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pharmaceutics
PHAR 331
Dr. Hani Shtaya
What is pharmaceutics?
• The art and applied science of dosage form design
– The interface between drug and body
• A broad field that draws from many disciplines
– Physical chemistry (organic and inorganic)
– Medicinal chemistry
– Anatomy, physiology
– Microbiology
– Atomic physics
– Engineering (chemical, material)
• Deals with many aspects of interactions both inside and
outside the body
• It’s not trivial to design and implement a dosage form that
is both safe and effective for the drug’s intended use!
Pharmaceutics is unique to pharmacy
• Physicians and other prescribers don’t learn
and apply physical pharmaceutical principles
• Chemists and engineers don’t learn a whole
lot of biology
• Anyone can read the latest review article of a
disease state and play armchair prescriber, but
it takes a pharmacist to know how to deliver a
drug safely and effectively!
PHARMACODYNAMICS
Site/mechanism of action, potency, efficacy, etc.
PHARMACOKINETICS
absorption, distribution, metabolism, excretion
ADME
From drug substance to
pharmaceutical preparation
• Active drug substance (active pharmaceutical ingredient -
API)
• Excipients (inactive pharmaceutical ingredients)
– Technological, biopharmaceutical and/or stability
reasons
– Diluents/fillers, binders, lubricants, desintegrants,
coatings, preservants and stabilizers, colorants and
flavourings
– Should always be stated in SPC (important in the case
of allergies)
From drug substance to
pharmaceutical preparation
• Pharmaceutical dosage form
– determines the physical form of the final pharmaceutical preparation
– is a drug delivery system which is formed by technological processing
(drug formulation)
– must reflect therapeutic intentions, route of administrations, dosing
etc.
• Pharmaceutical preparation (PP)
– particular pharmaceutical product containing active and inactive
pharmaceutical ingredients formulated into the particular dosage
form.
– Packed and labelled appropriately
– Two major types of PP according the origin:
• Manufactured in large scales by pharmaceutical industry
(original and generic preparations)
• Compounded individually in compounding pharmacies
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
6
Logistical considerations of dosage
form design
• Storage
– Rate of degradation (expiry)
• Liquid/solid?
• What conditions?
– Temperature
– Humidity
– What container
• How inert is it? What is the risk for contamination?
• Compatibility
– Active vs. active vs. “inert” ingredients
– Container (again)
• Organoleptic considerations
– Physical appearance, taste, smell, size
– “Pharmaceutical elegance”
• Manufacturing
– For a powder, how well does it flow?
What you must know to design a
dosage form
• Physicochemical properties of the drug
– Reactivity, stability
– Solubility, acid/base, solid state behaviour
• Biopharmaceutical considerations
– What is the intended site of action?
• Systemic? Topical?
– Where/how well is the drug absorbed?
– What is the intended onset of action?
• Immediate-release, sustained-release, pulse releases
Example: estrogen
• Indication: hormone replacement therapy for
treatment of symptoms of menopause
• Molecule administered is
– Conjugated estrogens
– Estradiol
– Estrone
• Dosage forms
– Tablets (Estrace®)
– Transdermal patch (Estraderm®, etc.)
– Transdermal gel (EstroGel®)
– Vaginal ring (Estring®)
Some questions
• About the drug
– Aqueous solubility, pKa, partition coefficient
– Chemical stability in solution
• About the dosage form
– Dissolution characteristics
– Transdermal characteristics
– Stability in storage
• About the biopharmaceutics
– Extent of absorption
– First-pass metabolism
– Intended use: topical vs. systemic?
Each dosage form caters to a different
need
• Compressed tablet
– Contains micronized estradiol
• Micronization improves dissolution
– 1 to 2 mg/day po
• Estradiol is highly metabolized
• Transdermal
– Bypasses first-pass metabolism
– Patch: 0.05 to 0.1 mg/day, applied twice weekly
– Gel: 0.75 mg/day
• Vaginal ring
– Topical application of estradiol for local symptoms
– Average 7.5 µg/day  90 days
The need for dosage forms:
1- Accurate dose.
2- To protect the drug substance from the destructive influences of
atmospheric oxygen or humidity (coated tablets, sealed ampuls).
3- Protection from gastric acid.
4- Masking taste and odour.
5- Placement of drugs within body tissues.
6- Sustained release medication.
7- Controlled release medication.
8- To provide optimal drug action from topical administration sites.
9- Insertion of drugs into body cavities (rectal, vaginal)
10- To provide liquid preparations of substances that are either insoluble or
unstable in the desired vehicle (suspensions)
11-To provide clear liquid dosage forms of substances (syrups, solutions)
Why the drug should be converted into dosage forms ?
They are classified according to:
Route of administration Physical form
Oral Solid
Topical Semisolid
Rectal liquid
Parenteral Gaseous
Vaginal
Inhaled
Ophthalmic
Otic
Types of dosage forms
Classification of pharmaceutical dosage forms
according to its physical properties
• Dosage forms
– Homogenous systems
– Dispersion systems – one phase (dispersed phase) is distributed throughout
another one (continuous phase, dispersion medium)
• According to the size of dispersed particles (1 nm- 0,5 mm) a molecular, colloidal
and coarse dispersions can be distinguished
• May require shaking before administration
• According to the overall physical properties of dosage forms (both
homogenous and dispersion systems) one can distinguish
– Gaseous dosage forms(Aerosols, inhalation)
– Liquid dosage forms(Ear drops, Elixirs, Syrup…..)
– Semisolid dosage forms(Creams Jellies Ointments )
– Solid dosage forms(Tablets ,Suppositories , Capsules ………)
– Light dosage forms(UV,  rays….)
Classification of pharmaceutical dosage forms
according to the route of administration
– Oral (Powders, tablets, capsules, solutions, emulsions, syrups, elixirs, magmas, gels,
cachets, pills.)
– Parenteral (Solutions, suspensions, emulsions.)
• IV, IM, SC, etc.
– Ophthalmic, otic
– Nasal(Solutions, sprays, inhalations.)
– Rectal, vaginal, urethral (Suppositories, tablets, ointments, creams, douches, foams.)
– Buccal
– Topical
– Transdermal (Ointments, creams, powders, pastes, lotions, plaster)
A list of dosage forms
• Solid dosage forms
– Powders
– Tablets
– Capsules (hard, soft)
– Suppositories*
– Ointment, cream, gel, etc.*
– Aerosol
– Lozenge
– Cigarette
• Liquid dosage forms
– Solutions
– Suspensions
– (Gas)
• Light
– UV
–  rays
• Many administration routes
– Oral
– Parenteral
• IV, IM, SC, etc.
– Ophthalmic, otic
– Nasal
– Rectal, vaginal, urethral
– Buccal
– Topical
Dosage Form Design: Pharmaceutical
and Formulation Considerations
Chapter 4
Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 17Pharmaceutics PHAR 331
1- The Need for Dosage Forms
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
18
1- The Need for Dosage Forms
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
19
1. To provide for the safe and convenient delivery of accurate dosage
2. For the protection of a drug substance from the destructive influence
of atmospheric oxygen or moisture.
Examples: coated tablets, sealed ampules
3. For the protection of a drug substance from the destructive influence
of gastric acid after oral administration.
Example: enteric coated tablets
4. To provide liquid preparations of substances that are either insoluble
or unstable in the desired vehicle.
Example: suspension
5. To conceal the bitter taste, salty or odor of a drug substance.
Examples: Capsules, coated tablets, flavored syrups
1- The Need for Dosage Forms
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
20
6. To provide liquid dosage forms of substances soluble in desired vehicle.
Example: solution
7. To provide extended drug action through controlled release mechanisms
Examples: controlled release tablets, capsules, suspensions
8. To provide optional drug action from topical administration sites
Examples: ointments, creams, ophthalmic, ear and nasal
preparations
9. To provide for insertion of a drug into one of the body’s orifices
Examples: rectal and vaginal suppositories
10. To provide for the placement of drugs within body tissues.
11. To provide for the optimal drug action through inhalation therapy.
Examples: inhalants and inhalations
12. In addition, many dosage forms permit ease of drug identification
