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Agilent Technologies — Technical Presentation (March 2015)
44 slides from Agilent Technologies's technical presentation, Mar 10, 2015
Slide 1: Applications of USP Apparatus 3: Reciprocating Cylinder
Applications of USP Ken Boda Apparatus 3: Reciprocating Cylinder Bryan Crist Agilent Technologies Current Trends in Pharmaceutical Dissolution Testing Workshop Pittcon 2015 Tuesday, March 10
Slide 2: Development of USP Apparatus 3
Development of USP Apparatus 3 While traditional paddle and basket apparatus offered a convenient means to evaluate most oral drug formulations with multiple pH over extended periods, it was difficult to change pH during the test and changes in agitation rates during the in-vitro test were seldom no
Slide 3: Development of USP Apparatus 3
Development of USP Apparatus 3 A presentation at the 1980 federation Internationale Pharmaceutique (F.I.P.) drew attention to acute problems associated with USP Apparatus 1 and 2 dissolution results. The conference inspired the concept for the USP Apparatus 3. As research progressed it became appare
Slide 4: Development of USP Apparatus 3
Development of USP Apparatus 3 VanKel worked with Professor Arnold Beckett to develop the Bio-Dis (Bio-relevant Dissolution) which was eventually adopted in USP XXII (1991) as USP Apparatus 3 Due to ICH, USP Apparatus 3 – Reciprocating Cylinder and Apparatus 4 – Flow Thru Cell were moved to <711> Di
Slide 5: USP Apparatus 3 Overview
USP Apparatus 3 Overview The USP Apparatus 3 – Reciprocating Cylinder (Bio-Dis) is an apparatus utilized for drug release profiling from extended release products because it can quickly and easily expose products to mechanical and physiochemical conditions which may influence the release of the prod
Slide 6: USP Apparatus 3 Overview
USP Apparatus 3 Overview USP <711> Apparatus 3 • 300 mL Vessel • Normally 200 mL to 275 mL vessel volume • Operational minimum – 150 mL vessel volume • Extended release tablets, capsules, beads • pH profile determination in multiple media • Harmonized between USP and EP • Not presently recognized by
Slide 7: USP Apparatus 3 Overview
USP Apparatus 3 Overview Reciprocating Cylinder - USP Apparatus 3 has seven reciprocating cylinders which consist of glass tubes with threaded ends to secure an upper cap and lower cap which hold screens to contain the dosage unit. This cylinder may also be referred to as the inner tube.
Slide 8: USP Apparatus 3 Overview
USP Apparatus 3 Overview Vessels – The apparatus consists of up to six sets of cylindrical, flat bottom 300 mL glass vessels which are filled with media and held in a water bath with a vessel rack. The vessels may also be referred to as the outer tubes. Confidentiality Label 8 May 18, 2015
Slide 9: USP Apparatus 3 Overview
USP Apparatus 3 Overview A motor and drive assembly reciprocates the cylinders vertically inside the vessels. The cylinders are allowed to move from row to row to expose the undissolved drug product to various pH levels. As the cylinder reciprocates vertically the drug product is constantly exposed
Slide 10: USP Apparatus 3 Overview
USP Apparatus 3 Overview When the test begins, the reciprocating cylinders descend slowly into the first row of the vessels. Then the reciprocating motion starts. After the programmed time for this row expires, the reciprocating cylinders rise above the vessels to drain for a programmed time, and au
Slide 11: Apparatus 3 Reciprocating Cylinder
Apparatus 3 Reciprocating Cylinder Confidentiality Label 11 May 18, 2015
Slide 12: Current Physical Parameters and Tolerances
USP Apparatus 3 Current Physical Parameters and Tolerances Temperature 37 0.5 C Dip rate (DPM) 5% of set speed Stroke Distance 10.0 0.1 cm Bottom screen Method specific Top screen Method specific (optional) 12
Slide 13: Media Volume Considerations
Media Volume Considerations • Each of the outer tubes is usually filled with 250 mL of medium. • Because there are 6 rows of outer tubes, 6 x 250 mL or 1500 mL of medium can be used in a single dissolution test. • If the proper conditions are not achieved with 1500 mL of medium, rows can be refilled
Slide 14: Mesh Size Considerations
Mesh Size Considerations Mesh size should be chosen in the same way a basket is selected: •Retain undissolved API product •Allow for maximum flow 14
Slide 15: Media Considerations - Surfactants
Media Considerations - Surfactants •If surfactants are used, regardless of speed, foam will occur and lead to lost volume and a mess •Use of an anti-foaming agent such as simethicone is recommended •Infant gas drops can be an inexpensive early check of feasibility 15
Slide 16: Background of Apparatus 3 Qualification
Background of Apparatus 3 Qualification Similar to Dissolution Apparatus 1 and 2, the qualification of USP Apparatus 3 had consisted of a combination of: •Physical parameter verification •PVT with USP Chlorpheniramine Maleate ER Tablets. Effective February 1, 2012, USP has removed the requirement fo
Slide 17: Current State of Qualification
