Dosage Forms I Exam I

Front 1

2 general requirements for FDA approval to market a drug product?

Back 1

1. demonstrated safety & efficacy
2. demonstrated process control & validation

Front 2

what are the 2 main stages of research and development

Back 2

pre-clinical and clinical

Front 3

T/F: the pre-clinical stage of research and development has the substages of drug discovery, biological characterization, preformulation, & initial formulations

Back 3

True

Front 4

what is the method of drug discovery?

Back 4

most today result from carefully designed rational research programs

Front 5

put the following steps of drug discovery in order?
lead, target, candidate, hit

Back 5

target-----hit-----lead----candidate

Front 6

this step of drug discovery is the identification and screening

Back 6

hit

Front 7

_________is the preclinical and then clinical drug development of drug discovery

Back 7

candidate

Front 8

identification and validation is which step in drug discovery

Back 8

target

Front 9

T/F: Lead is the identification and validation step of drug discovery

Back 9

False Lead is the identification and optimization step of drug discovery

Front 10

In which stage of research and development do you spend the most money?

Back 10

clinical

Front 11

the biological characterization of drug is its potential for use as a therapeutic agent and is charcterized by examinations of its
a. pharmacology
b. toxicology
c. disposition (what happens when u take it)
d. pharmacokinetics (how fast does it work)
e. all of the above

Back 11

E all of the above

Front 12

preformulation consists of what?

Back 12

physiocochemical properties
analytical method development

Front 13

In essence ________ ________ is the proess of turning an active compound into a form and strength sutiable for human use.

Back 13

dosage formulation

Front 14

once the physicochemical properties are understood, initial dosage forms aredeveloped for use in clinical trials; this is what stage of pre-clinical?

Back 14

initial formulations

Front 15

a comprehensive application delineating all aspects of the pre-clinical studies and the plan for clinical studies

Back 15

investigational new drug application

Front 16

the main purposes of investigational new drug (IND) application

Back 16

1. to protect the rights & safety of the human subjects
2. to ensure that teh investigational plan is sound

Front 17

FDA Review of IND

Back 17

1. 30 day safety review
2. review by experts

Front 18

what happens when IND is reviewed by experts?

Back 18

the application is forwarded to a specific division within the FDA, where it is reviewed by experts within the field

Front 19

what is the automatic time period during which teh drug cannot be administered to humans?

Back 19

30 day safety review

Front 20

For FDA drug classification system, drugs are classified by what 2 things?

Back 20

1. chemical type
2. therapeutic potential

Front 21

What are 3 phases of clinical research & development

Back 21

phases 1,2,& 3

Front 22

what is the purpose of phase 1?
Phase 2/?
phase 3?

Back 22

phase 1: mainly safety
phase 2: mainly effectiveness, but also short term safety
phase 3: safety, effectiveness, & dosage

Front 23

patients in this phase of testing are usually healthy volunteers?

Back 23

phase 1

Front 24

in which phase or phases are patients tested are those that are suffering from the indicated condition

Back 24

phases 2 & 3

Front 25

Number of patients used for each phase of teh clinical part of research and development?

Back 25

phase 1: 20-100
phase 2: up to several hundred
phase 3: several hundred to several thousand

Front 26

what is the length of testing for each phase of the clinical trials?

Back 26

phase 1: several month
phase 2: several months to 2 years
phase 3: 1 to 4 years

Front 27

what is the % of drugs completing each phase of the clinical trials?

Back 27

phase 1 :67%
phase 2: 45%
phase 3: 5-10%

Front 28

during _______ ________, the final formulation is completed as well as the packaging and labeling.

Back 28

clinical studies

Front 29

The new drug application has what kind of data?

Back 29

pre-clinical & clinical data

Front 30

what summaries are found in the new drug application?

Back 30

1.summaries of human pharmakinetics
2. bioavailability
3. microbiology (if it's an antibiotic)

Front 31

what are 4 points addressed in the new drug application?

Back 31

1. a presentation of pre-clinical & clinical data
2. summaries of human pharmacokinetics, bioavailability, microbiology
3. discussion of the benefits and risks of the drug's usage
4. complete proposed product labeling (including dosage)

Front 32

Describe new drug application

Back 32

integrates all data
typically 100K pages or more and takes on average a year to rvu.

Front 33

New Drug application is comprised of what 3 things?

Back 33

1. the application
2. the inspection
3. the decision

Front 34

The inspection for the new drug must comply with what?

Back 34

1. The quality standards contained in the application
2. The quality standards specified in the FDA's Current Good Manufacturing Practice Standards

Front 35

The decision for the new drug application consists of the complete response letter. What will the letter contain?

Back 35

It will either contain an approval stating that the application is approved or it will outline deficiencies and may recommend actions needed to be taken for approval.