through distinctiveness of color, shape, or identifying markings
1- The Need for Dosage Forms
 Examples Of Drugs with Low Usual doses
 Phenobarbital 30 mg Sedative
 Diphenhydramine HCl 25 mg Antihistamine
 Morphine sulfate 10 mg Narcotic Analgesic
 Digoxin 0.25 mg Cardiotonic
 Clotrimazole 10.00 Antifungal
 Chlorpheniramine maleate 4.00 Antihistaminic
 Glyburide 2.50 Antidiabetic
 Doxazosin Mesylate 2.00 Antihypertensive
 Levorphanol tartrate 2.00 Narcotic analgesic
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
21
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
22
2. General Considerations in Dosage
Form Design
Physiological factors
• Age
• Diurnal variation (fluctuations
that occur during the day)
• Pregnancy
• Sex
• Menopause
• Body weight
• Time of administration
• Tolerance
• Temperature
• Physiological reserve
 Route of drug entry into the body
 Physical form of the drug product
 Design and formulation of the product
 Method of manufacture of the product
 Physicochemical properties of the drug and
excipients
Physicochemical properties of the drug
product
Control and maintenance of location of drug
at the absorption site
Control of the release rate of the drug from
the drug product
Factors Affecting Drug
Presentation to the Body
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
23
2. General Considerations in Dosage
Form Design
• neonates - birth up to one month;
• infants - one month up to 2 years of age;
• children - 2 years up to 12 years; and
• adolescents - 12 years up to 16 years.
Center for Drug Evaluation and Research (CDER) May 1996 FDA
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
24
Design of Drug Products
• Effectiveness
• Safety
• Reliability
• Stability
– Physical
– Chemical
– Microbiological
2. General Considerations in Dosage
Form Design
•Pharmaceutical elegance
•Appearance
•Organoleptic properties
•Convenience
•Ease of use
•Dosing frequency
•Consumer acceptance
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
25
2.1. Preformulation Studies
11. Dissolution
Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical
industry, it may be defined as the amount of drug substance that goes into solution per
unit time under standardized conditions of liquid/solid interface, temperature and solvent
composition.
Dissolution is dependent on many factors, both intrinsic and extrinsic. The definition of
intrinsic dissolution rate, IDR ( Intrinsic Dissolution Rate) is the dissolution rate when
extrinsic factors are held constant for a pure substance.
IDR is influenced by Intrinsic factors
•Crystal habit
• Crystallinity
• Polymorphism
• Pseudo-polymorphism
• Particle size and surface area
extrinsic factors
Agitation
• Surface area of tablet or sample
• Temperature
• pH
• Buffer strength
• Viscosity of the dissolution medium
• Ionic strength of the dissolution medium
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
26
Solubility is based on the highest dose strength and is considered highly
soluble if soluble in 250 mL or less of aqueous media over the pH range of
1.0-7.5, otherwise considered to be poorly soluble.
2.1. Preformulation Studies
11. Dissolution
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
27
2.1. Preformulation Studies
 time for the drug to dissolve in the fluids at the absorption site
rate-limiting step in absorption
 Dissolution rate of drugs - increased by
 decreasing the particle size.
 increasing its solubility in diffusion layer
 use a highly water soluble salt of the parent substance.
11. Dissolution
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
28
2 methods in determining dissolution rates
1.Constant surface method
- intrinsic dissolution rate of the agent
- The intrinsic dissolution rate is defined as the dissolution rate of
pure substances under the condition of constant surface area,
agitation-stirring speed, pH and ionic-strength of the dissolution
medium. mg dissolved/min/cm square
2.Particulate dissolution
- Weighted amount of powdered sample + dissolution medium in
- influence of particle size, surface area, and excipients upon
the active agent
2.1. Preformulation Studies
11. Dissolution
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
29
rotating disc method
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
30
12. Membrane Permeability
2.1. Preformulation Studies
The drug molecule must first cross a biologic membrane. The
biologic membrane acts as a lipid barrier to most drugs and permits
the absorption of lipid-soluble substances by passive diffusion,
while lipid insoluble substances can diffuse across the barrier only
with considerable difficulty
pKa, solubility, and dissolution rate data can provide an
indication of absorption
Everted intestinal sac may be used to evaluate
absorption characteristics of drug substances.
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
31
2.1. Preformulation Studies
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
32
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
33
@ the octanol water partition coefficient is commonly used in
formulation development
(conc. of drug in octanol)
@ P =
( conc. Of drug in water)
P depends on the drug concentration only if the drug
molecules have tendency to associate in solution
@ in an ionizable drug, the following equation is applicable
(conc. Of drug in octanol)
P =
[1-α ] (conc. Of drug in water)
where α equals the degree of ionization
•
2.1. Preformulation Studies
13. Partition Coefficient
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
34
2.2 Drug and Drug Product Stability
• Physical stability
• Chemical stability
• Shelf life of 2-3 years is generally desired
extent a product retains within specified limits and through
its period of storage and use
Stability studies conducted in the preformulation phase:
Solid-state of the drug alone (active stability)
Solution phase (Accelerated)
with the expected excipients (incompatibility)
• Photolysis is prevented by:
1- suitable packing in amber colored bottles
2- packed in cardboard outers ????
3- aluminum foil over wraps
2.2 Drug and Drug Product Stability
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
36
2.2 Drug and Drug Product Stability
Rate of reactions
 The reaction rate is description of the drug concentration with respect
to time. Most commonly, zero-order and first-order reactions are
encountered in pharmacy
If the loss of drug is independent of the concentration of the reactants
and constant with respect to time (I.e 1 mg/mL/hour) the rate is called
zero order.
 If the loss of drug is direct proportional to the concentration remaining
with respect to time, it is called a first-order reaction and has the units
of reciprocal time that is, time-1.
Q10 Method of Shelf Life Estimation
Estimate shelf life for a product that has been stored or is
going to be stored under a different set of conditions.
37
37
1) Definition of drug stability and drug kinetics
Stability Study
It is defined as the study of the extent to which the properties of a drug substance or
drug product remain within specified limits at certain conditions . Properties may
be physical, chemical, microbiological, toxicological or performance properties
such as disintegration and dissolution.
Drug Kinetics : Change of drug concentration with respect to time
Accelerated Stability Testing
Studies designed to increase the rate of chemical or physical degradation by using
exaggerated storage conditions
Expiration Date
The FDA defines an expiration date as “the date placed on the container/labels of a
drug product designating the time during which a batch of the product is expected to
remain within the approved shelf life specifications if stored under defined conditions,
and after which it may not be used.”
2.2 Drug and Drug Product Stability
38
38
Rate of reactions
Importance of studying kinetics
It determines:
 Stability of drugs (t1/2)
 Shelf life ((t0.9)
 Expiration date
Stability of drugs (t1/2)
The half life (t1/2) is defined as the time necessary for a drug to decay by 50%
(e.g., From 100% to 50%, 50% to 25%, 20% to10%)
Shelf life (t0.9)
It is defined as the time necessary for the drug to decay to 90% of its original
concentration.
2.2 Drug and Drug Product Stability
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
39
Rate of Reaction
Expressing speed of a reaction:
• If C is the concentration, then the rate of reaction:
• where n=0,1 or 2 for zero, first & second order
reactions respectively
n
C
dt
dC

Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
40
Rate of Reaction-Zero order
• In this type of reaction, n=o and the reaction
rate is independent of the concentration of
the reacting substance.
• The rate of change is constant.
• Here, factors other than concentration of
reactants constitute the limiting factor e.g.
solubility or absorption of light
(photochemical reactions).
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
41
• Zero order Equation:
Ct= drug conc. at time t,
Co= drug conc. at time o
dt= change in time.
k=zero order rate constant
Rate of Reaction-Zero order
k
dt
dC

n
C
dt
dC

ktCC ot 
n=0
K = Concentration / time
mole / liter . second
= mg/ml sec
Conc
Time
Slope = -k0
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
42
Rate of Reaction-Zero order
half-life
ktCC ot 
For a zero order reaction, the time for 50% reaction, t½, is
given as:
k
C
k
C
t oo
2
2
1
2/1 
Suspensions are a special case of zero order kinetics, in which the concentration of
drug in solution depends on its solubility.
As the drug in solution decomposes, more of it is released from a reservoir of
suspended particles thereby making the concentration in solution constant
Determination of t0.9
Let c = 0.9 co and t= t0.9 k
C
tt o1.0
%90%90 
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
43
Drug X degrades by a zero-order process with a rate constant of 0.05 mg /ml .year at
room temperature. If a 1% weight/volume (w/v) solution is prepared and stored at room
temperature:
1. What concentration will remain after 18 months?
2. What is the half-life of the drug?
2-
1- C0 = 1% w/v = 10 mg/ml; t =18 months = 1.5 year
ktCC ot    mlmgxCt /91.95.105.010 
  yearsx
k
C
t o
10005.0/105.02
1
2/1 
Rate of Reaction-Zero order
half-life
year
x
k
C
t o
20
05.0
101.01.0
%90 
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
44
Rate of Reaction-First order
• n=1 and the reaction rate is dependent on the
concentration of one of the reactants in the
formulation.
• C is the concentration remaining un-decomposed, at time t
• k is the first order rate constant.
kC
dt
dC

n
C
dt
dC
 n=1
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
45
integration, the equation above gives:
rearrangement and conversion
to log in base 10:
ktCC ot  lnln
303.2
loglog
kt
CC ot 
kC
dt
dC


Rate of Reaction-First order
Log
Conc.
Time
Slope = -k/2.303
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
46
Determination of t1/2
Let t = t1/2 and
substitute in
K units = 0.693 / t1/2 = time-1
Determination of t0.9
Let t = t0.9 and
substitute in
Rate of Reaction-First order
half-life
oCktC lnln  KKt /693.0/2ln2/1 
2/0CC 
09.0 CC 
oCktC lnln 
Kt /105.09.0 
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
47
A 5 gm/100 ml solution of drug X is stored in a closed test tube at 25°C. If the rate of
degradation of the drug is 0.05 day−1, calculate the time required for the initial
concentration to drop to (a) 50% (half-life) and (b) 90% (shelf-life) of its initial value.
ktCC o  lnln
Rate of Reaction-First order
KKt /693.0/2ln2/1  Kt /105.09.0 
dayst 9.135.0/693.02/1  dayst 1.25.0/105.09.0 
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
48
ktCC ot 
k
C
k
C
t oo
2
2
1
2/1 
k
C
tt o1.0
%90%90 
ktCC o  lnln
KKt 693.0/2ln2/1 
Kt /105.09.0 
Zero order First order
Co
nc
Time
Slope = -k0
Log Conc.
Time
Slope = -k/2.303
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
49
Exercises??
• Determine the expression for rate constant, k
• Determine the expression for process half-life,
t1/2 , t0.9
• Write the exponential forms of the equation in
natural log and log in base 10.
• What is the significance of process half-life?
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
50
Determination of Order of Reaction..
• Half life method
– For a zero order reaction, t ½ is
proportional to initial concentration of
reactant (Co),
– t½ for a first order reaction is independent
of Co, .
• Graphical method – For a zero order, plot of
C vs. t is linear; for first order reaction, plot
of log (Co-Ct) vs. t is linear.
k
C
k
C
t oo
2
2
1
2/1 
KKt 693.0/2ln2/1 
ktCC ot  ktCC o  lnln
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
51
Example: A drug degrades
according to the following:
Time (min.) Conc. Log C
0 100 2
1 65.6 1.82
2 43.0 1.63
3 28.19 1.45
4 18.49 1.27
10 1.50 0.176
Plot c against t on semi log paper
and determine slope, K and t1/2
Solution:
log 28.195 = 1.45 and log 1.5 = 0.176
slope = 1.45 – 0.176 / 3 – 10 = 1.27 / -7 = - 0.181
Equation; log c = log co – Kt / 2.303
slope = -K/ 2.303
- 0.181 = - K / 2.303
K = 0.417 min-1
t1/2 = 0.693 / K
t1/2 = 0.693 / 0.417 = 1.66 minute
303.2
loglog
kt
CC o 
KKt 693.0/2ln2/1 
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
52
In the laboratory, one may collect a sample of data consisting of measured concentrations of
Drug A at different times. This sample data may look like the following :
Time (min C (M) Ln C
0 0.906 -0.098715973
0.9 0.8739 -0.134789326
9 0.5622 -0.575897621
11.2 0.5156 -0.662424008
17.5 0.3718 -0.989399204
23 0.2702 -1.308592853
27.7 0.2238 -1.497002483
32 0.1761 -1.736703263
35 0.1495 -1.900458886
43 0.1029 -2.273997636
47 0.086 -2.453407983
50 0.0697 -2.663554961
55 0.0546 -2.907721396
61 0.0393 -3.23653076
65 0.0324 -3.429596856
70 0.026 -3.649658741
We can see clearly that the graph of ln[C] vs
time is a straight line. Therefore the reaction
associated with the given data is a first order
reaction.
Stability of Valsartan under stress conditions
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
53
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
54
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
55
The concentration of drug X in aqueous solution drops by 10% per month when stored at
room temperature. What concentation will remain if a 5 mg/ml solution of the drug is
stored under the same condetions after 3 months???
1- If the degradation occurs by zero order? 2- If the degradation occurs by first order?
2- 5X0.9X0.9X0.9=3.65 mg/ml
ktCC ot  ktCC o  lnln
kCC o 09.0
5.01.0 /5
0   kCk mlmgfor
mg/ml.x.mC 5335053 
5-[(5X0.1) X3]=3.5 mg/ml
kCC o  ln9.0ln 0
105.0
9.0
ln
0
0

