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Scope

Dissolution
<1094> Overview

<711> <724>
Scope, General chapter

<711> Dissolution

<724> Drug Release

<1094> Capsules-Dissolution Testing and Related
Quality Attributes

Overview of Dissolution
Dissolution

Is defined as the process by which a solid enters in
the solvent to yield a solution

Dissolution

In the Pharmaceutical field, it may be defined as the
amount of drug substance that goes into solution
per units time under standardized condition
Dissolution Process

Initial mechanical lag

Wetting

Penetration

Disintegration

Disaggregation

Dissolution

Dissolution Theory
Noyes-Whitney Equation, 1897

Solid, A
Stagnant layer, L

Bulk solution

Rate = dm/dt = k(Cs-Cb)A

L
Dissolution Rate of Various Dosage Forms

Oral Solid Dosage Form

Active Pharmaceutical Ingredients (API) are
mixed with inactive excipient materials and
press into a tablet or filled into a capsule.
 Oral Solid Dosage Form
Dosage form is provided for:

To protect drug from Oxygen / Moisture

To protect drug from Gastric acid

To conceal the bitter taste or order

To retard drug irritation

To provide modified release mechanisms
Variation many occurs in:

Starting materials

Composition

Manufacturing process

Scale-up /down

Solid Dosage Form

Immediate Release Dosage form
Dosage form that release the dose of drug rapidly
within a short duration

Rapid disintegration

Rapid dissolution (0.5-2 hr, > 85%Q)

Rapid absorption

Rapid on set of therapeutic action
Solid Dosage Form

Modified Release Dosage form
Dosage form that release the dose of drug in
accordance with a pre-program drug delivery
rate for specific therapeutic advantage.

Modification Technique

Membrane thickness

Porosity

Viscosity

Molecular size

Complexation

Release action

Prompt release Prolonged release Sustain release

Conventional Modified release
Solid Dosage form in the body:

Active Pharmaceutical Ingredients (API) must
be “in solution” before it can be absorbed by
the blood and carried to the receptor site to
render the therapeutic effect.

Wetting in the stomach.

Disintegrate in the stomach.

Dissolution in the stomach, intestine

Permeation through the intestine wall

Absorption into the blood steam

Transit to the therapeutic site

Decomposition and Elimination

Quality Control Test: Development

1950s-Bloom of Tablets Technologies
-Concern About Rate limiting step
-General chapter<701> Disintegration
-Disintegration Test (USP XIV-XV)

1960s-Dissolution Test became a QC tool
(to ensure lot-to-lot consistency)
-General chapter<711> Dissolution
-Rotating bottle method
Quality Control Test: Development

1970-Apparatus 1, USP XVII, (12 monographs)

1978-Apparatus 2

1980-Apparatus suitability test ( 2 Tablets calibrators)

50mg Prednisone Tab, 300mg Salicylic acid tab
for 8 tests (2 conditions, 2 tablets, 2 App.)

1985-General chapter <724> Drug release (USP XXI)

for Extended Release, Delayed Release

1988-Apparatus 5, 6, 7 for TDS (USP XXI, Eng-Supp.)

1990-Apparatus 5,6, 7 for TDS (USP XXII)

1995-Apparatus 3, 4 , renumber App. (USP XXIII)

Quality Control Test: Development

1995-Starting point of Harmonization

1995-More than 470 monographs (Dissolution)

1996-Multiple Dissolution Test

Typically, a USP monograph for dosage forms may have

multiple dissolution or drug release tests when the
product is a modified-release dosage form (extended- or
delayed-release) or, in the case of immediate release, the
active ingredient is poorly soluble in aqueous solvents.
In any of these cases, the dissolution or drug release test
may be formulation dependent
Quality Control Test: Development

1997-Pool sample

2001-Calibration requirements were reduced to 4 tests

2006-<1092> Dissolution: Development and Validation

2006-USP 29, Harmonization in <711> Dissolution
<711> Dissolution App. 1-4 /<724> Drug release App. 5-7

2007-USP 30, Apparatus suitability test ->PVT
Calibrator Tablet-> RS Tablets
50mg Prednisone-> 10mg Prednisone

2009-USP 32, Eliminate Salicylic acid

Current PVT (New criteria GM and %CV)

Mesh size

40 Mesh USP 36 Mesh JP

 Quality Control Test: Development

2011-USP 34, Mesh Size Harmonization

2014-USP 37, > 750 monographs (Dissolution)
-USP 37 the 1st supplement, <1094> Capsules-

Dissolution Testing and Related Quality Attributes

2014-USP 37, the 2nd supplement, <724> were updated

2016-USP 38 (1), Make the change in <711> Dissolution

Dissolution: Relevant USP General Chapters

General Chapters—mandatory requirements

<701> Disintegration

<711> Dissolution

<724>Drug Release
Dissolution: Relevant USP General Chapters

Dissolution: Relevant USP General Chapters

General Chapters—informational

<1092> The Dissolution Procedure: Development and
Validation

<1094> Capsule-Dissolution Testing and Related
Quality Attributes

Dissolution: Relevant USP General Chapters

General Chapters—informational

<1087> Apparent Intrinsic Dissolution – Dissolution
Testing Procedures for Rotating Disk and
Stationary Disk

<1088> In Vitro and In Vivo Evaluation of Dosage Forms

<1090> Assessment of Drug Product Performance –
Bioavailability, Bioequivalence, and Dissolution
Dissolution: Relevant USP General Chapters

General Chapters Linked to Dissolution

Mandatory Chapters

<16> Automated Methods of Analysis

<21>Thermometers

<31>Volumetric Apparatus

<41> Weights and Balances

<621> Chromatography (HPLC)

<791> pH

<851> Spectrophotometry and Light-Scattering
(UV-Vis Spectroscopy)

Dissolution, Drug Release Test

To determine the rate and extend of
dissolution or release of the drug substance
form a drug product under specific condition
USP General Chapter

