Institute for International Research

In order to assure that a potential high variability in the dissolution results is not due to malfunction of the dissolution tester used, the dissolution equipment has to be properly qualified. The USP Prednisone Tablets RS are suitable for the performance verification of apparatus 1 (basket) and 2 (paddle) dissolution equipments. Experiments performed in the USP laboratory show that the Prednisone Tablets RS are sensitive to some of the dissolution equipment variables. Thus the results support the suitability of the Prednisone Tablets RS for performance verification test of apparatus 1 and apparatus 2 dissolution equipment.

• What are the dissolution equipment parameters which may contribute to the high variability in dissolution results?
• How USP Prednisone Tablets RS indicate a not "well controlled" dissolution equipment?
• What are the USP standards for performance verification test?

Dissolution testing has a unique and very important place in the quality by design approach to drug development. Dissolution is one of the critical quality attribute that scientist rely on evaluate the performance of the product. Hence the dissolution method has to be really robust early on in the drug development process. Dissolution method evolves with the transition of drug development through different phases of clinical development. Once the drug is approved dissolution method becomes a QC tool. Sometimes it's appropriate to develop a QC friendly method after the drug is approved. This presentation will evaluate the challenges to developing robust dissolution method from drug development to commercialization.

Stephen P. Mayock, Senior Manager, CATALENT PHARMA SOLUTIONS

ICH Q6A mentiones in its Decision Tree #7 the possibilty to waive dissolution in favor of disintegration if a relationship has been established. The classical correlation may be difficult because disintegration describes the completeness of a process in the domain of time whereas the kinetics of dissolution is mainly reduced to an certain degree after a given time. These are non analogous parameters. A different approach on the base of analyzing the process of dissolution and subdividing it into different steps will be presented. As known from pharmacokinetics the identification of the rate limiting step is pivotal.

• What is the difference between disintegration and dissolution testing?
• In which cases a substitution may be possible
• What should be considered for a sound substitution?

The dissolution systems for non-oral dose forms are relatively new and not well studied. While the science is the same, system differences require different approaches. Implants and stents are becoming more popular as alternative dose forms. Injectables and suppositories have different dissolution requirements and tests than conventional dose forms. This session explores various methods and theories for dissolution for non-oral dose forms.

• Background brief literature review.
• Advances in technology and dissolution science for these systems. Discussion of how new dissolution technologies will be required.
• Academic and pragmatic points will be presented and discussed.

In the early formulation dosage form development phase, understanding dissolution mechanism through understanding the intrinsic property of the API is an important effort for formulation dosage form and dissolution method development. Without establishing a dissolution method, biological relevant media can be chosen for various testing for API and dissolution. Information obtained in conjunction with animal data provides insight for decision making and risk management.

• Understand dissolution mechanism by understanding API intrinsic properties
• Decision for choosing critical drug substance physical properties for dosage form development. e.g., particle size, morphology, and polymorphs
• Impact of API property on dissolution method development
• How to use biological relevant media as a tool for risk management for formulation development

The control of convective diffusion properties through hydrodynamics is emerging as a critical, and perhaps the key factor in obtaining appropriately responsive, relevant and reliable dissolution measurements. Applicable to all types of dissolution measurements, this is especially relevant to flow-through techniques, producing a vast improvement in dissolution measurements. This session will focus on better understanding and controlling these factors along with the resulting advantages. The utility of a fully automated high-performance system will also be discussed relating to improved physicochemical and biological properties, formulation sensitivity, mathematical modeling and in vivo correlation. The following will be discussed:

• Understanding the role of convective diffusion and hydrodynamics
• Comparisons between radial and linear flow systems
• Optimization and modeling opportunities
• A fully automated high-performance system approach
• Improved in vivo / in vitro relationships and correlations

The concept of small volume dissolution arises from the need to analytically determine the rate of dissolution from low dose, generally high potency drugs. Novel drug delivery design, combinatorial products such as drug eluting stents (DES) and other implanted devices have demanded more from typical official dissolution and drug release apparatus. To maintain quantitative levels of analyte during the dissolution test, a reduction in vessel volume accompanied by an alteration of compendial dissolution apparatus may be required. The need to develop small volume dissolution apparatus stems from the need to provide accurate, reliable data for decision making during drug development stages and assurance of quality when the formulation reached full-scale production and to maintain future assurance of product quality and stability. This topic will explore the use of typical compendial USP apparatus, non-compendial modifications to the standard USP apparatus and non-USP apparatus designed to yield small volume dissolution methods with reliable results. In addition to the discussion regarding small volume apparatus, related issues concerning the apparatus calibration, method development and method validation of the modified dissolution apparatus will be reviewed.

G. Bryan Crist, Scientific Affairs Manager, VARIAN, INC.

As part of their ongoing Research & Development program in support of their healthcare products and technologies, Rohm and Haas has developed improved dissolution testing technology. This GI dissolution approach to dissolution testing incorporates gastric disintegration, solids transfer, gastric and intestinal dissolution, changing pH/composition of fluids, absorption, and clearance. It is capable of giving excellent Level A IVIVC and appears to be predictive across different dosage forms of the same drug. No mathematical model is needed to interpret the results. The data from the equipment is directly comparable to blood plasma concentration-time profiles. The technology holds great promise for demonstrating bio-equivalence and supporting SUPAC studies.

Lyn Hughes, PhD, Senior Scientist, Process Solutions, ROHM AND HAAS RESEARCH LABORATORIES