C
C
k
3105.05ln3ln xmC 
2944.1315.06094.13ln mC
mlmgmC /65.33 
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
56
Factors Affecting Rate of Reactions
• The rate of reaction (degradation of
pharmaceutical products) can be influenced
– temperature,
– moisture,
– solvent (pH, dielectric constant, etc),
– light (radiation),
– catalysts,
– oxygen and
– concentration of DRUG (s).
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
57
Arrhenius equation….
• For a reaction carried out at 2 diff. temp.,
 
12
12
1
2
303.2
log
TT
TT
R
E
k
k a 

k = reaction rate,
T = is absolute temperature in the Kelvin scale
R = gas constant, Ea = activation energy
If the activation energy at one temperature are known, one can easily
determine the rate constant at any other temperature. This is important
in the determination of expiration date of a new pharmaceutical product
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
58
The degradation of a new cancer drug follows first-order
kinetics and has degradation rate constants of 0.0001 h-1
at 60 ºC and 0.0009 h-1 at 80 ºC. What is its Ea?
 
333*353
333353
987.1*303.20001.0
0009.0
log

 aE
molcalEa /651.25
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
59
Example: The rate constant for first-order degradation of a drug (activation energy is 20.0
Kcal/mol) in a solution (5.0 mg/ml) at 70°C is 1.50 × 10-3 h-1.
1. Calculate the amount remaining after storage for one week at room temperature (25°C).
2. Calculate the amount remaining after one week if the drug is kept at 70°C.
3. Calculate the shelf life of the drug at room temperature.
4. Calculate the half-life of the drug at room temperature.
5. Calculate shelf- life of the drug at 70°C.
6. Calculate the half-life of the drug at 70°C.
7. Discuss what you learned from this exercise.
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
60
Concept of Q10
T
T
K
K
Q )10(
10


The Q10 temperature coefficient is a measure of the rate of change of
a biological or chemical system as a consequence of increasing the
temperature by 10 °C
Q 10 shelf life estimation
)10/(
10
19.0
29.0
)(
)( T
Q
Tt
Tt 

Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
61
)10/(
10
19.0
29.0
)(
)( T
Q
Tt
Tt 

)10/(
10
19.0
29.0
)(
)( T
Q
Tt
Tt 

Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
62
Q
Q
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
63
Example: The ampicillin monograph states that the reconstituted
suspension is stable for 14 days in a refrigerator. If the product is left
at room temperature for 6 h, what is the reduction in the expiration
period?
0.25 × 32 = 2.25 days
)10/(
10
19.0
29.0
)(
)( T
Q
Tt
Tt 

Shelf life= 14 / 32 = 1.56 days (Q = 3)?????
  )10/255(2
3
25.0
)5( CTt O
reduction
The question to be addressed here is:
Life at 25°C for 6 h (0.25 days) = how many hours at 5°C?
1.56 day(T=25O C) 14 day(T=5O C)
0.25 day(T=25O C) ??? day(T=5O C)
0.25 × 14/1.56 = 2.243 days
• ZONE I TEMPERATE
• ZONE II SUBTROPICAL
• ZONE III HOT & DRY
• ZONE IV HOT & HUMID
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
64
Stability Testing
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
65
Signs Of degradation Of Specific Dosage Forms
1. Tablets appearance, friability, harness, color, odor,
odor, moisture content, and dissolution
2. Capsules strength, moisture, color, appearance, shape,
brittleness, and dissolution
3. Oral solutions appearance, strength, pH, color, odor,
suspensions redispersibility (suspension), and clarity
(solutions)
4. Oral Powders appearance, strength, color, odor, moisture
5. Metered-dose strength, delivered dose per actuation,
number inhalation of metered doses, color of propellant, pressure,
aerosols valve, corrosion, spray pattern, absence of
pathogenic microorganism
6. Topical non metered appearance, odor, pressure, weight loss, net
aerosols weight dispensed, delivery rate, and spray
pattern
7. Topical Creams ointments, lotions, solutions, and gels:
appearance, color, homogeneity, odor, pH,
resuspendibility (lotions), consistency, particle
size, distribution, strength, weight loss
Signs Of Degradation Of Specific Dosage Forms
8. Ophthalmic Preparations appearance, color, consistency, pH, clarity
(solutions), particle size, resuspendibility
(suspensions, creams, ointments), strength,
and sterility
9. Parenterals strength, appearance, color, clarity,
particulate matter, pH, volume and
extractables (when plastic containers are
used), sterility, pyrogenicity, and closure
integrity
10. Suppositories strength, softening range, appearance, and
dissolution
11. Emulsion appearance, color, odor, pH, viscosity, and
strength
12. Transdermal seal strength of the drug reservoir,
decomposition products, membrane
integrity, drug strength, and drug release
rate
Responsibility of the Pharmacist
• Dispense oldest stock first and observe expiration dates.
• Store products under conditions stated in USP monographs and/or
labeling.
• Observe products for evidence of instability.
• Properly treat/label products that are repackaged, diluted, or mixed
with other products.
Responsibility of the Pharmacist
• Dispensing in proper container with proper closure
• Informing/educating patients concerning proper
storage and use of products
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
70
PHARMACIST:
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
71
PHARMACIST:
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
72
Pharmaceutical Ingredients
and Excipients
Pharmaceutical Ingredients
and Excipients
Pharmaceutical
ingredients added to
prepare a dosage form
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
73
Harmonization of Standards
• International harmonization of excipients
• Pharmaceutical industry is multinational
• Uniform standards needed ????
Pharmaceutical Ingredients
and Excipients
Pharmaceutical Ingredients
and Excipients
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
74
Inactive Ingredient Database -FDA
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
75
Pharmaceutics PHAR 331
Birzeit Univ. Doctor of Pharmacy Dr. H.
Shtaya
76

