Dissolution Development Chapter 1

Posted by : kaushik zala Saturday, August 15, 2015

1 Performing Filter Compatibility
1.2 Determining Solubility and Stability of Drug Substance in Various Media at 37°
1.3 Choosing a Medium and Volume
1.4 Choosing an Apparatus

1.1 Performing Filter Compatibility

Filtration is a key sample-preparation step in achieving accurate test results. The purpose of filtration is to remove undissolved drug and excipients from the withdrawn solution. If not removed from the sample solution, particles of the drug will continue to dissolve and can bias the results. Therefore, filtering the dissolution samples is usually necessary and should be done immediately if the filter is not positioned on the cannula. Filtration also removes insoluble excipients that may otherwise interfere with the analytical procedure during the analytical finish. Selection of the proper filter material is important and should be accomplished, and experimentally justified, early in the development of the dissolution method. Important characteristics to consider when choosing a filter material are type, size, and pore size. The filter that is selected based on evaluation during the early stages of dissolution method development may need to be reconsidered at a later time point. Requalification has to be considered after a change in composition of the drug product or changes in the quality of the ingredients (e.g. particle size of microcrystalline cellulose). Filters used in dissolution testing can be cannula filters, filter disks or frits, filter tips, or syringe filters. The filter material has to be compatible with the media and cannot adsorb the drug. Common pore sizes range from 0.20 to 70 µm, however, filters of other pore sizes can be used as needed. If the drug substance particle size is very small (e.g., micronized or nanoparticles), it can be challenging to find a filter pore size that excludes these small particles. Adsorption of the drug(s) by the filter may occur and needs to be evaluated. Filter materials will interact with dissolution media to affect the recovery of the individual solutes and must be considered on a case-by-case basis. Different filter materials exhibit different drug-binding properties. Drug binding is also dependent on the drug concentration. Therefore the adsorptive interference should be evaluated on sample solutions at different concentrations bracketing the expected concentration range. Where the drug adsorption is saturable, discarding an initial volume of filtrate may allow the collection of a subsequent solution that approaches the original solution concentration. Alternative filter materials that minimize adsorptive interference can usually be found. Prewetting of the filter with the medium may be necessary. In addition, it is important that leachables from the filter do not interfere with the analytical procedure. This can be evaluated by analyzing the filtered dissolution medium and comparing it with the unfiltered medium. The filter size should be based on the volume to be withdrawn and the amount of particles to be separated. Use of the correct filter dimensions will improve throughput and recovery, and also reduce clogging. Use of a large filter for small-volume filtration can lead to loss of sample through hold-up volume, whereas filtration through small filter sizes needs higher pressures and longer times, and the filters can clog quickly. Filters used for USP Apparatus 4 need special attention because they are integrated in the flow-through process. Undissolved particles may deposit on the filters, creating resistance to the flow. In the case of automated systems, selection of the filter with regard to material and pore size can be done in a similar manner to manual filtration. Flow rate through the filter and clogging may be critical for filters used in automated systems. Experimental verification that a filter is appropriate may be accomplished by comparing the responses for filtered and unfiltered standard and sample solutions. This is done by first preparing a suitable standard solution and a sample solution. For example, prepare a typical dissolution sample in a beaker and stir vigorously with a magnetic stirrer to dissolve the drug load completely. For standard solutions, compare the results for filtered solutions (after discarding the appropriate volume) to those for the unfiltered solutions. For sample solutions, compare the results for filtered solutions (after discarding the appropriate volume) to those for centrifuged, unfiltered solutions.

