MODERN PHARMACEUTICS

1. Presented by
P.PRASATH
M.PHARM FIRST YEAR (SEM-2)
DEPARTMENT OF PHARMACEUTICS
COLLEGE OF PHARMACY
MADRAS MEDICAL COLLEGE
CHENNAI 600-003.
1

2.  DISSOLUTION: is a process in which a solid
substances solubilises in a given solvent i.e. mass
transfer from the solid to the liquid phase.
 DISSOLUTION RATE:
 Is the amount of solid substance that goes in to solution
per unit time under standard condition of temperature,
pH and solvent composition and constant solid surface
area.
2

3.  There are two types of dissolution apparatuses.
1. Closed compartment apparatus:
 limited volume apparatus
 Operating under non-sink condition.
 e.g: Beaker type apparatus such as rotating basket and paddle.
2. open compartment (continuous flow through)apparatus:
 It is the one in which the dosage form is contained in a column
which is brought in continuous contact with fresh, flowing
dissolution medium (perfect sink condition).
 A third type called a dialysis systems are used for very poorly
aqueous soluble drugs for which maintenance of sink
condition would otherwise require large volume of dissolution
fluid.
3

4.  The apparatus must be simple and easy to operate under
variety of conditions.
 The dimensions and position in of all the components must
be precisely specified
 The apparatus must yield repeatable results
 The apparatus must be sensitive enough to reveal process
variations
 The apparatus should permit a uniform and non-turbulent
liquid agitation
 The apparatus should provide minimum mechanical
abrasion to the dosage form
4

5.  Evaporation of solvent medium must be eliminated.
 Medium must be maintained at a fixed temperature within a
specified narrow range
 Nearly perfect sink condition should be maintained
 Samples should be easily withdrawn without interrupting the
flow of the liquid
 The apparatus should allow inter-laboratory agreement
 The apparatus should be versatile and capable of evaluating
disintegrating, dense or floating tablets, or capsules, and
finely powdered drugs
5

6. 6

7.  It was first discovered by PERNAROWSKI. It is
basically closed compartment, beaker type comprising of
a cylindrical vessel with apparatus hemispherical bottom
of one litre capacity partially immersed in a water bath to
maintain the temperature at 37°C.
 A basket made of 22 mesh to hold the dosage form is
located centrally in the vessel at a distance of 2cm from
the bottom and rotated by a variable speed motor through
a shaft.
 The tablet is placed in a dry
basket.
7

8. A. Cylindrical vessel
B. Variable speed motor
C. Basket
D. Withdrawl ports
E. Waterbath
8

9. Useful for :
 Tablets
 Capsules
 Suppositories
 Delayed/enteric coated dosage forms
 Floating dosage forms
Agitation :
Stainless steel 316
Usual speed: 50 to 100 rpm
ADVANTAGES: limited area, capsules are placed in a
basket- float, used for non-official test such as
suppositories & microencapsulated particles.
DISADVANTAGES: clogged, light particles float,
corroded in presence of Hcl solution.
9

10.  The assembly is same as that for apparatus 1 except that the
rotating basket is replaced with a paddle which acts as a stirrer.
 This method was first discovered by levy & Hayes.
 The dosage form is allowed to sink to the bottom of the vessel.
 SINKERS are used to recommended to prevent floating of the
capsules and other floatable forms.
 The tablet is allowed to sink to the bottom of the vessel prior
to the rotation of the paddle, if the tablet floats, a wire or glass
helix is used.
10

11. 11

12. Useful for :
 Tablets
 Capsules
Agitation:
 Rotating stirrer
 Usual speed: 25 to 75 rpm
Standard volume: 900/1000 ml
Advantages:
 Easy to use
 Paddle method produces greater turbulence compared to
basket method .
Disadvantages:
 Some tablets and capsules tend to float . Hence sinkers
have to be used.
 Orientation of paddle is very important, else result vary.
 pH/media often change is difficult
12