Front 36

What is the phase of clinical studies that has post marketing?

Back 36

phase 4

Front 37

What happens in phase 4?

Back 37

following approval, the drug product is continually monitored in clinical investigations which adds to the understanding of the drug's effects.

Front 38

The 3 steps in post marketing?

Back 38

1. phase 4 clinical studies
2. adverse reaction reporting
3. comprehensive annual reports are required.

Front 39

what happens in adverse rxn reporting?

Back 39

The drug's sponsor is required to rvu and report to the FDA all adverse effects reported to them by all sources such as MDs, postmarketing studies, pharmacists, etc.

Front 40

In adverse rxn reporting, who reports to who?

Back 40

The drug's sponsor reports to the FDA

Front 41

what are orphan dz?

Back 41

rare dzs or conditions that affects fewer than 200,000 people in USA

Front 42

what is the problem with drugs and orphan dz?

Back 42

there is no reasonable expectation that costs of research and development for the dz indicated can be recovered by sales of the product.

Front 43

What is the purpose of developing IND for orphan drugs?

Back 43

the purpose is to provide incentives to develop drugs where there is an insufficient market incentive by:

1. giving financial support for clinical trials
2. 7 years of exclusive marketing rights

Front 44

What 4 variations are there in the drug development process?

Back 44

1. IND for orphan drugs
2. Treatment IND
3. Abbreviated new drug application
4. Supplemental new drug application

Front 45

This variation of the drug development process omits nonclinical laboratory studies and clinical studies except those pertaining to bioavailability

Back 45

abbreviated new drug application which is used for generic drugs

Front 46

Define supplemental new drug application?

Back 46

required for certain types of changes like in method of synthesis, formulation, analytical standards, container, manufaturing facilities...etc

Front 47

Define bioavalibality?

Back 47

fraction of an administered dose that reaches the systemic circulation

Front 48

Treatment IND is given for what reason?

Back 48

for patients with life threatening or severely debilitation illnesses, where no satisfactory alternative exists.

Front 49

Give examples of orphan dzs?

Back 49

cystic fibrosis and chronic lymphocytic leukemia

Front 50

Give examples of life threatening or severely debilitating illnesses that go thru treatment IND

Back 50

advanced AIDS
Alzheimer's dz
Advanced Parkinson's dz

Front 51

what is the purpose of treatment IND?

Back 51

to facilitate getting the drugs to these patients while in clincial trials.

Front 52

Give an example of treatment IND & explain?

Back 52

"treatment protocol" where the IND is filed during phase 1 or 2 to allow treatment for the ill patients

Front 53

The stage of drug development during which the physical & chemical properties of a drug substance are evaluated towards the formulation of a stable, safe, and effective dosage form.

Back 53

Preformulation

Front 54

what part of the drug is evaluated during preformulation?

Back 54

the physical and chemical properties

Front 55

what is the purpose of preformulation?

Back 55

to form a stable, safe, and effective dosage form

Front 56

the manner in which a drug is formulated is crucial for what?

Back 56

its bioavailability and acceptability by the patient

Front 57

solution, suspension, tablet, capsule, suppository represents what part of the drug?

Back 57

dosage form

Front 58

during preformulation, 4 points are considered by the physical pharmacist?

Back 58

1. drug is suitable for dosage formulation, for teh desired route of administration
2. drug has sufficient water solubility
3. drug has sufficient lipid solubility
4. drug is sufficiently stable

Front 59

Name the four drug properties that we are interested in?

Back 59

1. physical properties
2. dissolution
3. partitioning
4. stability

Front 60

most drugs are in what state?

Back 60

solid state

Front 61

Most solid drugs are what shape?

Back 61

crystalline

Front 62

Describe the arrangement of the crystalline form of the solid drug?

Back 62

has a repeating or periodic arrangement of the individual moleucles that creates teh crystal lattice

Front 63

T/F: Different molecular arrangements are possible within a solid. A particular arrangement defines the extrnal structure

Back 63

False: a particular arrangement defines the INTERNAL structure

Front 64

The internal structure determines what?

Back 64

the crystal habit

Front 65

Define habit in a crystal solid drug?

Back 65

It's the description of the outer appearance of a crystal

Front 66

How do you get different habits of crystalline form?

Back 66

Different habits can result from minor changes in the synthetic conditions

Front 67

Which solid form, crystalline or amorphous will dissolve faster?

Back 67

amorphous

Front 68

This type of solid form is without distince crystalline structure?

Back 68

amorphous form

Front 69

What is the arrangement of the amorphous form?

Back 69

has no repeating or periodic arrangement

Front 70

This form has random molecules with no crystal lattice, looser arrangement and in slight motion

Back 70

Amorphous form

Front 71

5 things that are affected by the form of the solid drug?

