Quiz 1 Flashcards
(125 cards)
1
Q
preformulation
A
research activities occurring between drug discovery and the filing of an IND prior to formulation/manufacturing development
2
Q
Goals of preformulation research
A
- choose the correct form (solid/salt) of the drug substance
- evaluate its physical and chemical properties
- understand the stability of the drug as a material under conditions leading to successful development of a viable dosage form
3
Q
Rule of 5
A
1st pass screen
states that acceptable systematic absorption is likely when at least 3 of the following criteria are met
molecular weight <500
c(logP) <5
H-bond donors <5
H-bond acceptors <10
4
Q
Rule of 5 Exceptions
A
- certain antibiotics
- anti fungals (think sporonox)
- Vitamins
- Aminoglycosides
5
Q
Biopharmaceutics Classification system
A
way of categorizing orally administered drugs according to the main factors that contribute to drug delivery by dissolution and passive drug absorption across GI epithelia
6
Q
Class 1
A
High solubility
High permeability
poses lowest risk for development; biowaivers often granted by the FDA
7
Q
Class 2
A
Low solubility
high permeability
dissolution rate-limited absorption; bioavailability can be improved by formulation/dosage form considerations
8
Q
Class 3
A
High solubility
low permeability
permeability rate-limited absorption; rate and extent of absorption of API may be variable throughout GI fluid
9
Q
Class 4
A
Low solubility
low permeability
presents significant problems for effective oral delivery
10
Q
If systematic absorption is greater than or equal to 90% of the administered dose
A
high permeability
11
Q
If systematic absorption is <90% the administered dose
A
low permeability
12
Q
If volume of simulated GI fluid required to dissolve the highest dose of an API is less than 250 mL
A
high aqueous solubility
13
Q
If volume of simulated GI fluid required to dissolve the highest dose of an API is greater than 250 mL
A
low aqueous solubility
14
Q
What is the average of volume of GI fluid?
A
250mL
15
Q
If delta pKa is greater than 0?
A
a salt forms
16
Q
If pKa is less than 0
A
a salt does not form
17
Q
What is the rate of dissolution directly proportional to?
A
the aqueous solubility
18
Q
API salts are more water soluble in a pH that?
A
favors ionization
19
Q
Between what two organs is there a pH jump?
A
the stomach and the duodenum
20
Q
In general the salt with the highest what is selected?
A
Ksp
21
Q
What are the most commonly marketed salts that go with basic API?
A
HCl salts
22
Q
What does the common ion effect do to solubility?
A
decreases it
23
Q
When a solution contains multiple feasible counterions for an API, the solubility of the drug is limited by?
A
the lowest solubility salt
24
Q
How much HCl does the stomach have?
A
160mM
25
Concentrations of the drug greater than Cs adj will do what?
Precipitate out of the stomach and reduce bioavailability
26
How are salts selected?
1. has to reproducibly form crystals for preparation of solid dosage forms
2. crystals cannot deliquesce following adsorption of environmental water
3. crystals must have mechanical properties conducive to solid dosage form manufacturing
4. salt form should not be less chemically stable than the free form
5. salt form should not be more toxic than the free form
27
powder
dry, bulk solid material consisting of very fine particles
28
medicated powders
intimate mixtures of dry, finely divided drugs and or chemical that may be intended for internal or external use
29
granule
any conglomeration of discrete particles; normally multi-component agglomerates consisting of API and excipient particles that have been bound together to enable manufacturing, handling, or administration
30
What are powders and granules commonly used in?
Tablets, hard gelatin capsules, topical, pulmonary, and suspensions
31
Powders and granules for reconstitution can’t be marketed or stored as ?
a liquid product
32
Degradation kinetics in solution/suspension forms are what compared to solids?
much faster
33
What often participates in degradation?
Liquid vehicle used in reconstitution
34
Who is the target populations for reconstitution?
Pediatrics
35
When is reconstitution prepared by pharmacists?
Rx medications
parenteral and peroral medication
multi-dose solutions or suspensions
36
When reconstitution is performed by patients?
non Rx medications
per oral medications
single dose suspensions/solutions
37
Dispensing
defined masses of API and excipients are weighed according to formulation
38
Comminution
homogenization of particle size and particle size distribution to improve flow and mixing properties
compounding scale: trituration
industrial scale: milling
39
Blending
dry powders blended to homogeneity; content uniformity measured to ensure reproducible dosing
compounding scale: blending/co-trituration
40
Glidants
improve flow properties of poorly flowing powders, to help enable homogenous mixing
tends to consist of colloidal or ultra fine particles
41
What do glidants reduce?
