Measurement of Intrinsic Drug Dissolution Rates Using Two Types of Apparatus

Transcription

1 Measurement of Intrinsic Drug Dissolution Rates Using Two Types of Apparatus Tacey X. Viegas,* Roxanne U. Curatella, Lise L. Van Winkle, and Gerald Brinker The authors determined the intrinsic dissolution rates of various model drugs by using a rotating disk system and a stationary disk system. The intrinsic dissolution rates and similarity factor values (f 2 ) were used to compare the dissolution profiles of each compound. DISTEK Tacey X. Viegas, PhD, is the executive director of pharmaceutical development at BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Dr., Birmingham, AL 35244, tel , fax , tviegas@ biocryst.com. Roxanne U. Curatella and Lise L. Van Winkle are development scientists at BioCryst Pharmaceuticals, Inc. Gerald Brinker is the president of Distek, Inc. (North Brunswick, NJ). *To whom all correspondence should be addressed The intrinsic dissolution rate is defined as the rate of dissolution of a pure pharmaceutical active ingredient when conditions such as surface area, temperature, agitation or stirring speed, ph, and ionic strength of the dissolution medium are kept constant. Determining this parameter allows the screening of drug candidates and aids in understanding their solution behavior under various biophysiological conditions (1). The implementation of sameness analysis has been presented and applied in a number of scientific guidelines for demonstrating formulation equivalencies among semisolids; immediate-release, solid oral; and extended-release, solid oral dosage forms. Test methods for these analyses involve the use of vertical diffusion cells, enhancer cells, and USP Apparatuses 1 and 2 (2). The evaluation of the intrinsic dissolution of active pharmaceutical ingredients (APIs) is a means to demonstrate chemical purity and equivalency. The need to demonstrate sameness among APIs has risen because of changes in bulk active synthesis final crystallization steps particle size and surface area polymorphism scale-up issues regarding batch size and manufacturing site. This article evaluates the use of a rotating pellet system (a rotary device) and a fixed pellet system (a stationary device). Test compounds were selected on the basis of their solubility in water, simulated gastric fluid (0.1 N HCl acid), and simulated intestinal medium (ph 7.2 buffer). The dissolution rates of these compounds were determined in a conventional dissolution apparatus setup, and the similarity factor (f 2 ) analysis method was used to compare the results. Materials and methods Materials used. USP-grade material of acetaminophen, ibuprofen, diclofenac sodium, isoniazid, dibucaine, propranolol hydrochloride (Spectrum Chemical Company, New Brunswick, NJ); milled ( m particle size) and micronized (2 5 m particle size) peldesine and its milled hy- 44 Pharmaceutical Technology JUNE

