ปฏ มา มณ สถ ตย เภส ชกรช านาญการพ เศษ. Scope. Dissolution Overview <1094>

Transcription

1 ปฏ มา มณ สถ ตย เภส ชกรช านาญการพ เศษ Scope <1094> Dissolution Overview <711> <724>

2 Scope, General chapter <711> Dissolution <724> Drug Release <1094> Capsules-Dissolution Testing and Related Quality Attributes Overview of Dissolution

3 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

4 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

5 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.

6 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

7 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

8 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

9 Quality Control Test: Development 1970-Apparatus 1, USP XVII, (12 monographs) 1978-Apparatus 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

10 Quality Control Test: Development 1997-Pool sample 2001-Calibration requirements were reduced to 4 tests 2006-<1092> Dissolution: Development and Validation 2006-USP 29, Harmonizationin <711> Dissolution <711> Dissolution App. 1-4 /<724> Drug release App 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

11 Quality Control Test: Development 2011-USP 34, Mesh Size Harmonization 2014-USP 37, > 750 monographs (Dissolution) -USP 37 the 1 st supplement, <1094> Capsules- Dissolution Testing and Related Quality Attributes 2014-USP 37, the 2 nd 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

12 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

13 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

14 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)

15 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

16 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

17 Change in <711> Dissolution USP38 USP 39 Hard and Soft gelatin capsules Gelatin coated Tablets Not conform to the Dissolution specification DOSAGE FORMS CONTAINING OR COATED WITH GELATIN Not meet the criteria in the three 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 Enzymeare to be used Enzymeare to be used Change in <711> Dissolution Repeat the test as follow Water,Medium ph < 6.8 Same medium + Pepsin NMT 750,00 units/l USP38 USP 39 Medium ph 6.8 Same medium + Pancreatin NMT 1750 USP units of protease activity/l Repeat the test as follow Medium ph 4.0 Same medium + Pepsin 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 : Bromelainin the Reagent Specification section Amount : NMT 30 gelatin-digesting units (GDU)/L Medium ph 6.8 Same medium + Pancreatin Pancreatin Activity -> Assay for protease activity (Casein power) in monograph for Pancreatin Amount : Protease activity NMT 2000 units/l

18 Change in <711> Dissolution USP38 USP 39 _ Medium containing Surfactantor 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 pretreatment 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

19 <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

20 <1094> Capsule-Dissolution testing and Release Quality Attributes Types of Capsules Soft-shell Capsules Softgels Hard-shell Capsules Hardgels Thicker shell More elasticity Thinner shell 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

21 <1094> Capsule-Dissolution testing and Release Quality Attributes Capsules manufacturing Process For soft capsules Formation of capsules, Filling Process, Sealing Process occur simultaneously Monitor in process control : Shell thickness Seam quality Capsule weight Fill weight Lubricant Gelatin ribbon Feeding 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)

22 <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

23 <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 Thepartial vapor pressure of water in a substance divided by the partial vapor pressure of pure distilled water at the sametemperature. Puredistilled water has a water activity of exactly one.

24 <1094> Capsule-Dissolution testing and Release Quality Attributes Protection of Shell At room temperature, Capsule shell can protect Light and Photodegradation Titanium oxide Water activity >0.40 aw O 2 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 water Softgels High-boiling point polyols (Glycrol or sorbital) Water Water Colorants, Flavors, Stabilizers, Buffers and Opacifiers

25 <1094> Capsule-Dissolution testing and Release Quality Attributes Hygroscopic Gelatin material Moisture change 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 H 2 O H 2 O

26 <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

27 <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 in the market ( for softgel and for hardgel) Grade depend on process, tissue source Grade is vary among supplier, between lots from same supplier

28 <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.

29 <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

30 <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 Fe 3+ and Al 3+ 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 Oxidizing agents Metal Ions Reducing Sugars High and Low Humidity Heat UV Light Cross-linking agent Environment factors

31 <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

32 <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

33 <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

34 <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

35 <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

36 <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

37 <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 Hard and Soft gelatin Capsules not con form to the Dissolution specification USP 39 NF 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

38 Change in <711> Dissolution USP38 USP 39 Hard and Soft gelatin capsules Gelatin coated Tablets Not conform to the Dissolution specification DOSAGE FORMS CONTAINING OR COATED WITH GELATIN Not meet the criteria in the three 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 Enzymeare to be used Enzymeare to be used Change in <711> Dissolution Repeat the test as follow Water,Medium ph < 6.8 Same medium + Pepsin NMT 750,00 units/l USP38 USP 39 Medium ph 6.8 Same medium + Pancreatin NMT 1750 USP units of protease activity/l Repeat the test as follow Medium ph 4.0 Same medium + Pepsin 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 : Bromelainin the Reagent Specification section Amount : NMT 30 gelatin-digesting units (GDU)/L Medium ph 6.8 Same medium + Pancreatin Pancreatin Activity -> Assay for protease activity (Casein power) in monograph for Pancreatin Amount : Protease activity NMT 2000 units/l

39 Change in <711> Dissolution USP38 USP 39 _ Medium containing Surfactantor 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 pretreatment 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

40 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.