13.  The apparatus consists of a set of cylindrical flat – bottomed
glass vessel equipped with glass reciprocating cylinders.
 stainless steel fittings and screens that are made of suitable
non adsorbing and nonreactive material(poly propylene).
 That are designed to fit the tops and bottoms of the
reciprocating cylinders, and a motor and drive assembly to
reciprocate the cylinders vertically inside the vessel.
13

14.  The vessels are partially immersed in a suitable water bath of
any convenient size that permits holding the temperature at
37°c ± 0.5°c during the test.
 The dosage unit is placed in reciprocating cylinder & the
cylinder is allowed to move in upward and downward
direction constantly.
 Release of drug into solvent within the cylinder vessel.
14

15. Useful for: Tablets, controlled release bead-type
formulations.
Standard volume: 200-250 ml.
Advantages:
1) Design is technically easy
2) Medium can be changed easily by removing the
dosage unit(inner cylinder) and placing it in another
medium. Easily automated.
Disadvantages:
1) small volume (max. 250 ml).
2) Little experience.
15

16.  The assembly consists of a reservoir and a pump for
the dissolution medium.
 A water bath that maintains the dissolution medium
at 37°c ± 0.5°c.
 The pump forces the Dissolution Medium upwards
flow through the cell holding the test sample.
16

17.  It may be used in either:
 closed mode – where the fluid is recirculated and, by
necessity is of fixed volume.
 open mode – when there is continuous replenishment
of the fluids.
 The material under test is placed in the vertically
mounted dissolution cell, which permits fresh solvent
to be pumped in from the bottom.
 The system allows a large quantity of medium to be
used which is an advantage for low solubility drugs
requiring a large amount of medium reaching the sink
condition.
17

18. 18

19. Useful for:
 Low solubility drugs.
 Implants.
 Powder granules.
 Capsules.
Advantages:
 1. Easy to change the pH.
 2. Feasibility of using large volume of dissolution fluid.
 3. Easy to maintaining Sink conditions.
Disadvantages:
 1. clogging of filter creates difficulties.
 2. High volumes of media.
19

20.  Use the paddle and vessel assembly from Apparatus 2 with
the addition of a stainless steel disk assembly designed for
holding the transdermal system is placed at the bottom of the
vessel.
20

21.  The disk assembly holds the transdermal system flat and is
positioned such that the release surface is parallel with the
bottom of the paddle blade
 The vessel may be covered during the test to minimize
evaporation.
Advantages:
 Less expensive
 Standard equipment (available with the manufacture)i.e.
apparatus can be modified and utilized apparatus 5.
Disadvantages:
 Disk assembly restricts the patch size.
 17 mesh is standard (others available )
 Accommodates patches of up to 90mm
21

22.  Use the vessel assembly from Apparatus 1 except to replace
the basket and shaft with a stainless steel cylinder stirring
element.
 The temperature is maintained at 32°C ± 0.5°C
 The dosage unit is placed on the cylinder at the beginning of
each test, to the exterior of the cylinder such that the long axis
of the system fits around the circumference of the cylinder &
removes trapped air bubbles.
 Place the cylinder in the apparatus, and immediately rotate at
the rate specified in the individual monograph.
22

23. 23

24. DESIGN:
 Vessel - In place of basket cylinder is used
 Shaft- stainless steel 316
 Sample-mounted to cuprophan (inner porous cellulosic
material) an entire system adheres to cylinder
 Dosage unit is placed in cylinder and release from side out
 Used for transdermal patches
 Adv: apparatus 1- apparatus 6.
 Dis Adv: large volume of medium is required. Drugs gets
diluted and causes difficulties in analysis of drug.
24

25.  The samples are placed on
disc-shaped holders using inert
porous cellulosic support which
reciprocates vertically by means
of a drive inside a glass container
containing dissolution medium.
 The test is carried out at 320C
and reciprocating frequency of
30 cycles/min.
25

26. 26

27.  Apparatus 7 is applied to transdermal patches and solid
oral dosage forms.
 It is particularly used for the drug release from osmotic
pumps and extended release tablets.
 Adv:
 This method is for selecting the volume of the medium
and for maximising the drug conc.that is suitable for
drug analysis. It can be automated.
 Dis Adv: Invesment on dissolution apparatus is high,
because the design is totally different from std.
equipment already available in the industry.
27