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pharmaceutics dosage form design chapt-4

  • 2. What is pharmaceutics? • The art and applied science of dosage form design – The interface between drug and body • A broad field that draws from many disciplines – Physical chemistry (organic and inorganic) – Medicinal chemistry – Anatomy, physiology – Microbiology – Atomic physics – Engineering (chemical, material) • Deals with many aspects of interactions both inside and outside the body • It’s not trivial to design and implement a dosage form that is both safe and effective for the drug’s intended use!
  • 3. Pharmaceutics is unique to pharmacy • Physicians and other prescribers don’t learn and apply physical pharmaceutical principles • Chemists and engineers don’t learn a whole lot of biology • Anyone can read the latest review article of a disease state and play armchair prescriber, but it takes a pharmacist to know how to deliver a drug safely and effectively!
  • 4. PHARMACODYNAMICS Site/mechanism of action, potency, efficacy, etc. PHARMACOKINETICS absorption, distribution, metabolism, excretion ADME
  • 5. From drug substance to pharmaceutical preparation • Active drug substance (active pharmaceutical ingredient - API) • Excipients (inactive pharmaceutical ingredients) – Technological, biopharmaceutical and/or stability reasons – Diluents/fillers, binders, lubricants, desintegrants, coatings, preservants and stabilizers, colorants and flavourings – Should always be stated in SPC (important in the case of allergies)
  • 6. From drug substance to pharmaceutical preparation • Pharmaceutical dosage form – determines the physical form of the final pharmaceutical preparation – is a drug delivery system which is formed by technological processing (drug formulation) – must reflect therapeutic intentions, route of administrations, dosing etc. • Pharmaceutical preparation (PP) – particular pharmaceutical product containing active and inactive pharmaceutical ingredients formulated into the particular dosage form. – Packed and labelled appropriately – Two major types of PP according the origin: • Manufactured in large scales by pharmaceutical industry (original and generic preparations) • Compounded individually in compounding pharmacies Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 6
  • 7. Logistical considerations of dosage form design • Storage – Rate of degradation (expiry) • Liquid/solid? • What conditions? – Temperature – Humidity – What container • How inert is it? What is the risk for contamination? • Compatibility – Active vs. active vs. “inert” ingredients – Container (again) • Organoleptic considerations – Physical appearance, taste, smell, size – “Pharmaceutical elegance” • Manufacturing – For a powder, how well does it flow?
  • 8. What you must know to design a dosage form • Physicochemical properties of the drug – Reactivity, stability – Solubility, acid/base, solid state behaviour • Biopharmaceutical considerations – What is the intended site of action? • Systemic? Topical? – Where/how well is the drug absorbed? – What is the intended onset of action? • Immediate-release, sustained-release, pulse releases
  • 9. Example: estrogen • Indication: hormone replacement therapy for treatment of symptoms of menopause • Molecule administered is – Conjugated estrogens – Estradiol – Estrone • Dosage forms – Tablets (Estrace®) – Transdermal patch (Estraderm®, etc.) – Transdermal gel (EstroGel®) – Vaginal ring (Estring®)
  • 10. Some questions • About the drug – Aqueous solubility, pKa, partition coefficient – Chemical stability in solution • About the dosage form – Dissolution characteristics – Transdermal characteristics – Stability in storage • About the biopharmaceutics – Extent of absorption – First-pass metabolism – Intended use: topical vs. systemic?
  • 11. Each dosage form caters to a different need • Compressed tablet – Contains micronized estradiol • Micronization improves dissolution – 1 to 2 mg/day po • Estradiol is highly metabolized • Transdermal – Bypasses first-pass metabolism – Patch: 0.05 to 0.1 mg/day, applied twice weekly – Gel: 0.75 mg/day • Vaginal ring – Topical application of estradiol for local symptoms – Average 7.5 µg/day  90 days
  • 12. The need for dosage forms: 1- Accurate dose. 2- To protect the drug substance from the destructive influences of atmospheric oxygen or humidity (coated tablets, sealed ampuls). 3- Protection from gastric acid. 4- Masking taste and odour. 5- Placement of drugs within body tissues. 6- Sustained release medication. 7- Controlled release medication. 8- To provide optimal drug action from topical administration sites. 9- Insertion of drugs into body cavities (rectal, vaginal) 10- To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle (suspensions) 11-To provide clear liquid dosage forms of substances (syrups, solutions) Why the drug should be converted into dosage forms ?
  • 13. They are classified according to: Route of administration Physical form Oral Solid Topical Semisolid Rectal liquid Parenteral Gaseous Vaginal Inhaled Ophthalmic Otic Types of dosage forms
  • 14. Classification of pharmaceutical dosage forms according to its physical properties • Dosage forms – Homogenous systems – Dispersion systems – one phase (dispersed phase) is distributed throughout another one (continuous phase, dispersion medium) • According to the size of dispersed particles (1 nm- 0,5 mm) a molecular, colloidal and coarse dispersions can be distinguished • May require shaking before administration • According to the overall physical properties of dosage forms (both homogenous and dispersion systems) one can distinguish – Gaseous dosage forms(Aerosols, inhalation) – Liquid dosage forms(Ear drops, Elixirs, Syrup…..) – Semisolid dosage forms(Creams Jellies Ointments ) – Solid dosage forms(Tablets ,Suppositories , Capsules ………) – Light dosage forms(UV,  rays….)
  • 15. Classification of pharmaceutical dosage forms according to the route of administration – Oral (Powders, tablets, capsules, solutions, emulsions, syrups, elixirs, magmas, gels, cachets, pills.) – Parenteral (Solutions, suspensions, emulsions.) • IV, IM, SC, etc. – Ophthalmic, otic – Nasal(Solutions, sprays, inhalations.) – Rectal, vaginal, urethral (Suppositories, tablets, ointments, creams, douches, foams.) – Buccal – Topical – Transdermal (Ointments, creams, powders, pastes, lotions, plaster)
  • 16. A list of dosage forms • Solid dosage forms – Powders – Tablets – Capsules (hard, soft) – Suppositories* – Ointment, cream, gel, etc.* – Aerosol – Lozenge – Cigarette • Liquid dosage forms – Solutions – Suspensions – (Gas) • Light – UV –  rays • Many administration routes – Oral – Parenteral • IV, IM, SC, etc. – Ophthalmic, otic – Nasal – Rectal, vaginal, urethral – Buccal – Topical
  • 17. Dosage Form Design: Pharmaceutical and Formulation Considerations Chapter 4 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 17Pharmaceutics PHAR 331
  • 18. 1- The Need for Dosage Forms Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 18