USP General Chapter

<711> Dissolution

USP General Chapter

<724> Drug Release

Testing Apparatus
Apparatus Name Test
1 Rotating Basket Dissolution
2 Rotating Paddle Dissolution
3 Reciprocating Cylinder Dissolution
4 Flow-Though cell Dissolution
5 Paddle Over disk Drug Release
6 Rotating Cylinder Drug Release
7 Reciprocating Holder Drug Release

Dissolution Oral solid dosage form: Tablets, Capsules

Drug Release Transdermal Delivery System (TDS)
USP General Chapter

USP General Chapter

<711> Dissolution

General chapter <711> Dissolution (USP 38)

INTRODUCTION

Dissolution requirement for oral dosage forms

Definition of Dosage unit

Enteric-coated dosage forms

Hard or soft gelatin capsules and gelatin coated tablets that
do not conform to the Dissolution specification

APPARATUS 1-4

PROCEDUE (For Immediate, Delayed and Extended)

INTERPETRATION
General chapter <711> Dissolution (USP 38)

INTRODUCTION

Dissolution for oral dosage forms

Definition of Dosage unit

Enteric-coated dosage forms

Hard or soft gelatin capsules and gelatin coated tablets that
do not conform to the Dissolution specification

APPARATUS 1-4

PROCEDUE (For Immediate, Delayed and Extended)

INTERPETRATION

General chapter <711> Dissolution (USP 39)

INTRODUCTION

Dissolution for oral dosage forms

Definition of Dosage unit

Enteric-coated dosage forms

FOR DOSAGE FORMS CONTAINING OR COATED WITH
GELATIN (If they dose not meet the criteria in the
Acceptance Table)

APPARATUS 1-4

PROCEDUE (For Immediate, Delayed and Extended)

INTERPETRATION
Change in <711> Dissolution
USP 38 USP 39
Hard and Soft gelatin capsules DOSAGE FORMS CONTAINING OR
Gelatin coated Tablets COATED WITH GELATIN
Not conform to the Not meet the criteria in the three
Dissolution specification Acceptance Table because of evidence
of the present of cross-linking in the
first stage.
Gelatin, cross-linking, pellicle see
more information in
<1094> Capsule-Dissolution testing
and Release Quality Attributes
Do not need to continue testing until
the last stage

Enzyme are to be used Enzyme are to be used

Change in <711> Dissolution

USP 38 USP 39
Repeat the test as follow Repeat the test as follow
Water, Medium pH < 6.8 Medium pH ≥ 4.0
Same medium + Pepsin Same medium + Pepsin
NMT 750,00 units/L Pepsin Activity -> Purified pepsin in the Reagent
Specification section
Amount : NMT 750,00 units/L
Medium pH > 4.0 and < 6.8
Same medium + Papain or Bromelain
Papain Activity ->Assay Monograph for Papain
Amount : NMT 550,000 units/L
Bromelain activity : Bromelain in the Reagent
Specification section
Amount : NMT 30 gelatin-digesting units (GDU)/L
Medium pH ≥ 6.8 Medium pH ≥ 6.8
Same medium + Pancreatin Same medium + Pancreatin
NMT 1750 USP units of protease Pancreatin Activity -> Assay for protease activity
activity/L (Casein power) in monograph for Pancreatin
Amount : Protease activity NMT 2000 units/L
Change in <711> Dissolution
USP 38 USP 39
_ Medium containing Surfactant or other Ingredients
Known to denature the Enzyme
Repeat the test by using a pretreatment step
• Similar to 2-stage dissolution
• Medium without surfactant + Enzyme
• Type and concentration according to medium pH
• Enzyme amount depends on the volume of pre-
treatment step, not final dissolution volume
• The volume of pre-treatment step is smaller than
the final dissolution volume
• Pre-Treatment should be under same dissolution
conditions as the rest of the test
• Should not exceed 15 minutes, and pre-treatment
time is part of total test time

Information

General Chapter
<1094> Capsule-Dissolution testing
and Release Quality Attributes
 <1092> Dissolution Procedure : Development and Validation

Preliminary Assessment

Method Development

Analytical

Automation

Validation

Acceptance criteria

References

<1094> Capsule-Dissolution testing and Release Quality Attributes

<1094> Capsule-Dissolution testing and Release Quality Attributes

INTRODUCTION

Types of Capsules

Manufacturing and Packaging Issues That Can Effect Dissolution Testing

CROSS-LINKING IN GELATIN CAPSULES

DISSOLUTION PROCEDURE DEVELOPMENT

METHOD VALIDATION

SUGGESTIONS FOR STARTING POINTS

CRITICAL QUALITY ATTRIBUTES

Shell Composition

Stability and storage Conditions

Formulation Development and Manufacturing for Liquid-Filled Capsules
<1094> Capsule-Dissolution testing and Release Quality Attributes

Types of Capsules

Soft-shell Capsules Hard-shell Capsules

Softgels Hardgels

• Thicker shell • Thinner shell

• More elasticity • More rigid

<1094> Capsule-Dissolution testing and Release Quality Attributes

Capsules manufacturing Process

For Hard capsules

Producing empty shells

Filling and sealing Process

High ability seal for liquid filling material

<1094> Capsule-Dissolution testing and Release Quality Attributes

Capsules manufacturing Process

For soft capsules

Formation of capsules, Filling Process, Sealing Process

occur simultaneously
Gelatin ribbon

Monitor in process control :

Shell thickness Feeding

Seam quality
Lubricant

Capsule weight

Fill weight

Die roll Softgel

<1094> Capsule-Dissolution testing and Release Quality Attributes

Fill material

Hydrophobic solutions
: oil
: combination of miscible liquid
: active ingredient in oil vehicles

Hydrophobic dispersions
: active ingredient dispersed or suspended in oil
or oil wax mixture
(semisolid)
<1094> Capsule-Dissolution testing and Release Quality Attributes

Fill material

Hydrophilic solution
: Water, liquid
: combination of water-miscible liquid
: active ingredient dissolved in water

Hydrophilic dispersions / suspensions
: active ingredient dispersions/suspensions
in hydrophilic vehicles
(polyethylene glycol)