28.  Formulation factors:
a. Vehicle g. Suspending agents
b. Diluents h. Surfactants
c. Binders & granulating agents i. Buffers
d. Disintegrants j. Complexing agents
e. Lubricants k. Colorants
f. Coatings l. Precipitation
 Processing factors:
a. Method of granulation
b. Compression force
28

29. 1)VEHICLES:
 vehicle or solvent system is the major component of liquid
orals and parenterals.
3 categories of vehicle:
 Aqueous vehicle-water, syrup, etc.
 Non-aqueous water miscible vehicle-propylene glygol,
glycerol, sorbitol.
 Non-aqueous water immiscible vehicle- vegetable oils.
29

30. 2)DILUENTS(fillers)
 Diluents are commonly added to the tablet and capsule
formulation if the required dose is inadequate to
produce the necessary bulk.
 Diluents may be organic or inorganic.
 Organic-carbohydrates are widely used
Eg:starch,lactose, MCC etc.
 Inorganic- dicalcium phosphate(DCP) is the most
common.
 Eg:drug-diluent interaction resulting in poor
bioavailability is that of tetracycline and DCP.
30

31. 3)DISINTEGRANTS
 These agent overcome the cohesive strength of tablet & break
them up on contact with water.
 A decrease in the amount of disintegrant - lower dissolution.
 Disintegrants like bentonite and veegum should be avoided
with lose dose drugs like digoxin,alkaloids & steroids.
 Microcrystalline cellulose is a very good disintegrating agent
but at high compression force, it may retard drug dissolution.
 Starch is not only an excellent diluents but also superior
disintegrant - hydrophilicity and swelling property.
31

32. 4)BINDERS OR GRANULATING AGENTS
 These materials are used to hold powders together to form
granules or promote cohesive for directly compressible
materials.
 The hydrophilic (aqueous) binder increase dissolution rate of
poorly wettable drug.eg: phenacetin
 Large amount of binder increase hardness & decrease
disintegration /dissolution rate of tablet.
 PEG6000 –deleterious binder for phenobarbital –it forms
poorly soluble complex with drug.
 Non aqueous binders such as ethyl cellulose also retard the
dissolution rate of drug.
32

33. 5)LUBRICANTS/ANTIFRICTIONAL AGENTS:
To aid flow of granules
To reduce interparticle friction
Sticking or adhesion of particles to dies and punches
 Lubricants are hydrophobic in nature (several metallic
stearate & waxes) which inhibit wettability, penetration
of water into tablet - decrease in disintegration and
dissolution.
 The best alternative use of soluble lubricants like SLS
and Carbowaxes which promote drug dissolution.
33

34. 6)COATINGS:
 The effect of various coatings on drug dissolution from
a tablet dosage form in following order:
 Enteric coat > sugar coat > Non-enteric film coat
 The dissolition profile of certain coating materials
change on aging;
 Eg: shellac coated tablets, on prolonged storage
dissolve more slowly in the intestine.
 This can be prevented by incorporating little PVP in the
coating formulation.
34

35. 7)SUSPENDING AGENTS/VISCOSITY BINDERS:
 Popular suspending agents are hydrophilic polymers
like vegetable gums (acacia,tragacanth,etc..)
 Semi-synthetic gums(CMC,MC) and synthetic gums
which primarily stabilize the solid drug particles by
reducing their rate – increase in the viscosity medium.
 These agents and some sugars are also used as a
viscosity imparters to affect palatability and porability.
 The macromolecular gums often form unabsorbable
complexes with drugs Eg: sodium CMC forms a poorly
soluble complex with amphetamine.
35

36. 8)SURFACTANTS
 They enhance the dissolution rate of poorly soluble drug -
lowering of interfacial tension, increasing effective surface
area - faster dissolution rate.
 E.g. Non-ionic surfactant Polysorbate 80 increase
dissolution rate of Phenacetin granules.
 Low conc. Of surfactant= decrease the surface tension and
increase the rate of dissolution.
 High conc. Of surfactant= tend to form micelles with the
drug and decrease the rate of dissolution.
36