  • 19. 1- The Need for Dosage Forms Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 19 1. To provide for the safe and convenient delivery of accurate dosage 2. For the protection of a drug substance from the destructive influence of atmospheric oxygen or moisture. Examples: coated tablets, sealed ampules 3. For the protection of a drug substance from the destructive influence of gastric acid after oral administration. Example: enteric coated tablets 4. To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle. Example: suspension 5. To conceal the bitter taste, salty or odor of a drug substance. Examples: Capsules, coated tablets, flavored syrups
  • 20. 1- The Need for Dosage Forms Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 20 6. To provide liquid dosage forms of substances soluble in desired vehicle. Example: solution 7. To provide extended drug action through controlled release mechanisms Examples: controlled release tablets, capsules, suspensions 8. To provide optional drug action from topical administration sites Examples: ointments, creams, ophthalmic, ear and nasal preparations 9. To provide for insertion of a drug into one of the body’s orifices Examples: rectal and vaginal suppositories 10. To provide for the placement of drugs within body tissues. 11. To provide for the optimal drug action through inhalation therapy. Examples: inhalants and inhalations 12. In addition, many dosage forms permit ease of drug identification through distinctiveness of color, shape, or identifying markings
  • 21. 1- The Need for Dosage Forms  Examples Of Drugs with Low Usual doses  Phenobarbital 30 mg Sedative  Diphenhydramine HCl 25 mg Antihistamine  Morphine sulfate 10 mg Narcotic Analgesic  Digoxin 0.25 mg Cardiotonic  Clotrimazole 10.00 Antifungal  Chlorpheniramine maleate 4.00 Antihistaminic  Glyburide 2.50 Antidiabetic  Doxazosin Mesylate 2.00 Antihypertensive  Levorphanol tartrate 2.00 Narcotic analgesic Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 21
  • 22. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 22 2. General Considerations in Dosage Form Design Physiological factors • Age • Diurnal variation (fluctuations that occur during the day) • Pregnancy • Sex • Menopause • Body weight • Time of administration • Tolerance • Temperature • Physiological reserve  Route of drug entry into the body  Physical form of the drug product  Design and formulation of the product  Method of manufacture of the product  Physicochemical properties of the drug and excipients Physicochemical properties of the drug product Control and maintenance of location of drug at the absorption site Control of the release rate of the drug from the drug product Factors Affecting Drug Presentation to the Body
  • 23. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 23 2. General Considerations in Dosage Form Design • neonates - birth up to one month; • infants - one month up to 2 years of age; • children - 2 years up to 12 years; and • adolescents - 12 years up to 16 years. Center for Drug Evaluation and Research (CDER) May 1996 FDA
  • 24. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 24 Design of Drug Products • Effectiveness • Safety • Reliability • Stability – Physical – Chemical – Microbiological 2. General Considerations in Dosage Form Design •Pharmaceutical elegance •Appearance •Organoleptic properties •Convenience •Ease of use •Dosing frequency •Consumer acceptance
  • 25. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 25 2.1. Preformulation Studies 11. Dissolution Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Dissolution is dependent on many factors, both intrinsic and extrinsic. The definition of intrinsic dissolution rate, IDR ( Intrinsic Dissolution Rate) is the dissolution rate when extrinsic factors are held constant for a pure substance. IDR is influenced by Intrinsic factors •Crystal habit • Crystallinity • Polymorphism • Pseudo-polymorphism • Particle size and surface area extrinsic factors Agitation • Surface area of tablet or sample • Temperature • pH • Buffer strength • Viscosity of the dissolution medium • Ionic strength of the dissolution medium
  • 26. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 26 Solubility is based on the highest dose strength and is considered highly soluble if soluble in 250 mL or less of aqueous media over the pH range of 1.0-7.5, otherwise considered to be poorly soluble. 2.1. Preformulation Studies 11. Dissolution
  • 27. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 27 2.1. Preformulation Studies  time for the drug to dissolve in the fluids at the absorption site rate-limiting step in absorption  Dissolution rate of drugs - increased by  decreasing the particle size.  increasing its solubility in diffusion layer  use a highly water soluble salt of the parent substance. 11. Dissolution
  • 28. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 28 2 methods in determining dissolution rates 1.Constant surface method - intrinsic dissolution rate of the agent - The intrinsic dissolution rate is defined as the dissolution rate of pure substances under the condition of constant surface area, agitation-stirring speed, pH and ionic-strength of the dissolution medium. mg dissolved/min/cm square 2.Particulate dissolution - Weighted amount of powdered sample + dissolution medium in - influence of particle size, surface area, and excipients upon the active agent 2.1. Preformulation Studies 11. Dissolution
  • 29. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 29 rotating disc method
  • 30. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 30 12. Membrane Permeability 2.1. Preformulation Studies The drug molecule must first cross a biologic membrane. The biologic membrane acts as a lipid barrier to most drugs and permits the absorption of lipid-soluble substances by passive diffusion, while lipid insoluble substances can diffuse across the barrier only with considerable difficulty pKa, solubility, and dissolution rate data can provide an indication of absorption Everted intestinal sac may be used to evaluate absorption characteristics of drug substances.
  • 31. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 31 2.1. Preformulation Studies
  • 32. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 32
  • 33. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 33 @ the octanol water partition coefficient is commonly used in formulation development (conc. of drug in octanol) @ P = ( conc. Of drug in water) P depends on the drug concentration only if the drug molecules have tendency to associate in solution @ in an ionizable drug, the following equation is applicable (conc. Of drug in octanol) P = [1-α ] (conc. Of drug in water) where α equals the degree of ionization • 2.1. Preformulation Studies 13. Partition Coefficient
  • 34. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 34 2.2 Drug and Drug Product Stability • Physical stability • Chemical stability • Shelf life of 2-3 years is generally desired extent a product retains within specified limits and through its period of storage and use Stability studies conducted in the preformulation phase: Solid-state of the drug alone (active stability) Solution phase (Accelerated) with the expected excipients (incompatibility)
  • 35. • Photolysis is prevented by: 1- suitable packing in amber colored bottles 2- packed in cardboard outers ???? 3- aluminum foil over wraps 2.2 Drug and Drug Product Stability
