Dissolution.ppt

Contents

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 Dissolution - Theory

 Factors influencing dissolution

 Equipment

 Precautions

 Multipoint dissolution

 Biopharmaceutics Classification System

 Acceptance criteria

Dissolution

 The amount of active ingredient in a solid dosage form dissolved per unit of time under standard conditions of liquid /solid interface, temperature and media composition.

 The dissolution test measures the rate at which a drug substance dissolves from the dosage unit.

The Stages in the Dissolution Process

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Solid dosage form

Dissolution

Disintegration from gross tablet size to particles of various sizes (depending

on formulation): <2 mm diameter

Deaggregation: breakdown into discrete particles that greatly increase surface area, providing solid-liquid interface and beginning

dissolution: <0.25 mm diameter

3 2 1

Rate measured by the dissolution test Rate measured by the

Mechanism of dissolution

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Dissolution test determines the cumulative amount of drug that goes into solution as a function of

time

Steps involved

 _{liberation of the solute or drug from the}

formulation matrix (disintegration)

 _{dissolution of the drug (solubilization of the drug}

particles) in the liquid medium

Mechanism of dissolution

First Step

 Cohesive properties of the formulated solid dosage form drug play a key role disintegration and

erosion

semi- solid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid

phase is the key factor  

If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be

Mechanism of dissolution

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Second Step

Dissolution Rate

 Modified Noyes and Whitney Equation:

)

(

)

(

c

c

k

c

c

vh

DS

k

R









Diffusion rate constant = D

Surface area = S

Volume of the dissolution media = v

Thickness of the saturated layer = h

Concentration of the API at saturation = Cs

Dissolution rate constant = k

Dosage forms to be tested for

dissolution

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 Immediate release dosage forms

• powders, granules / beads, tablets, capsules

 Controlled release dosage forms

• powders, granules / beads, tablets, capsules

 Transdermal systems

Classification of dosage forms based

on “Release of Drug”

Immediate release dosage forms:

  apparatus 1 or 2 (preferably 2)

Controlled release dosage forms:

  apparatus 1 or 2 using different media for QC

FACTORS INFLENCING THE RATE OF DISSOLUTION [email protected] Physicochemical characteristics  Solubility  pH

 API quantitation

Factors influencing during the analysis

 RPM

 Temperature

 Media volume

 Dropping and Sampling (sampling zone, timing, filtration, dilution)

 Degassing of Media

 Vibration

FACTORS INFLENCING THE RATE OF DISSOLUTION

 Proper alignment/geometry of dissolution apparatus

 dimensions of vessels, paddles, baskets, cylinders

 height, centering and wobble

 Proper validation of analytical method

 specified in USP Chapter <1225>

 Formulation of the dosage form

 Lubricant

Sink Conditions

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FACTORS INFLENCING THE RATE OF DISSOLUTION

Solubility:

Solubility of the API in 37◦C in water, other media (ie HCl) or buffers of different pH should meet “sink condition” (volume of medium at least three times that required in order to form a saturated solution of API).

FACTORS INFLENCING THE RATE OF DISSOLUTION

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 pH: water may be used as medium, however the effect of the formulation on the pH of water must be investigated and if it changes, the use of buffers or HCl should be considered.

 pH should have in-vivo relevance if possible;

FACTORS INFLENCING THE RATE OF DISSOLUTION

API quantitation:

UV is often used; for UV the applicant should have demonstrated:

a) non-interference with formulation components (spectra of API in the formula and in standard solutions should be

identical in shape/magnitude);

b) linearity (absorbance vs concentration) up to the highest expected concentration.

Note that these will be determined as part of routine validation.

Tester Equipment

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Stand

Spindle

Control

Base-Plate Motor

Vessel

Vessels

 Materials

 Glass

 Plastic--poor heat transfer

 1-Liter, 2 Liter, 4 liter in USP

 Evaporation is an issue with long tests

 Must be centered

 Need to be locked down

Medium

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 Water

 Different Buffers

 Surfactants (wetting agents/solubilizing agents)

 Sodium lauryl sulfate--purity issues

 Auto-injection/handling issues-Cetrimide, Tween

Typical Apparatus as per

USP

Apparatus 1: Rotating Basket (Ph.Eur./BP/JP) Apparatus 2: Paddle (Ph.Eur./BP/JP)

Basket

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Basket Position

USP: 25 ± 2 mm. (see Figure 3-7)

Basket

A USP: Cylindrical with spherical bottom, 160-210 mm high, inside diameter 98-106 mm, glass or plastic.

Vessel

USP: Midway between top of basket and top of fluid no closer than 1 cm to side of vessel.

