Heart Disease Prediction using machine learning.pptx
Unit 7-Modified Release Dosage Forms.pptx
1.
2. Introduction
Dosage form can be classified into immediate-release and modified-
release dosage forms.
Immediate-release (IR)/ conventional’ drug delivery : These provide
rapid onset of effect, following absorption in the gastrointestinal tract.
Limitations:
a. Drugs with short half-life---- require frequent administration---which
increases chances of missing dose of drug leading to poor patient
compliance and sub therapeutic level in blood.
A typical peak-valley plasma conc. time profile is obtained which
makes attainment of steady state condition difficult (Css)
The unavoidable fluctuations in the drug concentration may lead to
under medication or over medication.
2
b.
c.
3. Modified-release drug delivery: refers to the manipulation or
modification of drug release from a dosage form with respect to time,
course, and /or location
In contrast to conventional forms, modified release products provide
are delayed release, extended release (ER) and targeted-release systems.
Can be designed for all route of drug administration like oral,
parenteral, topical route.
1. Delayed-release dosage form: do not release the drug immediately
after administration through oral ( means have lag time between a
patient taking a medicine, and drug being detected in the blood).
Gastro-resistant dosage forms: start to release the drug when a
certain environmental pH is met.
Eg. Enteric coated formulation: design to pass through the stomach
unaltered, later to release their medication within the intestinal tract. 3
4. The purposes of such preparations are to prevent side effects related
to the drug presence in the stomach, protect the drug from
degradation in the highly acidic pH of the gastric fluid
2. Extended-release (ER): release the drug in a controlled manner,
at a predetermined rate, duration and location to achieve and
maintain optimum concentration of drug in blood.
at least a two-fold reduction in dose as well as frequency as
compared to an immediate release (conventional) dosage form.
Extended-release dosage form may be
a.
b.
c.
Sustained/ Prolonged release drug delivery system (SR-DDS)
Controlled release drug delivery system (CR-DDS)
Repeated action dosage forms (may be conventional )
4
5. (a) Sustained /Prolonged release (SR) DDS
drug release over a sustained period (release not definite
usually with first order release kinetics.
Preferably design for oral dosage forms
Drug is released slowly and rate of absorption is slow.
Onset of action is delayed.
(b) Controlled release (CR) DDS
per unit time)
deliver a constant supply of the active ingredient, usually at a zero-order
rate, drug release at a predetermined rate (release definite per unit time) for
a specific period of time.
Contains loading dose + maintenance dose.
Loading dose is immediately released to produce quick onset of action.
Maintenance dose is released at a controlled rate so that the plasma
concentration remains constant above Minimum Effective Concentration
(MEC). Plasma concentration comes down according to first order
elimination kinetics.
5
7. (c) Repeat action tablet:
more than one immediate release units are incorporated into a single
dosage form.
A dose of
administration,
the drug initially is released immediately after
which is usually equivalent to a single dose of the
conventional drug formulation.
After a certain period of time, a second single dose is released.
Advantage: No need of re-administration.
Disadvantage: that the blood levels still exhibit the “Peak and valley”
characteristic.
Targeted-release systems: Acts at particular target. May be site specific
targeting as well as receptor targeting, may be controlled and sustained
7
release
8. The rationale for extended-release (ERDF) pharmaceuticals
To reduce dose and hence reduce the side effect
Dosing frequency and improve patient compliance
Eliminate the fluctuations in blood concentration associated with
conventional delivery
To target the drug to a specific site in the body
Disadvantages of Extended-release dosage forms
High cost
Dose dumping
Prompt termination of therapy is not possible
Less flexibility in adjusting dosage regimens
(ERDF)
Need for additional patient education E.g : “Do not chew or crush the
dosage form, swallow fully without breaking
Drug absorbed at through specific absorption window in GIT cannot
8
ERDF
9. 9
Design of Modified Drug Delivery System
The performance of a drug depends upon its:
1. Release of drug from the dosage form.
2. Movement of the drug (Absorption) within the body.
Rate limited step in absorption in case of controlled DDS is release of
drug from formulation and in case of conventional it is permeation/
absorptoin
10. Desired characteristics of drug suitable for designing Sustained and
controlled release DDS
A. Biopharmaceutical characteristics
1. Molecular weight of the drug:
Less than 600 daltons (400 d optimum) are suitable for passive diffusion.