2 Figure 1: Rotating disk system (USP Wood apparatus). drochloride salt form (CAS , an immunomodulator developed by BioCryst Pharmaceuticals, Birmingham, AL); high-purity deionized water (VWR Scientific Products, West Chester, PA); and hydrochloric acid, citric acid monohydrate, and dibasic sodium phosphate (J.T. Baker, Phillipsburg, NJ). Apparatus. Two intrinsic dissolution apparatuses and kits were used. Table I compares the key features, strengths, and weaknesses of the two systems. All of the dissolution experiments were performed with the model 2100B dissolution system and the model 2230 autosampler from Distek, Inc. (North Brunswick, NJ). Rotating disk system (USP Wood apparatus).the rotating pellet or disk system used was the Wood apparatus from VanKel Industries, Inc. (Cary, NC) (see Figure 1). The apparatus consists of a steel punch, a die, and a base plate (3,4). The base of the die has three threaded holes for the insertion of screws and the attachment to the base plate. Test material was placed in the 0.8-cm (0.315-in.) diameter die cavity. The punch was inserted into the cavity and compressed with the aid of a benchtop Carver press for 4 5 min at 2000 psi. The base plate was then disconnected from the die to expose a smooth, compact pellet with a 0.5-cm 2 surface area. A Neoprene gasket was placed around the threaded shoulder of the die, which was then screwed onto the shaft holder, and the shaft was mounted on the stirring drive Table I: Comparison of the rotating and stationary disk systems. Feature Rotating Disk System Stationary Disk System Operation Rotating or forced shear-like dissolution Static or solvent shear-like dissolution operation. Similar to USP Procedure I. operation. Similar to USP Procedure II. Dissolution is achieved by shear-like Dissolution is achieved by moving a motion of the pellet in the dissolution volume of dissolution medium over the medium. Pellet faces down. pellet. Pellet faces up. Dissolution testing station Designed for apparatus similar to the Used with USP Apparatus 2 paddles on any VanKel VK7000 module. dissolution module. Dissolution vessel Standard, curved-bottom 1-L beaker. Flat-bottom, 1-L beaker. The flat surface diameter is 5.38 cm (2.12 in.) Shaft design Stainless steel rod with hollow die holder. Uses standard paddle from USP Apparatus 2. Die holder acts as a plastic screw cap and base. Introduction of compact Pellet and die assembly is introduced into Pellet and die assembly is introduced into the pellet into the dissolution the dissolution medium all at once, when dissolution medium one at a time with the aid medium the dissolution drive mechanism is lowered. of a pair of forceps. Die weight 515 g 144 g Die height 3.54 cm 1.27 cm Die diameter 5.38 cm 5.38 cm Die cavity diameter/area 0.8 cm/0.5 cm cm/0.5 cm 2 Recommended speed 50 rpm 50 and 100 rpm Miscellaneous Formation of air bubbles can interfere No air bubbles formed on the pellet surface. with dissolution rate. Small drop in No change in temperature because the device temperature of dissolution medium ( 2 C) is small and is totally submerged into the when the device is first lowered into the dissolution medium. vessel. Heat transfers out of the vessel through the shaft. 46 Pharmaceutical Technology JUNE

3 Figure 2: Stationary disk system (new apparatus). Table II: Intrinsic dissolution rates and similarity factor, f 2. Dissolution Rotating Stationary Compound Medium Disk System Disk System f 2 Acetaminophen Water Diclofenac sodium Water Isoniazid Water Propranolol HCl Water NA* Peldesine HCl Water NA* Dibucaine 0.1 N HCl Peldesine (milled) 0.1 N HCl Peldesine (micronized) 0.1 N HCl Ibuprofen ph 7.2 buffer *f 2 analysis is not necessary for rapidly dissolving compounds. mechanism of the dissolution apparatus. Once all six shafts were mounted, the dies were lowered into the dissolution vessel (curved bottom) containing 900 ml of dissolution medium at 37 C. The distance of the die face from the bottom of the vessel was set at 1 in. Dissolution was performed at 50 rpm. At appropriate time intervals, an automated sample collector removed aliquots from the dissolution medium. Stationary disk system. Figure 2 shows the stationary pellet or disk system that was used (Distek, Inc.). The apparatus consists of a steel punch, a die, and a base plate. The die base has three holes for the attachment of the base plate. The three fixed screws on the base plate are inserted through the three holes on the die and then fastened with the three supplied washers and nuts. Test material was placed in the 0.8-cm (0.315-in.) diameter die cavity. The punch was then inserted into the cavity and compressed with the aid of a benchtop Carver press for 4 5 min at 2000 psi. The base plate was then disconnected from the die to expose a smooth, compact pellet with a surface area of 0.5 cm 2.A Viton gasket was placed around the threaded shoulder of the die, and a polypropylene cap then was screwed onto the threaded shoulder. The assembly was next immersed, pellet side up, into the bottom of the dissolution vessel (flat bottom) containing 900 ml of dissolution medium at 37 C. A pair of forceps was used for this operation, and six dies were placed within 30 s. The dimensions of the flat portion at the bottom of the dissolution vessel permits the die assembly to settle in a horizontal position and without shifting during the stirring of the dissolution medium. The USP Apparatus 2 paddle was the stirring mechanism for the dissolution system. The bottom of the stirring paddle was 1 in. from the die face. Dissolution was performed at 50 rpm. Again, at appropriate time intervals, an automated sample collector removed aliquots from the dissolution medium. UV spectrophotometric analysis.analysis of each test compound was carried out using an UV visible spectrophotometer and 1- cm quartz cells. Reference standard solutions for each drug were prepared in the dissolution medium of choice to generate an absorbance versus concentration standard curve. The absorbance of the sample aliquots was used to determine the amount of drug recovered at each time point. Comparison of dissolution profiles. The cumulative amount of drug substance dissolved at any time point is the product of the drug concentration in the sample and the volume of media. Intrinsic dissolution takes into account the correction factor for reduced volume, whereby the amount of drug substance contained in each sample volume is added back to the cumulative amount at subsequent time points (5). The amount of drug dissolved per unit area is plotted against time. The slope of the line is the intrinsic dissolution rate in milligrams per square centimeter per minute. USP recommends that the earlier time points be used in the calculation of slope. Based on our experience, the use of at least five points from the earlier segment of the dissolution curve will provide meaningful data. The similarity factor f 2 compares the dissolution profiles for each compound tested by both apparatuses. The equation used in the calculation is where T R and T S are the cumulative percentages dissolved at each of the selected n time points of the rotary and stationary pellet systems, respectively. If the f 2 value is between 50 and 100, the intrinsic dissolution profiles are equivalent (6). 48 Pharmaceutical Technology JUNE

