Steps for Development of a Dissolution Test for Sparingly Water-Soluble Drug Products

Carol Noory, Nhan Tran, Larry Ouderkirk, and Vinod Shah
Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD

Abstract:
The development of a meaningful dissolution procedure for drug products with limited water solubility has been a challenge to both the pharmaceutical industry and the agencies that regulate them. Drug release is usually the rate limiting process for absorption of low solubility oral drugs. Both in vivo physiology and the physico-chemical characteristics of the drug are important to the oral absorption of poorly water-soluble drugs. In the body, natural surfactants aid in the dissolution and subsequent absorption of drugs with limited aqueous solubility. In vitro, various techniques have been used to achieve adequate dissolution of the sparingly water-soluble or water-insoluble drug products such as the use of mechanical methods (i.e., increased agitation and the disintegration method) or hydroalcoholic medium or large volumes of medium. The Food and Drug Administration (FDA) has evaluated commercial surfactants in vitro and compared them to naturally occurring surfactants and developed a stepwise procedure for developing dissolution tests for drugs with limited water solubility using these commercial surfactants. Because of the physiological relevance of surfactants, FDA generally prefers their use in the dissolution testing of sparingly water-soluble drug products.

Introduction:
The term "surfactant" is a convenient contraction for "surface active agent"(2). Surfactants play a major role in the absorption of drugs in the body(3). There are four major classifications of surfactants: anionic, cationic, nonionic, and amphoteric. The nonionic surfactant remains whole, has no charge in aqueous solutions, and does not dissociate into positive and negative ions. Because the nonionic surfactant does not dissociate in water, it can be used in combination with anionic or cationic surfactants. Anionic surfactants are water-soluble, have a negative charge and dissociate into positive and negative ions when placed in water. The negative charge lowers the surface tension of water and acts as the surface-active agent. Cationic surfactants have a positive charge, and also dissociate into positive and negative ions when placed in water. In this case, the positive ions lower the surface tension of the water and act as the surfactant. The amphoteric surfactant assumes a positive charge in acidic solutions and performs as a cationic surfactant, or it assumes a negative charge in an alkaline solution and acts as an anionic surfactant. Because of the unique characteristics of surfactants, small concentrations added to water will immediately form a stable mono-layer. As more surfactant is added, a bilayer is formed. If the concentration of surfactant is increased sufficiently, the bilayer becomes unstable and micelles are formed. The micelle consists of a hydrophilic shell and a hydrophobic core. In vivo(4,5), surfactants (anionic, nonionic or cationic) are available to solubilize drugs. Parameters such as temperature, environment, and pH will also influence the solubility of a drug inside the micelle(6).

Background:
The most widely used in vitro test available to determine the release rate of drug products is the in vitro dissolution test. Dissolution testing is used widely by both the pharmaceutical industry and regulatory agencies to assure the quality of drug products. This paper provides a step-wise procedure for developing a meaningful dissolution test for sparingly water-soluble and water-insoluble drug substances. Low-solubility drugs are usually lipophilic and drug release is usually the rate limiting process for oral drug absorption of these substances. A poorly soluble drug can be defined on the basis of administered dose and aqueous solubility. In vivo, the dissolution process depends on physicochemical parameters, which may be affected by the intraluminal conditions in the body. In vitro, dissolution depends on the drug product and dissolution test conditions such as composition and volume of dissolution test medium, pH, type of apparatus and agitation. In developing a dissolution test for sparingly-soluble or water-insoluble drug products, a variety of mechanisms have been used to increase drug solubility, including adding alcohol or other organic solvents to the aqueous media, increasing the volume of the dissolution medium, and increasing the rate of agitation. These methods lack physiological relevance. The FDA has previously evaluated the effect of naturally occurring surfactants and compared them with commercially available surfactants(7). Because of the physiological relevance of surfactants, FDA generally supports their use in the dissolution testing of sparingly water-soluble drug products. Commercial surfactants have been used successfully to enhance the dissolution of numerous water-insoluble and sparingly water-soluble drug products, for example, carbamazepine (6,8), griseofulvin (6,9), flucytosine (10), benorilate (11), sulfamethoxazole (12), prednisolone (13), danazol (14), megestrol acetate (13), prazosin HCl (13), quinesterol (13) and certain oral contraceptives(15).
Procedure

The following steps have been successfully used by FDA field laboratories to develop dissolution procedures for sparingly water-soluble and water-insoluble drug products. These steps evaluate the effect of pH, the type of surfactant (cationic- i.e., cetyltriammonium bromide [CTAB], anionic- i.e., sodium lauryl sulfate [SLS], and non-ionic- i.e., polysorbate [Tween]) and the concentration of the surfactant.