Larger molecules are not suitable e.g. peptides and proteins.
2. Aqueous solubility of the drug:
Good aqueous solubility with pH independent solubility serves as a good
candidate for oral controlled DDS. E.g. pentoxifylline.
Drug with pH dependent aqueous solubility (e.g. phenytoin) or drug
soluble in nonaqueous solvents (e.g. steroids) is suitable candidates for
parenteral controlled DDS (e.g. intramuscular depot).
Poorly water-soluble drugs are not suitable candidates for oral because
their dissolution is rate limited.
3. Ionization (pKa) of the drug
Drug that remains is unionized state at absorption site is a good
candidate like very week acidic drug (pKa
< 5) along entire length of GIT and are
design for oral delivery
> 8.0) and V
ery weak bases (pKa
suitable for CR/SR formulation
10
11. Drug that remains in ionized state (e.g. hexamethonium) are poor
candidates for oral drug delivery.
For acidic drug having pKa value 2.5-7.5, ionization is pH sensitive.
These drug remain unionized at gastric pH but ionized at intestinal pH.
So suitable for Gastroretentive drug delivery system
For basic drug having pKa 5 – 11, ionization is pH sensitive, Ionized
in gastric pH, Unionized in intestinal pH, Better absorbed from intestine.
Suitable for designing intestinal delivery system/colon delivery.
4. Partition coefficient
Partition coefficient is the fraction of drug in an oil phase to that of an
adjacent aqueous phase. The drug should be sufficiently lipid soluble
and water soluble. High partition coefficient compound are
predominantly lipid soluble and have very low aqueous solubility and
thus these compound persist in the body for long periods.
11
12. 5. Drug stability:
Drugs unstable in gastro-intestinal environment are poor candidates
for oral controlled DDS because bioavailability will be less. Drugs
that are unstable in the environment of the stomach, enteric coated
formulation can de design.
6. Mechanism of absorption:
Drugs absorbed by carrier mediated transport and those absorbed
through an “absorption window” are poor candidates e.g. several B-
vitamins.
7. Route of administration:
Oral route: Duration of action may be extended to 12 to 24 hours.
Maximum 1000mg can be given including additives.
8. Intramuscular / Subcutaneous route: Duration of action can be
prolonged from 24hours to 12 months. Maximum 2ml
administered through this route.
or 2 gm can be
12
13. 9. Transdermal route : 12 hours to several days. V
ery low dose drugs
(e.g. nitroglycerine) can be administered. Drugs with extensive first pass
metabolism is suitable. Suitable dose 50 mg (optimum upto 20 mg) for
patches.
Pharmacokinetic characteristics
1. Half life of drug: Half life of drug is 3-8 hr, not suitable for <2 & >8
hr. Half-lives shorter (Penecillin G) - than 2hrs - poor candidates of
sustained release dosage dose size will increase to maintain constant
release.
•Long half life (diazepam) more than 8hrs - sustained effect already
occurs
2. Rate of metabolism: Drug that is rapidly metabolized in the liver are
controlled release DDS. They are better
release formulation/transdermal.
not good candidate for oral
given by parenteral controlled
Even the drug that inhibit or induce the metabolism also not good
candidate for oral controlled release delivery.
13
14. Pharmacodynamic characteristics
Therapeutics range of a drug is wide
a) Therapeutic range:
good candidate for controlled DDS. In case of low therapeutics
range, can be designed but not very much suitable like
phenobarbiton, digoxin.
b) Therapeutic index: it is the ration of MSC to
– safer is the drug - TI>10.
MEC. Larger the ratio
c) Plasma concentration – Response relation
activity
ship: Drugs such as
its
reserpine whose pharmacological is independent of
plasma concentration are poor candidate for controlled DDS.
