Slide 1: Dissolution Studies Name: B.Vamsikrishna Reddy
Year : M.Pharm (Pharmaceutics)
College : Manipal College of Pharmaceutical Scieces(MCOPS), Manipal
Email id: firstname.lastname@example.org Name: Sneya Priya
Year : M.Pharm( Pharmaceutics)
College: Manipal college of Pharmaceutical Scieces(MCOPS), Manipal
Email id: email@example.com 1 Contents : Contents Definition
Processes involved in dissolution of solid dosage forms
Mathematics of Dissolution
Factor affecting the rate of Dissolution
Design of Dissolution Apparatus
Apparatus Used for Novel/Special Dosage form:
Data Presentation and Interpretation
In Vitro-In Vivo Correlation:
Method of Dissolution Enhancement
References 2 Definition: : Definition: 3 Slide 4: Processes involved in dissolution of solid dosage forms: 4 Mathematics of dissolution : Mathematics of dissolution Dissolution rate of the drug Given By Noyes and Whitney as follows:
When C is small (C<0.15Cs)
Eq2 is commonly referred to a sink condition ,which implies that sink conditions exist during the process of dissolution
Modified Noyes-Whitney equation:
dC/dT=DA Kw/o(Cs-C)/Vh 5 Factors affecting the rate of dissolution: : Factors affecting the rate of dissolution: Factors related to physiological properties of the drug
Factors related to drug product formulation
Effect of processing factor on the dissolution rate
Factor related to dissolution test parameter
Miscellaneous factors 6 Slide 7: 1. Factors related to physiological properties of the drug
a. Effect of solubility on dissolution:
The modified Noyes and Whitney’s equation shows that the aqueous solubility of the drug is the major factor that determines it’s dissolution rate.
b. Effect of particle size on dissolution:
The dissolution rate is directly proportional to the surface area of the drug.
Higher dissolution rate may be achieved through the reduction of the particle size.
If drug is hydrophobic ,reduction of particle size may lead to decrease effective surface area and hence a slower rate of dissolution 7 Slide 8: Cont…….
c. Effect of solid phase characteristics of drug on dissolution
Amorphicity and crystallinity, the two important solid-phase characteristics of the drugs affect their dissolution profile
d. Effect of polymorphism on dissolution:
The polymorphism and the state of hydration, solvation and/or Complexation markedly influence dissolution characteristics of the drug by change in solubility characteristics of drug.
Eg, tolbutamide, chloramphenicol. 8 Slide 9: 2. Factors related to drug product formulation:
Effect of granulating agent and binders:
The hydrophilic binder show better dissolution profile with hydrophobic drug like phenacetin, by imparting hydrophilic properties to the granule surface.
Large amount of strong binder increase hardness decrease disintegration and dissolution rate of the tablet.
PEG 6000 was found to be a deleterious binder for Phenobarbital as it forms a poorly soluble complex with the drug. 9 Slide 10: Cont….
b. Effect of disintegrant and diluents :
The type and amount of disintegrating agent implied in the formulation significantly control the overall rate of dissolution of dosage form.
Eg. effect of several disintegrating agents like Copagel, nymcel, primojel in manufacturing of Phenobarbital tablet . Copagel when added before granulation they remarkably reduced dissolution rate. But after granulation Copagel did not result in lowering the dissolution rate. 10 Slide 11: c. Effect of lubricant:
The nature, quality and quantity of lubricant added can affect the dissolution rate. 11 Slide 12: 3. Effect of processing factor on the dissolution rate:
a. Method of granulation: 12 Slide 13: Conti….
b. Effect of compression force on dissolution rate :
The compression force employed in tableting process influence apparent density, porosity, hardness, disintegration time and dissolution of tablets. 13 Slide 14: 4. Factors related to dissolution test parameter:
The excessive vibration of the dissolution apparatus considerably increases dissolution rates .
b. Vessel Design and Construction:
Minor changes in vessel shape may considerably alter the dissolution rates determined by the paddle method ,
Glass vessels with an inside bottom ﬂatter than speciﬁed gave a high bias in dissolution rates and those with an inside bottom of steeper curvature gave a low bias.
