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Simplified Biorelevant Media for Screening Dissolution ...

Simplified Biorelevant Media for Screening Dissolution Performance of Poorly Soluble Drugs e-mail: Thomas Zoeller and Sandra Klein1. Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, 9 Max von Laue Street, Frankfurt am Main 60438, Germany INTRODUCTION Middlesbrough, England); Tween 40 (polyoxyethylene S. imulation of gastrointestinal conditions is essential to sorbitan monopalmitate), sample # SURF7168 (ICI. adequately predict the in vivo behavior of poorly surfactants, Middlesbrough, England); Tween 60. soluble drugs. Simulating small intestinal conditions (polyoxyethylene sorbitan monostearate), with Biorelevant Media such as fasted state simulated lot # S753320040 (Cognis GmbH, Duesseldorf, Germany);. intestinal fluid (FaSSIF) and fed state simulated intestinal Tween 80 (polyoxyethylene sorbitan monooleate), fluid (FeSSIF) has become standard practice in many lot # 813530 (Th. Goldschmidt, Essen, Germany); and Dissolution laboratories (1 6).

8 Dissolution Technologies | NOVEMBER 2007 INTRODUCTIONS imulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of …

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Transcription of Simplified Biorelevant Media for Screening Dissolution ...

1 Simplified Biorelevant Media for Screening Dissolution Performance of Poorly Soluble Drugs e-mail: Thomas Zoeller and Sandra Klein1. Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, 9 Max von Laue Street, Frankfurt am Main 60438, Germany INTRODUCTION Middlesbrough, England); Tween 40 (polyoxyethylene S. imulation of gastrointestinal conditions is essential to sorbitan monopalmitate), sample # SURF7168 (ICI. adequately predict the in vivo behavior of poorly surfactants, Middlesbrough, England); Tween 60. soluble drugs. Simulating small intestinal conditions (polyoxyethylene sorbitan monostearate), with Biorelevant Media such as fasted state simulated lot # S753320040 (Cognis GmbH, Duesseldorf, Germany);. intestinal fluid (FaSSIF) and fed state simulated intestinal Tween 80 (polyoxyethylene sorbitan monooleate), fluid (FeSSIF) has become standard practice in many lot # 813530 (Th. Goldschmidt, Essen, Germany); and Dissolution laboratories (1 6).

2 However, due to their Texapon K12 P (sodium dodecyl sulfate), lot #. complex composition, these Media are expensive and, to CS70910002 (Cognis GmbH, Duesseldorf, Germany) were date, need to be prepared on the day of the experiment. all of analytical grade and donated by their manufacturers. The aim of the present study was to develop Media that Triton X-100 (polyoxyethylene octyl phenyl ether) was are easier to prepare and are stable over a longer period, purchased from Merck KGaA, Darmstadt, Germany, and but can still serve the purpose of forecasting in vivo triethanolamine (min 98%), lot # 38H0128, was purchased performance. Criteria for developing Simplified test Media from Sigma Aldrich, Steinheim, Germany. also include cost-effectiveness and the ability to ade- Ketoconazole standard (lot # 10004924) was a donation quately reflect the physicochemical properties of the of Janssen Pharmaceutica (Beerse, Belgium). Glyburide Biorelevant Media FaSSIF or FeSSIF (see Table 1).

3 Another (lot # 024K0701) was purchased from Sigma Aldrich, objective was to create mixed micelles like those formed Steinheim, Germany. Tamoxifen citrate (lot # SRP 01106t). by natural bile components. For this purpose, sodium was obtained from Sequoia Research Products Ltd., taurocholate and lecithin were replaced with different Pangbourne, UK. Nizoral , lot # 03EL8333 (Janssen-Cilag types and concentrations of surfactants, and the GmbH, Neuss, Germany); Euglucon N, lot # 40E500. physicochemical properties of the resulting mixtures were (Aventis Pharma Deutschland GmbH, Frankfurt, Germany);. screened. Subsequently, Simplified Media with and Tamoxifen Hexal 20 mg, lot # 61MR19 (HEXAL AG, corresponding physicochemical properties were used for Holzkirchen, Germany) were purchased commercially. Dissolution experiments. Since their oral bioavailability White opaque gelatin capsules (Wepa Nr. 35758 according and Dissolution rate performance have been reported to DAB 10; size 1; mL) were purchased from Wepa to depend on the presence of Dissolution enhancers (1, 3, Apothekenbedarf GmbH & Co KG, Hillscheid, Germany.)