adhesion and friction between blend components
42
Colloidal Silicon Dioxide
Cab-o-sil, Aerosil, colloidal silica
colloidal, spherical particles
diameter < 1 um
hydrophobic
glidant
43
Talc
Altalc, Luzenac Pharma, hydrous magnesium silicate
ultra fine/very fine, regularly shaped particles
diameter 10-70 um
hydrophobic
glidant
44
Corn Starch
ultra fine, spherical particles
diameter 2-20um
hygroscopic
glidant
45
Granulation
powder blends are agglomerated into aggregate particles usually consisting of API & excipients
aggregates are held together by binders
compounding scale: wet massing
industrial scale: wet granulation
46
Drying
granulating liquid is evaporated; binder dries and hardens resulting in coarse dry particles
compounding scale: tray drying
industrial scale: fluid bed drying
47
Sizing
dried particles are passed through a screen to break any clumps that may have formed during drying
compounding scale: sieving
48
Wet Granulation
powder blend mixed by high RPM blades
granulating solution added until wet mass reaches desired consistency
49
Fluid bed drying
wet mass transferred to dryer
warm air blown through wet mass; granultating liquid evaporated and removed
50
Binders
polymeric materials as part of the powder blend or introduced via granulation solution
becomes viscous when introduced to water
51
Hydroxypropylmethylcellulose
Hypromellose, HPMC
can be used as a binder in either wet granulation or dry granulation
used as a film-coating polymer and an extended release polymer
52
polyvinylpyrolidone
povidone, kollidon, plasdone, PVP
introduced as a binder solution during wet granulation
53
hydroxypropylcellulose
Klucel, HPC
used as a binder in wet granulation
commonly used as film polymer
54
Acacia
acacia gum, gum arabic
used as a binder in wet granulation
used as an extended release polymer
55
pregelatinized starch
prejel, pharma-gel, lycatab PGS
used as a binder in wet granulation
introduced as a dry component, activated when granulated with water
56
solid oral dosage forms
contain single discrete dose of API, allowing accurate convenient dosing
most common type of dosage form dispensed in pharmacies
57
Advantages of solid oral dosage forms
inexpensive cost to patients/manufacturers
patient compliance/adherence is great
no medical/professional intervention
simple to take correctly
taste/smell/odor masking
fewer special storage instructions
more chemically and physically stable
stop effects of medication by inducing vomiting
sometimes crush/chew or open/empty to aid swallowing
formulate specific delivery profiles
58
Disadvantages of solid oral dosage forms
sometimes crush/chew or open/empty
slower onset of action (especially relative to parenterals)
swallowing may be difficult/impossible for certain populations/circumstances
could be variable absorption, 1st pass metabolism
compression properties of API may be limiting
manufacturing process is less conducive to compounding
59
Aesthetic coating
dissolve on contact with GI fluid; product identification and branding
60
Barrier Coating
dissolve on contact with GI fluid; protects tablet core contents from de-stabilizing influence
61
Functional coating
prolongs drug release from core in some controlled fashion; may dissolve, partially dissolve, gel or remain intact
62
Coating solutions/suspensions are xxx components of a tablet
formulated
63
How are film coats applied?
by spraying a solution or suspension onto core surfaces, which dries to form solid film layer
64
Water soluble film-forming polymers
Hypromellose, Methylcellulose, Povidone, hydroxyethyl cellulose, gelatin
65
water insoluble film forming polymer
ethylcellulose, methacrylic polymers
66
enteric film forming polymer
hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic polymers
67
Titatnium dioxide is an
opacifier
68
Propylene glycol, polyethylene glycol, glycerol are all examples of
plasticizers
69
FD&C pigments/dyes are
colorants
70
What are some examples of tablet classification?
Route of Admin
Manufacturing Method
Delivery Technology
Coating type
dimensions
71
Hard gelatin capsules anatomy
cap
tapered rim
body
locking grove
72
tablet anatomy
face
band
land
film coating
73
Hard gelatin capsules enclosure formulation
gelatin (animal collagen-derived)
hydroxypropylmethylcellulose
74
Soft gelatin capsule enclosure formulation
gelatin (animal collagen-derived)
hydroxypropylated starch, l-carrageenan
75
shell material has a sol-gel temperature of approximately?
37 degrees C
76
At room temperature, the shell polymer is
a solid
77
At body temperature, the shell polymer quickly
liquifies, dissolves into GI fluid
78
Hard gelatin capsules contain how much additional plasticizer?
13-16%
79
soft gelatin capsules contain how much additional plasticizer?
5-8%
80
Hard gelatin capsule fill types
powder/granulate - typically IR
pellet mixture - typically XR
paste
capsule
tablet
81
soft gelatin capsule fill types
solution
suspension
powder
82
The larger the hard gelatin capsule the smaller the?