Current State of USP Apparatus 3 Qualification Similar to requirements for Enhanced Mechanical Qualification, the absence of PVT should require additional steps to assure the apparatus is suitable for its intended use. Current State of Qualification: • Certification of Components • Documentation of
Slide 18: Current State of Qualification
Current State of USP Apparatus 3 Qualification Operational Checks: Before each run with the USP apparatus 3 system, the analyst should perform the following checks on the apparatus to ensure integrity: Reciprocating cylinder glass tubes are free from residue, scratches and cracks Screens of appropri
Slide 19: Applications for USP Apparatus 3
Applications for USP Apparatus 3
Slide 20: Applications For USP Apparatus 3
Applications For USP Apparatus 3 Immediate release • Metoprolol • Ranitidine Testing products with the addition of beads. • Extended Release • Chewable Tablets Controlled Release – Site specific Microparticles Confidentiality Label 20 May 18, 2015
Slide 21: Regulatory Expectation for Drug Release Methods
Regulatory Expectation for Drug Release Methods Method and specifications should provide: • Characterization of release • 80% release or asymptote • Evaluate release with various conditions: agitation, media composition, pH, temp, etc… • Discrimination by process validation samples • Consistent perf
Slide 22: Apparatus 3 for Immediate Release
Apparatus 3 for Immediate Release FDA published the “Evaluation of USP Apparatus 3 for Dissolution Testing of Immediate Release Products. When Apparatus 3 is reciprocated at the extreme low end of the agitation range, such as 5 DPM, hydrodynamic conditions equivalent to Apparatus 2 at 50 rpm were ac
Slide 23: Apparatus 3 and Immediate Release - Metoprolol
Apparatus 3 and Immediate Release - Metoprolol USP 3 at 5 DPM appears equivalent with USP 2 at 50 RPM Evaluation of USP Appparatus 3 for Dissolution Testing of Immediate-Release Products Lawrence X. Yu, Jin T. Wang and Ajaz S. Hussain; US Food and Drug Administration, Office of Pharmaceutical Scienc
Slide 24: Apparatus 3 and Immediate Release - Ranitidine
Apparatus 3 and Immediate Release - Ranitidine Release profiles for 2 of 6 generic ranitidine products failed to pass f2 although they were all bioequivalent in vivo In this case, USP apparatus 2 seems over discriminating. Evaluation of USP Appparatus 3 for Dissolution Testing of Immediate-Release P
Slide 25: Apparatus 3 and Immediate Release
Apparatus 3 and Immediate Release Although this apparatus was developed for extended release products, App 3 may be used for testing IR products with high solubility. Apparatus 3 can produce similar dissolution profiles to Apparatus 2 paddle and certainly avoids the coning issues associated with the
Slide 26: Apparatus 3 with Beads for Better IVIVC
Apparatus 3 with Beads for Better IVIVC Case Study 1 A USP 3 Reciprocating Cylinder Apparatus was used for the testing of HPMC extended release matrix tablets. Traditional testing with Basket and Paddle apparatus provided low discrimination between various tablet formulations. Plastic beads were uti
Slide 27: Apparatus 3 with Beads for Better IVIVC
Apparatus 3 with Beads for Better IVIVC Case Study 1 The plastic beads were round synthetic polymeric material with a density of 1.1 g/cm3 and diameter of 8 mm. Glass beads, with a density of 2.5 g/cm3 were evaluated but they sank to the bottom of the cylinder and did not exert the desired mechanica
Slide 28: Apparatus 3 with Beads for Better IVIVC
Apparatus 3 with Beads for Better IVIVC Case Study 1 - Summary: The method was able to predict in vivo performance and enabled the development of a level A IVIVC. It was noted that high mechanical forces in vitro were necessary to provide a satisfactory correlation with in vivo data. The use of bead
Slide 29: Apparatus 3 with Beads for Chewable Tablets
Apparatus 3 with Beads for Chewable Tablets Beads Case Study 2 Workshops held by FIP and AAPS have outlined guidelines for the dissolution and drug release testing of novel dosage forms indicating that the reciprocating cylinder apparatus may be suitable for testing of chewable tablets. The addition
Slide 30: Apparatus 3 with Beads for Chewable Tablets
Apparatus 3 with Beads for Chewable Tablets Beads Case Study 2 1.5 mm Beads (left) 6.0 mm Beads (right) Confidentiality Label 30 May 18, 2015
Slide 31: Beads Case Study 2 - Summary
Apparatus 3 with Beads for Chewable Tablets Beads Case Study 2 – Summary Chewable tablets often contain highly soluble API but they are very difficult to disintegrate and eventually solubilize in traditional Apparatus 1 basket or Apparatus 2 Paddle due to the lack of mechanical shear. Chewable formu
Slide 32: Characterizing Drug Release at Specific Sites in the GI Tract
Apparatus 3 Characterizing Drug Release at Specific Sites in the GI Tract Studies were conducted on several Mesalazine products to evaluate the enteric coating properties of drugs for inflammatory Bowel disease (IBD). High concentrations of API are needed in the lower GI tract to treat chronic IBD.