<1094> Capsule-Dissolution testing and Release Quality Attributes

Fill material

Solid Fill
: mixture of excipients and active ingredients
<1094> Capsule-Dissolution testing and Release Quality Attributes

Fill material

<1094> Capsule-Dissolution testing and Release Quality Attributes

Protection of Shell
At room temp., Capsule shell can protect the fill from

Oxygen and its effects

Light and its effects, because of Titanium oxide

Bacteria, Yeats and Molds because of low water activity

Water activity, aw
The partial vapor pressure of water in a substance
divided by the partial vapor pressure of pure distilled water
at the same temperature. Pure distilled water has a water
activity of exactly one.
<1094> Capsule-Dissolution testing and Release Quality Attributes

Protection of Shell

At room temperature, Capsule shell can protect…

Titanium oxide
Light and
Photodegradation

Water activity >0.40 aw

O2 and its Effects

Bacteria, Yeast, Mold grow in a water activity ≥ 80 aw

<1094> Capsule-Dissolution testing and Release Quality Attributes

Composition of shell of Softgels and Hardgels

A polymer : Gelatin
: Starch
: Cellulose derivative (Hypromellose, HPMC)
: Other polymers

A plasticizer
Hardgels Softgels
• water • High-boiling point polyols (Glycrol or sorbital)
• Water

Water

Colorants, Flavors, Stabilizers, Buffers and Opacifiers
<1094> Capsule-Dissolution testing and Release Quality Attributes

Hygroscopic Gelatin

Moisture change
material

13-16%

<1094> Capsule-Dissolution testing and Release Quality Attributes

Hygroscopic Gelatin

Gelatin shell can reactive depending on storage condition

Moisture can be absorb by gelatin shell

An increase in water content of the shell affects the

properties of capsules

H2O

H2O
<1094> Capsule-Dissolution testing and Release Quality Attributes

Hygroscopic Gelatin

<1094> Capsule-Dissolution testing and Release Quality Attributes

Disadvantages of gelatin shell

Hygroscopic materials not suitable into capsules

Hygroscopic materials can absorb water in the shell

Make the shell very brittle lead to crumble into pieces

<1094> Capsule-Dissolution testing and Release Quality Attributes

What is gelatin ?

Hydrolyzed form of collagen

Collagen is an animal protein in nature

Gelatin is produce from Bovine bone, Porcine skin

Used as a gelling agents in a variety of applications:
• Food
• Cosmetics
• Photography
• Pharmaceuticals

<1094> Capsule-Dissolution testing and Release Quality Attributes

Gelatin grade

Gelatin is graded from the strength of the gel is forms

Its grade measure as Bloom strength

Bloom strength

Ability of gel formed by gelatin at control condition
and is a function of MW, concentration of gelatin and gel pH

Resultant of gel’s resistance to compression

Bloom strength is reported in Bloom-grams or grams

High Bloom strength -> High Quality -> High cost

Bloom strength ranging from 50-300 in the market
(150-200 for softgel and 220-280 for hardgel)

Grade depend on process, tissue source

Grade is vary among supplier, between lots from same supplier
<1094> Capsule-Dissolution testing and Release Quality Attributes

Bloom strength device

Oscar T. Bloom, 1952

Bloom Test
The test determines the weight in grams
by a plunger (a diameter of 0.5 inch)
to depress the surface of the gel at
a specified temperature 4 mm
without breaking it.
The result is expressed in Bloom (grades).

<1094> Capsule-Dissolution testing and Release Quality Attributes

Gelatin chemical structure

Protein with some potentially reactive side chains

Can form covalent and hydrogen bonds between
itself and another chain

Often will form helices, etc.
<1094> Capsule-Dissolution testing and Release Quality Attributes

What is cross-linking ?

Cross-linking is the “formation of strong chemical
linkages beyond simple hydrogen and ionic bonding
between gelatin chains.”

Cross-linking is the covalent bonding of the amine
group of a lysine side chain

Reaction is generally irreversible

Renders gelatin water insoluble

Reaction catalyzed by a number
of chemical and environmental
factors

But can be disrupted by Enzyme

<1094> Capsule-Dissolution testing and Release Quality Attributes

What is cross-linking ?

Gelatin also forms ionic cross-linking (salt bridges),
typically between carboxylate (anionic) and ammonium
(cationic) side chains of amino acids

Ionic cross-linking is weaker than
covalent cross-linking

Can be disrupted by :

Enzyme

Changing the ionic strength

Changing the pH of the medium

<1094> Capsule-Dissolution testing and Release Quality Attributes

What is cross-linking ?

A weaker type of cross-linking involves complexation of
free carboxylic acid groups from two gelatin molecules
with trivalent metal ions such as Fe3+ and Al3+

Cations come from dyes, colorants

Can be disrupted by :

Enzyme

Changing the ionic strength

Changing the pH of the medium

<1094> Capsule-Dissolution testing and Release Quality Attributes

What can cause cross-linking in gelatin ?

Aldehydes and Ketones

APIs with carbonyl groups
resulting the aldehyde formation Cross-linking agent

Oxidizing agents

Metal Ions

Reducing Sugars

High and Low Humidity

Heat
Environment factors

UV Light
<1094> Capsule-Dissolution testing and Release Quality Attributes

Pellicle

Cross-linking can be visually confirmed with seeing
thin membranes or gelatinous masses call “Pellicle”

Pellicle is : swollen,
: thin,
: tough,
: rubbery,
: water-insoluble membrane.

Not disrupted easily by gentle agitation

<1094> Capsule-Dissolution testing and Release Quality Attributes

Cross linking Evidence

Observations
(Gelatinous mass, pellicles, swelling w/o rupture)

Instrumental Techniques
(C13-NMR, FTIR, MRI, etc.)

Switching capsule shells with fresh
<1094> Capsule-Dissolution testing and Release Quality Attributes

Pellicle and Impact

Acts as a barrier to dissolution and restricts
release of the drug.