37. 9)BUFFERS:
 Buffers of different pHs are used in the dosage forms for the
following reason:
1)Buffers provide right atmosphere for drug dissolution.
e.g. buffered aspirin tablets.
2)Buffers provide right atmospheric condition for better stability
of drug. E.g. buffered pilocarpine solution.
 However, certain buffer systems containing potassium cations
inhibit the drug absorption as seen with vit-B2 &
sulphanilamide.
 Buffer system for a salt of drug should contain the same cation
as the drug salt & no introduce additional cations
37

38. 10)COMPLEXING AGENTS:
 Complex formation has been used to alter the
physicochemical and biopharmaceutical properties of a
drug.
 The complexed drug may have altered stability,
solubility, molecular size, partition coefficient and
diffusion coefficient
 Eg: complexation has been used to enhance drug
bioavailability are :
38

39.  Enhanced dissolution through formation of soluble
complex Eg: ergotamine tartarate-caffeine complex and
hydroquinone-digoxin complex.
 Enhanced lipophilicity for better membrane
permeability Eg: caffeine-PABA complex.
 Enhanced membrane permeability Eg: enhanced GI
absorption of heparin (normally not absorbed from the
GIT) in presence of EDTA which chelates Ca and Mg
ions of membrane.
39

40. 11)COLORANTS:
 Even a very low conc. of water-soluble dye can have a
inhibitory effect on dissolution of several crystalline
drugs.
 The dye molecules get adsorbed onto the crystal faces
and inhibit drug dissolution Eg: brilliant blue retards
dissolution of sulphathiazole.
 cationic dyes are more reactive than the anaionic ones
due to their greater power for adsorption on primary
particles.
40

41. 12)PRECIPITATION/CRYSTAL GROWTH INHIBITORS:
 Precipitation or crystal growth inhibitors such as
PEG,HPMC,PEG,PVA and similar, such hydrophilic polymers
prevent or prolong supersaturation thus preventing
precipitation or crystallization by-
1)Increasing the viscosity of the vehicle
2)Preventing conversion of a high energy metastable polymorph
in to stable, less soluble polymorph.
3)Adsorbing on the faces of crystal thus reducing the crystal
growth
41

42. 1. METHOD OF GRANULATION
 Wet granulation process is the most conventional technique
and thought to yield tablets that dissolve faster than those
made by other granulation methods.
LIMITATIONS:
1. Formation of crystal bridge by the presence of liquid
2. Liquid may act as a medium for affecting chemical reactions
such as hydrolysis.
3. Drying step may harm the thermolabile substances
42

43.  The method of direct compression has been utilized
to yield tablets that dissolve at a faster rate.
 One of the recent method is agglomerative phase of
communition(APOC).
 This process involves grinding of drugs in an ball
mill for time long enough to affect spontaneous
agglomeration
 Tablets were stronger and showed rapid dissolution
43

44. 2. COMPRESSION FORCE
 The compression force is applied during tabletting that
influences density, porosity, hardness, disintegration time &
dissolution of tablet.
 4 different types of curves are obtained by plotting
compression force (vs) rate of dissolution.
44

45.  On the one hand: higher compression force increase
the density & hardness of the tablet, decrease
porosity hence penetrability of the solvent into the
tablet, retards wettability by forming a firmer & more
effective sealing layer by the lubricant, so decrease
dissolution rate of tablet.
 On the other hand: higher compression force cause
deformation, crushing or fracture of the drug particles
into smaller one or convert spherical granules into
disc shaped particles - increase in the effective
surface area so increase in dissolution rate.
45

46.  A combination of both the curves A and B is also possible as
shown in curves C and D.
 In short, the influence of compression force on the dissolution
is difficult to predict and a through study on each formulation
should be made to ensure better dissolution and drug
absorption.
46

47.  In vitro dissolution refers to the process of dissolution
(release) of drug from a dosage form as measured in an in
vitro dissolution apparatus.
 In vivo dissolution refers to the process of dissolution of drug
in the GIT.
 Correlation is a relationship between in vitro dissolution rate
and in vivo input (absorption rate) as used in bioequivalence
guidance.
47