Back 71

1. Flow properties
2. mechanical properties
3. bioavailability
4. melting point
5. solid state stability

Front 72

Give an example of solid state stability

Back 72

Hygroscopicity which is water uptake unto a solid or liquid and which can change the stability of the drug

Front 73

Define polymorphism?

Back 73

capacity for appearing in many forms

Front 74

Depending on crystallization conditions, some drug solids may have at least ________ different molecular arrangements, each giving distinct ___________ species, or polymorphs

Back 74

two
crystalline

Front 75

The different properties of polymorphs?

Back 75

1. intermolecular interactions
2. solubility

Front 76

define matastable?

Back 76

being in an unstable & transient but relatively long lived state of a chemical or physical system

Front 77

Give an example of a molecule with weak molecular interactions

Back 77

amorphous solids b/c they're metastable

Front 78

Which polymorph would be more soluble?

Back 78

metastable polymorphs more soluble than their more stable counterparts b/c of weaker interactions

Front 79

A drug that may crystallize as a combo of pure drug and the solvent of crytallization is called what?

Give ex?

Back 79

solvate

hydrate where water is part of the crystal

Front 80

changes in hydrate form can affect what?

Back 80

solubility

Front 81

How do hydrates affect solubility? explain

Back 81

hydrates are generally less soluble thatn their anhydrous counterparts.
This is because of the energetics of dissolution (the water and drug are holding on to each other more tightly)

Front 82

how do hydrates affect bioavailability?

Back 82

since there is less dissolution of the drug from the water, there is less bioavilability of the drug

Front 83

Particle size of a solid drug can affect what 3 things?

Back 83

1. dissolution rate
2. particle settling in suspensions
3. particle flow

Front 84

The smaller the particle the ________ the dissolution

Back 84

faster

Front 85

The smaller the particle the _________ the surface area

Back 85

greater

Front 86

How did dissolution rate affect griseofulvin as a drug

Back 86

micronization reduced the dose needed by 50% b/c the faster the dissolution the great the bioavailability

Front 87

How did dissolution rate affect nitofurantoin?

Back 87

crystals of the drug were too small and dissolution was too fast. The result was was nausea.

Front 88

what are some factors that determine particle flow as a solid drug property?

Back 88

1. particle cohesiveness
2. particle density
3. particle shape
4. particle size

Front 89

What are 3 variables affected by particle flow?

Back 89

1. mixing & pouring
2. speed of processing during manufacture
3. settling and stratification during handling, mixing, and storage

Front 90

Define stratification?

Back 90

process of arranging in layers

Front 91

Particle cohesivenss of particle flow is affected by what 2 things?

how does each work in affecting particle cohesiveness?

Back 91

electrostatic charge
adsorbed moisture

Electrostatic charge can affect particle interactions
Adsorbed moisture can make the powder sticky

Front 92

A drug must be in _________ to be absorbed and to cause an _________.

Back 92

solution
effect

Front 93

a homeogenous mixture of 2 or more substances

Back 93

solution

Front 94

define a solute

Back 94

the molecular, atomic, or ionic component of a sol'n that is dissolved by the solvent

Front 95

the component of a sol'n that dissolves the solute

Back 95

solvent

Front 96

what are the 4 sol'ns that we need to know & give an example of each

Back 96

1. gas/liquid carbonated h2o, holothane
2. liquid/liquid miscible liquids (eg alcohol in H2O)
3. solid/solid drug in polymer
4. solid/liquid drug in water

Front 97

define miscible liquids

Back 97

liquids that completely dissolve in each other in all proportions

Front 98

this process involves the relocation of a solute molecule from an environment where it is surrounded by identical molecules into a cavity in a liquid where it becomes surrounded by non-identical molecules, with which it may interact to varying degrees

Back 98

process of dissolution

Front 99

each step of the dissolution process involves what?

Back 99

energy

Front 100

T/F: the overall dissolution process can be endothermic or exothermic

Back 100

True

Front 101

tell the difference btwn endothermic & exothermic

Back 101

endo: heat is absorbed
exo: heat is given off or evolved

Front 102

what are the steps in the dissolution of a crystalline solute

Back 102

1.removal of solute molecule
2. creation of a hole in the SOLVENT
3. placement of SOLUTE in the hole
***** See picture in notes under drug dissolution******

Front 103

the concentration of a solute in a saturated solution at a certain temperature

Back 103

solubility

Front 104

How is solubility expressed?

Back 104

the # of mL of solvent needed to dissolve 1gm of solute

Front 105

Relate the solubility of a sol'n to how much solvent is needed for 1 gm of solute

Back 105

the more mL of solvent needed for each gm of solute, the less soluble the sol'n will be.
ex: <1ml of solvent for 1gm of solute means the sol'n is very soluble whereas >10,000mL of solvent for 1gm of solute means the sol'n is very insoluble

Front 106

besides # of mL solvent/gm of solute, how else is solubility expressed?