4 7 10), ketoconazole, glyburide and tamoxifen citrate were Sodium taurocholate (PCA code 2012), lot # 2003040161, selected as model drugs for these experiments. Based on was acquired from Prodotti Chimici e Alimentari , these observations, it was assumed that drug release from Basaluzzo (AL), Italy, and egg-phosphatidylcholine, their formulations would be sensitive to the composition Lipoid EPCS ( pure), was kindly donated by Lipoid of the test Media . Thus, they appeared to be optimal GmbH, Ludwigshafen, Germany. All other compounds candidates to prove the applicability of the new set of were of analytical grade and purchased commercially. Media . Media Preparation MATERIALS AND METHODS The Biorelevant Media FaSSIF and FeSSIF (see Table 1. Materials for compositions) were prepared on the day of the Brij 35 (polyoxyethyleneglycol dodecyl ether), experiment. FaSSIF was prepared as follows: g sodium lot # 602D0048B (Uniqema, Wilton, UK); Span 80 (sorbitan taurocholate was dissolved in approximately 500 mL of monooleate), lot # 813530 (Th.

5 Goldschmidt, Essen, the blank FaSSIF. The weight of this mixture was checked Germany); Tween 20 (polyoxyethylene sorbitan and noted ( weight 1 ). Then mL of a methylene monolaurate), sample # SURF17728 (ICI surfactants, chloride solution containing 100 mg/mL lecithin (= g lecithin, weight 2 ) was added. This produced an emulsion ( , the resulting product was turbid). The methylene 1. Corresponding author. chloride was then evaporated under vacuum using a Dissolution Technologies | NOVEMBER 2007. 8. 8 11/8/2007 1:52:11 PM. Rotavap (type R-114, Buechi, Essen, Germany) at a differed slightly from those proposed in the literature (11, temperature of about 40 C. About 10 min at 500 mbar 12) but, in the hands of the present investigators, resulted followed by 30 min at about 50 mbar led to complete in micellar solutions with more reliable physicochemical removal of the methylene chloride. The result was a clear, parameters, particularly in terms of osmolality and ionic micellar solution having no perceptible odor of methylene strength (13).

6 Chloride. After cooling to room temperature, the weight Simplified Media containing different types and amount of the solution was checked again. The water lost to of surfactants were prepared using blank FaSSIF and evaporation was replaced with demineralized water to FeSSIF ( , the relevant buffers without sodium obtain a total weight corresponding to the sum of taurocholate and lecithin) as the basis. After the weight 1 and weight 2. Finally, the volume was brought surfactant(s) were added, the Media were placed in the to 2 L with blank FaSSIF. ultrasonic bath for 15 min and then stirred for another Likewise, FeSSIF was prepared by first dissolving g 15 min on a magnetic stirrer. Subsequently, various sodium taurocholate in 500 mL of blank FeSSIF, checking physicochemical parameters such as pH, surface tension, and noting the weight ( weight 1 ). Subsequently, mL critical micelle concentration, osmolality, and buffer of a methylene chloride solution containing 100 mg/mL capacity were measured and compared with those of lecithin (= g lecithin, weight 2 ) was added, resulting the Biorelevant Media .