14
15. Design,
forms
development and characterization of modified release dosage
Classification of oral controlled release systems
A. Continuous controlled release systems: such dosage form release the
drug for prolonged period of time in entire
terminal region of small intestine)
These are further classify
1. Dissolution controlled release systems
(a) Matrix (or monolith) systems
(b) Encapsulation / Coating systems
length of GIT (especially upto
2. Diffusion controlled release systems
(a) Matrix systems
(b)Reservoir systems
3. Dissolution and diffusion controlled release systems
a.
b.
c.
d.
e.
Ion-exchange resin – Drug complexes
Osmotic pressure controlled systems
pH independent formulation
Slow dissolving salts and complexes
Hydrodynamic pressure controlled system. 15
16. B. Delayed transit and then continuous release systems: these
formulation are design to retain in stomach for a duration and hence
delayed their gastric transit. So the drug should be stable in stomach
and should be better absorb from upper part of intestine. May be
Altered density systems
Mucoadhesive systems
Size-based system
C. Delayed release systems: these system
part of intestine.
release the drug in lower
Intestinal release systems
Colonic release systems
The drug for this type of system are:
a.
b.
c.
d.
Gastric labile
Produce some side effect in gastric region i.e. gastric distress
Better absorb from the intestine
Have the local action in intestine or colon 16
17. Dissolution controlled release systems
Control – Dissolution of the drug from the polymer matrix or
encapsulated forms.
• The dissolution process at a steady state is described by Noyes
Whitney equation:
dc/dt = (DAKo/w/Vh) (Cb - Cs)-----------(Modified by Brunner)
= k (Cs - Cb).................... (Initial
dC/dt = dissolution rate
V = volume of the solution
k =intrinsic dissolution rate constant
D = diffusion coefficient of drug through pores
h = thickness of the diffusion layer
A= surface area of the exposed solid
Cs = saturated solubility of the drug
Cb = conc. of drug in the bulk solution
Noyes Whitney equation)
Noyes- Whitney‟s equation represents first order dissolution rate
17
process, for which the driving force is concentration gradient.
18. This is true for in-vitro dissolution which is characterized by non-sink
conditions.
In vitro sink condition can be maintain if Cb is always less than 10 % of
Cs. In this situation, Whitney‟s equation represents zero order dissolution
rate (Sink condition: Concentration in receptor compartment is maintained
at lower level compared to its concentration in donor compartment)
Dissolution controlled release systems may be of
(a)Matrix (or monolith) systems
(b)Encapsulation / Coating systems
Matrix (or monolith) systems
Since the drug (water soluble) homogeneously dispersed throughout a rate
controlling medium matrix system.
The waxes used for such system are beeswax, carnauba wax,
hydrogenated castor oil etc.
These waxes control the drug dissolution by controlling fluid penetration
into the matrix, by altering the porosity of tablet, decreasing its wettability
or by itself dissolved at a slower rate. Release will be effected
18
by
dissolution or erosion of polymer matrix.
19. Encapsulation/Coating
Devices):
dissolution controlled system (Reservoir
Encapsulation involves coating of individual particles, or granules
of drug with the slowly dissolving material.
The particles obtained after coating can be compressed directly into
tablets as in spacetabs or placed in capsules as in the spansule
products.
As the time required for dissolution of coat is a function of its
thickness (varying thickness 1- 200 micron) and the aqueous
solubility of the polymer.
By using one of several microencapsulation techniques the drug
particles are coated or encapsulated with slowly dissolving materials
like cellulose, PEGs, polymethacrylates, waxes etc.
19
20. Several technique for microencapsulation are
a)
b)
Coaservation/ phase separation: for water soluble polymer
Interfacial
polymers
polymerization: for water-insoluble &water soluble
c)
d)
Precipitation method: organic solvent-soluble Polymer
Solvent evaporation: for solvent-soluble polymers, volatile solvent
are used
Mechanism:
Dissolution followed
by erosion
20
21. 2. Diffusion controlled release systems
Rate controlling step is the diffusion of dissolved drug through a
polymeric barrier rather than dissolution rate
Since the diffusional path length increases with time as the
insoluble matrix is gradually depleted by the drug and the release of
drug is never zero order.