Back 106

molality
molarity
percentage

Front 107

4 factors governing the solubility of a solid in a water

Back 107

1. nature of the solid
2. nature of the solute
3. nature of the solvent
4. Temperature

Front 108

T/F: metastable polymorph is more soluble than its more stable counterpart

Back 108

True

Front 109

the 2 natures of the solid in sol'n w/ water

Back 109

polymorph
pseudoopolymorph

Front 110

define pseudopolymorph

Back 110

anhydrous crystals are generally more soluble than hydrates & therefore have better bioavailibility

Front 111

give an example of a pseudopolymorph drug

Back 111

ampicillin

Front 112

2 things must be considered for a solute's solubility in water

Back 112

1. molecular structure of the solute
2. ionization state of the solute

Front 113

what defines the molecular structure of the solute's solubility?

Back 113

size, shape, and substituent groups can all be important for solubility

Front 114

what happens in a molecular structure of a solute that has hydrophilic substituents?

Back 114

most can form H+ bonds with H2O.

Front 115

the effect of hydrophilic substituents on water solubility can be dramactic. give an ex of this

Back 115

phenol is 100x more soluble than benzene b/c that alcohol group in phenol increases its solubility dramatically

Front 116

Again with regard with molecular structure of a solute, how does size and shape compare with the substituent grp in affecting the solubility?
Give ex?

Back 116

the bulk of a molecule can be more important than the substituent.
ex of this is estradiol where the corticosteroid ring structure & 2 hydroxyl grps have a solubility of 5mcg/ml

Front 117

__________ __________is one of the most important physiocochemical properties determined during preformulation since it affects both water and lipid solubility

Back 117

the ionization state of the solute

Front 118

the ionization state of the solute affects what 4 things?

Back 118

1. dosage formulation
2. absorption
3. distribution
4. excretion

Front 119

T/F: most drugs have ionizable groups where they are either weak bases, weak acids, or amphoteric

Back 119

True

Front 120

which part of the drug is generally the most water soluble form?

Back 120

the ionized form

Front 121

The degree of ionization is a fxn of medium pH and can be measured by ______.

Back 121

pKa or dissociation constant

Front 122

define pKa?

Back 122

it's the pH at which the drug is 50% ionized

Front 123

be familiar with the henderson hasselbalch equation for acid & base

Back 123

ACID: pH= pKa + log [A-]/[HA]

BASE: pH=pKa + log [B]/[BH+]

Front 124

99.9% of the drug will be ionized at 3 pH units below (for a ______) or above (for an ________) the drug's _______.

Back 124

base
acid
pKa

Front 125

relate ionization of a drug with its pH?

Back 125

for a weak acid drug, it will be unionized in acidic pH. As the pH increases, it will become ionized & therefore its solubility will increase

Front 126

be familiar with modified henderson hasselbalch equations for acid & base?J

Back 126

ACID: pH=pKa + log [S-So]/[So]

BASE: pH = pKa + log [So]/ [S-So]

Front 127

what does S & So stand for?

Back 127

S is the overall solubility of the drug
So is the solubility of the unionized form (S= So+[ ] of ionized form)

Front 128

3 things that pertain to the nature of the solvent in affecting solubility?

Back 128

1. pH of the solvent
2. solvent polarity
3. presence of solubilizing agents

Front 129

how does the solvent pH affect the solubility

Back 129

it affects the drug's ionization state

Front 130

how does the solvent polarity affect the solubility?

Back 130

changing the solvent's polarity to better match the drug's polarity is often used as a method to improve solubility (like dissolves like)

Front 131

how is the polarity of a solvent measured?

Back 131

it's measured by its dielectric constant, w/c is the ability of a solvent to separate oppositely charged ions.

Front 132

name 5 types of solvents

Back 132

1. H2O
2. glycerin
3. propylene glycol
4. ethanol
5. PEG 400

Front 133

Some solvents can also be used as __________ to help solublize drugs

Back 133

co-solvents

Front 134

Chloroform is a type of solvent. why is it not a good co-solvent?

Back 134

b/c it's not miscible in H2O

Front 135

give a couple of examples of solubilizing agents?

Back 135

surfactants, cyclodextrins

Front 136

What is the fxn of co-solvents? what is the exception?

Back 136

When you use co-solvents, you want to decrease the polarity of the solvent.
The exception would be in inhalers where you want to INCREASE polarity

Front 137

How does temperature affect solubility?

