Dissolution Method Development for Immediate Release …

1 Dissolution Method Development for Immediate Release Solid Oral Dosage Forms Quick Start Guidelines for Early Phase Development Compounds . David Fortunato email: Johnson and Johnson Pharmaceutical Research and Development Spring House, PA. Introduction tion and analytical Method Development processes. I. n the Pharmaceutical Industry,as product devel- For example,does the label claim for the proposed opment continues to multiply at increasingly dosage strengths reflect free base or salt formula- faster rates, Dissolution Method Development tions? Quickest results are obtained when the Early must be able to keep pace with the increased Phase Development Teams are able to supply the number of products that are entering the pipeline. Dissolution Scientist with excipients,placebo granu- For many of these products,initial Dissolution lations and capsule shells.

2 methods and their corresponding assays must be developed as living processes which must be able Analytical Assay Development to adapt to change as the product changes. Even Preliminary analytical assay Development must be though many of these early formulations may not initiated prior to the assay of any samples. The Disso- survive to full Development ,the Dissolution Scientist lution Scientist must have some way of analyzing the must be assured that the data obtained from these samples. Since this is at the beginning of the Method initial methods is accurate. The Dissolution Scientist and assay Development processes,this work does may use the following techniques to develop both not require a lot of time. The initial assay parameters the Dissolution and assay methods when quick may be determined with drug substance dissolved in answers are required for initial formulations.

3 In this a Dissolution medium. Hopefully,the preliminary article, assay is defined,as an assay for Dissolution information received from the Early Phase Develop- use only,not an HPLC assay for impurities. ment Teams would include specific UV or HPLC assay Communication between the Dissolution Scien- parameters. If a UV assay,important parameters tist and the Early Phase Development Teams is would be wavelength of detection and cell path essential for the expedient Development of usable length. If an HPLC assay,important parameters would Dissolution and assay methods . The Early Phase be column type,mobile phase and Method of detec- Development Teams may be comprised of formula- tion. The Dissolution Scientist must understand that tors and the chemists who have developed the drug assay parameters and Dissolution medium may substance assay methods .

4 Any information supplied change as the formulations evolve. to the Dissolution Scientist prior to start of the work Generally,the simplest assay Method to develop greatly facilitates the Dissolution Method develop- utilizes UV/VIS Spectrophotometry. This assay ment process. Specific information about the drug Method may be used provided the API has a UV chro- substance solubility,drug substance stability as a mophore and no UV interference is observed with the function of pH,and BCS Classification will direct the proposed excipients and/or capsules shells used in Dissolution Scientist to the expedient selection of a the Dissolution Scientist may run a proper Dissolution medium. For example,the drug series of UV scans to determine the proper wave- substance may be highly soluble in N HCl,but length for the assay.

5 Generally,several scans are run was the solubility determined immediately or over a which include a blank of the Dissolution medium 24-hour period with constant sonication? The alone,a standard solution,and a placebo formulation dissolved drug substance may be stable over a 7-day dissolved in either the Dissolution medium or a stan- period,but was the solution stored at 4 C or at room dard solution. A UV assay may be used if the Dissolu- temperature? The details are important! Additional tion Scientist is able to choose a wavelength region information such as potential dosage strengths, where the excipients and/or capsule shell do not potential formulations,the type and range of excipi- absorb and a reasonable response is obtained from ents,the type (hard gelatin or soft gelatin) and sizes the API.

6 Once a wavelength has been chosen,the of capsule shells,reference standard information Dissolution Scientist must choose the most appro- including purity values,and any current analytical priate cell path length that covers a wide linear range. methodologies will allow the Dissolution Scientist to If no wavelength is available which meets these determine the direction of both the initial dissolu- criteria,then an HPLC assay must be developed. 12 Dissolution Technologies | AUGUST 2005. Communication with the Early Phase Development Early Phase Development Teams that are developing the Teams facilitates the Development of an HPLC assay. Hope- products have similar expectations for Dissolution methods . fully,information such as column type,mobile phase and The primary goal for both groups is the Development of a Method of detection may be obtained from preliminary discriminating Method ,which must be able to provide the assay Development with the drug substance.

7 Generally, ability to detect small changes in the formulation or manu- Dissolution HPLC assays are developed for one peak;conse- facturing processes. quently,shorter columns could be used to develop assays Discriminating Dissolution methods may be difficult to with 1 to 2 minute run times. A variety of detection methods develop for BCS Class 1 compounds. These compounds are may include UV,Refractive Index and Fluorescence. highly permeable and highly soluble. The Development of a Very often,the Early Phase Development Teams require discriminating Method and the determination of a Q Time quick answers,which will guide their next steps;conse- and Q Value are not limited by poor solubility. Several types quently,minimum analytical validation work is required for of Dissolution media may be used which will provide accept- very early,initial batches.

8 The Dissolution Scientist must be able results. Complete recovery of the API may be achieved assured the parameters are rugged enough to provide for a variety of formulations within 10 minutes with several confident answers for even the earliest of batches. Again, types of Dissolution media. the Dissolution Scientist must realize the assay parameters Discriminating Dissolution methods are the most difficult may change as the formulation evolves. More comprehen- to develop for BCS Class 4 compounds. These compounds sive assay validation may be completed once the final are poorly permeable and poorly soluble. The poor solu- formulations have been determined. Once a usable analyt- bility limits media selection,apparatus type and speed,Q. ical assay has been determined,the initial parameters for Time and Q Value selection.

9 Filtration and solution stability must be established prior to Once the initial Dissolution medium has been chosen the completion of any Dissolution samples. based upon the solubility and stability information of the Initially,the Dissolution Scientist must complete a drug substance,the Development of the Dissolution Method successful filtration experiment. The Dissolution Scientist may begin. The Dissolution apparatus and rotational speed must first determine the volume of filtrate that must be must be chosen. Generally,paddles at 50 RPM are used for discarded to obtain complete recovery of the API. Generally, tablets and baskets at 100 RPM are used for capsules. a different filter should be used if the discard volume exceeds However,this is only a starting point. Remember,the goal is 20 mL. The filtered samples should be obtained with sepa- to develop a discriminating Method .

10 If the Dissolution rate filters using a solution equivalent to 20% of the lowest proceeds too quickly,the Dissolution test may produce a dosage form dissolved in the volume of Dissolution medium profile that levels off too early to show discrimination proposed for the Dissolution Method . The filtered samples between the formulations. If the Dissolution proceeds too are compared against an unfiltered portion of the same solu- slowly,the Dissolution apparatus,rotational speed or disso- tion. The goal is to achieve to recovery of the lution medium may have to be changed to produce a API for a minimum of six replicate samples. Centrifugation discriminating Dissolution profile. For Immediate Release may be used if adequate recovery cannot be achieved. products,an ideal profile approaches 100% recovery of the The Dissolution Scientist must be assured the sample and API within 45 to 60 minutes.