RX440 Exam 1

The cost of making a drug is roughly

1 billion

about ______________ drugs have to be screened before one new drug makes it to the market

10,000

the major difference between preclinical and clinical drug development is that clinical testing involves evaluation in __________

humans

compliance is a major goal in formulation development. What is compliance and how does this help?

compliance - the act of following prescription regimen correctly

In formulation development, it is important to consider what formulation will promote compliance for making it easier for patients to take

DRUG >>>> DOSAGE FORM (BOXES)

preformulation to formulation

types of typical preformulation studies performed prior to formulation

1. physical description

2. micoscopic exam

3. melting point

4. polymorphism

5. solubility

6. dissolution

7. PKA/dissolution constant

8. membrane permeability

9. particle size

to formulate a drug into a dosage form, we need additional chemicals called __________

excipients

as the particle size of a drug powder goes down, its total ________ __________ goes up, and dissolution rate also _______ ( inc/dec?)

surface area

increases

a drug has two polymorphic forms, form I and form II. The melting point for form I is 79C and form II is 114C.

1. which form is likely to have a higher solubility

2. which form is likely to have greater stability

1. higher solubility = lower melting point > form I

2. high stability = higher melting point > form II

what are the characteristics that polymorphism can impact

1. strength of the material

2. solubility

3. melting points

4. stability

solubility is a _______________ property of a material, whereas _____________ is a kinetic property

1. thermodynamic

2. dissolution

the ________ coefficient is a good measure of the membrane permeability of a drug molecule

partition

when a drug is added to an equal mixture of an organic phase (typically octanol) and water, the ratio of concentrations in which the drug distributes itself between these two phases is the _____________

partition coefficient

A drug has a logP value of 6. would the drug be hydrophilic or hydrophobic? how do you know?

very hydrophobic (1,000,000 octanol/water)

higher the logP, the more hydrophobic

what is the BCS system of drug classification? describe each of the four classes with respect to solubility and permeability.

Class I = high permeability, high solubility

class II = high permeability, low solubility

class III = low permeability, high solubility

class IV = low permeability, low solubility

which BCS class is most amenable to alteration by preformulation scientists?

class II - they can work to fix solubility issues

which BCS class is least likely to make it to the market due to issues pertaining to bioavailability?

class IV

what is the ionic product of water? from this value, derive an equation for pH.

ionic product = Kw

Kw = [H3O][OH-] = 1 x 10^-14 mol/L

the neutral pH of pure water is 7.0 only when the tempature of water is what?

24/25C

when the temperature increase, the neutral pH of water __________

decreases

the pH of the intestinal absorption site is 3 units below the pKa value of a weakly acidic drug (pka-pH = 3)

what is the percent unionized for this drug?

is this drug likely to have issues with solubility or membrane permeability?

99.9% unionized - membrane permable

0.1% ionized - soluble

likely have issues with solubility (highly hydrophobic)

example of antifungal perservative (prevents microbial growth)

(methyl, ethyl, butyl) parabens, benzoic acid, sodium benzoate

example of antimicrobial preservative (prevents microbial growth)

benzalkonium chloride, chlorbutanol, phenol

ex of a stabilizing agent (prevents decomposition)

antioxidants - ascorbic acid, sodium asorbate, sodium metabisolfate

chelating agents - edetic acid, edetate disodium

example of diluent/filler (increases bulk of formulation)

microcrystalline cellulose, starch, lactose, mannitol

example of a binding agent (causes adhesion)

sodium carboxymethyl cellulose, ethyl cellulose, gelatin

example of a surfactant (helps dispersion)

sodium lauryl sulfate (SLS)

example of an enteric coating agent (for protection)

cellulose acetate phthalete (CAP), shellac

example of an ointment base

petrolatum, polyethylene glycol (PEG)

diffusion is the flow of mass from a high _________ to a low ____________

concentration

define the terms in Fick's first law of diffusion: J = -D (dc/dx)

J = mass flux

D = diffusion coefficient of the solute (cm2/sec)

dc = change in concentration (g/cm3)

dx = change in position in barrier

units for diffusion coefficient

cm2/sec

what equation allows for the calculation of the diffusion coefficient (D) from dissolution testing

the Noyes and Whitney equation

t/f the diffusional boundary layer is a hypothetical layer that explains deviations from Fick's laws.

true

what is the difference between disintegration and dissolution

disintegration - "quick an dirty" main concern is breaking down into smaller parts. cheaper and easier to do

dissolution - dissolving into a solution, drug is run through liquids to measure how much drug remains (going into solution). very complex

the USP disintegration test is conducted at ________C to stimulate conditions of body temperature

37.4C

the polymer associated with human skin and bones is _______

collagen

who was the first to propose the structure of polymers in 1922

herman staudinger

If A and B are two monomeric units, write the structure of:

statistical copolymer:

alternating copolymer:

block copolymer:

graft copolymer:

statisical - random ex: ABBABAABBBBAABABABAABBABBBA

alternating - ABABABABABAB

Block - AAAA-BBBBB-AAAA

Graft - AAAA (BBBB-branch) AAAA (BBBB-) AA

t/f the molecular weight of synthetic polymers cannot be expressed as a single number

true

t/f the weight average molecular weight (Mw) is always greater than, or equal to, number average molecular weight (Mn)

True

the ratio of Mw to Mn is known as

polydispersity (Pd)

polymer MW can be expressed as ________ average or ___________ average molecular weight. the ratio of the two is termed ___________

number

weight

polydispersity

what are the two main components to studying the flow of materials? what are their units?