Classified into reservoir system and monolithic system.
Reservoir devices:-
These systems are hollow in which core of drug is surrounded in
Water insoluble polymer membrane (but permeable) like HPC, EC,
polyvinyl acetate
Drug release mechanism is involve its partition in to the membrane
and exchange with fluid surrounding the particle or tablet.
Dose dumping is the major drawback.
The permeability of membrane depend on thickness of the
coat/concentration of coating solution & on the nature of polymer
21
22. The rate of drug release from the reservoir system can be explained
by Fick ‟s Law of diffusion as per the following equation.
dC/dt = DSK(C1-C2)/h = DSKΔC/h
Where Where,
S = is the active diffusion area.
22
23. D = is the diffusion coefficient of the drug across the coating
membrane.
h = is the diffusional path length (thickness of polymer coat)
ΔC = is the concentration difference across h.
K = is the partition coefficient of the drug between polymer and
external medium.
the
Coating like Coated Beads/Pellets and Microencapsulation technique
is used for the preparation.
2. Matrix diffusion controlled system
In these system the drug is dispersed in swellable hydrophilic
substances or in a mixture of insoluble matrix of rigid non-swellable
hydrophobic materials + swellable hydrophilic
Insoluble plastics such as PVC (poly-vinyl chloride) and fatty
materials like stearic acid, beeswax etc are the material used for rigid
matrix.
23
24. Hydrophilic gums may be of natural
origin (Guar gum, tragacanth), semi
synthetic (HPMC, CMC, Xanthan gum) or
synthetic (poly acryl amides) are the
material generally used for such matrices.
The equation describing drug release for
this system is given by T. Higuchi.
½
C = KH t
The release of highly water soluble drug
can be sustained by using swellable matrix
systems.
24
25. For formulation, gum and drug are granulated together and
compressed into tablet.
Not preferably used as
shows very slow release
25
26. The mechanism of drug release from this system involves absorption
of water (resulting hydration, gelling and swelling of gum) and
desorption of drug via swelling controlled diffusion mechanism .
As the gum swells and the drug diffuses out of it, the swollen mass
devoid of drug appear transparent or glass like and so the system is
sometimes called as glassy hydrogel.
3. Dissolution and diffusion controlled release systems
Drug is encased in a partially soluble membrane
As the system come in contact with medium (water), the soluble part
of membrane get solubilized and creating the pores in membrane.
The medium enter through these pores and solubilize the drug. The
dissolved drug diffused out.
Polymer like Ethyl cellulose (water insoluble) and Methyl cellulose or
poly-vinyl-pyrrolidone (PVP) (water soluble) are used together to form
the membrane.
26
27. Ion-exchange resin – Drug complexes
Controlled release delivery of drug that ionize in acidic drug and basic
pH can be obtained by forming the complex with insoluble, nontoxic,
anionic and cationic ion exchanger resin (IER), respectively.
The drug release slowly by diffusion from the resin structure. Basic
drug like noscapine, phenylpropanolamine, phenterimine etc.
27
28. Ion exchangers are developed by polymerization reactions
Complexes between IER and drugs are known as ion exchange
resonates.
A typical cation-exchange resin is prepared by the copolymerization
of styrene and di-vinyl-benzene. Sulphonic acid /Carboxylic acid
groups are attached styrene-di-vinyl-benzene polymer .
In case of anionic exchanger Quaternary ammonium
/Polyalkylamine
copolymer.
groups attached to a styrene and divinylbenzene
Osmotic pressure controlled systems
The
diffusion
pressure exerted by water molecules on the semi-
permeable membrane is called as osmotic pressure.
28
29. Osmotic drug release systems use osmotic pressure as a driving
force for the controlled delivery of drugs. A simple osmotic pump
consists
osmotic
of an
agent)
osmotic core (containing drug with or without an
and is coated with a semi-permeable membrane.