Capsule shell opening is delayed or stopped
by pellicle formation on the internal or
external gelatin surface

Lower and/or incomplete dissolution in vitro

In severe situations,
can lead to problems in
vivo as well

<1094> Capsule-Dissolution testing and Release Quality Attributes

Other polymers

Carrageenans, polysaccharides extracted from sea weeds

Iota carrageenans for softgel

Kappa carrageenans for hardgel

Modified corn, Potato, pea starches

M0dified celluloses such as HPMC

Advantages

Non-crosslinking

Being handle wider pH ranges

Toleranc of high fill temperature
<1094> Capsule-Dissolution testing and Release Quality Attributes

HPMC capsule

No cross-linking

Plant derived

Able to be enteric coated

Higher cost, fewer vendors

Limited knowledge compared to gelatin

APIs w/ carbonyl groups or potential aldehyde
generation are prone to cross linking

<1094> Capsule-Dissolution testing and Release Quality Attributes

Way to solve the problems

Proper formulation development

Capsule shell selection

Excipients

Use HPMC instead?

Proper packaging

Humidity

Light

Free Radicals
<1094> Capsule-Dissolution testing and Release Quality Attributes

Proper formulation development

Capsule shell selection

Source of collagen

Bovine bones, Porcine bones, Fish skins

Manufacturing

Excipients

Not crosslinking agent

Use HPMC instead?

If API is causing cross-linking, you may want to
consider a HPMC capsule

<1094> Capsule-Dissolution testing and Release Quality Attributes

Packaging selection

Protect from humidity, light

Avoid over use of desiccant

Bottles / Rayon coilers can release furfural
(Furfural = Heterocyclic aldehyde)

Blister packs may be advantageous for sensitive
formulations
<1094> Capsule-Dissolution testing and Release Quality Attributes

Dissolution step of capsule

Rupture of the capsule shell

The water permeate the walls

The polymer becomes hydrated and swells

When fully hydrated, the sell starts to dissolve

Release and dispersion of the fill material

Dissolution of the active ingredient

<1094> Capsule-Dissolution testing and Release Quality Attributes

Dissolution Behavior of Capsules

Properties of capsule shell material

Properties of the fill material

Interaction between capsule shell material
and fill material
<1094> Capsule-Dissolution testing and Release Quality Attributes

Pellicle and Impact on dissolution results

The result in slower release of the drug or no lease at all

The degree of cross-linking is not uniform

Make a higher variability in the dissolution results

Apparatus I Apparatus II

<1094> Capsule-Dissolution testing and Release Quality Attributes

Failure with Cross-linking

If cross-linking is seen, the failure occurs

You do not need to continue testing until the last stage

Enzyme can be added to the dissolution medium to
overcome this problem
<1094> Capsule-Dissolution testing and Release Quality Attributes

Failure with Cross-linking

If cross-linking is seen, the failure occurs

You do not need to continue testing until the last stage

Enzymes are to be used

Change in <711> Dissolution

When Enzymes are to be used

USP 38 NF 33 2015

Hard and Soft gelatin Capsules not con form to the
Dissolution specification

USP 39 NF 34 2016

Product contains gelatin and

Product does not meet dissolution specification and

Evidence of cross-linking is observed

Do not need to continue testing until the last stage
Change in <711> Dissolution
USP 38 USP 39
Hard and Soft gelatin capsules DOSAGE FORMS CONTAINING OR
Gelatin coated Tablets COATED WITH GELATIN
Not conform to the Not meet the criteria in the three
Dissolution specification Acceptance Table because of evidence
of the present of cross-linking in the
first stage.
Gelatin, cross-linking, pellicle see
more information in
<1094> Capsule-Dissolution testing
and Release Quality Attributes
Do not need to continue testing until
the last stage

Enzyme are to be used Enzyme are to be used

Change in <711> Dissolution

USP 38 USP 39
Repeat the test as follow Repeat the test as follow
Water, Medium pH < 6.8 Medium pH ≥ 4.0
Same medium + Pepsin Same medium + Pepsin
NMT 750,00 units/L Pepsin Activity -> Purified pepsin in the Reagent
Specification section
Amount : NMT 750,00 units/L
Medium pH > 4.0 and < 6.8
Same medium + Papain or Bromelain
Papain Activity ->Assay Monograph for Papain
Amount : NMT 550,000 units/L
Bromelain activity : Bromelain in the Reagent
Specification section
Amount : NMT 30 gelatin-digesting units (GDU)/L
Medium pH ≥ 6.8 Medium pH ≥ 6.8
Same medium + Pancreatin Same medium + Pancreatin
NMT 1750 USP units of protease Pancreatin Activity -> Assay for protease activity
activity/L (Casein power) in monograph for Pancreatin
Amount : Protease activity NMT 2000 units/L
Change in <711> Dissolution
USP 38 USP 39
_ Medium containing Surfactant or other Ingredients
Known to denature the Enzyme
Repeat the test by using a pretreatment step
• Similar to 2-stage dissolution
• Medium without surfactant + Enzyme
• Type and concentration according to medium pH
• Enzyme amount depends on the volume of pre-
treatment step, not final dissolution volume
• The volume of pre-treatment step is smaller than
the final dissolution volume
• Pre-Treatment should be under same dissolution
conditions as the rest of the test
• Should not exceed 15 minutes, and pre-treatment
time is part of total test time

Limitation in USP 38

Enzyme and Surfactant

Limitation in USP 38

Addition of enzyme

Addition of enzymes either pancreatin or pepsin will
digest the denatured gelatin.

USP allows to add enzyme to dissolution medium
when specification failures are observed

Limitation in USP 38

Dissolution testing of capsules

“For hard or soft gelatin capsules and gelatin coated
tablets that do not conform to the Dissolution
specifications, repeat the test as follows:
– Where water or medium with a pH of less than 6.8,
the same Medium may be used with the addition of
purified pepsin that results in an activity of 750,000
Units or less per 1000 ml
– For media with a pH of 6.8 or greater pancreatin can
be added to produce not more that 1750 USP Units of
protease activity per 1000 ml.
Limitation in USP 38

Pepsin

Digestive enzyme in stomach which converts proteins
to peptides

For cross-linking, this is used to clean gelatin proteins
in places other than cross-linking site and allow rupture

Typically obtained from glandular layer of hog stomach

Peak activity at pH 2, good activity to ~pH 4.5

Pepsin activity generally felt sufficient to deal with mild
to moderate cross-linking

Limitation in USP 38

Pancreatin

Mixture of digestive enzymes created by exocrine cells
of pancreas

Typically porcine/bovine origin

Has good protease activity

Peak Activity at pH 6.8,
good between 6-8

Pancreatin able to handle
mild cross-linking

Pancreatin has been reported in the past to show a
higher failure rate vs. pepsin in cross-linking
Limitation in USP 38

Limitation

No good enzymes for pH 4-6.8

Pancreatin levels too low?