Back 137

since dissolution is usually an endothermic process where energy is needed to break bonds in a solid, greater heat (higher temps) would generally increase the solubility of the solid

Front 138

what are some common methods for altering the solubility? (4)

Back 138

1. altering the solid
2. altering the solute
3. altering the solvent
4. adding solubilizing agents

Front 139

how can u alter the solubility of a solid

Back 139

1. create the desired solid form
2. form a solid sol'n or despersion

Front 140

how can u improve the drug's solubility by altering the solid?

Back 140

a drug can be dissolved or finely dispersed in a water soluble solid. This can be done by separating the drug where all the crystals are separated and then mixing them with something hydrophilic

Front 141

what 2 approaches can alter the solute?

Back 141

creating salts
creating prodrugs

Front 142

of all the ways of affecting solubility, what is a very common form?

Back 142

salt formation where you alter the solute; 50% of drugs are done this way

Front 143

which types of drugs can theoretially be transformed into a salt?

Back 143

every drug that has acid or base properties

Front 144

what is the general process of salt formation

Back 144

an ionized drug forms an ionic interaction with a counterion in a solvent containing a strong acid or base

Front 145

in salt formation, what happens to salt?

Back 145

the salt gets crystalized from the solvent

Front 146

how does salt formation affect solubility?

Back 146

it can either decrease or increase drug's solubility

Front 147

what are 2 reasons one would use salt formation to decrease drug solubility?

Back 147

stability
taste

Front 148

how does stability of drug relate to a decrease in solubility when salt formation occurs?
why is this?

Back 148

a solid drug (ie in suspension) is more chemically stable than drug molecules in solution. this is b/c chemical breakdown generally occurs to drug molecules in sol'n

Front 149

how does salt formation to decrease drug solubility affect taste?
why is this?

Back 149

a decrease in drug solubility can help mask a bad taste; this is b/c drugs must be in sol'n (therefore soluble) in order to interact w/ taste bud chemoR

Front 150

give an ex of a drug salt that decreases drug solubility & increase stability

Back 150

propoxyphene napsylate is less solube than prooxyphene hydrochloride & thus more stable under aqueous conditions of manufacture

Front 151

give an ex of a drug salt that decreases drug solubility & mask taste?

Back 151

same drug as the one for stability: proposyphene napsylate is less bitter than propoxyphene hydrochloride b/c its less soluble

Front 152

2 features of why one would want salt formation of a drug to increase solubility

Back 152

1. salt formation can improve drug's water solubility significantly

2. a very low intrinsic solubility (less than 1mg/ml) indicates the need for a salt form for the drug.

Front 153

how does salt formation of a drug increase solubility?

Back 153

b/c of the greater degree of ionic dissociation of salt molecules, there is a greater degree of interaction with water molecules

Front 154

give 2 ex of drugs where their salt formation is more soluble & in what form are they used?

Back 154

1. phenytoin is very slightly soluble in water therefore used an oral suspension while phenytoin sodium is more soluble in water & therefore used for injection

2. ampicillin is slightly soluble in water & is used as an oral suspension while ampicillin sodium is very soluble in water & therefore used for injection

Front 155

T/F: the solubility of the ionized drug needs salt formation b/c it's less soluble than it's unionized form

Back 155

False: the unionized drug needs a salt formation b/c it's less soluble than its ionized form

Front 156

what are some examples of salts for basic drugs?

Back 156

the following anions:
1. hydrochloride
2. sulfate
3. tartrate
4. maleate
5. citrate
6. mesylate
7. succinate

Front 157

what are the salts used for acidic drugs?

Back 157

cationic
1. sodium
2. potassium
3. calcium

Front 158

give 4 drug names that use the hydrochloride salt to form a salt drug?

Back 158

1. pseudoephedrine hydrochloride
2. diphenhydramine "
3. propoxyphene "
4. clindamycin "

Front 159

give a drug name that uses the sulfate salt to form a salt drug?

Back 159

terbutaline sulfate

Front 160

name a drug that uses the salt tartrate to form a salt drug?

Back 160

metoprolol tartrate

Front 161

maleate salt can form what drug?

Back 161

chlorpheniramine maleate

Front 162

citrate salt can form what 2 drugs?

Back 162

tamoxifen citrate & fntanyl citrate

Front 163

mesylate can form what drug?

Back 163

doxazosin mesylate

Front 164

succinate can form what drug?

Back 164

metoprolol succinate

Front 165

sodium can form what 2 drugs?

Back 165

phenytoin sodium & ganciclovir sodium

Front 166

potassium can form what drug?

Back 166

clavulanate potassium

Front 167

calcium can form what drug?

Back 167

leucovorin calcium

Front 168

what are 7 properties of pharmaceutical salts we need to look at?

Back 168

1. pH of sol'ns of drug salts
2. taste (palatability)
3. toxicity
4. lower % of active drug
5. hygroscopicity
6. polymorphism
7. corrosiveness

Front 169

relate pH of salt to its formed sol'n?