The semipermeable membrane has an orifice for drug release from
the “pump.” The dosage form,
water
after coming in contact with the
aqueous fluids, imbibes at a rate determined by the
of
fluid
core
29
permeability
formulation.
of the membrane and osmotic pressure
30. Osmogens are dissolved in the biological fluid, which creates
osmotic pressure build up
outside the pump through
inside the pump and pushes medicament
delivery orifice. They include inorganic
salts and carbohydrates. Mostly, potassium chloride (245 atm),
sodium chloride (356 atm), and mannitol (38 atm), sucrose (150
atm), sorbitol (84 atm) used as osmogens.
B. Delayed transit and then continuous release systems:
Gastroretentive drug delivery system
Dosage form is retained in the stomach so that drug absorption in
the upper gastrointestinal tract can be maximized
those for local action in the stomach (e.g. to treat H. pylori), drugs
which have a narrow absorption window in the small intestine and
drugs which are degraded in the colon.
Several approach are used for Gastro-retention like
Mucoadhesion, floating based, density based etc.
30
31. High Density Systems: - These systems, which have a density of ~3
g/cm3, are retained in the rugae of the stomach and are capable of
withstanding its peristaltic movements. Above a threshold density of
2.4–2.8 g/cm3, such systems can be retained in the lower part of the
stomach .
Diluents such as barium sulphate (density = 4.9), zinc oxide, titanium
dioxide, and iron powder must be used to manufacture such high-
density formulations
31
32. Mucoadhesive system
Mucoadhesive polymers could theoretically adhere a dosage form to the
stomach mucosa to retain it in the stomach.
Polycarbophil, chitosan, poly(acrylic acid), hydroxy propyl cellulose
(HPC), and sodium carboxy methyl cellulose (CMC) are mucoadhesive
polymers
Floating system
Dosage form should float on the stomach contents, thus avoiding gastric
emptying. Have density less than 1.04 gm/cm3
Swellable polymers such as Methocel, carbopol
Gas generating agents like bicarbonate and citric or tartaric acid are
used.
NaHCO3(aq) + HCl(aq) → NaCl(aq) + CO2(g) + H2O(l)
Size increasing systems
A dosage form that swells and increase in size as soon as it reaches the
stomach to avoid being able to pass through the pyloric sphincter.
Swellable polymers such as Methocel (hydroxy propyl methyl
cellulose),
investigated
polyethylene oxide, and xanthan gum have all been
32
33. C. Delayed release systems: these system release the drug
part of intestine.
in lower
Intestinal release systems (Gastroresistant coatings)
Colonic release systems
Intestinal release systems (Gastro-resistant coatings)
Membrane controlled extended release, except that the membrane is
designed to disintegrate or dissolve at a pre-determined point.
The most common trigger for delayed release coatings is pH.
Gastro-resistant coatings are polymer coatings which are insoluble
at low pH, but are soluble at higher pH (e.g. somewhere between pH
5–7 depending on the polymer)
This approach is most commonly used for releasing drug in the
small intestine.
Gastro-resistant coating of formulations has two functions: i) to
protect the stomach from the drug or ii) to protect acid-sensitive drugs
from the stomach environment.
33
34. Colonic drug delivery
Disorders like inflammatory bowel diseases, ulcerative colitis,
Chron's disease, infectious diseases and colon cancer are using site
specific drug delivery system.
Suitable for peptide and protein drugs. These drugs are destroyed
and inactivated in acidic environment of stomach or by pancreatic
enzymes (or) by parenteral route which is inconvenient and
expensive. Polymer like Cellulose Acetate Phthalate (CAP/pH 5),
Eudragit L 100 (pH 6), Eudragit S 100 (pH 7), polysaccharides
34
like chitosan
35. General mechanisms of drug release from dosage forms
Several mathematical models are applied on in-vitro release data
to evaluate release kinetics as well as mechanism of drug release from
modified release dosage form.
2
First to fourth model give the value of correlation coefficient (“ R
” ) and last one give the value of exponent (n).
2
Model with Highest value of R ” is consider as best fitted model.
The value of exponent (n) indicate the mechanism of drug release.
1.
2.
3.
4.
5.
Zero Order Release Model
First Oder Release Model
Higuchi Release Model
Hixson-Crowell Release Model
Release kinetics,
2
Compare R
Korsmeyer-Peppas Release mechanism Model
35
time Cum.