Plastic vessels provide more perfect hemispheres than glass vessels 14 Slide 15: Conti…
c. Temperature Control:
drug solubility is temperature dependent, careful temperature control during the dissolution process is very important..
The dissolution ﬂuid s should be maintained at 37±0.50C as even slight temperature variations may have a signiﬁcant effect on tablet dissolution.
d. Dissolution medium;
Surface tension of the dissolution medium :
pH of the dissolution medium
Viscosity of the dissolution medium
Deaeration of the Dissolution Medium: 15 Slide 16: 5. Miscellaneous factors:
The adsorption has an influence on the dissolution rate of a slightly soluble solid.
Adsorption isotherms can be employed to calculate the approximate amount of adsorbent required to increase the slower dissolution rate
The sorption from the atmosphere into tablets containing microcrystalline cellulose is very rapid.
The relative density of the tablets was found to decrease, resulting in increases disintegration time with increase in water sorption rate constants.
Moisture has shown to influence the dissolution rate of many drugs from solid dosage form. 16 DESIGN OF DISSOLUTION APPARATUS : DESIGN OF DISSOLUTION APPARATUS The ideal features of a dissolution apparatus are:
Must be simply designed
Must be enough sensitive
Uniform hydrodynamic ﬂow is essential
An easy means of introducing the dosage form
Provide minimum mechanical abrasion to the dosage form
The medium must be maintained at a ﬁxed temperature
Samples should be easily withdrawn 17 COMPENDIAL APPARATUS: : COMPENDIAL APPARATUS: Apparatus 1 (rotating basket )
Apparatus 2 (paddle assembly)
Apparatus 3 (reciprocating cylinder )
Apparatus 4 (flow-through cell)
Apparatus 5 (paddle over disk )
Apparatus 6 (cylinder)
Apparatus 7 (reciprocating holder) 18 Apparatus 1 (rotating basket ): : Apparatus 1 (rotating basket ): 19 Apparatus 2 (paddle assembly) : Apparatus 2 (paddle assembly) 20 Slide 21: Conti……
In the case of hard-gelatin capsules and other ﬂoating dosage forms, a ‘‘sinker’ ’ is required to weight the sample down until it disintegrates and releases its contents at the bottom of the vessel
Typical sinker designs are... (A) 3-prong sinker; (B) JP basket sinker; and (C) helical-spring sinker.
A B C 21 Apparatus 3 (reciprocating cylinder ) : Apparatus 3 (reciprocating cylinder ) 22 Apparatus 4 (flow-through cell) : Apparatus 4 (flow-through cell) 23 Apparatus 5 (paddle over disk ) : Apparatus 5 (paddle over disk ) 24 Apparatus 6 (cylinder) : Apparatus 6 (cylinder) 25 Apparatus 7 (reciprocating holder) : Apparatus 7 (reciprocating holder) There are several variants to this apparatus, which is based on a sample holder that oscillates up and down in the medium vessel.
The sample holder may take the form of a disk, cylinder, or a spring on the end of a stainless steel or acrylic rod, or it may simply be the rod alone. 26 Slide 27: 27 Apparatus Used for Novel/Special Dosage form: : Apparatus Used for Novel/Special Dosage form: 28 DATA PRESENTATION AND INTERPRETATION : DATA PRESENTATION AND INTERPRETATION The USP 28 assesses dissolution in a three- stage series of tests with the amount of drug dissolved after a speciﬁed time being expressed as a percentage of the nominal content of the dosage form.
The time at which the sample is to be tested is speciﬁed in the monograph, as is the so-called Q-value, the minimum percentage dissolved at that time.
In the ﬁrst stage (S1), six units are tested and the pass criteria are that the amount of drug dissolved from each unit at the speciﬁed time should be no less than Q + 5% . Failure at S1 requires a second stag test (S2) to be performed on an additional six units. 29 Slide 30: To pass the test at 2nd stage, the average content dissolved from the combined two stage s (i.e. ., 12 units) should be equal to or greater than Q with no unit being less than Q - 15 % . Failure leads to stage 3 where a further 12 units are tested.