volume
83
Shapes of soft gelatin capsules
ovoid, ovule
capsule, barrel, elongated
spheroid, spherule
84
antioxidant
used to minimize/slow api/excipient degradation by oxidation
85
surfactant/wetting agent
used in solid oral dosage forms where API/excipients are hydrophobic; helps dosage form interact with aqueous fluids
86
antimicrobial preservative
used in solid oral dosage forms when microbial growth is problematic
87
diluent
provides bulk weight to core/fill materials; should be free-flowing powder
examples: sucrose and mannitol
88
Lactose
lactose monohydrate, lactose anhydrous, spray-dried lactose
diluent
water soluble
very compressible
89
Microcrystalline Cellulose
MCC, Avicenna
diluent
very compressible
absorbs water and swells
90
Calcium phosphate
Di-Tab, A-Tab, Tri-Tab, emcompress
diluent
very compressible
inorganic excipient
91
disintegrant
imbibes water from GI fluid and swells
swelling disrupts mechanical bonds
examples: potato starch and starch
92
Sodium starch glycolate
explotab, explosol, primojel, carboxymethyl starch
disintegrant
93
Crospovidone
cross-linked polyvinylpyrroloidone, polypasdone
disintegrant
94
Croscarmellose Sodium
Ac-Di-Sol, carboxymethylcellulose sodium
disintegrant
95
Tablet making process
1. specified weight of powders/granules filled into a die
2. tons of applied pressure deforms particles in die
3. table core ejected from die, maintains shape imposed during compression
96
Why does the tablet core maintain shape after it is ejected?
the formation of inter-particulate non bonded interactions
97
What does tooling determine?
The size and shape of the tablet
98
Rectification
on compounding scale
empty shells placed in a frame; oriented so that caps and bodies are all in the same direction
99
Separation
on the compounding scale
oriented caps and bodies are separated from one another
100
Filling
on the compounding scale
fill material spread over feed-frame; consistent volume of powder/granulate added to each individual body
101
Repositioning
on compounding scale
caps secured on filled bodies; filled capsules ejected from frame
102
Capsule outputs
compounding scale: 100-1000s of capsules per hour
industrial scale: 40,000-175,000 capsules per hour
103
Which is the more efficient process: tablets or capsules?
tablets
104
lubricant (boundary)
reduces friction between formulation components and manufacturing equipment; prevents materials from sticking to equipment
105
Magnesium sterate
lubricant
water insoluble
very small colloidal particles coat larger formulation particles
molecular structure of aliphatic tails helps absorb mechanical energy
106
What are some examples of insoluble lubricants?
magnesium stearate
stearic acid
glyceryl behenate
107
What is an example of a soluble lubricant?
Polyethylene glycol
108
Powder consolidation occurs during tableting and powder xxx occurs during encapsulation
tamping
109
Drug delivery
dissolution of api molecules into a physiological fluid
110
In conventional PO admin products are swallowed whole and the drug dissolves?
in the stomach
111
PO formulations may dissolve in the small intestines following?
rapid gastric emptying or gastric bypass surgery
112
immediate release
solid oral dosage forms designed to release the majority of API via dissolution into the GI fluid within 30 minutes
113
Immediate release tablets
may not have film coat layer
if film coated its dissolution is rapid
aims to dissolve the majority of API into solution in <30 min
114
IR tablet delivery
1. rapid dissolution of water soluble film coating
2. consolidate composite disintegrates into aggregate particles
3. de-aggregation occurs, results in primary particles
4. dissolution occurs
5. ADME processes
115
IR delivery from hard gelatin capsules
1. Dissolution of gelatin
2a. Slug or granules/pellets disintegrate into aggregate particles
2b primary particles dissolve and ADME processes occur
3a. Deaggregation occurs and primary particles dissolve, ADME processes occur
116
IR Soft gelatin capsule solution fill delivery
miscible base mixes with GI fluid and ADME processes occur
117
IR soft gelatin capsule suspension fill
1. miscible base mixes with GI fluid
2. primary particles dissolve
3. ADME processes occur
118
Dissolution
kinetic process by which API molecules dissolve out of solid particles at a rate initially proportional to their saturation solubility in the aqueous GI fluid
119
(dC/dt) = (DACs)/(Vh)
Noyes-Whitney equation
attempt to model initial dissolution rate; how fast molecules dissolve out of a particle
C = concentration delivered
D = diffusivity in water
A = surface are of particles
Cs = saturation solubility in GI fluid
V = volume of GI fluid (250mL)
h = width of static diffusion layer
120
h is inversely proportional to ?
the dissolution rate
121
(dWs/dt)= - (DA/h)(Cs-(Wd/V))
Nernst-Bruner Equation
initial dissolution rate
Ws = mass remaining in solid
Wd= mass delivered over time
D = diffusivity in water
A = surface area of particles
Cs = saturation solubility in GI fluid
V = volume of GI fluid
h = width of static diffusion layer
122
Initial dissolution rate assumes that change in particle radius is ?
negligible
123
Trituration affects the initial surface area of particles, so therefore it will influence?
dC/dt
124
When the number of particles remains constant, dissolution causes ?
a decrease in surface area
125
(Ws/W0)^(1/3) = 1 - (DCst/phr0)
Hixson-Crowell Cube Root Dissolution model
delivery from monodisperse spherical particles whose radius changes over time
Ws = mass remaining in solid at time t
W0 = initial mass in the solid at time t=0
D = diffusivity in water
Cs = saturation solubility in GI fluid
p = density of the solid
h = width of static diffusion layer
r0 = particle radius