1. stress (dynes/cm2) = g/cm *s

2. strain = 1/sec

what are the units of viscosity? derive the units from the stress/strain equation

n = F dr/ A dv = dynes cm / Cm2 cm/sec = dynes * sec / cm 2

final = g / cm * sec

three types of non newtonian flow behavior

1. pseudoplastic (shear thinning)

2. dilatant (shear thickening)

3. bingham plastic

where does simple fit in?

list an instrument used to measure the viscosity of a newtonian and a non newtonian matieral

newtonian flow = oswalt viscometer

non newtonian = cone and plate

_________ is a special case of time dependent shear-thinning behavior that is particularly useful in formualting disperse systems for pharmaceutical applications

thixotropy

the typical size of a corse dispersion is _________ micrometers

10-50

t/f suspensions, as a rule, consist of saturated solutions of the dispersed phase suspended in a dispersion medium

true

advantages of using a suspension over a tablet dosage form

- poorly soluble drugs

- taste masking

- certain drugs with hydrolytic degradation pathways

- dose flexibility

- ease of administration

the velocity of settling in stoke's law is a special type of velocity termed as _________ velocity (v). v is directly proportional to _______ _______ and _______ gradient, and inversely proportional to __________.

1. terminal

2. particle size

3. density

4. viscosity

three mechanisms of instability in suspensions

1. aggregation

2. caking

3. crystal (particle) growth

flocculation is a mechanism of controlled aggregation, with the primary goal of preventing ______________.

caking

____________- are an example of flocculating agents

electrolytes, polymers, surfactants

three methods to determine instability in suspensions and emulsions

-particle size measurements using microscopy

-determination of sedimentation rate

- subjecting to freeze-thaw cycles

t/f a suspension degrades by zero order, even though a drug may degrade at first order

true

list two pharmaceutical applications of emulsions

1. delivery of oils/oil soluble drugs through -oral -topical - IV for nutritional source of fatty acids

2. formulation applications - -taste masking of unpalable oils, sustained delivery, protection of some unstable drugs

emulsifying agent in milk and mayo

milk - casein

mayo - lecithin (egg yolk)

three theories that can explain the mechanism by which surfactants stabilize emulsions

1. surface tension theory

2. interfacial film theory

3. oriented wedge theory

the partition coefficient is critical in determining preservative concentration in an emulsion. explain.

LogP determines if it is hydrophilic or lypophilic, it will tell you which is preservative is more compatible.

preservative concentration will need to be determined to tell you what phase its in.

microemulsions tend to be thermodynamically ______________

stable

the important components of an aerosol include a pressurized package, a package concentrate, and a ______________

propellant

t/f the particle size range that can carry a drug to the alveoli is roughly 0.4 to 1 micron

true

t/f aseptic conditions are maintained in aerosols, which limits contamination

true

what layer of the skin are veins and arteries located

dermis

the single most important barrier to drug absorption is a layer of the skin known as

strateum corneum

strateum corneum is about ________mm thick, and is very hygroscopic, absorbing 4-5 times its weight in water

10mm

the strateum corneum contains a sulfur containing fibrous protein called

keratin

the _________ fat layer is the common location for SC parenteral injections

subcutaneous

the layer of the skin called the __________ contains collagen and elastin and also blood vessels

dermis

t/f salicylic acid is an example of a keratolytic agent, which can break down keratin

true

drug absorption through the skin is termed as _______________________ absorption

percutaneous

does the skin retain its barrier property even after skin has been excised? why?

yes, passes slowly through

amount of drug penetrated vs time

as tie increase, amount of drug pentrated increases (upward curve)

what is cutaneous biotransformation

catabolic enzyme activity in the dermis

what is dermal clearance

dermal blood perfusion

t/f permeation enhancers may work by increasing hydration of the skin, decreasing the consisting of the lipoprotein matrix, or by increasing the diffusion coefficient of the drug molecule.

true

three methods of permeation enhancement

chemical agents

iontophoresis

sonophoresis

t/f for transdermal patches, the site of application needs to be rotated to account for dermal clearance

true

four types of ointment bases, in order of increasing hydrophilicity

1. oleaginous

2. absorption

3. water removed

4. water soluble (most hydrophilic)

t/f the fusion method for preparing ointments uses heat

true

t/f unlike the small intestine, the rectum does not have villi or microvilli

true

t/f the administration of drugs through the rectal suppository route has the benefit of partially bypassing the hepatic first pass effect

true

t/f the buffer capacity of the rectum is low

true

cocoa butter has two primary polymorphs: the alpha form and the beta form. the _________ form is the more desirable form for suppository formulations

beta form

PEGs or ______________ _________, constitute some of the most commonly used suppository bases

polyethylene glycols

the normal volume of the tear fluid in the cul-de-sac is roughly

7-8 mL

tear fluid is also called

lacrimal fluid

the typical volume of a drop is

50 uL

t/f the bioavailability of opthalmic solutions is very low, typically 1% of less.

true

ophthalmic drugs have to be adjusted for what?

tonicity

what is buffering? what is the normal pH of lacrimal fluid?

buffering = maintaing pH

pH = 7.4

the adult nasal cavity is highly vascularized and has microvilli. what survival function does this high vascularity and surface serve?

warm, humidify, and filter inhaled air.

liquid formulations intended for administration into the ear may also be called _________ or aural preparations. these use viscous vehicles to ensure maximal contact time

otic

the dried secretions of sweat and sebaceous glands is called ___________. this may contain epithelial cells, fallen hair, dust, and other foreign bodies

cerumen

vehicles used in otic suspensions could be aqueous, such as __________ or non aqueous such as ____________---

aqueous - PEG/glycerin

non aqueous - mineral oil