1.2 Determining Solubility and Stability of Drug Substance in Various Media at 37°

Physical and chemical characteristics of the drug substance need to be determined before selecting the proper dissolution medium. When deciding the composition of the medium for dissolution testing, it is important to evaluate the influence of buffers, pH, and if needed, different surfactants on the solubility and stability of the drug substance. Solubility of the drug substance is usually evaluated by determining the saturation concentration of the drug in different media at 37° using the shake-flask solubility method (equilibrium solubility). Alternative methods for solubility determination may also be used. To level out potential ion effects between the drug and the buffers used in the media, mixtures of hydrochloric acid and sodium hydroxide are used to perform solubility investigations; this is in addition to the typical buffer solutions. In certain cases, it may be necessary to evaluate the solubility of the drug at room temperature (i.e., 20°). The pH of the clear supernatant should be checked to determine whether the pH changes during the solubility test. Typical media for dissolution may include the following (not listed in order of preference): diluted hydrochloric acid; buffers (phosphate or acetate) in the physiologic pH range of 1.2–7.5; simulated gastric or intestinal fluid (with or without enzymes); and water. For some drugs, incompatibility of the drug with certain buffers or salts may influence the choice of buffer. The molarity of the buffers and acids used can influence the solubilizing effect, and this factor may be evaluated. For poorly soluble dugs, aqueous solutions (acidic or buffer solutions) may contain a percentage of a surfactant [e.g., sodium dodecyl sulfate (SDS), polysorbate, or lauryldimethylamine oxide] to enhance the solubility of the drug. The surfactants selected for the solubility investigations should cover all common surfactant types, i.e., anionic, nonionic, and cationic. When a suitable surfactant has been identified, different concentrations of that surfactant should be investigated to identify the lowest concentration needed to achieve sink conditions. Typically, the surfactant concentration is above its critical micellar concentration (CMC). Table 1 shows a list of some of the surfactants used in dissolution media. CMC values are provided with references when available. The list is not comprehensive and is not intended to exclude surfactants that are not listed. Other substances, such as hydroxypropyl β-cyclodextrin, have been used as dissolution media additives to enhance dissolution of poorly soluble compounds. The U.S. Food and Drug Administration maintains a database of dissolution methods, including information on dissolution media that have been used.1 It is important to control the grade and purity of surfactants because use of different grades could affect the solubility of the drug. For example, SDS is available in both a technical grade and a high-purity grade. Obtaining polysorbate 80 from different sources can affect its suitability when performing high-performance liquid chromatography (HPLC) analysis. There may be effects of counter-ions or pH on the solubility or solution stability of the surfactant solutions. For example, a precipitate forms when the potassium salt for the phosphate buffer is used at a concentration of 0.5M in combination with SDS. This can be avoided by using the sodium phosphate salt when preparing media with SDS

Table 1. Commonly Used Surfactants with Critical Micelle Concentrations Routinely, the dissolution medium is buffered, however, the use of purified water as the dissolution medium is suitable for products with a dissolution behavior independent of the pH of the medium. There are several reasons why purified water may not be preferred. The water quality can vary depending on its source, and the pH of the water is not as strictly controlled as the pH of buffer solutions. Additionally, the pH can vary from day to day and can also change during the run, depending on the active substance and excipients. Use of an aqueous–organic solvent mixture as a dissolution medium is discouraged; however, with proper justification this type of medium may be acceptable. Investigations of the stability of the drug substance should be carried out, when needed, in the selected dissolution medium with excipients present, at 37°. Sufficient time should be allowed to complete or repeat the analytical procedure. This elevated temperature has the potential to decrease solution stability (degradation). Physical stability may be of concern when precipitation occurs because of lower solubility at room or refrigerated temperature. 1.3 Choosing a Medium and Volume When developing a dissolution procedure, one goal is to have sink conditions, which are defined as having a volume of medium at least three times the volume required to form a saturated solution of drug substance. When sink conditions are present, it is more likely that dissolution results will reflect the properties of the dosage form. A medium that fails to provide sink conditions may be acceptable if it is appropriately justified. The appropriate composition and volume of dissolution medium are defined by the solubility investigations. The use of surfactants needs to be justified by data that show low solubility in the aqueous media. The chosen concentration of surfactant also needs to be justified by providing dissolution profiles in media containing the surfactant at concentrations higher and lower than the chosen concentration. The use of enzymes in the dissolution medium is permitted, in accordance with general chapter Dissolution 711 , when dissolution failures occur as a result of cross-linking with gelatin capsules or gelatin-coated products. A discussion of the phenomenon of cross-linking and method development using enzymes can be found in proposed Surfactant CMC (% wt/volume) Ref. Anionic Sodium dodecyl sulfate (SDS), Sodium lauryl sulfate (SLS) 0.18–0.23% (1–3) Taurocholic acid sodium salt 0.2% (2) Cholic acid sodium salt 0.16% (2) Desoxycholic acid sodium salt 0.12% (2) Cationic Cetyltrimethyl ammonium bromide (CTAB, Hexadecyltrimethylammonium bromide) 0.033%–0.036% (0.92–1.0 mM) (4,5) Benzethonium chloride (Hyamine 1622) 0.18% (4 mM) (1) Nonionic Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate, Tween 20) 0.006%–0.093% (2) Polysorbate 80 (Polyoxyethylene (80) sorbitan monooleate, Tween 80) 0.002 %– 0.082% (2) Caprylocaproyl polyoxyl-8 glycerides (Labrasol) 0.01% (3) Polyoxyl 35 castor oil (Cremophor EL) 0.02% (6) Polyoxyethylene 23 lauryl ether (Brij 35) 0.013% (7) Zwitterion Lauryldimethylamine N-oxide (LDAO) 0.023% (8

