802 Final Exam Cards

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

1. amorphous polymorph will good solubility and acceptable stability

2. crystalline polymorph with acceptable solubility and good stability

3. meta-stable polymorph with higher solubility and low stability

4. 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

1. directly compressible excipients

2. glidants

3. coloring agent

4. 1 +2

5. 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

1. tablets with sugar coating for taste masking

2. gelatin coated tablets

3. tablet to treat vaginal infections

4. 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

1. sublingual tablets would not disintegrate quickly in the mouth

2. sublingual tablets will have very high hardness

3. sublingual tablets will never require flavoring agents

4. 1 + 2

5. 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?

1. tendency to ionize in physiological environment

2. small particle size

3. acceptable taste

4. 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

1. high solubility

2. high permeability

3. good safety margin

4. 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