Surfactant/Enzyme incompatibility

SLS and other surfactants can denature enzymes

Key Change in USP 39

Key Change

Increase in Pancreatin Levels

New Enzymes!

Papain

Bromelain

Pre-treatment with Enzyme

Key Change in USP 39

Increase in pancreatin

Previous graph also shows reason for increase from
1750 to 2000 units/L

Key Change in USP 39

Papain

Derived from unripe green papaya

Commonly used as meat tenderizer, dietary
supplement, etc.

Digests protein substrates more extensively than
pancreatin

Optimal pH 4-7 for most substrates, pH 5 for gelatin

Powder stable 2 years at 2-8°C
Key Change in USP 39

Bromelain

Derived from stem of pineapple

Commonly used as meat tenderizer, anti-inflammatory
agent, etc.

Digests protein substrates more extensively than
pancreatin

Optimal pH 4.5-7.5 for most substrates, pH 4.5 for
gelatin

Powder stable 1.5-3 years at < 8°C

Key Change in USP 39

Papain and Bromelain in dissolution

Both suitable for use between pH 4-6.8

Papain used in activity of NMT 550,000 Units/L

Activity determination explained in Papain monograph,
under Assay

Bromelain used in activity of NMT 30 gelatin-digesting
units (GDU)/L of dissolution media

Activity determination determined in Reagent
Specifications, Bromelain
Key Change in USP 39

Enzyme Choice

Pepsin now clarified for use with pH ≤ 4.0

Pancreatin for use with pH ≥ 6.8

For pH 4.0 – 6.8, you can use either Papain or Bromelain

Enzyme Stability

Stable for a long time at refrigerated conditions (2-8˚C)

When enzymes are added to media, stability is reduced

Media with enzyme should be used within 4 hours

Best to prepare and store buffer, and add enzymes when
needed on day of use

Limitation in USP 38

For dissolution medium containing of surfactant

Surfactant can denature enzyme/inhibit its activity

Key Change

For dissolution medium containing of surfactant

Pretreatment with Enzyme

Media addition method

Media changeover method

Apparatus III method

Key Change

Pre-treatment surfactant

Media addition method

Media changeover method

Key change

Pre-treatment surfactant

Media addition method

Advantages Disadvantages
Single vessel Less total units of enzyme in media
Dosage don’t need Enzyme in media for all samples,
to be move potential issues for LC analysis

Key change

Pre-treatment surfactant

Media changeover method

Advantages Disadvantages
Suited to basket methods Mishandling of dosage form
More units of enzyme May require 2 dissolution unit
Key change

Pre-treatment surfactant

Apparatus III method

Perform pre-treatment in row 1 in Media A

Row 2 for Media B

Key Change in USP 39

For dissolution medium containing of surfactant

Pretreatment with Enzyme

Media addition method
USP 39 NF 34, 2016

Pre-treatment

Similar to 2-stage dissolution

First stage -Medium without surfactant + Enzyme

The volume of pre-treatment step is smaller than the final
dissolution volume

Type and concentration of enzyme according to medium pH

Enzyme amount depends on the volume of pre-treatment step,
not final dissolution volume

Pre-Treatment should be under same dissolution conditions as
the rest of the test

Should not exceed 15 minutes, and pre-treatment time is part of
total test time

Final stage – Medium with surfactant add to final dissolution
volume

Change in <711> Dissolution

USP 38 USP 39
Hard and Soft gelatin capsules DOSAGE FORMS CONTAINING OR
Gelatin coated Tablets COATED WITH GELATIN
Not conform to the Not meet the criteria in the three
Dissolution specification Acceptance Table because of evidence
of the present of cross-linking in the
first stage.
Gelatin, cross-linking, pellicle see
more information in
<1094> Capsule-Dissolution testing
and Release Quality Attributes
Do not need to continue testing until
the last stage

Enzyme are to be used Enzyme are to be used

Change in <711> Dissolution
USP 38 USP 39
Repeat the test as follow Repeat the test as follow
Water, Medium pH < 6.8 Medium pH ≥ 4.0
Same medium + Pepsin Same medium + Pepsin
NMT 750,00 units/L Pepsin Activity -> Purified pepsin in the Reagent
Specification section
Amount : NMT 750,00 units/L
Medium pH > 4.0 and < 6.8
Same medium + Papain or Bromelain
Papain Activity ->Assay Monograph for Papain
Amount : NMT 550,000 units/L
Bromelain activity : Bromelain in the Reagent
Specification section
Amount : NMT 30 gelatin-digesting units (GDU)/L
Medium pH ≥ 6.8 Medium pH ≥ 6.8
Same medium + Pancreatin Same medium + Pancreatin
NMT 1750 USP units of protease Pancreatin Activity -> Assay for protease activity
activity/L (Casein power) in monograph for Pancreatin
Amount : Protease activity NMT 2000 units/L

Change in <711> Dissolution

USP 38 USP 39
_ Medium containing Surfactant or other Ingredients
Known to denature the Enzyme
Repeat the test by using a pretreatment step
• Similar to 2-stage dissolution
• Medium without surfactant + Enzyme
• Type and concentration according to medium pH
• Enzyme amount depends on the volume of pre-
treatment step, not final dissolution volume
• The volume of pre-treatment step is smaller than
the final dissolution volume
• Pre-Treatment should be under same dissolution
conditions as the rest of the test
• Should not exceed 15 minutes, and pre-treatment
time is part of total test time
Failure still occurs

If failure is still seen with enzyme, then you fail.

