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On June 13th and 14th, SOTAX Corporation hosted the 2nd Annual Workshop and Seminar on USP Apparatus 4 in Horsham, PA. This years meeting focused on industry applications as well as uses for IVIVC. Below is a short summary of the event.

On the first day, Dr Eric Beyssac, Professor of Pharmaceutics, University of Auvergne, Clermont-Ferrand, France presentation entitled “Establishing In Vitro and In Vivo Correlations for Modified Release Products” outlined the different parameters for in vitro and in vivo used to perform IVIVC, the rationale for the development of IVIVC, the development of IVIVC for a new formulation and the interest and limits in IVIVC. Examples were given with discussions on the importance of IVIVC to fix in vitro dissolution limits.

The workshop in the afternoon was also conducted by Dr Beyssac and focused on an introduction to the USP 4 method with hands on demonstration. His presentation “Application of USP 4 for API and specific drug dosage forms”  began with a brief introduction to dissolution testing and its goals for QC,  a development tool, validation of the formulation and importance of IVIVC. It was clear that under certain circumstances more than one type of apparatus is needed to evaluate all dosage forms. A review was given of the different cell types, open and closed loop configurations as well as comparison to USP 2. Dr Beyssac explained the difference between a laminar and turbulent flow and how to achieve those, thus minimizing hydrodynamics and controlling how the dosage form resides in the flow cell.  Examples were given of a poorly soluble compound in an open loop set up, using Nifedipine compared with the flow cell method. Another application of USP 4 provided solutions for multiparticulate dosage forms where USP 1 and USP 2 methods cause lower release for heavy pellets compared with lighter ones, formation of a heap of pellets within the stagnant zone under the paddle, and difficulty testing pH sensitive release pellets where a pH change is needed. Examples were also given for in vitro testing of suspensions using USP 4. Challenges for suspensions include limited solubility, uniform sample preparation and introduction, wettability, and minimizing variability during the experiment. Paddle methods tend to cause problems with homogeneity in the vessel, dispersion in the vessel with areas of high concentration or agglomeration. Using the flow cell, it was shown that samples can be easily introduced and weighed if necessary before the test, a reduction of variability, and a prevention of agglomeration using glass beads.
His work on dissolution testing of oily suspensions, emulsions, and soft gelatin capsules using the dual chambered flow cell solved sample preparation and introduction challenges compared with USP 2, as well as dealing with oils that tend to float in vessels. The last example given was using the implant cell where challenges such as limited volume, a simulation of in vivo conditions where a very slow flow is required, as well as a discussion of real time and accelerated testing. At the end of the workshop, a demonstration was given on how to load several commercially available samples into the variety of flow cells.

On the second day, a series of applications were presented by industry.

Michael Wang, Merck & Co., presented “Predicting in vivo Performance of BCS II/IV Compounds By Dissolution on USP 4 Apparatus”. In vitro dissolution for several compounds were conducted on USP 4 apparatus in biorelevant media to support their clinical formulation development. The results were successfully applied in the prediction of their in vivo performance i.e. in ranking formulations and food effect. In addition, the in vitro tests on USP 4 apparatus have been demonstrated an important tool in understanding the possible in vivo dissolution mechanism for the formulations. An IVIVR was established for a compound based on the dissolution and animal study results.

Dr Diane J. Burgess, Department of Pharmaceutical Sciences, University of Connecticut, USA presented “In Vitro and In Vivo Correlation of MR Parenterals: Use of USP Apparatus 4”
IVIVC issues are more challenging for MR parenterals compared to MR oral products and an important factor that is often overlooked is stability of the therapeutic agent in the release media. In vivo factors that influence release from MR parenterals can be: injection site specific; delivery system specific; and drug specific. Dr Burgess showed results of her work with microsphere, liposomes and dialysis bags.

