Quiz 1 Flashcards
preformulation
research activities occurring between drug discovery and the filing of an IND prior to formulation/manufacturing development
Goals of preformulation research
- 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
Rule of 5
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
Rule of 5 Exceptions
- certain antibiotics
- anti fungals (think sporonox)
- Vitamins
- Aminoglycosides
Biopharmaceutics Classification system
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
Class 1
High solubility
High permeability
poses lowest risk for development; biowaivers often granted by the FDA
Class 2
Low solubility
high permeability
dissolution rate-limited absorption; bioavailability can be improved by formulation/dosage form considerations
Class 3
High solubility
low permeability
permeability rate-limited absorption; rate and extent of absorption of API may be variable throughout GI fluid
Class 4
Low solubility
low permeability
presents significant problems for effective oral delivery
If systematic absorption is greater than or equal to 90% of the administered dose
high permeability
If systematic absorption is <90% the administered dose
low permeability
If volume of simulated GI fluid required to dissolve the highest dose of an API is less than 250 mL
high aqueous solubility
If volume of simulated GI fluid required to dissolve the highest dose of an API is greater than 250 mL
low aqueous solubility
What is the average of volume of GI fluid?
250mL
If delta pKa is greater than 0?
a salt forms
If pKa is less than 0
a salt does not form
What is the rate of dissolution directly proportional to?
the aqueous solubility
API salts are more water soluble in a pH that?
favors ionization
Between what two organs is there a pH jump?
the stomach and the duodenum
In general the salt with the highest what is selected?
Ksp
What are the most commonly marketed salts that go with basic API?
HCl salts
What does the common ion effect do to solubility?
decreases it
When a solution contains multiple feasible counterions for an API, the solubility of the drug is limited by?
the lowest solubility salt
How much HCl does the stomach have?
160mM
Concentrations of the drug greater than Cs adj will do what?
Precipitate out of the stomach and reduce bioavailability
How are salts selected?
- has to reproducibly form crystals for preparation of solid dosage forms
- crystals cannot deliquesce following adsorption of environmental water
- crystals must have mechanical properties conducive to solid dosage form manufacturing
- salt form should not be less chemically stable than the free form
- salt form should not be more toxic than the free form
powder
dry, bulk solid material consisting of very fine particles
medicated powders
intimate mixtures of dry, finely divided drugs and or chemical that may be intended for internal or external use
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
What are powders and granules commonly used in?
Tablets, hard gelatin capsules, topical, pulmonary, and suspensions
Powders and granules for reconstitution can’t be marketed or stored as ?
a liquid product
Degradation kinetics in solution/suspension forms are what compared to solids?
much faster
What often participates in degradation?
Liquid vehicle used in reconstitution
Who is the target populations for reconstitution?
Pediatrics
When is reconstitution prepared by pharmacists?
Rx medications
parenteral and peroral medication
multi-dose solutions or suspensions
When reconstitution is performed by patients?
non Rx medications
per oral medications
single dose suspensions/solutions
Dispensing
defined masses of API and excipients are weighed according to formulation
Comminution
homogenization of particle size and particle size distribution to improve flow and mixing properties
compounding scale: trituration
industrial scale: milling
Blending
dry powders blended to homogeneity; content uniformity measured to ensure reproducible dosing
compounding scale: blending/co-trituration
Glidants
improve flow properties of poorly flowing powders, to help enable homogenous mixing
tends to consist of colloidal or ultra fine particles
What do glidants reduce?
adhesion and friction between blend components
Colloidal Silicon Dioxide
Cab-o-sil, Aerosil, colloidal silica
colloidal, spherical particles
diameter < 1 um
hydrophobic
glidant
Talc
Altalc, Luzenac Pharma, hydrous magnesium silicate
ultra fine/very fine, regularly shaped particles
diameter 10-70 um
hydrophobic
glidant
Corn Starch
ultra fine, spherical particles
diameter 2-20um
hygroscopic
glidant
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
Drying
granulating liquid is evaporated; binder dries and hardens resulting in coarse dry particles
compounding scale: tray drying
industrial scale: fluid bed drying
Sizing
dried particles are passed through a screen to break any clumps that may have formed during drying
compounding scale: sieving
Wet Granulation
powder blend mixed by high RPM blades
granulating solution added until wet mass reaches desired consistency
Fluid bed drying
wet mass transferred to dryer
warm air blown through wet mass; granultating liquid evaporated and removed
Binders
polymeric materials as part of the powder blend or introduced via granulation solution
becomes viscous when introduced to water
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
polyvinylpyrolidone
povidone, kollidon, plasdone, PVP
introduced as a binder solution during wet granulation
hydroxypropylcellulose
Klucel, HPC
used as a binder in wet granulation
commonly used as film polymer
Acacia
acacia gum, gum arabic
used as a binder in wet granulation
used as an extended release polymer
pregelatinized starch
prejel, pharma-gel, lycatab PGS
used as a binder in wet granulation
introduced as a dry component, activated when granulated with water
solid oral dosage forms
contain single discrete dose of API, allowing accurate convenient dosing
most common type of dosage form dispensed in pharmacies
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
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
Aesthetic coating
dissolve on contact with GI fluid; product identification and branding
Barrier Coating
dissolve on contact with GI fluid; protects tablet core contents from de-stabilizing influence
Functional coating
prolongs drug release from core in some controlled fashion; may dissolve, partially dissolve, gel or remain intact
Coating solutions/suspensions are xxx components of a tablet
formulated
How are film coats applied?
by spraying a solution or suspension onto core surfaces, which dries to form solid film layer
Water soluble film-forming polymers
Hypromellose, Methylcellulose, Povidone, hydroxyethyl cellulose, gelatin
water insoluble film forming polymer
ethylcellulose, methacrylic polymers
enteric film forming polymer
hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic polymers
Titatnium dioxide is an
opacifier
Propylene glycol, polyethylene glycol, glycerol are all examples of
plasticizers
FD&C pigments/dyes are
colorants
What are some examples of tablet classification?