  • 36. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 36 2.2 Drug and Drug Product Stability Rate of reactions  The reaction rate is description of the drug concentration with respect to time. Most commonly, zero-order and first-order reactions are encountered in pharmacy If the loss of drug is independent of the concentration of the reactants and constant with respect to time (I.e 1 mg/mL/hour) the rate is called zero order.  If the loss of drug is direct proportional to the concentration remaining with respect to time, it is called a first-order reaction and has the units of reciprocal time that is, time-1. Q10 Method of Shelf Life Estimation Estimate shelf life for a product that has been stored or is going to be stored under a different set of conditions.
  • 37. 37 37 1) Definition of drug stability and drug kinetics Stability Study It is defined as the study of the extent to which the properties of a drug substance or drug product remain within specified limits at certain conditions . Properties may be physical, chemical, microbiological, toxicological or performance properties such as disintegration and dissolution. Drug Kinetics : Change of drug concentration with respect to time Accelerated Stability Testing Studies designed to increase the rate of chemical or physical degradation by using exaggerated storage conditions Expiration Date The FDA defines an expiration date as “the date placed on the container/labels of a drug product designating the time during which a batch of the product is expected to remain within the approved shelf life specifications if stored under defined conditions, and after which it may not be used.” 2.2 Drug and Drug Product Stability
  • 38. 38 38 Rate of reactions Importance of studying kinetics It determines:  Stability of drugs (t1/2)  Shelf life ((t0.9)  Expiration date Stability of drugs (t1/2) The half life (t1/2) is defined as the time necessary for a drug to decay by 50% (e.g., From 100% to 50%, 50% to 25%, 20% to10%) Shelf life (t0.9) It is defined as the time necessary for the drug to decay to 90% of its original concentration. 2.2 Drug and Drug Product Stability
  • 39. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 39 Rate of Reaction Expressing speed of a reaction: • If C is the concentration, then the rate of reaction: • where n=0,1 or 2 for zero, first & second order reactions respectively n C dt dC 
  • 40. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 40 Rate of Reaction-Zero order • In this type of reaction, n=o and the reaction rate is independent of the concentration of the reacting substance. • The rate of change is constant. • Here, factors other than concentration of reactants constitute the limiting factor e.g. solubility or absorption of light (photochemical reactions).
  • 41. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 41 • Zero order Equation: Ct= drug conc. at time t, Co= drug conc. at time o dt= change in time. k=zero order rate constant Rate of Reaction-Zero order k dt dC  n C dt dC  ktCC ot  n=0 K = Concentration / time mole / liter . second = mg/ml sec Conc Time Slope = -k0
  • 42. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 42 Rate of Reaction-Zero order half-life ktCC ot  For a zero order reaction, the time for 50% reaction, t½, is given as: k C k C t oo 2 2 1 2/1  Suspensions are a special case of zero order kinetics, in which the concentration of drug in solution depends on its solubility. As the drug in solution decomposes, more of it is released from a reservoir of suspended particles thereby making the concentration in solution constant Determination of t0.9 Let c = 0.9 co and t= t0.9 k C tt o1.0 %90%90 
  • 43. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 43 Drug X degrades by a zero-order process with a rate constant of 0.05 mg /ml .year at room temperature. If a 1% weight/volume (w/v) solution is prepared and stored at room temperature: 1. What concentration will remain after 18 months? 2. What is the half-life of the drug? 2- 1- C0 = 1% w/v = 10 mg/ml; t =18 months = 1.5 year ktCC ot    mlmgxCt /91.95.105.010    yearsx k C t o 10005.0/105.02 1 2/1  Rate of Reaction-Zero order half-life year x k C t o 20 05.0 101.01.0 %90 
  • 44. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 44 Rate of Reaction-First order • n=1 and the reaction rate is dependent on the concentration of one of the reactants in the formulation. • C is the concentration remaining un-decomposed, at time t • k is the first order rate constant. kC dt dC  n C dt dC  n=1
  • 45. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 45 integration, the equation above gives: rearrangement and conversion to log in base 10: ktCC ot  lnln 303.2 loglog kt CC ot  kC dt dC   Rate of Reaction-First order Log Conc. Time Slope = -k/2.303
  • 46. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 46 Determination of t1/2 Let t = t1/2 and substitute in K units = 0.693 / t1/2 = time-1 Determination of t0.9 Let t = t0.9 and substitute in Rate of Reaction-First order half-life oCktC lnln  KKt /693.0/2ln2/1  2/0CC  09.0 CC  oCktC lnln  Kt /105.09.0 
  • 47. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 47 A 5 gm/100 ml solution of drug X is stored in a closed test tube at 25°C. If the rate of degradation of the drug is 0.05 day−1, calculate the time required for the initial concentration to drop to (a) 50% (half-life) and (b) 90% (shelf-life) of its initial value. ktCC o  lnln Rate of Reaction-First order KKt /693.0/2ln2/1  Kt /105.09.0  dayst 9.135.0/693.02/1  dayst 1.25.0/105.09.0 
  • 48. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 48 ktCC ot  k C k C t oo 2 2 1 2/1  k C tt o1.0 %90%90  ktCC o  lnln KKt 693.0/2ln2/1  Kt /105.09.0  Zero order First order Co nc Time Slope = -k0 Log Conc. Time Slope = -k/2.303
  • 49. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 49 Exercises?? • Determine the expression for rate constant, k • Determine the expression for process half-life, t1/2 , t0.9 • Write the exponential forms of the equation in natural log and log in base 10. • What is the significance of process half-life?
  • 50. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 50 Determination of Order of Reaction.. • Half life method – For a zero order reaction, t ½ is proportional to initial concentration of reactant (Co), – t½ for a first order reaction is independent of Co, . • Graphical method – For a zero order, plot of C vs. t is linear; for first order reaction, plot of log (Co-Ct) vs. t is linear. k C k C t oo 2 2 1 2/1  KKt 693.0/2ln2/1  ktCC ot  ktCC o  lnln
  • 51. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 51 Example: A drug degrades according to the following: Time (min.) Conc. Log C 0 100 2 1 65.6 1.82 2 43.0 1.63 3 28.19 1.45 4 18.49 1.27 10 1.50 0.176 Plot c against t on semi log paper and determine slope, K and t1/2 Solution: log 28.195 = 1.45 and log 1.5 = 0.176 slope = 1.45 – 0.176 / 3 – 10 = 1.27 / -7 = - 0.181 Equation; log c = log co – Kt / 2.303 slope = -K/ 2.303 - 0.181 = - K / 2.303 K = 0.417 min-1 t1/2 = 0.693 / K t1/2 = 0.693 / 0.417 = 1.66 minute 303.2 loglog kt CC o  KKt 693.0/2ln2/1 
