Dissolution is an ever-evolving test with the development of novel dosage forms and increased quality expectations from regulators. There are many “hot topics” in dissolution testing, but probably the most pressing is the need for clinically relevant dissolution specifications and the methodology needed to achieve this goal. Other hot topics are in vitro release methods for the many special dosage forms; USP initiatives and general chapters on items such as semi solid dosage forms, gelatin capsules, two-tier testing with enzyme addition to media, chewable tablets, validation and method development; and the Apparatus 1 and 2 performance verification test.
Clinically Relevant Methods and Specifications
The regulatory agencies typically ask sponsors to support the discriminatory ability of their selected methods. This request is guided by suggestions to compare dissolution profiles of formulations that are intentionally manufactured with meaningful variations of the most relevant critical manufacturing parameters (e.g., ±10–20% change to the ranges of these parameters). The emphasis is now on method development that uses design of experiments (DOE) to establish the critical factors that influence the dissolution rate. The DOE can analyze the dissolution parameters (e.g., media concentration, speed, and deaeration) or the product attributes (e.g., excipient ratios, particle size, compression). The ultimate goal is to understand release mechanisms and determine if the dissolution method can show change in the critical quality attributes. Laboratories are putting more resources into method development and establishment of an in vitro–in vivo correlation/relationship.
Developing methods without excessive variability is a necessity to set a specification that is not so tight that lots will be rejected, especially those on stability, possibility creating a recall situation. The goal should be to set a specification that separates the bioequivalent and bioinequivalent batches. The FDA no longer accepts specification limits set at ±3 standard deviations and stipulates that variability is no longer a consideration in setting dissolution specifications (1). Variability with extended-release products can be especially troublesome as the practice of trying to include all the values within a certain specification window may lead to specifications greater than the ±10% stated in the FDA guidance (2). The challenge is to develop methods with only moderate variability. One way to determine causes of variability is to observe the dissolution of the product in the vessel. Many causes of variability (e.g., coning, sticking tablets, pellicles, erosion patterns, disintegration characteristics of both immediate- and extended-release products, and dosage form position) can easily be seen. In addition, all six vessels should be observed to see the uniformity of the dissolution pattern among all the dosage units tested. Understanding whether the cause of variability is from the actual dissolution method, which often can be discerned by observation, or from a formulation or manufacturing issue is an ongoing challenge.
The choice of dissolution medium is critical to developing a dissolution method that is indicative of the release mechanism. A medium that is similar to the environment at the site of absorption, sometimes called “targeted medium” (3) or “biorelevant medium” is best. For those products containing drugs other than Biopharmaceutics Classification System (BCS) Class 1 (4) that dissolve in 15 min, the method should show a gradual profile. There should be at least two points below 85% dissolved. This will assure that an f2 analysis can be applied to the comparison of different batches or products. The use of a surfactant needed to solubilize the product should be justified by showing the chosen surfactant concentration is not much higher than that needed for sink conditions and does not give a rapid dissolution (e.g., greater than 80% in 15 min). The very important point of the dissolution method goes back to the earlier statement on developing a discriminating method.
In Vitro Release Testing for Special Dosage Forms
There has been a rapid evolution of dissolution testing methods for emerging special dosage forms. Numerous interesting dosage form platforms have been introduced in the last 15 years. The quality of all of these dosage forms, other than solutions, would be easily measured if a discriminating in vitro release test were in place. The quest for in vitro release tests has been the subject of workshops and publications. A position paper written by the FIP Dissolution Working Group (5) summarizes the most up-to-date information on in vitro release testing. The method development goals and media choices are not too different from those of conventional dosage forms, but the apparatus selection is more challenging due to the unique nature of the special dosage forms. However, the apparatus used for these dosage forms are still typically USP Apparatus 1 and 2. In the case of orally disintegrating tablets (ODT), disintegration testing may also be suitable. Apparatus 4 has utility for a number dosage form types, for example, stents, implants, nanoparticles, ophthalmics, suppositories, and liquid-filled capsules. Apparatus 3 may be used for beaded products, liquid-filled capsules, and chewable tablets. Modifications of Apparatus 7 have also been useful for implants and stents. The vertical diffusion cell is commonly used with semisolids, plus another option is the ointment cell, also known as the enhancer cell. For microparticulate parenterals, dialysis sac methods show utility. For chewing gums and chewable tablets, a chewing gum apparatus based on the design published in Pharm Europa April 2008 is a possibility. This instrument will be the subject of a USP collaborative study in the near future.
Initiatives by USP
At USP, the former Biopharmaceutics Expert Committee has now become part of the newly named General Chapters–Pharmaceutical Dosage Forms USP Expert Committee for the 2010–2015 revision cycle. The members are J. DeMuth (Chair), D. Aldrich, D. Long, M. Gonzalez, V. Gray, A. Parr, P. Curry, M. Hussain, R. Heasley, J. Kraemer, T. Tice, A. Hickey, R. Elliott, J. Suggett, R. Skwierczynski, J. Shabushnig, M. Houghton, W. Lambert, J. Mitchell, G. Poochikian, B. Nickerson, K. Thakker, M. Yazdanian, S. Varia, and G. Radebaugh.
USP is holding a workshop on June 11–12, 2012 on the issues and general chapters mentioned in the following discussion.
General Chapter <1094> Dissolution Procedure: Liquid-Filled Capsules.
This general chapter proposal was published in Pharmacopeial Forum Volume 38, Number 1 (2012). [Note: Pharmacopeial Forum is now available free online; register on the USP website, www.usp.org.] This new general chapter covers all types of liquid-filled capsules, including dietary supplements. The fill type can be a liquid or dispersion. The content of the chapter includes method development aspects (e.g., surfactants, sink conditions, cross-linking, enzymes, apparatus, and sampling). Validation, QbD concepts, and the rupture test are discussed.