Step 1: Evaluation of medium (pH Effect):
The first step is to determine the solubility of the product using standard aqueous dissolution media as listed in the USP, including 0.1N HCl, pH 4.5 sodium acetate buffer and pH 6.8 phosphate buffer. The volume of the medium is maintained at 900-1000 mL and either the basket method (100-120 rpm) or the paddle method (50-75 rpm) is used. Initial testing is carried out using two units of the highest strength of the innovator (brand name) product, in each of the three media. Dissolution aliquots are analyzed at several time points (30, 60, 90, 120 minutes etc.) to generate dissolution profiles in each test medium. This initial run allows the analyst to efficiently evaluate the effect of pH on the product. The preferred medium is then selected based on these results. If the product exhibits poor dissolution, then the need for a surfactant is evaluated as in Step 2.

Step 2: Evaluation of the Surfactant:
Various drugs may react differently to a given surfactant depending on the drug's chemical properties. To select a surfactant, one from each type of surfactant (cationic, anionic and non-ionic) may be tried. Our laboratories have evaluated SLS, Brij, Tween and CTAB; however, in most instances SLS has been used successfully. Using the pre-selected medium (from Step 1) add 2% of a surfactant from each category. In one run (six vessels) three surfactants can be tested (2 dosage units each). In as few as two runs, one may thus be able to select an appropriate surfactant. In some cases, however, the selection of an appropriate surfactant may take longer. However, if the surfactants are pre-screened according to their characteristics, the time could be minimized. There may also be instances where the use of surfactant may not influence dissolution rate profile.

Step 3: Evaluation of Surfactant Concentration:
The concentration of the surfactant needs to be adjusted to maximize the sensitivity of the method that is developed. The aim is to use the lowest amount of surfactant needed to solubilize the drug substance in the dosage form to achieve greater than 85% dissolution in a reasonable amount of time, i.e., 120 minutes or less. Generally, gradually increasing the percent amount of surfactant (0.1, 0.25, 0.5, 0.75, 1.0, 2.0) are evaluated. The FDA has found that the addition of a small amount of surfactant, below the critical micelle concentration (CMC), is often sufficient to solubilize certain drug products.
After performing all of the above steps, sufficient information is available on the effects of pH, surfactant type and concentration to determine if a suitable dissolution method can be developed. The following table contains dissolution methodology developed by the FDA field laboratories. After evaluating the marketed dosage forms of a given drug product (brand name and generic), this information has been forwarded to the USP for incorporation in the respective monographs. TABLE

Product	Recommendation
Carbamazepine Tablets	Paddle 75 rpm, 900mL, 1.0% SLS/Water, 30-75%/15 min.; "Q"=NLT 85%/60 minutes
Clofibrate Soft Gelatin Capsules	Paddle 75 rpm, 900mL, 5.0% SLS/Water, "Q"=NLT 75%/180 minutes
Cortisone Acetate Tablets	Paddle 50, 1000 mL 0.5% SLS/Water, "Q"=NLT 75%/45 minutes
Danazol Capsules	Paddle 75 rpm, 900mL, 0.75% SLS/Water , "Q"=NLT 75%/30 minutes
Dicumerol Tablets	Basket 100 rpm, 1000 mL 0.1 TRIS buffer pH 9.0, "Q"=NLT 85%/15 minutes
Glyburide Tablets (non micronized)	Paddle 75 rpm, 900mL, 0.5% CTAB in pH 9.0 borate buffer, "Q"=NLT 80%/60 minutes
Griseofulvin Capsules	Paddle 50 rpm, 1000 mL 0.54%SLS/ Water, "Q"=NLT 80%/20 minutes
Medroxyprogesterone Acetate Tablets	Paddle 50rpm, 900 mL 0.5%SLS/Water; "Q"=NLT 75%/45 minutes
Megestrol Acetate Tablets	Paddle 75rpm, 900 mL 1.0% SLS/Water; "Q"=NLT 75%/60 minutes
Metolazone Tablets	Paddle 75rpm, 900 mL 2.0% SLS/Water, "Q"=NLT 75%/90 minutes
Prazosin HCl Capsules	Basket 100 rpm, 900 mL 2.0%SLS/0.1N HCl "Q"=NLT 80%/60 minutes
Quinestrol Tablets	Paddle 50 rpm, 500 mL 0.29% SLS/Water,"Q"=NLT 80%/30 minutes
Spironolactone/Hydrochlorothiazide Tablets	Paddle 50rpm, 900 mL 0.1% SLS/ 0.1N HCl, "Q"=70%/60 minutes

Conclusion:
The use of surfactants for the dissolution of sparingly aqueous-soluble drug products is well documented. Naturally occurring surfactants solubilize sparingly-soluble drugs in the body and help in the absorption process. Use of surfactant in the dissolution medium is physiologically relevant and can be successfully used for dissolution testing of drug products. For example, the dissolution of carbamazepine is carried out in 0.75% SLS. This dissolution test parameters has been correlated with in vivo performance of the products (16). A dissolution medium containing surfactant can better simulate the environment of the gastrointestinal tract than a medium containing organic solvents or other non-physiological substances, making the dissolution test conditions more useful in evaluating drug quality. A sensitive, reliable in vitro dissolution procedure used to determine the quality of a product, as well as to predict its bioavailability is of primary interest to FDA drug regulators.

References
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