  • 52. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 52 In the laboratory, one may collect a sample of data consisting of measured concentrations of Drug A at different times. This sample data may look like the following : Time (min C (M) Ln C 0 0.906 -0.098715973 0.9 0.8739 -0.134789326 9 0.5622 -0.575897621 11.2 0.5156 -0.662424008 17.5 0.3718 -0.989399204 23 0.2702 -1.308592853 27.7 0.2238 -1.497002483 32 0.1761 -1.736703263 35 0.1495 -1.900458886 43 0.1029 -2.273997636 47 0.086 -2.453407983 50 0.0697 -2.663554961 55 0.0546 -2.907721396 61 0.0393 -3.23653076 65 0.0324 -3.429596856 70 0.026 -3.649658741 We can see clearly that the graph of ln[C] vs time is a straight line. Therefore the reaction associated with the given data is a first order reaction.
  • 53. Stability of Valsartan under stress conditions Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 53
  • 54. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 54
  • 55. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 55 The concentration of drug X in aqueous solution drops by 10% per month when stored at room temperature. What concentation will remain if a 5 mg/ml solution of the drug is stored under the same condetions after 3 months??? 1- If the degradation occurs by zero order? 2- If the degradation occurs by first order? 2- 5X0.9X0.9X0.9=3.65 mg/ml ktCC ot  ktCC o  lnln kCC o 09.0 5.01.0 /5 0   kCk mlmgfor mg/ml.x.mC 5335053  5-[(5X0.1) X3]=3.5 mg/ml kCC o  ln9.0ln 0 105.0 9.0 ln 0 0  C C k 3105.05ln3ln xmC  2944.1315.06094.13ln mC mlmgmC /65.33 
  • 56. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 56 Factors Affecting Rate of Reactions • The rate of reaction (degradation of pharmaceutical products) can be influenced – temperature, – moisture, – solvent (pH, dielectric constant, etc), – light (radiation), – catalysts, – oxygen and – concentration of DRUG (s).
  • 57. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 57 Arrhenius equation…. • For a reaction carried out at 2 diff. temp.,   12 12 1 2 303.2 log TT TT R E k k a   k = reaction rate, T = is absolute temperature in the Kelvin scale R = gas constant, Ea = activation energy If the activation energy at one temperature are known, one can easily determine the rate constant at any other temperature. This is important in the determination of expiration date of a new pharmaceutical product
  • 58. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 58 The degradation of a new cancer drug follows first-order kinetics and has degradation rate constants of 0.0001 h-1 at 60 ºC and 0.0009 h-1 at 80 ºC. What is its Ea?   333*353 333353 987.1*303.20001.0 0009.0 log   aE molcalEa /651.25
  • 59. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 59 Example: The rate constant for first-order degradation of a drug (activation energy is 20.0 Kcal/mol) in a solution (5.0 mg/ml) at 70°C is 1.50 × 10-3 h-1. 1. Calculate the amount remaining after storage for one week at room temperature (25°C). 2. Calculate the amount remaining after one week if the drug is kept at 70°C. 3. Calculate the shelf life of the drug at room temperature. 4. Calculate the half-life of the drug at room temperature. 5. Calculate shelf- life of the drug at 70°C. 6. Calculate the half-life of the drug at 70°C. 7. Discuss what you learned from this exercise.
  • 60. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 60 Concept of Q10 T T K K Q )10( 10   The Q10 temperature coefficient is a measure of the rate of change of a biological or chemical system as a consequence of increasing the temperature by 10 °C Q 10 shelf life estimation )10/( 10 19.0 29.0 )( )( T Q Tt Tt  
  • 61. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 61 )10/( 10 19.0 29.0 )( )( T Q Tt Tt   )10/( 10 19.0 29.0 )( )( T Q Tt Tt  
  • 62. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 62 Q Q
  • 63. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 63 Example: The ampicillin monograph states that the reconstituted suspension is stable for 14 days in a refrigerator. If the product is left at room temperature for 6 h, what is the reduction in the expiration period? 0.25 × 32 = 2.25 days )10/( 10 19.0 29.0 )( )( T Q Tt Tt   Shelf life= 14 / 32 = 1.56 days (Q = 3)?????   )10/255(2 3 25.0 )5( CTt O reduction The question to be addressed here is: Life at 25°C for 6 h (0.25 days) = how many hours at 5°C? 1.56 day(T=25O C) 14 day(T=5O C) 0.25 day(T=25O C) ??? day(T=5O C) 0.25 × 14/1.56 = 2.243 days
  • 64. • ZONE I TEMPERATE • ZONE II SUBTROPICAL • ZONE III HOT & DRY • ZONE IV HOT & HUMID Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 64 Stability Testing
  • 65. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 65
  • 66. Signs Of degradation Of Specific Dosage Forms 1. Tablets appearance, friability, harness, color, odor, odor, moisture content, and dissolution 2. Capsules strength, moisture, color, appearance, shape, brittleness, and dissolution 3. Oral solutions appearance, strength, pH, color, odor, suspensions redispersibility (suspension), and clarity (solutions) 4. Oral Powders appearance, strength, color, odor, moisture 5. Metered-dose strength, delivered dose per actuation, number inhalation of metered doses, color of propellant, pressure, aerosols valve, corrosion, spray pattern, absence of pathogenic microorganism 6. Topical non metered appearance, odor, pressure, weight loss, net aerosols weight dispensed, delivery rate, and spray pattern 7. Topical Creams ointments, lotions, solutions, and gels: appearance, color, homogeneity, odor, pH, resuspendibility (lotions), consistency, particle size, distribution, strength, weight loss
  • 67. Signs Of Degradation Of Specific Dosage Forms 8. Ophthalmic Preparations appearance, color, consistency, pH, clarity (solutions), particle size, resuspendibility (suspensions, creams, ointments), strength, and sterility 9. Parenterals strength, appearance, color, clarity, particulate matter, pH, volume and extractables (when plastic containers are used), sterility, pyrogenicity, and closure integrity 10. Suppositories strength, softening range, appearance, and dissolution 11. Emulsion appearance, color, odor, pH, viscosity, and strength 12. Transdermal seal strength of the drug reservoir, decomposition products, membrane integrity, drug strength, and drug release rate
  • 68. Responsibility of the Pharmacist • Dispense oldest stock first and observe expiration dates. • Store products under conditions stated in USP monographs and/or labeling. • Observe products for evidence of instability. • Properly treat/label products that are repackaged, diluted, or mixed with other products.
  • 69. Responsibility of the Pharmacist • Dispensing in proper container with proper closure • Informing/educating patients concerning proper storage and use of products
  • 70. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 70 PHARMACIST:
  • 71. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 71 PHARMACIST:
  • 72. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 72 Pharmaceutical Ingredients and Excipients Pharmaceutical Ingredients and Excipients Pharmaceutical ingredients added to prepare a dosage form
  • 73. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 73 Harmonization of Standards • International harmonization of excipients • Pharmaceutical industry is multinational • Uniform standards needed ???? Pharmaceutical Ingredients and Excipients Pharmaceutical Ingredients and Excipients
  • 74. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 74 Inactive Ingredient Database -FDA
  • 75. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 75
  • 76. Pharmaceutics PHAR 331 Birzeit Univ. Doctor of Pharmacy Dr. H. Shtaya 76