General Chapter <711> Dissolution
Two categories of revisions are considered for this chapter. There are many analytical issues related to the two-tier test in General Chapter <711> that need attention. In this test, enzyme is added to the existing dissolution medium when dissolution failures occur with gelatin formulations (hard and soft gelatin capsules and gelatin-coated tablets). A large USP Expert Panel on Use of Enzymes has been discussing the many analytical questions and problems associated with the two-tier test. Some of these issues are associated with enzyme use. Enzymes denature the cross-linked gelatin and are critical to the test. Enzyme activity occurs at an optimal pH, and in some cases, the pH of the method medium is not at this optimal level. The search is on for an enzyme that is active at pH 4-6.8. The enzyme activity must be determined before use because the activity can influence the ability to denature the gelatin cross-linking. The method to determine the activity needs to be examined and harmonized. In addition, enzyme concentration can influence the performance, and severely cross-linked gelatin may require a higher enzyme concentration than that listed in <711>. There is also the problem of surfactant media that denature the enzyme making it useless to act on the cross-linked gelatin. One approach that can be used is to presoak the product with the enzyme before adding the surfactant, but detailed validation of this method is necessary. A stimuli article related to these analytical issues will be published after feedback from the Workshop mentioned above is provided.
The other category of revision to <711> is an effort to revise or add to the tolerances under the Apparatus section, mainly with USP Apparatus 1 and 2. The effort may include some measure of harmonizing with instructions of the ASTM document E 2503-07, Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus and the USP toolkit (www.usp.org). Topics such as vessels, vibration, wobble measurements, centering, sinkers, deaeration, and baskets are under review.
Another initiative pertinent to <711> is the new acceptance criteria of the performance verification test (PVT) for Apparatus 1 and 2 that were adapted in 2010. The new acceptance criteria include a geometric mean and standard deviation. There is a “single-stage” test consisting of two consecutive runs of six (or eight, depending on apparatus configuration) and a “two-stage” test in which one run is evaluated, and if it does not pass the criteria, another run is performed. The USP website has a calculation tool that analysts can use to evaluate if a PVT test passes or fails (http://www.usp.org/ USPNF/compendialTools.html). The valid use of the PVT requires the choice of one- or two-stage testing before beginning the test. The use of this compendial tool/worksheet is not valid if the choice of one- or two-stage testing is made after examining the data. The PVT is valuable to show the analyst if the equipment is properly operational. The PVT is always preceded with a mechanical calibration.The USP website toolkit is a very comprehensive source for information on mechanical calibration.
The major sources of dissolution equipment variability continue to be vibration, vessels, and deaeration. A detailed discussion of the performance test and industry trends on the use of enhanced mechanical calibration and PVT with the USP Prednisone Tablets is found in the May, 2011 Special Edition of Dissolution Technologies. A webinar on PVT was presented in November 2010 and is available at the USP website, http://www.usp.org/education/pe/courses.html. The webinar is based on questions received by USP staff about the new procedure and criteria for the PVT.
General Chapter <1092>: Method Development and Validation
This general chapter is undergoing a major reorganization and update. The updated topics include an additional section on automation, a special review of data handling, more details on method development (especially media selection), and an in-depth discussion of deaeration. More information on the use of USP Apparatus 3 and 4 will be included.
General Chapter <1088> In Vitro and In Vivo Evaluation of Dosage Forms
This chapter has been updated, and the revision can be seen in PF 37 (5). The revisions include a case study and comments regarding the possibility of an IVIVC with an immediate-release BCS Class 2 dosage form.
Other USP Initiatives
The performance tests for topicals and semisolids will be covered in the new General Chapter <1724> Topicals and Semisolids. USP is considering new chapters that deal with method development for other oral dosage forms such as ODT, buccal, and suspensions. Functional tablet splitting may be the topic of a new general chapter. Some minor revisions are planned for General ChapterApparent Intrinsic Dissolution. The General ChapterDisintegration and Dissolution of Dietary Supplements has been revised to include a dissolution test for folic acid that uses Apparatus 3. Dissolution testing continues to present challenges. The practitioners of dissolution testing are proactive by disseminating knowledge and guidance in workshops, programs, literature, and webinars. The AAPS in vitro Release and Dissolution Testing Focus Group, the AAPS Bioequivalence Focus Group, and the AAPS QbD and Product Performance Focus Group are very active in this endeavor. Analysts are encouraged to keep their knowledge up to date and gather information to stay in tune with the increased regulatory expectations for meaningful and accurate dissolution tests.
References
- Marroum, P. 2012. Clinically Relevant Dissolution Methods and Specifications. American Pharmaceutical Review 15(1): 36–41.
- Guidance for Industry: Extended Release Solid Oral Dosage Forms: Development, Evolution, and Application of In Vitro/In Vivo Correlations, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), U.S. Government Printing Office: Washington, DC, September 1997.
- Marques, M et al. 2011. Simulated Biological Fluids with Possible Application in Dissolution Testing. Dissolution Technologies 18(3):15–28.
- FDA Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), U.S. Government Printing Office: Washington, DC, 1999.
- Brown, C. et al. 2011. FIP/AAPS Joint Workshop Report: Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms. Dissolution Technologies 18(4): 51–64.
Author Biography
Vivian A. Gray has experience in all aspects of dissolution testing. Her consulting company is V. A. Gray Consulting, Inc., www.vagrayconsulting.net. Vivian is also Managing Director of Dissolution Technologies, www.dissolutiontech.com. She co-authored a book titled “Handbook of Dissolution Testing”, Third Edition.