A Review of the 2nd Annual USP 4 Workshop and Seminar

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

On the first day, in a presentation entitled “Establishing In Vitro and In Vivo Correlations for Modified Release Products,” Dr Eric Beyssac, Professor of Pharmaceutics, University of Auvergne, Clermont-Ferrand, France, outlined the different in vitro and in vivo parameters 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 for establishing in vitro dissolution limits

The afternoon workshop, also conducted by Dr Beyssac, 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 as a development tool, formulation validation, and the 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, and a comparison to USP 2. Dr Beyssac explained the difference between laminar and turbulent flow and how to achieve them in order to minimize hydrodynamics and control how the dosage form resides in the flow cell. A comparison between an open-loop setup and the flow-cell method was given using a poorly soluble compound, nifedipine, as an example. In another example, USP 4 provided solutions for multiparticulate dosage forms where USP 1 and USP 2 methods caused lower release for heavy pellets compared with lighter ones, formation of a mound of pellets within the stagnant zone under the paddle, and difficulty testing pH-sensitive release pellets when a pH change is needed. Examples were also given for in vitro testing of suspensions using USP 4. Challenges for suspensions include limited solubility, sample preparation and introduction, wettability, and variability during the experiment. Paddle methods tend to cause homogeneity problems 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, reducing variability, and agglomeration can be prevented using glass beads. His work on dissolution testing of oily suspensions, emulsions, and soft gelatin capsules using the dual chambered flow cell solved USP 2 sample preparation and introduction challenges, and dealing with oils that tend to float in vessels. The last example discussed was the implant cell with challenges such as limited volume, a simulation of in vivo conditions when a very slow flow is required, and 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 was presented by industry representatives.

Michael Wang, Merck & Co., presented “Predicting In Vivo Performance of BCS II/IV Compounds By Dissolution on USP Apparatus 4.” In vitro dissolution for several compounds was conducted using USP Apparatus 4 in biorelevant media to support clinical formulation development. The results were successfully applied in the prediction of in vivo performance (i.e., ranking formulations and food effect). In addition, it was demonstrated that in vitro tests on USP Apparatus 4 are 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, 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 specific to injection site, delivery system, and drug. Dr Burgess showed results of her work with microspheres, 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 eluent volume allow reproducible monitoring of low drug levels that elute from a single stent. 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 medium that permits fitting the in vivo elution curve to the in vivo porcine profile. The FDA has accepted this 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 behavior of three suspensions was evaluated using USP Apparatus 4. The impact of these studies on the formulation process and their relevance to bioequivalence studies were 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 Form.” 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 for the development of 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. Using this technique, apparent dissolution rate can be determined without the use of drug compaction. Other powder methods such as the sprinkle method or capsule filling can be challenging. He showed physicochemical parameters such as particle size and specific area results that 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. In the first case study, which involved two injectable suspensions, he showed examples of sample size calculation, the effect of sample size and flow rate, and the effect on discrimination ability. He concluded that the dissolution rate is limited by saturation and flow rate for large sample sizes, and faster flow rates give better distinguishing abilities. Although smaller sample sizes give better distinguishing abilities, 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.” The dissolution behaviors of four commercially available hydroxypropyl methylcellulose (HPMC) capsules were investigated in different physiologically relevant media by USP dissolution Apparatus 1 and 4. Dissolution differences among the capsules shells were discussed. He concluded that USP Apparatus 4 provided valuable complementary information to standard USP 1 and 2 methods.

Dr Lijuan Tang, Primera PharmaLab, presented “Selection of Biorelevant Dissolution Media for Poorly Water-Soluble Drugs.” New FDA rules for ANDA submissions require both fasted and fed bioequivalence studies to obtain approval status. It is always a challenge for formulators and analysts to develop a discriminatory and biorelevant dissolution method suitable for evaluating a poorly water-soluble drug. The case study discusses a selection of dissolution media for three bioenhanced formulations of a poorly water-soluble new chemical entity. It focuses on the dissolution data interpretation and analysis; general practice on selecting different dissolution media; and in vivo bioavailability data.

For presentation transcripts go to sotaxusa@sotax.com

SOTAX Corporation (Horsham, PA, USA), SOTAX (Canada) Ltd. (Brampton, ON, Canada), SOTAX AG (Basel, Switzerland), and SOTAX China (Shanghai, China), the worldwide market leader in USP Apparatus 4 Flow- Through Dissolution, has released the new and improved CE 7smart USP 4 Apparatus with a micro-volume autosampler.

In recent years, the Flow-Through Dissolution method has been submitted for a variety of products including drug-eluting stents, implants, suppositories, MR tablets, and a number of injectable suspensions.

As a result of the commitment to our existing customers in the medical device industry as well as our customers performing small-volume dissolution, SOTAX has engineered a new automated sampling solution to increase performance, productivity, and ease of use for the R&D and QC labs. Using a minimum volume of 5 mL in a closed-loop setup, the upgraded apparatus can now be controlled via firmware, eliminating the need for software control, further improving the ease of use and transition from R&D to QC. Methods with sampling times as well as a temperature printout can be programmed with the touch screen of the CE 7smart. Further improvements have been made internally to improve robustness for use with solvents and to minimize tubing volumes for smaller volumes. New cell types include optional glass for 12- and 22.6-mm flow cells as well as a variety of custom manufactured cells and holding devices.

Our new small-volume autosampler can accurately sample up to 29 points as low as 150 �L into capped HPLC vials. A syringe module withdraws samples from the closed-loop media reservoirs with extreme accuracy. Special attention was also taken to prevent carryover with a rinse and blow-out function. Studies have shown comparable data between manual and automated sampling. Withdrawn samples can also be cooled with an optional Peltier cooling rack if drug degradation is an issue.

To further increase productivity in the QC lab, a single system can be easily converted into a double system allowing for simultaneous testing of up to 14 samples.

These improvements add to the many advantages and flexibility of USP 4 testing and provide discriminatory and reproducible results that are easily validated and automated for a robust and rugged QC method.

If you are interested in feasibility studies or development assistance with USP 4 testing, please contact our new development lab at contact@sps-pharma.com or visit us at www.sps-pharma.com.

Cary, North Carolina, USA

Varian, Inc., introduced the new Fiber Optic UV Dissolution System at the 34th Annual Meeting & Exposition of the Controlled Release Society held July 7-11, 2007, at the Long Beach Convention Center in Long Beach, California.