48.  In vitro-in vivo correlation is a predictive mathematical model
describing the relationship b/w in vitro property (release from
a dosage form, usually rate and extent of drug dissolution or
release) and a relevant in vivo response (plasma drug conc. Or
amount of drug absorbed).
 The in vitro method must reflect the bioavailability (in vivo)
profile of the dosage form, in order to assure biologic
response.
 For Eg: plasma drug conc. or amount of drug absorbed.
 The drug product should exhibit the same specifications
throughout the shelf life.
48

49.  In vitro dissolution testing is important for:
1. Providing process control and quality assurance.
2. Determining consistent release characteristics of the product
over time.
3. To ensure batch-to-batch consistency in the physiological
performance of a drug product by use of such in vitro values.
4. To serve as a tool in the development of a new dosage form
with desired in vivo performance.
5. To assist in validating or setting dissolution specifications
(i.e. the dissolution specifications are based on the
performance of product in vivo).
49

50.  2 basic approaches by which the correlation b/w dissolution
testing and bioavailability
1. By establishing a relationship, usually linear, between the in
vitro dissolution and the in vivo bioavailability parameters.
2. Modifying the dissolution methodology on the basis of
existing bioavailability and clinical data.
50

51. In vitro In vivo
Dissolution rate Absorption rate (or absorption time)
Percent of drug dissolved Percent of drug absorbed
Percent of drug dissolved Max. plasma conc.(C max)
Percent of drug dissolved Serum drug conc.
51

52. LEVELA:
 A level A correlation represents a point-to-point
relationship between the in vitro dissolution and the in
vivo rate of absorption (or in vivo dissolution)
 i.e. the in vitro dissolution and in vivo absorption rate
curves are superimposable and the mathematical
description for both the curve is same.
52

53. LEVEL B:
 A level B correlation uses the principles of statistical
moment analysis.
 The mean in vitro dissolution time is compared with the
mean in vivo dissolution
 This type of correlation uses all of the in vitro and in
vivo data, it is not considered as a point-to-point
correlation .
 It does not uniquely reflect the actual in vivo plasma
drug level curve.
53

54. LEVEL C:
 A level C correlation establishes a single point
relationship between one dissolution parameter (e.g.
t50% dissolved 4 hr in the dissolution test is correlated)
and one pharmacokinetic parameter (e.g. AUC or Cmax).
 This level does not reflect the complete shape of the
plasma concentration-time curve.
 This type of correlation can be useful in early
formulation development and in-process quality control
procedure.
54

55. MULTIPLE LEVEL C:
 A multiple level C correlation involving one or several
pharmacokinetic parameters to the amount of drug
dissolved at various time points.
 This level can be useful as level A IVIVC from a
regulatory perspective.
 If the drug is highly permeable and in vitro dissolution
is the rate limiting step
55

56.  1 IVIVC should be developed using two or more
formulations with different release rates
-only one release rate is sufficient if dissolution is
condition-independent.
 2 Invitro dissolution profiles should be generated
using an appropriate dissolution methodology.
-dissolution method used should be same for all the
formulations
 3 A bioavailability study should be conducted to
determine the in vivo plasma concentration time
profiles for each of the formulations
56

57.  4 In vivo absorption profile is plotted against the in
vitro dissolution profile to obtain a correlation.
57

58.  Lachman/liberman’s the theory and practice of industrial
pharmacy, fourth edition 2013
pg.no.182-213.
 Leon shargel, susanna wu-pong, Andrew B.C YU, applied
biopharmaceutics & pharmacokinetics,
5th edition pg.no. 411-452.
 CVS Subrahmanyam textbook of biopharmaceutics &
pharmacokinetics-concept & applications first edition 2010
pg.no. 49-57,163-171.
 D M Brahmankar, Sunil B.Jaiswal Biopharmaceutics and
Pharmacokinetics-A treatise third edition 2015 pg.no.52-59,
335-339.
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59. Tank u…
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