio of salt to the acid or base (optimal ration is 1:1) total buffer concentration
what is the need for buffering pharmaceutical formulations
maintain solubility of weak acidic or basic drugs
improve stability
maximize preservative efficacy (think ocular formulations)
reduce discomfort and irritation
what is the relationship between pH and pKa and ionization state
the farther away from zero the higher the ionization state (scale from -4 to 4)
which of the follwoing statements is true
1: pKa value does not tell you whether the compound is acidic or basic
2: druggs with multiple pKa values exist
3: pKa value can help understand the ionization of drug inside the body
4: 1+2
5: all of the above
all of the above
Note 
Flashcard (27)