Route of Admin
Manufacturing Method
Delivery Technology
Coating type
dimensions
Hard gelatin capsules anatomy
cap
tapered rim
body
locking grove
tablet anatomy
face
band
land
film coating
Hard gelatin capsules enclosure formulation
gelatin (animal collagen-derived)
hydroxypropylmethylcellulose
Soft gelatin capsule enclosure formulation
gelatin (animal collagen-derived)
hydroxypropylated starch, l-carrageenan
shell material has a sol-gel temperature of approximately?
37 degrees C
At room temperature, the shell polymer is
a solid
At body temperature, the shell polymer quickly
liquifies, dissolves into GI fluid
Hard gelatin capsules contain how much additional plasticizer?
13-16%
soft gelatin capsules contain how much additional plasticizer?
5-8%
Hard gelatin capsule fill types
powder/granulate - typically IR
pellet mixture - typically XR
paste
capsule
tablet
soft gelatin capsule fill types
solution
suspension
powder
The larger the hard gelatin capsule the smaller the?
volume
Shapes of soft gelatin capsules
ovoid, ovule
capsule, barrel, elongated
spheroid, spherule
antioxidant
used to minimize/slow api/excipient degradation by oxidation
surfactant/wetting agent
used in solid oral dosage forms where API/excipients are hydrophobic; helps dosage form interact with aqueous fluids
antimicrobial preservative
used in solid oral dosage forms when microbial growth is problematic
diluent
provides bulk weight to core/fill materials; should be free-flowing powder
examples: sucrose and mannitol
Lactose
lactose monohydrate, lactose anhydrous, spray-dried lactose
diluent
water soluble
very compressible
Microcrystalline Cellulose
MCC, Avicenna
diluent
very compressible
absorbs water and swells
Calcium phosphate
Di-Tab, A-Tab, Tri-Tab, emcompress
diluent
very compressible
inorganic excipient
disintegrant
imbibes water from GI fluid and swells
swelling disrupts mechanical bonds
examples: potato starch and starch
Sodium starch glycolate
explotab, explosol, primojel, carboxymethyl starch
disintegrant
Crospovidone
cross-linked polyvinylpyrroloidone, polypasdone
disintegrant
Croscarmellose Sodium
Ac-Di-Sol, carboxymethylcellulose sodium
disintegrant
Tablet making process
- specified weight of powders/granules filled into a die
- tons of applied pressure deforms particles in die
- table core ejected from die, maintains shape imposed during compression
Why does the tablet core maintain shape after it is ejected?
the formation of inter-particulate non bonded interactions
What does tooling determine?
The size and shape of the tablet
Rectification
on compounding scale
empty shells placed in a frame; oriented so that caps and bodies are all in the same direction
Separation
on the compounding scale
oriented caps and bodies are separated from one another
Filling
on the compounding scale
fill material spread over feed-frame; consistent volume of powder/granulate added to each individual body
Repositioning
on compounding scale
caps secured on filled bodies; filled capsules ejected from frame
Capsule outputs
compounding scale: 100-1000s of capsules per hour
industrial scale: 40,000-175,000 capsules per hour
Which is the more efficient process: tablets or capsules?
tablets
lubricant (boundary)
reduces friction between formulation components and manufacturing equipment; prevents materials from sticking to equipment
Magnesium sterate
lubricant
water insoluble
very small colloidal particles coat larger formulation particles
molecular structure of aliphatic tails helps absorb mechanical energy
What are some examples of insoluble lubricants?
magnesium stearate
stearic acid
glyceryl behenate
What is an example of a soluble lubricant?
Polyethylene glycol
Powder consolidation occurs during tableting and powder xxx occurs during encapsulation
tamping
Drug delivery
dissolution of api molecules into a physiological fluid
In conventional PO admin products are swallowed whole and the drug dissolves?
in the stomach
PO formulations may dissolve in the small intestines following?
rapid gastric emptying or gastric bypass surgery
immediate release
solid oral dosage forms designed to release the majority of API via dissolution into the GI fluid within 30 minutes
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
IR tablet delivery
- rapid dissolution of water soluble film coating
- consolidate composite disintegrates into aggregate particles
- de-aggregation occurs, results in primary particles
- dissolution occurs
- ADME processes
IR delivery from hard gelatin capsules
- 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
IR Soft gelatin capsule solution fill delivery
miscible base mixes with GI fluid and ADME processes occur
IR soft gelatin capsule suspension fill
- miscible base mixes with GI fluid
- primary particles dissolve
- ADME processes occur
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
(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
h is inversely proportional to ?
the dissolution rate
(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
Initial dissolution rate assumes that change in particle radius is ?
negligible
Trituration affects the initial surface area of particles, so therefore it will influence?
dC/dt
When the number of particles remains constant, dissolution causes ?
a decrease in surface area
(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