Sampling Point

USP: No significant wobble.

Eccentricity Centering (or tilt)

USP: ± 2 mm at all points.

Speed (rpm) as specified in monograph ± 4%

(100 rpm typical)

USP: 9.4-10.1-mm diameter; 2-mm vent in drive disk.

Shaft

Media temperature 37.0 ± 0.5 °C.

Media as in monograph ± 1% (typical 900 mL); USP states dissolved gases must not interfere. Samples required: USP specifies 6 + 6 + 12 sequenced until specification is met. No significant vibration.

Apparatus 1 - Basket

• capsules

• beads

• delayed release / enteric coated dosage forms

• floating dosage forms

• surfactants in media

 Advantages

• breadth of experience (more than 200 monographs)

• full pH change during the test

Apparatus 1 - Basket

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Disadvantages

Screen can clog with excipients/gelatinous material

Particles can rapidly fall out and then form a mound

underneath the basket

Cleaning/drying critical

Inspection for wear

Miss-shaped or warped

Always handle at the rim

Straightness of shaft

Baskets-USP Apparatus 1

 Mesh size

Apparatus 2 - Paddle

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 Useful for

• tablets

• capsules

• beads

• delayed release / enteric coated dosage forms

 Advantages

• easy to use

• robust

• can be easily adapted to apparatus 5

• long experience

Apparatus 2 - Paddle

 Disadvantages

• pH/media change is often difficult

• limited volume  sink conditions for poorly soluble drugs ?

• hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,floating) and

therefore may significantly affect drug dissolution

• sinkers shall be used for floating dosage forms

Eg. For Coning

Paddle

A

Paddle Position Paddle

(see Figure 3-9)

Centering (or tilt)

USP: ± 2 mm at all points.

Vessel

USP: Cylindrical with spherical bottom; 160-210 mm high, inside diameter 98-106 mm, glass or plastic (same vessel as specified for Apparatus 1).

Eccentricity

USP: No significant wobble.

Sampling Point

USP: Midway between top of blade and top of fluid; no closer than 1 cm to side of vessel.

Media temperature 37.0 ± 0.5 °C.

Media as in monograph ± 1% (typical 900 mL); USP states dissolved gases must not interfere. Samples required: USP 6 + 6 + 12

sequenced until specification is met. No significant vibration.

Speed (rpm) as specified in monograph ± 4%

(50 rpm typical)

Shaft

USP: 9.4-10.1-mm diameter;

lower part polyfluorocarbon coated if desired.

Sinker types

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JP/ USP / Ph. Eur. 5.3 Sinker

a small loose piece of nonreactive material such as

not more than a few turns of wire helix may be attached to dosage units that would otherwise float …“

Apparatus 3 –

Reciprocating

Apparatus 3 –

Reciprocating cylinder

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 Useful for

• tablets

• beads

• controlled release formulations

 Standard volume

• 200-250 ml per station

 Advantages

• easy to change the pH

• pH-profiles

• hydrodynamics can be directly influenced by varying the dip rate

 Disadvantages

• small volume (max. 250 ml)

• little experience

Apparatus 4 – Flow-Through

Cell

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 Useful for

• low solubility drugs

• Micro-particulates

• implants

• suppositories

Apparatus 4 – Flow-Through

Cell

 Advantages

• easy to change media pH

• pH-profile possible

• sink conditions

• different modes a) open system b) closed system

 Disadvantages

 Deaeration necessary

 high volumes of media

PRECAUTIONS

DURING DISSOLUTION

De-aeration of Medium

 Surfactants not practical due to foaming

 Methods

 USP method--heat, filtration,vacuum

 Helium sparging--heat? Helium shortage?

 Automated methods-temperature dispensed

Bubbles

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 Troubles from non-deaerated medium

 Slow down (barrier) or speed up (buoyant)

 Bubbles adhere to screens

 Particles adhere to bubbles that may be clinging to

the vessel walls

 Basket carries down the bubble on surface

Observations

 Particle disintegration pattern/must disperse freely

 Floating (chunks), spinning

 Coning, mounding

 Gumming, swelling

 Capping, clam shell

Observations

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 Center/off-center, sticking

 Particles adhering to apparatus/vessel

 Ballooning, rubbery mass, pellicles

 Particle size (snowflake, fine)

 Look on surface around shaft

 Disintegration and shell dissolution rate

Dissolution medium

 correctly degassed ?

 correct amount used (900/500 ml) ?

 correct amount dosed (weight/volume) ?

 dosing procedure gentle (resaturation/spillage) ?

 buffer correct (pH + 0.05 units, buffer salts, molarity) ?

 correct temperature during test (32°C / 37°C + 0.5°C)?