It is not permissible to add additional enzymes

Use other techniques with a validation method

Information

General Chapter
<1094> Capsule-Dissolution testing
and Release Quality Attributes
<1094> Capsule-Dissolution testing and Release Quality Attributes

INTRODUCTION

Types of Capsules

Manufacturing and Packaging Issues That Can Effect Dissolution Testing

CROSS-LINKING IN GELATIN CAPSULES

DISSOLUTION PROCEDURE DEVELOPMENT

METHOD VALIDATION

SUGGESTIONS FOR STARTING POINTS

CRITICAL QUALITY ATTRIBUTES

Shell Composition

Stability and storage Conditions

Formulation Development and Manufacturing for Liquid-Filled Capsules

USP General Chapter

USP General Chapter

<711> Dissolution
 General chapter <711> Dissolution (USP 39)

INTRODUCTION

Dissolution for oral dosage forms

Definition of Dosage unit

Enteric-coated dosage forms

FOR DOSAGE FORMS CONTAINING OR COATED WITH
GELATIN (If they dose not meet the criteria in the
Acceptance Table)

APPARATUS 1-4

PROCEDUE (For Immediate, Delayed and Extended)

INTERPETRATION

Dissolution Tester for App1, App2

Water bath

Heating Device

Table contain at least six
positions, six dosage unit
can be tested at one time

Vessels and covers

Speed-regulating Device

Apparatus 1, Apparatus 2
Dissolution Tester for App1, App2

Water bath and Heater Device

Convenient size, Transparent

Hold the temperature inside the vessel at 37 ± 0.5°

Dissolution Tester for App1, App2

Speed-regulating Device

Apparatus 1

Routinely used speed is 50-100 rpm

Speed out side a range of 50 to 150 rpm
are unacceptable

Speed < 50 rpm make the medium
irreproducibilty of hydrodynamic

Speed > 150 rpm make the
turbulence into the medium

Speed accuracy is ± 4%
Dissolution Tester for App1, App2

Speed-regulating Device

Apparatus 2

Routinely used speed is 25-75 rpm

Speed < 25 rpm make the medium
irreproducibilty of hydrodynamic

Speed > 100 rpm make the
turbulence into the medium

Speed accuracy is ± 4%

Dissolution Tester for App1, App2

Vessel

Glass / Other Inert

Trasparent

Cylidrical

Hemisphere bottom

Capacity of 500 ml - 1 L

Height is 160-210 mm

Inside diameter is 98-106 mm

Special capacity are 0.5, 2, 4 L

With a fitted cover
Dissolution Tester for App1, App2

Vessel cover

Apparatus 1 (Rotating Basket)

Shaft

Stainless steel, Type 316
or other inert

Shaft axis is not more
than 2mm at any point
from vertical axis

Sampling point = A

25 mm± 2 mm

Wobble ± 1 mm (lower rim)
Apparatus 1 (Rotating Basket)

Basket

The 40 mesh basket

Gold coated basket may be used

Gold coated thick is 2.5 μm
or 0.0001 inch

Apparatus 1 (Rotating Basket)

Basket

Mesh is openings per linear inch

Opening have 0.38 mm aperture

Wire diameter is 0.25 mm
Apparatus 1 (Rotating Basket)

Basket Shaft

Metallic or other inert

Suitable coating

Gold, Teflon coated shaft may be used

Apparatus 2 (Rotating Paddle)

Shaft and Paddle

Metallic or other inert

Suitable coating

Shaft axis is not more
than 2mm at any point
from vertical axis

Sampling point = A

25 ± 2 mm

Sinker may be use
Shaft

Sinker
• A non-reactive material
USP Sinker
• A Few Turn Wire Helix
• Alternative Sinker

Other Sinker
• Other validated sinker may be used
Special Apparatus

• Stationary Basket assembly • Basket for USP Felodipine

Extended Release Tablets

35 /112

Procedure for App1, App2

Immediate Release Dosage Forms

Immediate Release Dosage Forms

Pool sample Immediate Release Dosage Forms

Extended- Release Dosage Forms

Delayed- Release Dosage Forms
Procedure for Immediate Release

Verify that the equipment is clean

Check the water level in the bath (Type II water)

Power on the Instrument

Dissolution Test

Heater

Procedure for Immediate Release

Set Apparatus 1 or 2

Vertical axis

Center

Set Vessel

Center
Procedure for Immediate Release

Adjust the Apparatus

25 ± 2 mm

Procedure for Immediate Release

Place the dissolution medium

Water, 0.1 N HCl, Buffer (pH ± 0.05)

Volume 900, 750, 500, 250 ml (± 1%), Sink condition

The measurement volume made 20-25 °

Remove gas in the medium, if necessary

Temperature to 37 ± 0.5°, use immediately
Procedure for Immediate Release

Deaeration method

Heat the medium to about 41°c, while stirring gentry

Immediately filter under vacuum , with stirring
(Nylon filter porosity 0.45μm)

Continue stirring under vacuum about 5 min

Procedure for Immediate Release

Deaeration Effect
Lack of deaeration can effect on dissolution

Bubbles on the surface of the glass create
great turbulence

For most disintegrating dosage form higher
dissolution rate my be observed

If dissolved gasses are shown to interfere,
they must be removed prior to he test
Procedure for Immediate Release

Handling sample

Always handle sample units with groves (not cotton)
or forceps which will not scratch or damage the surface
of dosage units

Procedure for Immediate Release

Record each sample unit weight

Sample are chosen at random and to be weighted
Procedure for Immediate Release

Load sample

Take care to exclude air bubble from the sample surface

App 1 : Place 1 unit in dry basket
: Lower the basket to the position before start

App 2 : Allowed 1 unit to sink to the bottom before start

Procedure for Immediate Release

Immediately operate the apparatus (Start)

Speed 50, 75, 100 rpm. (± 4%)

Time : Single time is given such as 30, 45, 60 min
Procedure for Immediate Release

Visual inspect

Record any unusual observation

Procedure for Immediate Release

Visual inspect

Most immediate release
tablets disintegrate very
rapidly and will reaggregate
in the form of a cone on the
bottom of the vessel

During the dissolution
process, some excipient
may be visible on the
bottom of the vessel at the
end of the test
Visual inspect

Visual inspect
Cross-linking
Visual inspect
Product Movement, Center, off center, sticking

Visual inspect
Air Bubbles
 Visual inspect
Air Bubbles

Procedure for Immediate Release

Have sampling equipment ready for the test.
Procedure for Immediate Release

Have sampling equipment ready for the test.