Slide 33: Characterizing Drug Release at Specific Sites in the GI Tract
Apparatus 3 Characterizing Drug Release at Specific Sites in the GI Tract Tests were GI Segment Transit time Medium pH value conducted at 10 Simulated Gastric Fluid DPM with 220 mL of Stomach 120 min USP 24 sine pepsin 1.2 the various media (SGFsp) and transit times Duodenum 10 min Phosphate Buffer
Slide 34: Characterizing Drug Release at Specific Sites in the GI Tract
Apparatus 3 Characterizing Drug Release at Specific Sites in the GI Tract Dissolution behavior of different mesalazine dosage forms in Phosphate Buffer pH 7.2 Ph. Eur., expressed as mean + SD. Drug Release Characteristics of Different Mesalazine Products Using USP Apparatus 3 to Simulate Passage Thr
Slide 35: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK The Impact of Float-A-Lyzer (Spectrum Labs) Dialysis Membranes for the Dissolution of Particles • Naeema Jafar Malik, MPharm4 • Dr. Nikoletta Fotaki, Associate Professor, University of Bath, Department of Pharmacy and Pharmacology, School of Pharmacy, Bath, Uni
Slide 36: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK Project focused on the surrogate testing of paracetamol, ibuprofen and carbamazepine oral suspensions with the use of several Float-A-Lyzer (Spectrum Labs) membranes: • 0.1-0.5 kD • 0.5-1.0 kD • 3.5-5.0 kD to determine the feasibility of utilizing dialysis memb
Slide 37: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK Drug pKa Oral MW BCS MWCO Volume Wavelength [29] suspension Class membranes Size of (nm) strength flotalyzer required for testing absorbance of drug Paracetamol 9.86 120mg/5ml 151.17 III 0.1-0.5 kD 5ml 243 0.5-1.0 kD 3.5-5.0 kD Carbamazepine 13.94 100mg/5ml 236
Slide 38: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK Modifications were made to USP Apparatus 3 reciprocating cylinder. The Float-A-Lyzers were prepared • Rinsed and soaked surfaces 10-minutes with 10% ethanol to remove glycerin on the surface. • Rinsed and soaked in purified water for 15-20 min. • Add 2.5mL of t
Slide 39: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK USP Apparatus 3 – Modified Reciprocating Cylinder The device was placed on a modified shaft to fit in the apparatus. Each sample was reciprocated at 30 DPM (dips per minute) for typically 180 minutes and samples were taken at 30 minute intervals. Apparatus III
Slide 40: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK USP 1 vs. USP 3 Paracetamol suspension in 3.5-5.0 kD, Ibuprofen suspension in 3.5-5.0 kD dose 60mg (2.5mL) in phosphate dose 50mg (2.5mL) in phosphate buffer 6.8 buffer 6.8 40
Slide 41: Case Study #2 – University of Bath, UK
Case Study #2 – University of Bath, UK As expected, the release through the 90 membrane suppresses the 80 dissolution rate since the product 70 must first dissolve then diffuse through the membrane. 60 0.1-0.5 kD % Dissolved 50 Highest drug release was observed 0.5-1.0 kD with the largest MWCO membr
Slide 42: Summary
Summary The greatest value in developing effective dissolution and drug release methods with USP Apparatus 3 is not in the fulfillment of regulatory requirements, but in providing accurate, reliable data for decision making during drug development stages and assurance of quality when the product rea
Slide 43: References
References United States Pharmacopeia, Rockville, MD, USA European Pharmacopoeia 8.0; Methods of Analysis 2.9.3 Dissolution test for solid dosage forms; The European Directorate for the Quality of Medicines and HealthCare; 8th Edition, 2014 Agilent Bio-Dis III Testing Station Operators Manual and Se
Slide 44: Questions?
The Medfour| of Confidence
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