Drug
release
0 0.0
1 20
2 35
3 55
4 80
36. Zero order release kinetics
Release kinetics independent of concentration of drugs in the
dosage form
Refers to the process of constant drug release
V
alue of release constant (K0) and correlation coefficient (R2) can
be determine by plotting a graph between cumulative amount of
drug released vs. time.
A straight line will be result whose slope will be K0 and intercept
will be C0
Zero order release can be represented as
C = C0 + K0t
Where C0 = Initial Concentration/amount of drug (Qo), C =
cumulative concentration/ amount (Q) of drug release at time “t”
Ko = Zero order release constant, t = time in hours
36
37. First order release kinetics :
Release kinetics dependent on the concentration of drugs in dosage
form
Value of release constant (K1) and correlation coefficient (R2) can be
of
be
determine by plotting a graph between log cumulative percentage
drug remaining (log Cr )
result whose slope will be
log
Higuchi’s model
Cumulative percentage of
to release vs. time. A straight line will
- K1 /2.303 and intercept will be log C0
Cr = log C0 – K1 t / 2.303
drug released vs. square root of time.
½
C = KH t
Drug release rate is proportional to the reciprocal of the square root
time.
of
37
38. A straight line will be result whose slope will be KH
Hixson-Crowell cube root law
To evaluate the drug release with changes in the surface area
diameter of the particles/tablets:
and the
3√ C0 -3 √Ct = kHC . t
Where Ct is the Concentration of drug released in time t.
C0 is the initial Concentration of the drug in the tablet
KHC is the rate constant for the Hixson-Crowell rate equation, as the
cube root of the percentage of drug remaining in the matrix v/s time.
38
39. 120
120
y = 3.6987x +
19.743
R' =0.8842
j
t
g
~ 100
..II
100
80 ~ 80
.1
.,!
60
.
.
.~
.i
60
·
~
40 "
E
...
40
..
.l
.E
.
20 20
o
~
• 0 0
0 5 10 15
Time(hrs)
a
20 25 30 0 5 10 15
Time (hrs)
b
20 25 30
2.5
120
s:
100
v= 20.193x-0.4547
R'=0.9941
v= -0.0481x +
1.9827
R' =0.9894
.
.
2
J
"
I
I
.!
.
.5 80
60
40
.
e5
1.5
-"
e
~
!
.!
.
~
~
"
~ 1
-
..
.e
.
JI
"
E 20
"
.9
0.5
v
..
.
0
-20 1 2 3 4 5 6
0
Square root of time (hrs]
0 20 30
lO Time (hrs)
c d
(a) In vitro drug release modified release formulation (b) Zero order
release model (c) first order release model (d)Higuchi release model
39
40. Mechanism of drug release
When a drug delivery system is introduced in the appropriate dissolution
medium then it swell and exist in following three front:
Swelling front: The boundary between the glassy polymer and its rubber
phase.
Diffusion front: The boundary between the Solid as undissolved drug and
the dissolved drug in the gel layer.
Erosion front:
medium.
The boundary between the matrix and the dissolution
In controlled or sustained release formulations, diffusion, swelling and
erosion are the three most important rate controlling mechanisms.
The drug release from the polymeric system is mostly by the diffusion and
is best described by fickian diffusion.
40
41. But in case of formulation containing swelling polymers, other
process in addition to diffusion play an important role
drug release mechanisms.
in exploring the
Due to swelling considerable volume expansion take
moving diffusion boundaries complicating the solution
low of diffusion
place leading to
of fick‟s second
Korsmeyer- Peppas model or Power low
Drug release is a function of the exponent (n) of time.
Mt / M∞ = Ktn
Where Mt/M∞ is the fraction of drug release, t is the
kinetic constant.
release time, K is a
n is an exponent that characterizes the Mechanism of release is termed as
release exponent. The value of release exponent changes with change the
geometry of tablets.
41
42. To determine the value Log cumulative % of drug remaining to be
n can
release v/s log time (hr) was plotted and from the slope, value of
be calculated.