Back 169

--salts prepared from weak bases yield more acidic solutions
--salts prepared from weak acids yield more alkaline solutions

Front 170

give 2 ex of drug salts with their pH?

Back 170

1. minocycline HCl IV sol'n has pH of 2-2.8
2. ganciclovir Na IV sol'n has pH of 11.

Front 171

give an ex of salt drug & taste effect?

Back 171

potassium salt drugs tend to have a metallic taste

Front 172

be familiar with drug salt toxicity and % activity of a drug?

Back 172

--some salts are more toxic than others
-- sometimes more of a drug is needed when combined with a salt b/c less of the drug is active when it's combined with a salt

Front 173

a synthetic drivative of a drug that is transformed in vivo to liberate an active drug molecule

Back 173

prodrug

Front 174

a prodrug approach is used to do what?

Back 174

alter the solute (remember a solute can be altered by adding a salt or by using a prodrug)

Front 175

how are most prodrugs formed?

Back 175

they are created with an ester linkage that is cleaved in vivo with the help of esterases

Front 176

what are some pharmacolgical purposes for synthesizing a prodrug?

Back 176

1. biostability/ prolonged action
2. targeting (targeting brain-- lipophilic to cross BBB)
3. solubility

Front 177

what are some pharmaceutical purposes for synthesizing a prodrug?

Back 177

1. taste
2. stability
3. solubility

Front 178

give an example of how a drug decreases solubility?

Back 178

becomes more lipophilic which could improve absorption, distribution and other drug properties

Front 179

For erythromycin, its prodrug EES is given to decrease solubility, tell 3 reasons why?

Back 179

1. better tasting- drug is in suspension
2. bypasses gastric degradation-- erythromycin degrades rapidly in acidic conditions
3. better absorption--more lipohilic

Front 180

1 A prodrug can also increase solubility, what would be a good reason for this?
2 How is it most commonly done?
3 give examples of drugs

Back 180

1. reason: to create a more water soluble prodrug for inje.ction
2. a phosphate group is added to create a phosphate ester derivative. in vivo phosphate ester linkages are cleaved by phophatases.
3. clindamycin phophate, fosphenytoin sodium, dexamethasone sodium phosphate

Front 181

T/F: a phosphate ester is the same as a phosphate salt

Back 181

False: it is not the same.

Front 182

Give an ex of a phosphate salt

Back 182

disopyramide phosphate

Front 183

For some of the more poorly water soluble drugs, the drug's __________ rate will be the most important determinant of its oral _____________.

Back 183

dissolution
bioavailability

Front 184

What can be the rate limiting step for absorption for a poorly water soluble drug

Back 184

it would be the drug's dissolution rate

Front 185

The dissolution of a solid in a liquid basically occurs in 2 consecutive stages, what are they?

Back 185

1. an interfacial rxn that liberates solute molecules from the solid phase
2. diffusion of the liberated molecules away from the solid into the bulk liquid

Front 186

what is the static boundary layer?

Back 186

the area which is very highly [ ] w/ drugs & also known as the stagnant layer.

Front 187

The overall rate of mass transport of the solute from the solid in a liquid will be what?

Back 187

it will be determined by the slowest stage, which is usually diffusion through a static boundary layer

Front 188

what are the factors affecting dissolution rates (Noyes-Whitney)

Back 188

A: total surface area of the undissolved solid
Cs: drug solubility
C: concentration of solute in the bulk liquid
k: dissolution rate constant

Front 189

How does "A" or the total SA of the undissolved solid affect dissolution rate

Back 189

--size of particles: as size decreases, SA increases
--dispersibility of teh powder in the dissolution medium: if the particles clump, they will inhibit H2O acces & therefore dissolution will be slower

Front 190

How does "C" or [ ] of solute in the bulk liquid affect dissolution?

Back 190

volume of the dissolution medium: increase volume, decrease [ ] for ex, taking med w/ a glass of water

any process that removes dissolved solute from the dissolution medium; this is absorption of the drug

Front 191

how does "k" of dissolution rate constant affect dissolution?

Back 191

thickness of the stagnant boundary layer w/c can be decreased by agitation or shaking

diffusion coefficient of solute in the dissolution medium which decreases by an increase in liquid viscosity so the more viscous the sol'n the lower the dissolution
**** if you know something won't dissolve in syrup, dissolve it in H2O first then mix it w/ more viscous sol'n

Front 192

define partition:

Back 192

to move as a molecule from 1 phase to another
ex: between polar and nonpolar phases

Front 193

what is the importance of partitioning btn polar & nonpolar phases?

Back 193

1. traversing the lipid bylayer
2. other relevant partitioning phenomena

Front 194

drugs that traverse a partiular membrane by passive diffusion must __________ into it.