Dissolution medium

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 Importance of degassing:

 insufficient degassing may result in decreased

dissolution rates of several drugs

 e.g. prednisone tablets but also a range of poorly

soluble drugs are very sensitive to the amount of dissolved gases in the dissolution medium

Deaeration method USP

 heat the dissolution medium to about 41°C

 vacuum filter through a 0.45-µm-porosity membrane into a flask, stirring with a magnetic stirrer

 continue to draw a vacuum and stir for an additional 5 min

 gently transfer the medium directly into the vessel

 rotating the apparatus 2 shafts to speed equilibration to 37°C is discouraged!!!

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Alternative deaeration methods

 the USP states that : other validated deaeration techniques for removal of dissolved gases may be used

 other techniques include:

 heating

 sonication

 vacuum

Sample Introduction

 Where does the dosage unit land??

 Suspensions

 Pipettes, automated delivery, location of sample

introduction

 Film coated tablets-sticky-sinkers may be needed

Manual Sampling

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 Syringe

 Plastic or glass

 Cannula/needle

 Stainless steel

 Bent or straight

 Filter - end of probe, in line, after sampling

Sampling

 Collect the sample while running.

 take each sample at the correct time point

 sampling time points (+ 2%)

 use a single glass syringe for each vessel

 sample from the right location within the vessel

 between media surface and top of the paddle blade

 n.l.t. 10 mm from vessel wall

 Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the

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Sampling

 always use a suitable filter  check filter adsorption

 check the clearity of the filtered sample

 filter the sample immediately after sampling

Physical conditions of the apparatus

 vessels scrupulously clean ?

 vessel surface smooth and curvature appropriate ?

Apparatus 1

 the conditions of the baskets, particularly of their clips is critical

 check all baskets for corrosion and blocked meshes before using them

Time

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 Where a single time specification is given, the test may be concluded in a shorter period if the requirement for minimum amount dissolved is met.

Regular Problems in Dissolution

 Handling of surfactants

 Cleaning

 Deaeration

 Vibration

 Standard preparation with alcohol

 Sensitive to fluid flow in vessel

 Fluid Flow

 Basket mesh size

 Coning with paddle

 In-residence probes/automation

Documentation

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 Bad habits

 Writing on scrap paper

 No observations documented

 Forget rpm and temperature at beginning and end

of run--Let temperature stabilize!

 Forget log book entries

Multi-point dissolution

In multipoint dissolution

 multiple (≥ 3) samples are withdrawn from the

dissolution medium during dissolution testing

 at pre-determined time points and

 each sample is analysed for the % API dissolved

 A graph of % API dissolved against time:

Multi-point dissolution

Example of dissolution

profile

0 10 20 30 40 50

WITHDRAWAL TIME IN MINUTES

D is so lu ti o n ( % )

Comparative dissolution

testing

The principle

 _{Two or more products or batches containing the same}

API are compared

 _{The strength of products / batches may or may not be}

the same (depending on purpose of test)

 _{The dissolution conditions are similar, e.g.}

• Apparatus, medium, volume, rotation speed & temp.

• Minimize possible experimental differences in

conditions

 Samples are taken at the same time points and the data

(dissolution profiles) compared

 _{Calculations: correct for volume change of dissolution}

Bioequivalence Tool

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f₁

 Calculates the percent difference between the two dissolution profiles at each time point and is a measurement of the relative error between the two curves

f₂ or similarity factor

 Predict bioequivalence from dissolution and examines waivers

Comparative dissolution testing

Profile similarity determination

Two conditions to determine if the dissolution profiles of two products/batches in a particular dissolution

medium are similar:

1. If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are

considered to be similar

 No calculations are required

If this is not the case, apply point 2

2. Calculate the f2 value (similarity factor):

 If f2 ≥ 50, the profiles are normally regarded

Comparative dissolution testing

Similarity factor f2

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n = number of time points

R(t) = mean % API dissolved of reference product at time point x T(t) = mean % API dissolved of test product at time point x

 Minimum of 3 time points (zero excluded)

 12 units (each in own dissolution vessel) for each product (for “official” purposes)

 Only one measurement should be considered after both products have reached 85 % dissolution

Comparative dissolution testing

Dissolution conditions (study

design)

Apparatus (choice)

• _{Paddle, 50 (75) rpm or} • _{Basket, 100 rpm}

Dissolution media

All three media for full comparison

1. Buffer pH 6.8 or simulated intestinal fluid without enzymes

2. Buffer pH 4.5

3. 0.1 M HCl or buffer pH 1.2 or simulated gastric fluid without enzymes

Volume of media 900 ml or less Temperature 37°C ± 0.5°C

Typical time points

Immediate release tablets

(capsules)