V
alue of n will tell about the mechanism of drug release form
formulation like
a.
b.
n = 0.45----Fickian diffusion, simple diffusion (non-swelling)
0.45 < n < 0.89----Anomalous or non-fickian diffusion means
Swelling (dominant), diffusion and erosion controlled release.
both
c. n = 0.89 or above----case-2 relaxation
means erosion of polymeric chain.
or supercase transport-2
Comparative drug release study
1. Model independent model
Used in this case, a comparative study
between two product.
of drug release or dissolved
One is taken as
formulation).
reference/standard or another as test (design
42
43. Model independent mathematical approach to compare the
dissolution profile using two factors, f1 and f2.
(a) Difference Factor (f1)
The difference factor (f1 ) calculates the
and
percent (%) difference
between the two curves at each time point
relative error between the two curves
is a measurement of the
Where, n = number of time points
Rt = % dissolved at time t of reference product (pre change)
Tt = % dissolved at time t of test product (post change)
Application: F1 is specially used to compare two dissolution profiles
(difference), being necessary to consider one of them as the reference
standard product. To indicate the differences between two, F1 value should
be >15-50 (FDA guideline). The value ≤15 indicate similarity. Useful when
43
sample point are less in number (three or less).
44. (b) Similarity Factor
f2 is inversely proportional to the average squared difference
between the two release profile.
The factor f2 measures the closeness between the two profiles.
FDA has set a public standard of f2 value between 50–100 to
indicate similarity between two dissolution profiles.
The value <50 indicate difference.
Useful when sample point are more in number (more than three).
44
45. 2.StatisticalAnalysis for comparison
(a) Student’s t-Test:
Calculated „t‟ value (mean) is compared with tabulated value of
„t‟ if the calculated value exceeds the tabulated value, then the null
hypothesis should be rejected and indicate the significant differences
between the dissolution profile of two formulation or vice versa.
One character of only two product can be compared at one time
(b) ANOVA Method (Analysis of V
ariance)
Determine the F value (critical factor/variance). Compare the
variance of different groups of data and predict whether the data are
comparable or not.
Minimum three sets of data are required for comparison and can
compare one character (like dissolution) in case of one way ANOV
A
and two characters ( in case of two wayANOV
A)
45
46. In vitro/In vivo evaluation of modified release dosage forms
In-vitro evaluation parameters of modified releases delivery system depends
upon the type of system as well as route of delivery. We
sustained release tablet.
are taken a case of oral
Almost all evaluation parameters are similar to that of
Evaluation of modified tablets
Official Tests:
conventional tablets.
Weight variation
Disintegration (not for modified release formulation except conventional
enteric coated formulation)
Dissolution or percent drug release in case of modified release
formulation
Drug content in case of single unit system and drug loading/entrapment
efficiency in case of multiple unit system.
Swelling index study in case of modified release formulation specifically
for Sustained /controlled system.
Gastric residence time in case of Gastroretentive system
46
1.
2.
3.
4.
5.
6.
47. Non-Official Tests:
GeneralAppearance, Shape (official
Thickness of tablets
Hardness
Friability (official test in IP)
Unique identification marking
in IP) and Size of tablet
1.
2.
3.
4.
5.
6. Organoleptic properties
47
48. Dissolution Test
Rate of dissolution/ release is directly related to the efficacy of the drug.
Rate of dissolution is a good index for comparing the bioavailability of two
tablet products of the same drug.
Official Dissolution TestApparatus
Type I.P. USP B.P. E.P.