Mel Merciadez , Cordis Corporation presented “A Novel Method for the Elution of Sirolimus in Drug Eluting Stents" A sensitive and robust method for the determination of elution of the active drug substance, Sirolimus, in drug eluting coronary stents was developed using a USP Apparatus 4 elution system. The closed loop configuration of the elution apparatus and the low volume of elution eluent allow the low drug levels that elute from a single stent to be reproducibly monitored. The USP apparatus profile over 24 hours mirrors the 30 day in-vivo porcine profile, providing an in vitro release method that captures the entire release profile of the stent. The method discriminates between common purposely-made manufacturing and formulation defects. The method employs an elution media which permitted fitting the in-vivo elution curve to the in-vivo porcine profile. The method has been accepted by FDA as a release method for the elution of Sirolimus in cardiovascular stents.
Dr Daniel Abran, Sandoz Inc presented “Experience with bioequivalence study of suspensions; relevance of dissolution data".  The dissolution behaviors of three suspensions were evaluated using the USP 4 apparatus. The impact of these studies on the formulation process as well as their relevance to bioequivalence studies was discussed. He concluded that the impact of particle size and dissolution parameters can be discriminated using the USP 4 method. The technique developed by Dr Abran and his team is used for submissions.

Eldomar Cabotage, Lilly, presented “Performance testing of a suspension dosage forms”. He discussed a challenging in vitro dissolution method development for a limited solubility product. Early development determined USP 2 to be inappropriate due to lack of sink conditions, sample introduction issues, paddle speeds, and a fast release. USP 4 was chosen to develop a real time test and a QC method. His method development on USP 4 was discussed.

Dr Eric Beyssac, University of Auvergne, presented “In vitro dissolution test of API as a quality control for drug dosage form development”.  He discussed the key parameters in drug dosage form development with emphasis on the importance of API and intermediate product characterization. Dr Beyssac presented traditional intrinsic methods and apparent dissolution using the powder flow cell.  Apparent dissolution rate can be determined with out the use of compaction of the drug using this technique. Other powder methods such as the sprinkle method or filling a capsule can be challenging. He showed that physicochemical parameters such as particle size and specific area with results were obtained using the powder flow cell.

Dr Hitoshi Masui, PharmEng Innovations presented "Flow-Through Dissolution Testing of Low Solubility Drugs: Effects of Near Saturation and Supersaturation." He observed deviations from expected dissolution behavior during flow-through dissolution tests due to near-saturation and supersaturation effects. These deviations were described and their origins were explained theoretically. The first case study involved 2 injectable suspensions where he showed examples of how to calculate sample size, the effect of sample sizes, flow rate and their effect on discrimination ability. He concluded that the dissolution rate is limited by saturation and flow rate for large sample sizes and that faster flow rates give better distinguishing abilities. However, smaller sample sizes give better distinguishing abilities but lower concentrations give a weaker analytical signal. In his second case study, he performed dissolution testing of an API. He developed a cup holder for the intrinsic device and put it into a standard 22.6 mm flow cell. He also performed this test using the powder flow cell. His results were discussed.

Stuart Ritchie, Eurand presented “Influence of Different HPMC Capsule Shells on the Dissolution of Immediate-Release and Extended-Release Formulations of Propranalol HCl” His presentation on the dissolution behaviors of four commercially available hydroxypropyl methylcellulose (HPMC) capsules were investigated in different physiologically relevant media by USP dissolution apparatus I and IV.  Dissolution differences among the capsules shall was discussed. He concluded that USP Apparatus 4 provided his work valuable complimentary information to standard USP 1 and 2 methods. 

Dr Lijuan Tang, Primera PharmaLab, presented  “Selection of  Bio-relevant Dissolution Media for Poorly Water-soluble Drugs” With the new rules from the FDA, ANDA submission now requires both fasted and fed bio-equivalence studies to obtain approval status.  It is always a challenge for formulators and analysts to develop a discriminatory and bio-relevant dissolution method suitable for evaluating a poorly water-soluble drug.  The case study discusses a selection of dissolution medium on three bio-enhanced formulations of a poorly water-soluble new chemical entity.  It will focus on the dissolution data interpretation and analysis; general practice on selecting different dissolution media; and In Vivo bioavailability data.

Marc Finn
National Sales and Marketing Manager
Correspondence to marc.finn@sotax.com
Presentation transcripts at sotaxusa@sotax.com

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