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Rationale:

1. Condition 1

 ≥ 85% dissolution of both products within 15 minutes

 15 minute time point thus essential

2. Condition 2, for calculation of f2

 a minimum of 3 points are required

 Only one measurement should be

considered after 85 % dissolution (both tablets)

 20 minute time point thus first possible one (if 15 minute fails 1st condition)

Biopharmaceutics Classification

System

 To provide recommendations for requesting a waiver of in vivo bioequivalence studies for immediate release (IR) solid oral dosage forms where the API is classified as Class 1 according to the Biopharmaceutics Classification System

Biopharmaceutics Classification System

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Based on drug solubility and permeability, the

following Biopharmaceutics Classification System (BCS) is recommended in the literature (Amidon 1995):

 The solubility of a drug is determined by dissolving the highest unit dose of the drug in 250 mL of buffer adjusted between pH 1.0 and 8.0.

 A drug substance is considered highly soluble when the dose/solubility volume of solution are less than or equal to 250 mL.

Biopharmaceutics Classification System

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 High-permeability drugs are generally those with an extent of absorption that is greater than 90% in the absence of documented instability in the gastrointestinal tract or those whose permeability has been determined experimentally.

Acceptance criteria

Acceptance criteria

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 The dissolution testing machine was observed to be sitting on a bench top that was vibrating.

 The dissolution test apparatus could be felt to be vibrating when a hand was placed on the dissolution tank surface.

Calibration of the dissolution units are deficient in that:

Only 2 of the 4 USP calibrator tests (for units utilizing paddles and baskets) are performed to qualify a new dissolution apparatus of an existing apparatus being returned to service after a major repair. For example, apparatus… which used both paddles and baskets, was repaired. This unit was calibrated for baskets with prednisone tablets and for paddles with prednisone tablets. Calibration with salicylic acid tablets was not performed.   Calibration is not performed at a minimum every 6-months using all

4 USP calibrator tests if the unit is used for paddles and baskets and using 2 USP calibrator tests of the unit is dedicated to paddles or baskets. Rather calibration is performed using 1 USP calibrator test for non-dedicated units or is performed every …using 1 USP calibrator test for dedicated units.

The amount of alcohol used to bring the predinisone standard into solution is not recorded in the calibration data. (No more than 5% of the total volume of the standard solution may be used). Calibration does not include testing of the baskets on the

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 The serial number of the thermometer used in calibration of the dissolution units is not recorded.

 A stopwatch is used to calibrate the rotation of the dissolution apparatus. However, the time from the stopwatch is not recorded in the raw data; only the units’ RPMS are recorded.

 Also, the serial number of the stopwatch used is not recorded.

The procedure for calibration of the laboratory dissolution units is outdated and unclear as follows:

The procedure does not describe how to prepare the standard solution used in calibration testing.

The procedure does not specify how to prepare the medium used in testing, i.e. graduated cylinders.

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The filters used in dissolution testing and in calibration of the dissolution units have not been evaluated for the adsorption of the active drug.

The 1,000 ml plastic graduated cylinders used in dissolution testing are not calibrated.

….Quality Unit review of Analytical Laboratory Investigation Reports (ALIRs) failed to confirm the accuracy and completeness of the finished reports in that additional information had to be added and clarified in the ALIRs during the inspection. For

example, for …capsule questionable

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The firm failed to adequately follow SOP…”Dissolution Apparatus Calibration and Testing” in that the composition and concentration of the standard solution should be a close approximation of that of the sample solution.

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 The firm lacks systems to ensure that all electronic data generated in the QC laboratory is secure and remains stored unaltered. For example:

 The multi-bath dissolution system

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The firm has failed to adequately investigate and implement corrective actions for malfunctioning laboratory equipment.

The …Multidose Dissolution Workstations used to drop samples into dissolution bath vessels malfunctioned approximately 15 times per month over the past two years. This malfunction has resulted in what appears to be OOS dissolution results and samples must be retested.

Summary of 483 warnings

 Failure to investigate Out of Specification results

 Do not have or follow SOP’s

 Inadequate calibration program or compliance

 Bubbles in vessel observed

 Unvalidated methods or computer programs

 Validation of robotics

Dissolution Resources

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Websites

Dissolution Technologies at www.dissolutiontech.com www.dissolution.com

Dissolution Resources

 FDA Guidances

 USP General Chapters and Stimuli Articles and Revisions

 New <1092> Dissolution validation and method development

 American Association of Pharmaceutical

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