Question and Answer Section

William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph.D. and Will Brown, United States Phamacopeia, authored responses to each of the questions.
*Note: These are opinions and interpretations of the authors, and are not necessarily the official viewpoints of the USP
Email for correspondence: web@usp.org

Q Are there any pharmacopeial general procedures to evaluate the drug release of implantable devices?
A There are no pharmacopeial standard procedures for the drug release/dissolution testing of implantable devices.The drug release/dissolution test for this kind of product should be developed in a case–by–case approach,because you need to consider the device design,the drug load,the physico–chemical properties of the drug, the release mechanism, the duration of the release or treatment,the dose released,the characteristics of the site where the device will be implanted,etc. Some of the dissolution equipment that could be used for this kind of product are not even described in any pharmacopeia.You can find information regarding the drug release/dissolution tests for implantable devices in the Chemical Abstracts and also at www.NCBI.NLM.NIH.GOV (access free of charge).When developing a new implantable device, it is advisable to work directly with the regulatory authorities of the countries where this product is going to be marketed in the very early stages of the product development. Depending on its design and release mechanism,this kind of device may require a drug release/dissolution test with unusual conditions. From the beginning of your project, the regulatory authorities must be informed of the reasons for the selection of these test conditions. If the product is going to be marketed in the USA,it will be advisable to contact the FDA Office for Combination Products (www.fda.gov/oc combination). As far as we know,the only USP monograph for a product that could be considered an implantable device is the one for Pilocarpine Ocular system,page 1733 of USP 29. The drug release test in this monograph uses very unusual test conditions.

QDuring development of a dissolution test for a tablet containing a poorly soluble drug,very high percentages,well above 100%,of the drug release are being obtained.What could be the possible reasons for these results?
There are some possible reasons for having dissolution results well above 100% of the label claim.The interference of excipients or components of the dissolution medium on the quantitative step of the dissolution test must be evaluated. This evaluation is done by carrying out the dissolution test with the placebo and running the quantitative method to verify that the components of your formulation do not interfere with the quantitation of the drug dissolved.Also,you need to verify that the filter selected is the appropriate type. The filter needs to have a porosity that will retain all the suspended particulates in the medium to prevent attenuation of the signal leading to an overestimation of drug concentration.Most of the filters used in dissolution testing are in the range of 0.45 μm up to 70 μm,but because of the characteristics of the formulation,it may be necessary to use filters with smaller porosity.

Q What is sink condition? How is it performed on tablets and pooled samples? Which is the importance of the sink condition in the development of dissolution tests?
A Sink conditions describe a dissolution system that is sufficiently dilute so that the dissolution process is not impeded by approach to saturation of the compound of interest. Sink conditions affect the production of the sample but not the condition of the solution upon sampling.Thus,any concerns regarding the subsequent pooling of samples are unnecessary. The only physical measurement required is that of solubility at the test temperature. Once the solubility is known,the volume of medium or the acceptability of a particular medium can be determined.Typically,sink conditions are considered to exist if,at the dissolution of 100% of the highest strength of the product to be tested,a concentration of not more than ¹/₃ of saturation will be achieved.

Q Differences in the dissolution results were observed when using glass and plastic dissolution vessels.What should be the recommended procedure in a case like that?
A As part of the development of a dissolution test,you may want to verify what type of dissolution vessel is the most appropriate for your formulation. Depending on the characteristics of your formulation and the drug present in it,adsorption on the walls of the plastic vessel may occur.As a consequence,lower and very variable dissolution results can be obtained. If this kind of interference is observed,your dissolution method should specify what type of dissolution vessel should be used to run this particular test.You need to do the same kind of evaluation when using automated sampling,because most of the components of these systems are made of polymeric materials,and when doing manual sampling with plastic syringes. In addition,the filter needs to be evaluated with respect to adsorption of the drug and leachables. Finally,bear in mind that while plastic materials can often adsorb drug compounds,glass has also been shown to be active (D. K. Bempong,et al.Development of a Dissolution Method for Levothyroxine Sodium Tablets. Pharm.Forum 25 (1),1999).

Q It was observed that the quality of the surfactant used in the dissolution medium affects the results in the dissolution test.What should be done?
A The presence of related compounds and a low content of the surfactant can affect the amount of drug dissolved in the dissolution medium and can interfere with the quantitative step of the test. One of the surfactants that is well known for this kind of problem is sodium lauryl sulfate,mainly when the amount of drug released is measured by HPLC.The use of surfactants with high purity and high content can eliminate this problem.

Q If in a USP monograph,the quantitation of the amount of drug dissolved is by a UV method,can this method be replaced by an HPLC test?
A In the USP General Notices,page 7 of USP 29,it says that alternative methods can be used if they provide advantages in accuracy,sensitivity,precision,selectivity,or adaptability to automation or computerized systems.However,pharmacopeial standards and procedures are interrelated;therefore, where a difference appears or in the event of dispute,only the results obtained by the procedure given in the pharmacopeia are conclusive.
Editors Note:The following Question deals with ointments and creams. We consulted with a technical advisor that tests this dosage form regularly,Kailas Thakker,Ph.D.,who supplied the response. Her email address is kailas.thakker@asi-rtp.com.

Q I am working with Ointments and Creams.I just wanted to know is there any guidelines for Dissolution of Ointments,Gel and Creams.The Active Ingredient in my Topical preparations which I�m studying is not soluble in any aqueous media.It is freely soluble in THF or can be extracted from the matrix at higher temperature.Can THF be used as Dissolution medium? If YES,then what are the limitations.And secondly,can the temperature of the dissolution bath be raised higher than say 60°C for those topical formulations which leave the Active Ingredient on heating.
A For semisolids, the receiving medium composition can have up to significant amount of organic solvent but pure THF is probably a stretch. Buffers or solubilizing agent in aqueous phase with some proportion of organic solvent may be a better choice.Also,for semisolids,you don�t have to release more than 30% (less than 30% is OK too) of the active ingredient in the medium as long as the assay method is sensitive enough to detect the active ingredient.The temperature should have some biological relevance– 32 °C or 37 °C is commonly used.