DRAFT NOTES ON THE CONDUCT OF SOLUBILITY STUDIES

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1 August 2017 Draft working document for comment DRAFT NOTES ON THE CONDUCT OF SOLUBILITY STUDIES (August 2017) DRAFT FOR COMMENT Should you have any comments on the attached text, please send these to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, World Health Organization, 1211 Geneva 27, Switzerland; kopps@who.int; fax: (+41 22) ; and to Mrs Xenia Finnerty (finnertyk@who.int), by 8 October Working documents are sent out electronically and they will also be placed on the Medicines website for comment. If you do not already receive directly our draft guidelines please let us have your address (to bonnyw@who.int) and we will add it to our electronic mailing list World Health Organization 2017 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. Please send any request for permission to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) ; kopps@who.int. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

2 page SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/17.699: DRAFT NOTES ON THE CONDUCT OF SOLUBILITY STUDIES 32 Development of the proposal for conduct of solubility studies by Dr John Gordon in connection with the Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms Proposal discussed with experts from national quality control laboratories and specialists in assessing bioequivalence data Proposal discussed during Joint meeting on regulatory guidance for multisource products with regulators, the Medicines Quality Assurance Group and the Prequalification of Medicines Team - Assessment Group, and Regulatory Systems Strengthening held in Copenhagen, Denmark Revision of text including feedback received Mailing and posting of the working document on the WHO website for public consultation Compilation of comments received Presentation to fifty-second meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Further follow-up action as required March 2017 April June July 2017 August 2017 September 2017 October October

3 page 3 45 DRAFT NOTES ON THE CONDUCT OF SOLUBILITY STUDIES The objective of this document is to provide some guidance on the design and conduct of solubility studies undertaken for the purpose of active pharmaceutical ingredient (API) classification within the Biopharmaceutics Classification System (BCS). This document draws on information from the following sources: Equilibrium solubility experiments for the purpose of classification of active pharmaceutical ingredients according to the Biopharmaceutics Classification System (1). Appendix 2 of the Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO TRS1003, Annex 6, Appendix 2); Determinação da Solubilidade Aplicada à Bioisenção de acordo com o Sistema de Classificação Biofarmacêutica. Farmacopeia Brasileira (2016) (2). A study protocol should be developed for each solubility study before it is undertaken in order to specify the details for that specific experiment. In general, equilibrium solubility experiments should be employed. However, in exceptional cases where the API is not available in sufficient quantities or it is prohibitively expensive, experiments where the highest therapeutic single dose (consult with the World Health Organization (WHO)) is examined in a 250 ml volume, or a proportionally smaller amount examined in a proportionally smaller volume of buffer can be considered. As these are equilibrium solubility experiments, small volumes of solubility media (e.g. 50 ml) may be employed without issue if the available experimental apparatus will permit it. Characterization of the solid API used in the solubility may be necessary. The depth of the characterization will depend on the existing knowledge of the solid-state properties of the API in question. For example, if it has been established that the API exists as a single polymorphic form then less solid-state characterization is necessary. Experimental considerations The shake flask method for solubility determination is recommended so a mechanical (orbital) shaker should be employed. The shaker should be capable of maintaining a temperature of 37 ± 1 C and a stirring speed between 50 and 150 rpm. A shaker speed of approximately 60 rpm is suggested; however, the shaking speed should be optimized based on the shape of the flask and volume of the liquid in order to prevent particle agglomeration and ensure particle contact with the diluent. Optimally vortex formation should be avoided. With an optimized agitation rate, it is expected that samples will generally reach equilibrium quickly, often within 24 hours (3). Successful agitation of poorly soluble APIs may require the experimental method to address issues such as poor wettability and the tendency of the API to float on the surface of the solubility medium. In such cases, it may be necessary to include tools such as glass microspheres to aid in the