Back 194

partition

Front 195

The drug must have what properties to cross membrane?

Back 195

it should have both some aqueous and lipid solubility

Front 196

besides the lipid bylayer, name 5 other partitions that drugs could go through?

Back 196

1. into fat
2. into microorganisms
3. into plastic
4. btwn oil & water: seen in emulsions
5. btwn chromatographic phases: for drug analysis or separating drugs analytically

Front 197

Fxn of partition coefficient?

Back 197

during preformulation, the ability of a drug to partition btwn 2 poorly miscible (polar & nonpolar) phases is determined by measuring the partition coefficient of the drug

Front 198

If a drug is more lipophilic, how would it affect P (partition coefficient)

Back 198

it would increase it

Front 199

what is the partition coefficient equation?

Back 199

P= [Co]/[Cw]
Co is the drug's [ ] in an organic (nonpolar) phase
Cw: drug's [ ] in the aqueous (polar) phase.

Front 200

What is one of the most important methods for determining a drug's lipophilicity?

Back 200

measuring a drug's partition coefficient

Front 201

what factors determine P?

Back 201

choice of organic phase
effect of ionization

Front 202

which organic solvent best mimics membrane properties?

Back 202

octanol which is the most common organic solvent used

Front 203

what are the 3 oragnic solvents mentioned that determine P?

Back 203

octanol: best mimics membrane properties
butanol: mimics buccal membrane
chloroform: mimics BBB

Front 204

For ionizable drugs, what has the higher P? what does say about polarity of the drug?

Back 204

unionized has higher P which means the drug is less polar

Front 205

where is P generally studied?

Back 205

it's studied over a range of pHs similar to what is found in the GI tract, as a means of estimating where absorption of the drug might be greatest.

Front 206

where might be the absorption of the drug be the greatest?

Back 206

it's more likely absorbed in regions w/ pHs favoring the unionized form

Front 207

what are some factors to consider for GI absorption?

Back 207

1.ionized form of the drug can partition in some cases. an ex of this is very lipophilic corticosteroids
2. ionization is an equilbrium process: when unionized drug is absorbed, some remaining ionized drug becomes unionized to maintain the equilibrium
3. the SA of the absorption site is often more important. SA is greatest in SI-far greater than in the stomach therefore most drugs and nutrients get absorbed there.

Front 208

the extent to which a drug product retains, within specified limits, and throughout its period of storage & use the same properties & characteristics that it possessed at the time of its manufacture

Back 208

drug stability

Front 209

what is the drug product

Back 209

finished dosage form that contains an active drug + inactive ingredient

Front 210

what is the shelf life?

Back 210

period btwn date of manufacture of a drug product & the exp date.

Front 211

what are the properties to be considered relevant to stability of a drug?

Back 211

1. chemical properties
2. physical properties
3. microbiolgical properties

Front 212

what are the drug's chemical properties & what affect can changes in these properties do?

Back 212

it's the chemical integrity where the drug must stay intact.
if there is changes in these properties, therapeutics can be affected, toxicity, and organoleptic properties can also be affected

Front 213

what are some examples where changes in the chemical property of the drug led to toxicity?

Back 213

1. tetracycline can epimeriz and dehydrate to potentially fatal nephrotoxic cpd
2. penicillins can decompose in acidic sol'ns to possibly allergenic cpds.

Front 214

one of 2 moleucles that differ only in the spatial arrangement around a single carbon atom

Back 214

epimerize

Front 215

what causes fanconi's syndrome

Back 215

nephrotoxicity from tetracycline epimerization. rare syndrome

Front 216

what does organoleptic properties mean?

Back 216

susceptible to sensory impressions such as sight, sound, & taste which is a big one

Front 217

give 2 ex of organoleptic properties?

Back 217

1. epinepherine can oxidize to a therapeutically active, but intensely colored product
2. erythromycin can dehydrate to a therapeutically active, but worse tasting cpd.

Front 218

how do physical properties affect stability of a drug?

Back 218

this is also critical b/c crystal structure changes & leads to polymorphism

Front 219

changes in physical structures can affect what?

Back 219

therapeutics & organoleptic properties

Front 220

ex of therapeutics that can be affected with physical properties changes

Back 220

blood levels can change from dissolution changes

Front 221

ex of organoleptic properties that can be affected with physical properties changes?

Back 221

dissolution in suspensions where drug in sol'n elicits taste

Front 222

what are the microbioligical properties that can affect stability

Back 222

microbial invasion of a drug product is consdiered a stability probelm which can be unappealing and even deadly

Front 223

what are the 6 mechanisms of chemical degradation?

Back 223

1. hydrolysis
2. oxidation
3. photolysis
4. dehydration
5. isomerization
6. polymerization

Front 224

what is the most common mechanisms of chemical degradation?