Type 1 Paddle Basket apparatus Basket apparatus Paddle apparatus
apparatus
Type 2 Basket Paddle apparatus Paddle apparatus Basket apparatus
apparatus
Type 3 Reciprocating Flow through Flow through
cylinder cell apparatus cell apparatus
Type 4 Flow through
cell apparatus
Type 5 Paddle over
disk
Type 6 Rotating cylinder
Type 7 Reciprocating
holder
49. 49
Official Dissolution TestApparatus and specific application
Type USP Rotation speed
Type 1 Basket apparatus 50-100 rpm, may Immediate drug release (IDR)
go upto 150 rpm Delayed release (DR)
Extended / modified release
(ER)
Type 2 Paddle apparatus 25-50 rpm IDR, DR, ER
Type 3 Reciprocating 6-35 rpm IDR,ER
cylinder
Type 4 Flow through N/A ER, Poorly solubleAPI
cell apparatus
Type 5 Paddle over 25-50 rpm Transdermal patches
disk
Type 6 Rotating cylinder N/A Transdermal patches
Type 7 Reciprocating 30 rpm ER
holder
50. 1. USPDissolution apparatus I ( Basket method)
Design:
V
essel: -Made of borosilicate glass.
Semi hemispherical bottom
Capacity 1000ml
Shaft : -Stainless steel 316
Speed 50-100 rpm.
Water bath :-Maintained at 37±0.5ºC
Dosage form is kept in basket.
Screen: 40x40 mesh (0.015 inches opening),
wire diameter 0.01 inch (same as IP)
20x20 mesh (0.034 inches opening)
wire diameter 0.016 inch
USE: Tablets, capsules, floating dosage forms
and modified release system, multiple unit system.
51. 2. USPDissolution apparatus II ( Paddle
Design:
Vessel: -Same as basket apparatus
Shaft: - Fused with blade at bottom
Stirring elements:- Coated with teflon
For laboratory purpose
stainless steel is used
Rotation Speed:- 25-50 rpm
Water-bath: -Maintains at 37±0.5°C
method)
Sinkers : -Platinum wire used to prevent
tablet/capsule from floating.
Dosage form should remain at the bottom center of vessel
USE: Conventional as well as modified release table. Not
suitable for floating system
53. Dissolution testing and interpretation IPstandards
*D is the amount of dissolved active ingredient specified in the individual
monograph (Suppose 80 %), expressed as a percentage of the labelled content.
** Percentages of the labelled content.
Sr.no. Quantity Number of Acceptance criteria
Stage/leve tablets tested
l
1 S1 6 Each unit is not less than D* + 5 per
cent**.
2 S2 6 Average of 12 units (S1 +S2) is equal to
or greater than D, and no unit is less
than D –15 per cent**.
3 S3 12 Average of 24 units (S1+S2+S3)is equal to
or greater than D, not More than 2 units
are less than D – 15 per cent** and no
unit is less than D – 25 per cent**.
54. Disintegration test (U.S.P.) :
Disintegration test is not performed for controlled & sustained
release tablets.
Specific test
Swelling index (S I):One tablet from each formulation is kept in a petri
dish containing pH 7.4 phosphate buffers. The tablet was removed every
three hour interval up to 12 hour and excess water blotted carefully
using filter paper. % S.I = (final wt-initial wt/initial wt) x 100
Floating lag time and duration of floating
The buoyancy lag time (seconds- expected upto 30 seconds) and
Duration of floating were determined in the USP Dissolution apparatus
II in an acidic environment (0.1N HCL, 900 ml, 50 RPM).
The time interval between introduction of the tablets in to the
dissolution medium and its buoyancy to the top of the dissolution
medium is taken as buoyancy lag time and duration of buoyancy is
observed visually.
55. In-vivo testing
1. Pharmacodynamic study: Therapeutic activity as well as toxicity
study. Perform on
commonly used.
Pharmacokinetic
Standard as well
suitable animal model. Mice, rat, rabbit models are
2. study:
as test
performed in suitable animals model.
formulation given to the suitable animal
groups. Blood will withdraw at specific time interval and the
concentration of drug in blood is determine by suitable analytical
technique like HPLC, HPTLC, LC-MS etc. Plot a graph between
time and concentration. Here you will find three parameters like
AUC, Tmax and Cmax. By
be
using AUC, bioavailability can be
determined.
method), Cut
method.
Specific test:
AUC can measured by Planimeter (physical
& weigh method, Trapezoidal method and square count
For gastro retentive formulation: Radio graphs using X-ray equipment
to see the condition either floating, swelling or settling due to high
density.
Gama Scintigraphy : for targeting of a formulation a specific organs 55