Procedure for Immediate Release

Sampling

The sampling zone :
The midway between the medium surface and the
top of apparatus, NLT 1 cm from the vessel wall
Procedure for Immediate Release

Sampling

The sampling time :
The giving time ± 2%

Do not stop the agitation while sampling

Temperature :
Temperature should be measure
a second time at least, after the
last sample is pulled and before
the shaft has stopped

Procedure for Immediate Release

Procedure for Immediate Release

Immediately filter the sample withdraw

Use the suitable filter

Inert

Suitable pore size

Not absorb sample

Not contain substances
that extractable by
dissolution medium
that would interfere the
method analysis

Procedure for Immediate Release

Determine the quantity of drug, directed the method
in the monograph

Compare the solution withdraw with the known
concentration standard solution

Assay
Interpretation for Immediate Release

Acceptance criteria
Stage Sample tested Acceptance criteria

S1 6 Each unit is NLT Q+5%

S2 6 Average of 12 units ≥ Q,
no unit is LT Q-15%
S3 12 Average of 24 units ≥ Q,
NMT 2 units are LT Q-15%,
no unit is LT Q-25%

Procedure for Pool Sample IR

Combine equal volumes of 6 or 12 filtered solution

Assay

Pool sample Std. solution

Interpretation for Pool Sample IR

Acceptance criteria

Stage Sample tested Acceptance criteria

S1 6 Average amount dissolves is NLT Q+5%

S2 6 Average amount dissolves is ≥ Q+5%
S3 12 Average amount dissolves is ≥ Q

Procedure for Extended Release

Sampling-Time Points Dissolution Profile

Generally three points

Time are expressed in hrs.
Sampling time : ±2%

Medium replacement

Equal volume, Temp. 37°C

Correct the volume change
Interpretation for Extended Release

Acceptance criteria,USP
Stage Sample tested Acceptance criteria

L1 6 No individual value lies outside each of the stage range, and

no individual value is LT the stated amount at the final test
time
L2 6 Average value lies within each of the stated range, and is
NLT the stated amount at the final test time, none is MT
10% outside each of the stated range, and none is MT 10%
below the stated amount at the final test time
L3 12 Average value lies within each of the stated range, and is
NLT the stated amount at the final test time, NMT 2 units
are MT 10% outside each of the stated range, and NMT 2
units are MT 10% below the stated amount at the final test
time, and none is MT 20% outside each of the stated range,
and none is MT 20% below the stated amount at the final
test time

Procedure for Delayed-Release

Method A Method B
Acid stage Acid stage
• 0.1 N HCl, 750 ml • 0.1 N HCl, 1000 ml
• Run time : 2 hours • Run time : 2 hours
• Withdraw • Withdraw

Buffer stage Buffer stage

• Add 0.20 M Na3PO4, 250 ml (37˚) • Drain an acid away
• Adjust pH to 6.8 (in 5 min) • Add pH 6.8 PO4 buffer, 1L (37˚)
• Run time : 45 min or …. • Run time : 45 min or …
• Withdraw
• Withdraw
Interpretation for Delayed-Release

Acceptance criteria, USP

Acid stage

Stage Sample tested Acceptance criteria

A1 6 No individual value exceeds 10% dissolved
A2 6 Average value is NMT 10% dissolved, and
no individual unit is MT 25% dissolved
A3 12 Average value is NMT 10% dissolved, and
no individual unit is MT 25% dissolved

Interpretation for Delayed-Release

Acceptance criteria, USP

Buffer stage

Stage Sample tested Acceptance criteria

B1 6 Each unit is NLT Q+5%
B2 6 Average value is ≥ Q, and no is LT Q-15%
B3 12 Average value is ≥ Q, NMT 2 units are LT
Q-15%, NMT 10% dissolved, and no , and
no is LT Q-25%
Apparatus 3 (Reciprocating cylinder)

Water bath, holding temperature 37± 0.5°

Heating Device

Table

Vessels and cap

Reciprocating Device
Dip rate within ± 5%
Stroke distance 9.9-10.1 cm

Apparatus

Screens

Inert fittings (Stainless steel type 316)

Apparatus 3 (Reciprocating cylinder)

Apparatus 3 (Reciprocating cylinder)

Vessel

Glass / Other Inert

Trasparent

Cylidrical, flat-bottom

With an evaporation cap

Apparatus 3 (Reciprocating cylinder)

Apparatus

Evaporation Cap

Inert fittings

Upper Mesh Screen

Glass cylinder

Lower Mesh screen

Vessel
Procedure for App 3

Immediate Release Dosage Forms

Extended- Release Dosage Forms

Delayed- Release Dosage Forms

Acid
stage Buffer
stage

Apparatus 4 (Flow-Though Cell)

Water bath

Heating Device, maintain the medium at 37±0.5˚

Reservoir and pump

Inert tubing

Flow-Though Cell
Apparatus 4 (Flow-Though Cell)

Reservoir and pump

Pump delivery range 240-960 ml per hour

Flow rate 4, 8, 16 ml per min

Constant flow ± 5%

Flow-Though Cell

Transparent and Inert

Cell is mounted with filter

Usually filled with small 1-mm dimeter glass beads

One 5-mm dimeter glass bead at the apex

Apparatus 4 (Flow-Though Cell)

Pump
Procedure for App 4

Immediate Release Dosage Forms

Extended- Release Dosage Forms

Delayed- Release Dosage Forms

Low solubility drugs

Special dosage forms such as Inlay tablets

USP General Chapter

USP General Chapter

<724> Drug Release
General chapter <724> Drug Release (USP 39)