Back 224

hydrolysis & also oxidation

Front 225

define hydrolysis

Back 225

cleavage of a molecule by reaction w/ H2O

Front 226

what are some ex of functional groups susceptible to hydrolytic cleavage?

Back 226

1. esters like in aspirin, procaine, cocaine, & physostigimine
2. amides like in dibucain & chloramphenicol
3. lactams like in penicillins, cephalosporins, chlordiazepoxide
4. lactones like in pilocarpine, spironolactone
****know general structure of each class see notes under chemical degradation mechanisms

Front 227

define oxidation

Back 227

refers to the removal of electrons

Front 228

a type of oxidation that involves the uncatalyzed oxidation of a substrate by molecular O2

Back 228

autoxidation

Front 229

this type of oxidation is a slow process

Back 229

autoxidation b/c O2 is not very reactive

Front 230

molecular oxygen is a ________ __________ & has 2 unpaired electrons with parallel spins

Back 230

triplet diradical

Front 231

what are some other oxygen species that might be more reactive than molecular oxygen

Back 231

superoxide O2-
hydrogen peroxide H2O2
hyroxyl radical OH

Front 232

which reactive O2 is formed with the aid of a metal catalyst

Back 232

Hyroxyl radical which is very reactive

Front 233

free radical mechanism of oxidation involves what 3 things?

Back 233

1. initiation
2 propagation
3. termination

Front 234

This formation of substrate free radicals necessary for the propagation of the chain?

Back 234

initiation

Front 235

what is the formula for initiation?

Back 235

RH + In -----> R + InH

Front 236

the 3 features of initiation

Back 236

1. involves hydrogen abstraction
2. can occur through autooxidation by molecular O2 or w/ other chain initiating radical
3. chain initiating radicals are generated by the action of light, heat transition metals (iron & copper) or reactive cpds (peroxides)

Front 237

what happens in propagation & what is the rxn

Back 237

free radicals grow in #
R + O-O ------> R-O-O
R-O-O + RH -------> R-O-O-H + R

Front 238

free radicals combine to form chemically inert products

Back 238

termination of free radicals

Front 239

what are the rxns for termination?

Back 239

2R-O-O ------> inert products
R + R-O-O -----> inert products
2R -----> inert products

Front 240

what are some functional groups that are susceptible to oxidation & drug ex of each

Back 240

1. phenols -----> morphine
2. catechols ------> epinephrine
3. thols
4. polyunsaturated hydrocarbons

Front 241

this type of chemical degradation is due to chemicl breakdown caused by lite usually by complex mechanisms

Back 241

photolysis

Front 242

what is the most common photolytic mechanism

Back 242

photoxidation

Front 243

define potoxidation

Back 243

include certain hydrolysis + dehydration rxns

Front 244

Give example of a drug that can undrgo photolysis

Back 244

sodium nitroprusside in aqueous sol'n which is used in IV infusions. Shelf life in the dark is 1 yr. Once exposed to light, its shelf life becomes 4 hours!

Front 245

a chemical degradation where a water molecule is eliminated from the chemical structure?

Back 245

dehydration

Front 246

give an ex of dehydration?

Back 246

erythromycin where deydration occurs under acidic conditions to yield a less active product

Front 247

what happens in a physical dehydration degradation?

Back 247

removal of water from a crystal hydrate (this is a type of polymorphism). This process can cause a change in solubility

Front 248

give an ex of some drugs that can undergo physical dehydration degradation?

Back 248

theophyllin hydrate & ampicillin trihydrate

Front 249

conversion of a drug to its optical or geometric isomer

Back 249

isomerization

Front 250

define optical

Back 250

isomerism about an asymmetric carbon atom

Front 251

synonym for cis-trans isomerism

Back 251

geometric isomer

Front 252

give an example of a drug that undergoes isomerization?

Back 252

amphotercin B

Front 253

what is the significance of isomerization?

Back 253

1. 50-60% of drugs are chiral cpds
2. enantiomers can have different bilogical properties w/ ex of albuterol vs levlbuterol
3. drugs marketed as pure enantiomer may racemize w/ ex of thalidomide which undergoes base catalyzed raceization in aqueous media

Front 254

1 of a pair of molecular entities which are mirror images of each other & non super impossable

Back 254

enantiomers

Front 255

the partial conversion of 1 enantiomer into another

Back 255

racemize

Front 256

geometric isomers can differ in their physiochemical properties, what are they?

Back 256

solubility
stability
compatibility w/ other cpds

Front 257

this type of chemical degradation has 2 or more drug molecules that combine to form a complex molecule

Back 257

polymerization

Front 258

give an ex of polymerization? side effect

Back 258

concentrated solutions of aminopenicillins
ampicillin & amoxicillin can form dimers, w/c are thought to be allergenic