41 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

42 Limitation in USP 38 Limitation No good enzymes for ph 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

43 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

44 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 for most substrates, ph 4.5 for gelatin Powder stable years at < 8 C Key Change in USP 39 Papain and Bromelain in dissolution Both suitable for use between ph 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

45 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 , 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

46 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

47 Key change Pre-treatment surfactant Media addition method Advantages Single vessel Dosage don t need to be move Disadvantages Less total units of enzyme in media Enzyme in media for all samples, 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

48 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

49 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 USP38 USP 39 Hard and Soft gelatin capsules Gelatin coated Tablets Not conform to the Dissolution specification DOSAGE FORMS CONTAINING OR COATED WITH GELATIN Not meet the criteria in the three 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 Enzymeare to be used Enzymeare to be used

50 Change in <711> Dissolution Repeat the test as follow Water,Medium ph < 6.8 Same medium + Pepsin NMT 750,00 units/l USP38 USP 39 Medium ph 6.8 Same medium + Pancreatin NMT 1750 USP units of protease activity/l Repeat the test as follow Medium ph 4.0 Same medium + Pepsin 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 : Bromelainin the Reagent Specification section Amount : NMT 30 gelatin-digesting units (GDU)/L Medium ph 6.8 Same medium + Pancreatin Pancreatin Activity -> Assay for protease activity (Casein power) in monograph for Pancreatin Amount : Protease activity NMT 2000 units/l Change in <711> Dissolution USP38 USP 39 _ Medium containing Surfactantor 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 pretreatment 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

51 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

52 <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

53 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

54 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 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%

55 Dissolution Tester for App1, App2 Speed-regulating Device Apparatus 2 Routinely used speed is 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 mm Inside diameter is mm Special capacity are 0.5, 2, 4 L With a fitted cover

56 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)

57 Apparatus 1 (Rotating Basket) Basket The 40 mesh basket Gold coated basket may be used Gold coated thick is 2.5 μm or inch Apparatus 1 (Rotating Basket) Basket Mesh is openings per linear inch Opening have 0.38 mm aperture Wire diameter is 0.25 mm

58 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

59 Shaft Sinker A non-reactive material

60 USP Sinker A Few Turn Wire Helix Alternative Sinker Other Sinker Other validated sinker may be used

61 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

62 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

63 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 Remove gas in the medium, if necessary Temperature to 37 ± 0.5, use immediately

64 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

65 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

66 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

67 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

68 Visual inspect Visual inspect Cross-linking

69 Visual inspect Product Movement, Center, off center, sticking Visual inspect Air Bubbles

70 Visual inspect Air Bubbles Procedure for Immediate Release Have sampling equipment ready for the test.

71 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

72 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

73 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

74 Interpretation for Immediate Release Acceptance criteria Stage Sample tested Acceptance criteria S1 6 Each unit is NLTQ+5% S2 6 Averageof 12 units Q, no unit is LT Q-15% S3 12 Averageof 24 units Q, NMT 2 units are LT Q-15%, no unit is LT Q-25% Procedurefor Pool Sample IR Combine equal volumes of 6 or 12 filtered solution Assay Pool sample Std. solution

75 Interpretationfor 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 Generally three points Time are expressed in hrs. Sampling time : ±2% Medium replacement Dissolution Profile Equal volume, Temp. 37 C Correct the volume change

76 Interpretationfor Extended Release Acceptance criteria,usp Stage Sample tested Acceptance criteria L1 6 No individual value liesoutside each of the stage range, and no individual value is LT the stated amount at the finaltest time L2 6 Average value lies within each of the stated range, and is NLT the stated amount at the finaltest time, none is MT 10% outside each of the stated range, and none is MT 10% below the stated amount at the finaltest time L3 12 Average value lies within each of the stated range, and is NLT the stated amount at the finaltest 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 finaltest 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 0.1 N HCl, 750 ml Run time : 2 hours Withdraw Acid stage 0.1 N HCl, 1000 ml Run time : 2 hours Withdraw Buffer stage Add 0.20 M Na3PO4, 250 ml (37 ) Adjust ph to 6.8 (in 5 min) Run time : 45 min or. Withdraw Buffer stage Drain an acid away Add ph 6.8 PO4 buffer, 1L (37 ) Run time : 45 min or Withdraw

77 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%

78 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 cm Apparatus Screens Inert fittings (Stainless steel type 316) Apparatus 3 (Reciprocating cylinder)

79 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

80 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

81 Apparatus 4 (Flow-Though Cell) Reservoir and pump Pump delivery range 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

82 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

83 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

84 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 than 2mm at any point from vertical axis 25 ± 2 mm A = Sampling point A

85 Apparatus 5 (Paddle over disk) 41.2 mm Apparatus 5 (Paddle over disk) 17 Mesh screen watchglass Clips Holding wire screen

86 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 within the tolerance of ± 15 min or ± 2% of the state time

87 Apparatus 5 (Paddle over disk) USP 37 USP 38 The system may be attached to the disk by applying a suitable adhesive to the disk assembly. Dry for 1 minute. Press the system, release surface side up, onto the adhesive-coated side of the disk assembly. The system may be attached to the disk by appropriate and validated procedure such as use of an adhesive, double-face adhesive tape, screen, or membrane. Press the system, release surface side up, onto the adhesive-coated side of the disk assembly. Apparatus 5 (Paddle over disk) Acceptance criteria,usp Stage Sample tested Acceptance criteria 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

88 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

89 Apparatus 6 (Rotating cylinder) Shaft and Cylinder Metallic or other inert Suitable coating Shaft axis is not more than 2mm at any point from vertical axis 25 ± 2 mm A = Sampling point A Apparatus 6 (Rotating cylinder)

90 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 within the tolerance of ± 15 min or ± 2% of the state time Apparatus 6 (Rotating cylinder) Acceptance criteria,usp Stage Sample tested Acceptance criteria 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

91 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

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

93 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

94 Apparatus 7 (Reciprocate Holder) Acceptance criteria,usp Stage Sample tested Acceptance criteria 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

95 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.

96