7 Media with corresponding in an emulsion. The methylene chloride was then physicochemical properties (see Table 2 for the target evaporated under the conditions described for FaSSIF values and the accepted tolerances) were then selected until a clear, micellar solution with no perceptible odor of for solubility and Dissolution experiments. methylene chloride was obtained. After cooling to room temperature, the weight of the solution was checked Physical Chemical Evaluation of the Media again, and the water lost to evaporation was replaced The pH of all test Media was measured with a pH meter. with demineralized water to obtain a total weight The buffer capacity was quantified by potentiometric corresponding to the sum of weight 1 and weight 2. titration with N hydrochloric acid. The osmolality was Finally, the volume was brought to 2 L with blank FeSSIF. measured by semi-micro osmometry (osmometer type These methods of manufacturing FaSSIF and FeSSIF ML, No.)

8 A0299, Knauer, Berlin, Germany), and the surface Table 1. Composition and Physicochemical Properties of FaSSIF and FeSSIF. FeSSIF FaSSIF. Sodium taurocholate 3 mM Sodium taurocholate 15 mM. Lecithin mM Lecithin 3 mM. NaH2PO4 g Acetic acid g NaCl g NaCl g NaOH pellets qs ad pH NaOH pellets g Deionized water qs ad 1 liter Deionized water qs ad 1 liter pH pH Osmolality [mOsmol/kg] ~ 270 Osmolality [mOsmol/kg] ~ 670. Buffer capacity [mEq/pH/L] ~ 12 Buffer capacity [mEq/pH/L] ~ 72. Surface tension [mN/m] 54 Surface tension [mN/m] 48. Table 2. Physicochemical Parameters of the Test Media : Target Values and Tolerances. Simulated FeSSIF Simulated FaSSIF. Parameter target value range of tolerance target value range of tolerance pH Osmolality [mOsmol/kg] 270 15 670 15. Buffer capacity [mEq/pH/L] 12 2 72 2. Surface tension [mN/m] 54 2 48 2. Dissolution Technologies | NOVEMBER 2007. 9. 9 11/8/2007 1:52:11 PM. tension was determined with a bubble-pressure HPLC Analysis tensiometer (No.

9 100517A, Sita Messtechnik GmbH, All samples were analyzed by HPLC. The detailed HPLC. Dresden, Germany). conditions are specified in Table 3. Selection of Model Drugs and Formulations RESULTS AND DISCUSSION. In the first set of experiments, the BCS class II As a first step, drug release from Nizoral tablets was compound ketoconazole was used as a model drug. The determined in the Biorelevant Media FaSSIF and FeSSIF. solubility of the pure drug and the Dissolution rate of a and their corresponding blank buffers (see Figure 1). marketed ketoconazole formulation in the Simplified In the second step, the aim was to generate Media with Dissolution Media were compared with results in FaSSIF physical chemical properties corresponding to those and FeSSIF (with and without addition of bile obtained in FaSSIF and FeSSIF. Measurement of the components). In the second part of the study, the physicochemical parameters indicated that pH, osmolality, applicability of the Simplified Media to other poorly and buffer capacity of blank FaSSIF and blank FeSSIF are soluble compounds was evaluated.

10 Two additional BCS not influenced by the presence of the surfactants tested. Class II drugs, namely the weak acid glyburide and the In contrast and as expected, the surface tension of the weak base tamoxifen, were used for this purpose. Another Media prepared with various synthetic surfactants was aspect of that part of the study was to prove the markedly influenced by the type and concentrations of discriminatory power of the Simplified test Media . For the surfactants (see Figure 2). Concentrations above the critical micelle concentration (CMC) were used for all latter purpose, it would be optimal to use a set of good . experiments. To adequately reflect the physicochemical and bad batches of a well-characterized formulation and, parameters of FaSSIF and FeSSIF, only those surfactants in an ideal case, to also correlate Dissolution results with resulting in surface tensions of 52 56 mN/m in blank the corresponding in vivo data. However, neither different FaSSIF or 46 50 mN/m in blank FeSSIF were selected for batches of a formulation nor in vivo data were available at subsequent solubility and Dissolution experiments.


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