SCOPE

The test is provided to determine Dissolution or Drug release
of Transdermal System (TDS) and other dosage forms

APPARATUS 5-7

APPARATUS

PROCEDUE

TIME

INTERPETRATION

Apparatus 5 (Paddle over disk)

Water bath, maintain the medium at 37±0.5˚

Heating Device

Table

Vessels and covers

Speed-regulating Device
Speed within ± 4%

Apparatus 5

Disk assembly
Apparatus 5 (Paddle over disk)

Water bath and Heater Device

Convenient size

Hold the temperature inside the vessel at 32 ± 0.5°

Apparatus 5 (Paddle over disk)

Shaft and Paddle

Metallic or other inert

Suitable coating

Shaft axis is not more A
than 2mm at any point
from vertical axis

25 ± 2 mm

A = Sampling point
Apparatus 5 (Paddle over disk)

41.2 mm

Apparatus 5 (Paddle over disk)

17 Mesh screen Holding wire screen
Clips watchglass
Apparatus 5 (Paddle over disk)
USP 37 USP 38
Disk Assembly Disk Assembly

Screen and watchglass

Holding wire screen

Apparatus 5 (Paddle over disk)

Procedure for TDS

Place the stated volume in the vessel, temp 32 ±0.5˚

Apply the TDS to the disk assembly

Place the disk assembly flat at the bottle of vessel

Immediately operate apparatus

Sampling point = A

Time points, at least 3,
expressed in hours A
min
within the tolerance of ± 15 min
or ± 2% of the state time
Apparatus 5 (Paddle over disk)
USP 37 USP 38
The system may be attached to the The system may be attached to the
disk by applying a suitable adhesive disk by appropriate and validated
to the disk assembly. procedure such as use of an
Dry for 1 minute. adhesive, double-face adhesive
Press the system, release surface tape, screen, or membrane.
side up, onto the adhesive- coated Press the system, release surface
side of the disk assembly. side up, onto the adhesive- coated
side of the disk assembly.

Apparatus 5 (Paddle over disk)

Acceptance criteria,USP
Stage Sample Acceptance criteria
tested

L1 6 No individual value lies outside the stage range

L2 6 Average value (L1+L2) lies within the stated range,

none is MT 10% outside the average of the stated range

L3 12 Average value (L1+L2+L3) lies within the stated range,

NMT 2 units are MT 10% outside the average of the
stated range, and none is MT 20% outside the average
of the stated range
Apparatus 6 (Rotating cylinder)

Water bath

Heating Device

Table

Vessels and covers

Speed-regulating Device
Speed within ± 4%

Apparatus 6

Apparatus 6 (Rotating cylinder)

Water bath and Heater Device

Convenient size

Hold the temperature inside the vessel at 32 ± 0.5°
Apparatus 6 (Rotating cylinder)

Shaft and Cylinder

Metallic or other inert

Suitable coating A

Shaft axis is not more

than 2mm at any point
from vertical axis

25 ± 2 mm

A = Sampling point

Apparatus 6 (Rotating cylinder)

Apparatus 6 (Rotating cylinder)

Procedure for TDS

Place the stated volume in the vessel, temp 32 ±0.5˚

Apply the TDS to the cylinder

Place the in the apparatus

Immediately operate apparatus

Sampling point = A

Time points, at least 3,
expressed in hours
min
within the tolerance of ± 15 min
or ± 2% of the state time

Apparatus 6 (Rotating cylinder)

Acceptance criteria,USP
Stage Sample Acceptance criteria
tested

L1 6 No individual value lies outside the stage range

L2 6 Average value (L1+L2) lies within the stated range,

none is MT 10% outside the average of the stated range

L3 12 Average value (L1+L2+L3) lies within the stated range,

NMT 2 units are MT 10% outside the average of the
stated range, and none is MT 20% outside the average
of the stated range
Apparatus 7 (Reciprocate Holder)

Water bath

Heating Device

Table

Vessels and covers

Speed-30 cycles/min

Amplitude ~ 2 cm

Holder

Apparatus 7 (Reciprocate Holder)

Water bath and Heater Device

Convenient size

Hold the temperature inside the vessel at 32 ± 0.5°
Apparatus 7 (Reciprocate Holder)

Holder

Apparatus 7 (Reciprocate Holder)

Holder
Transdermal Delivery System Oral Extended-release Tablets
Osmotic Pump Tablets

Osmotic Pump Tablets

Transdermal Delivery System Oral Extended-release Tablets
Apparatus 7 (Reciprocating Holder)
Osmotic Pump Tablets

Apparatus 7 (Reciprocating Holder)

Procedure for TDS, Extended Release Tablets

Place the stated volume in the vessel, temp 32 ±0.5˚

Apply sample to the Holder

Suspend the holder to the tester

Reciprocate at about 30 cycle/min

Amplitude of about 2 cm

Sampling point = A

Time points, at least 3,
expressed in hours
within the tolerance of ± 15 min
or ± 2% of the state time
Apparatus 7 (Reciprocate Holder)

Acceptance criteria,USP
Stage Sample Acceptance criteria
tested

L1 6 No individual value lies outside the stage range

L2 6 Average value (L1+L2) lies within the stated range,

none is MT 10% outside the average of the stated range

L3 12 Average value (L1+L2+L3) lies within the stated range,

NMT 2 units are MT 10% outside the average of the
stated range, and none is MT 20% outside the average
of the stated range

USP Apparatus
Apparatus Suitability

To determine the dimensions of apparatus
The critical parameters have to be monitored
periodically during use

Volume and Temp. of dissolution medium

Rotation speed (App.1, App.2)

Dip rate (App.3)

Flow rate (App.4)

To determine the performance as of the test
By The Performance Verification Test (PVT)

Apparatus Suitability

The Performance Verification Test (PVT)

Since 1978, USP calibration with disintegrating 50-mg
Prenisone and non-disintegrating 300-mg Salicylic acid
Tablet calibrators for qualifying the dissolution
apparatus.

2001, 10-mg prednisone tablet

2007, The PVT was used determine the performance of

the dissolution test only for Apparatus I, II and V.