Recent In Vitro Release Testing Activities, Including FDA and USP

The FDA, USP, and the dissolution testing community have been very active in providing increased guidance for tablet and capsule dissolution. The areas specifically include immediate-release dosage forms, disintegration, capsules, split tablets, discriminatory methods, and alcohol dose dumping. 

FDA guidances 

The FDA has recently issued a number of useful guidances¹. For example, the guidance, “Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments,” gives instructions for how to assess the effect on dissolution when the dosage forms are delivered in a vehicle such as apple sauce. The guidance, “Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation,” provides the way to compare dissolution results of split versus nonsplit tablets. The guidance, “Quality Attribute Considerations for Chewable Tablets,” provides instructions for developing a dissolution testing method for chewable tablets. 

While the FDA guidances, “Drug Products, Including Biological Products, that Contain Nanomaterials” and “Liposome Drug Products” are not particularly helpful in providing suggestions for in vitro testing methods for nanomaterials and liposomes, they do give some pertinent information on these dosage forms. 

A summary of recent guidances would not be complete without a reference to the finalized guidance, “Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances.” This important guidance for highly soluble immediate- release dosage forms gives 0.1 N HCL, paddle at 50 rpm (or basket at 100 rpm), 500 milliliters as the prescribed conditions and sets the specification at 80 percent in 30 minutes. It also states that showing discriminatory power is not necessary for these fast-dissolving dosage forms. 

USP 

USP has provided in vitro testing methods for dosage forms other than conventional tablets and capsules in a proposed new chapter, <1711> “Oral Solid Dosage Forms—Dissolution Testing.” The dosage forms discussed in the chapter include effervescent tablets, chewable tablets, sublingual tablets, orally disintegrating tablets, gastroretentive tablets, granules or pellets administered with food or beverages, and lozenges. Another proposed chapter, <1236> “Solubility Measurements,” provides instructions on how to determine the solubility of drug substances and the composition of biorelevant media. The USP general chapter <701> “Disintegration” has revision proposals that combine and add dosage form testing procedures. 

USP has also proposed two new monographs for capsule shells: hard gelatin capsule shells and hard hypromellose capsule shells. These monographs have storage conditions and other tests worth examining. These chapters and monograph proposals are available for viewing and comment for free at usppf.com. 

By now, everyone involved with dissolution testing should know about papain and bromelain, the two additional enzymes (along with pepsin and pancreatin) that can be used in the media when testing crosslinked capsules. The activity of these enzymes is important. Bromelain is listed as a reagent in the reagent specification section in USP, and its activity determination can be found within that description. For papain, there is a monograph, which includes a casein digestive power test. 

USP is updating the premier resource for method development and validation for conventional dosage forms: <1092> “USP General Informational Dissolution Procedure: Development and Validation.” The USP general informational chapter <1088> “In Vitro and In Vivo Evaluation of Dosage Form” is also going through an update. 

Other publications 

Members of the AAPS in vitro release and dissolution testing community have published informative and interesting papers on alcohol dose dumping (DOI: 10.1186/s41120- 017-0014-9), strategy to developing discriminatory methods (DOI: 10.1208/s12249-018-1197-7), and a review article on USP Apparatus 2 performance verification testing (DOI: 10.14227/DT260119P6). The August 2018 issue of Dissolution Technologies was a special edition of review articles that included the topics of in vivo and in vitro correlations (DOI: 10.14227/DT250318P20), disintegration (DOI: 10.14227/DT250318P30), and fiber optics (DOI: 10.14227/ DT250318P70). 

Reference 

1. https://www.fda.gov/drugs/ guidancecomplianceregulatoryinformation/ guidances/default.htm.