The average of the total of the 24 units thus tested should be equal to or greater than Q. No more than two units should be less than Q -15 % an d no unit should be less than Q -25 % .
In the delayed- release products there is a similar three-tiered approach for both the acid-dissolution and buffer -dissolution stages.
For extended- release the levels are denoted as L1, L2, and L3. 30 In Vitro-In Vivo Correlation : In Vitro-In Vivo Correlation The in vitro in vivo correlation (IVIVC) is a scientific approach to describe the relationship between an in vitro property of a dosage from (e.g, the rate (or) extent of drug release) and a relevant in vivo response (e.g, plasma drug concentration (or) amount of drug absorbed).
Need of IVIVC:
To serve as a surrogate for in vivo bioavailability and to support biowaivers.
To reduce the number of human studies during the formulation development 31 Slide 32: Conti….
Three correlation levels have been defined in the IVIVC FDA guidance. 32 Biopharmaceutics Classification System (BCS): : Biopharmaceutics Classification System (BCS): Class I: High Solubility - High Permeability
Class II: Low Solubility - High Permeability
Class III: High Solubility - Low Permeability
Class IV: Low Solubility - Low Permeability 33 Slide 34: Conti….
For class II-drugs, according to the Biopharmaceutics classification system the dissolution rate is the limiting factor for the drug absorption rate.
Also for class IV-drugs the dissolution rate can be the limiting factor.
An enhancement in dissolution rate is important to attain suitable blood-levels of these drugs. 34 METHODS OF DISSOLUTION ENHANCEMENT : METHODS OF DISSOLUTION ENHANCEMENT I. PHYSICAL MODIFICATION
A. Particle size reduction
B. Modification of the crystal habit
C. Drug dispersion in carriers
Eutectic mixtures 35 Slide 36: D. Complexation
Molecular Encapsulation with Cyclodextrins
E. Solubilization by surfactants:
II. CHEMICAL MODIFICATIONS
Alteration of pH of drug microenvironment
III. OTHER TECHNIQUES
Nanotechnology approaches 36 Calibration of Dissolution Apparatus: : Calibration of Dissolution Apparatus: Different types of calibrations are:
requirement for the analyst to perform apparatus suitability test using USP Calibration tablets.
USP Calibration tablets come with certification identification appropriate range and reference standard.
USP Prednisone Tablets 10 mg (disintegrating type).
USP Salicylic Acid tablets 300mg (non-disintegrating type). 37 Slide 38: Physical Calibration:
Following parameters should be checked:
Paddle shaft centring
Rotations per minute (RPM)
Temperature of the vessels dissolution medium 2, 5 clock test
Wobbling of the shaft 38 Dissolution Profile Comparison: : Dissolution Profile Comparison: 39 Slide 40: 40 Conclusion : Conclusion The increasing importance of dissolution testing in the development and routine commercial production of pharmaceuticals has become acknowledged within the industrial, academic, and regulatory communities
Improvements in dissolution testing instrumentation and an awareness of the importance of correlating invitro data with in vivo performance have offered the possibility of more rapidly developing safer and more efficacious drugs. 41 References : References William. L and Wilkins. Remington The science and practice of pharmacy, 21st ed., Vol 1. p. 672-88
Brahmankar. D.M , Sunil B. Jaiswal. Biopharmaceutics and Pharmacokinetics A Treatise 5th ed. P. 19-49
Dressman J. , Kramer Johannes. Pharmaceutical Dissolution Testing, 1st ed. P. 39-65
Swarbrick J. Encyclopdia of Pharmaceutical Technology, 3rd ed. ,vol-2 p. 908-928
Cardot J. M. ,Beyssac E. ,Alric M. InVitro-InVivo Correlation:Importacne of Dissolution in IVIVC. Dissolution Technologies. 2007
USP 29 NF The official compendia of standards. Asian edition. United ststes pharmacopoeial convention, INC; 2006- p.2673-269
Ye. Lee, Herman Lam, Xue-Ming zhary . Chung Chow Chan. Analytical method validation and instrument performance verification. Wiley-inter science US; 2004 .p.55 42 THANK YOU : THANK YOU 43