Routinely, the dissolution medium is buffered, however, the use of purified water as the dissolution medium is suitable for products with a dissolution behavior independent of the pH of the medium. There are several reasons why purified water may not be preferred. The water quality can vary depending on its source, and the pH of the water is not as strictly controlled as the pH of buffer solutions. Additionally, the pH can vary from day to day and can also change during the run, depending on the active substance and excipients. Use of an aqueous–organic solvent mixture as a dissolution medium is discouraged; however, with proper justification this type of medium may be acceptable. Investigations of the stability of the drug substance should be carried out, when needed, in the selected dissolution medium with excipients present, at 37°. Sufficient time should be allowed to complete or repeat the analytical procedure. This elevated temperature has the potential to decrease solution stability (degradation). Physical stability may be of concern when precipitation occurs because of lower solubility at room or refrigerated temperature

1.3 Choosing a Medium and Volume When developing a dissolution procedure, one goal is to have sink conditions, which are defined as having a volume of medium at least three times the volume required to form a saturated solution of drug substance. When sink conditions are present, it is more likely that dissolution results will reflect the properties of the dosage form. A medium that fails to provide sink conditions may be acceptable if it is appropriately justified. The appropriate composition and volume of dissolution medium are defined by the solubility investigations. The use of surfactants needs to be justified by data that show low solubility in the aqueous media. The chosen concentration of surfactant also needs to be justified by providing dissolution profiles in media containing the surfactant at concentrations higher and lower than the chosen concentration. The use of enzymes in the dissolution medium is permitted, in accordance with general chapter Dissolution 711 , when dissolution failures occur as a result of cross-linking with gelatin capsules or gelatin-coated products. A discussion of the phenomenon of cross-linking and method development using enzymes can be found in proposed