4 page de-aggregation of the particles with agitation or sonication (3). Once wetting is successfully achieved, the solubility experiment should proceed toward equilibrium. The ph-solubility profile of the API should be determined over the ph range of Measurements should be made in triplicate under at least three ph conditions, ph 1.2, 4.5 and 6.8 using, for example, 0.1 M HCl solution or simulated gastric fluid without enzymes ph 1.2, acetate buffer ph 4.5 and ph 6.8 phosphate buffer solution. If there are any known solubility minima in aqueous media within that ph range, data should be collected at that ph. Pharmacopoeial buffer solutions are recommended for use in solubility experiments. The ph should be verified after addition of the API and at the end of the experiment with a calibrated ph meter. If the ph of the buffer changes upon addition of the solute, adjustment of the ph with an appropriate acid or base solution may be sufficient to address the issue, or a buffer with a stronger buffering capacity may be required. A general chapter on equilibrium solubility measurements has just been adopted for inclusion in the Brazilian Pharmacopoeia. This chapter recommends preliminary testing to assess the amount of API required and the length of time required for the experiment. The chapter makes the following recommendations for preliminary experiments: based on API solubility data available in the literature, weigh an excess of at least 10% by mass and transfer to an erlenmeyer containing adequate volume of buffer solutions ph 1.2, 4.5 and 6.8. Check for the presence of undissolved solid. In the case of absence of solubility data in literature, weigh enough to verify the presence of undissolved solid; homogenize and measure the ph value; cap the erlenmeyer and adapt it to the orbital shaker (temperature of 37.0 ± 1.0 C; stirring speed between 50 and 150 rpm); samples should be collected over time to establish a plateau for the amount of solute dissolved and also to monitor stability of the API at each ph; when removing aliquots and replacing the solution, the sum of the collected volumes should not exceed 10% of the total medium; filter the samples during collection (filter on end of probe or inline); quantify the API using a validated analytical method; measure the ph value of the buffer solutions after establishing the time to obtain equilibrium Subsequent to the preliminary experiment described above, the chapter makes the following recommendations for the pivotal solubility experiments: in triplicate, for each ph condition to be evaluated, weigh approximately a 10% excess amount of API (as determined during the preliminary test) and transfer to an erlenmeyer containing adequate volume of ph 1.2, 4.5 and 6.8 buffer solutions; homogenize and measure the ph value. Withdraw an aliquot and quantify the API; secure the erlenmeyers to the orbital shaker with controlled temperature and shaker speed;

5 page collect an aliquot of the supernatant solution at the time equilibrium was established in the preliminary experiment; filter the sample during collection; record the ph value of the solution at the end of the experiment; quantify the API. A validated, stability-indicating analytical method should be employed for solubility determination of APIs, e.g. high-performance liquid chromatographic (HPLC) analysis (see chapter Highperformance liquid chromatography in The International Pharmacopoeia (4)) or an alternative, validated stability-indicating assay. An advantage of an HPLC method over a spectrophotometric method is that the HPLC method can also be employed to detect impurities and instability (3). Determine the solubility in mg/ml. Calculate the relative standard deviation (RSD) between the obtained solubility results. The RSD results should be no more than 10% between the replicates of each test condition. Based on the solubility calculated in mg/ml, a dose solubility volume (DSV) can be calculated to determine the volume of liquid necessary to completely dissolve the highest single therapeutic dose of the API (in mg) at the ph of lowest solubility. A study report should be created after the experiment detailing the actual experimental conditions, results (raw data plus mean values with standard deviations) and any observations such as, for example, the degradation of an API due to ph or buffer composition. The section describing the experimental conditions should include initial and equilibrium ph of solutions and de facto buffer concentrations. If applicable, filter adsorption studies should be documented. Any deviations from the protocol should be noted and justified. REFERENCES 1. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fifty-first report. Geneva, World Health Organization. WHO Technical Report Series, No. 1003, 2017, Annex Determinação da Solubilidade Aplicada à Bioisenção de acordo com o Sistema de Classificação Biofarmacêutica. Farmacopeia Brasileira, Apley M. et al. Determination of Thermodynamic Solubility of Active Pharmaceutical Ingredients for Veterinary Species: A New USP General Chapter. Pharmacopeial Forum 41(3) May The International Pharmacopoeia, 6th edition, On CD-ROM only ***