general information chapter Capsules–Dissolution Testing and Related Quality Attributes 1094 . Another option is to use media that follow more closely the composition of fluids in the stomach and intestinal tract. These media may contain physiological surface-active ingredients, such as taurocholate. They may contain emulsifiers (lecithin) and components such as saline solution that increase osmolality. Also, the ionic strength or molarity of the buffer solutions may be manipulated. The media are designed to represent the fed and fasted state in the stomach and small intestine. These media may be very useful in modeling in vivo dissolution behavior of immediate-release (IR) dosage forms, in particular those containing lipophilic drug substances, and may help in understanding the dissolution kinetics of the product related to the physiological make-up of the digestive fluids. Results of successful modeling of dissolution kinetics have been published, mainly for IR products. In the case of extended-release dosage forms with reduced effect of the drug substance on dissolution behavior, the use of such media needs to be evaluated differently. In vitro performance testing does not necessarily require media modeling the fasted and postprandial states (9,10). An acid stage is part of the testing of delayed-release products by Method A or Method B in chapter 711 . For poorly acid-soluble drugs or drugs that degrade in acid there is a challenge of detecting the drug, therefore guaranteeing passing the 10% limit. This would be handled on a case-by-case basis. Possible resolutions include the addition of surfactant to the acid stage, or adjustment of the specifications. During selection of the dissolution medium, care should be taken to ensure that the sample is suitably stable throughout the analysis. In some cases, antioxidants such as ascorbic acid may be used in the dissolution medium to stabilize the drug. There are occasions where such actions are not sufficient. For compounds that rapidly degrade to form a stable degradant, monitoring the degradant alone or in combination with a drug substance may be more suitable than analyzing only the drug substance. In situ spectroscopic techniques tend to be less affected by degradation when compared with HPLC analysis. For compendial Apparatus 1 (basket) and Apparatus 2 (paddle), the volume of the dissolution medium can vary from 500 to 1000 mL, with 900 mL as the most common volume. Usually, the volume needed for the dissolution test can be determined in order to maintain sink conditions. In some cases, the volume can be increased to between 2 and 4 L, using larger vessels and depending on the concentration and sink conditions of the drug; justification for this approach is expected. In practice, the dissolution medium is usually changed to maintain the volume at 500–1000 mL. Alternatively, it may be preferable to switch to other compendial apparatus, such as a reciprocating cylinder (Apparatus 3), reciprocating holder (Apparatus 7), or flow-through cell (Apparatus 4). Certain applications may require low volumes of dissolution media (e.g., 100–200 mL) when the use of a paddle or basket is preferred. In these cases, an alternative, noncompendial apparatus (e.g., small-volume apparatus) may be used. 1.4 Choosing an Apparatus The choice of apparatus is based on knowledge of the formulation design and the practical aspects of dosage form performance in the in vitro test system. In general, a compendial apparatus should be selected. For solid oral dosage forms, Apparatus 1 and Apparatus 2 are used most frequently. When Apparatus 1 or Apparatus 2 is not appropriate, another official apparatus may be used. Apparatus 3 (reciprocating cylinder) has been found especially useful for chewable tablets, soft gelatin capsules, delayed-release dosage forms, and nondisintegrating-type products, such as coated beads. Apparatus 4 (flow-through cell) may offer advantages for modified-release dosage forms and immediate-release dosage forms that contain active ingredients with limited solubility. In addition, Apparatus 4 may have utility for soft gelatin capsules, beaded products, suppositories, or injectable-depot dosage forms, as well as suspension-type extended-release dosage forms for oral or parenteral use, or ocular application. Apparatus 5 (paddle over disk) and Apparatus 6 (rotating cylinder) are useful for evaluating and testing transdermal dosage forms. Apparatus 7 (reciprocating holder) has application to non-disintegrating, oral modified-release dosage forms, stents, and implants, as well as transdermal dosage forms. For semisolid dosage forms, the generally used apparatus include the vertical diffusion cell, immersion cell, and flow-through cell apparatus with the insert for topical dosage forms (see Semisolid Drug Products—Performance Tests 1724 ). Some changes can be made to the compendial apparatus; for example, a basket mesh size other than the typical 40-mesh basket (e.g., 10-, 20-, or 80-mesh) may be used when the need is clearly documented by supporting data. Care must be taken that baskets are uniform and meet the dimensional requirements specified in 711 . A noncompendial apparatus may have some utility with proper justification, qualification, and documentation of superiority over the standard equipment. For example, a small-volume apparatus with mini paddles and baskets may be considered for low-dosage strength products. A rotating bottle or dialysis tubes may have utility for microspheres and implants; peak vessels for eliminating coning; and modified flow-through cells for special dosage forms including powders and stents.