4 Table III: Effect of distance on the intrinsic dissolution rates of milled peldesine. Rotating Stationary Distance (in.) Speed (rpm) Disk System Disk System Mean Column RSD (%) Table IV: Effect of speed on the intrinsic dissolution rates of milled peldesine. Rotating Stationary Distance (in.) Speed (rpm) Disk System Disk System f 2 * *f 2 values do not change when speed is adjusted. Validation of optimal stirring distance from the pellet surface and stirring speed. The distance between the pellet and the bottom of the flask (rotating disk system) and between the pellet and the paddle blade (stationary disk system) was set at 1 in. (2.54 cm) in the experiments described previously. The experiments were repeated with milled peldesine as the test substance and by adjusting the distances in both systems to 0.5 and 1.5 in., respectively. In another set of experiments the distance was set at 1 in., but the paddle stirring speed was increased to 100 rpm. Sample aliquots were taken as before and assayed for drug concentration. Dissolution curves were constructed and similarity factor analyses were performed to determine the differences in intrinsic dissolution rates associated with changes in distance and speed. Results and discussion The amount of drug dissolved per unit area when plotted against time produced linear curves with correlation coefficients higher than in each case. Figure 3, for example, illustrates the dissolution of acetaminophen in deionized water. Table II compares the intrinsic dissolution rates of the compounds tested using both the rotary and the stationary disk systems. The similarity of the apparatuses was calculated by the similarity factor analysis, f 2.The performances of both devices were comparable in the case of acetaminophen, diclofenac sodium, isoniazid, dibucaine, and ibuprofen (i.e., f 2 50), which means that the difference in dissolution profiles is 10%. Milled peldesine ( m particle size) had an f 2 value of 39, suggesting a 10% difference in the two systems. But when peldesine was micronized (2 5 m particle size) the difference was 10% (i.e., f 2 63). The differences in f 2 values for the same compound may suggest that before intrinsic dissolution testing, the test substance must be well characterized, especially in terms of particle-size distribution. A narrower particle-size range would be desirable. As expected, the micronized drug appeared to have a faster dissolution rate than did the milled drug. The hydrochloride salts of propranolol and peldesine appeared to swell and completely dissolve in less than 10 min. In the case of peldesine hydrochloride, the intrinsic dissolution rate was approximately 2.5 times faster when the rotary disk apparatus was used. We attribute this difference to swelling properties of this compound and the breaking away of tiny pieces of compressed pellet. The number of sampling intervals for each test compound depended on its solubility and the dissolution medium used. Standard deviations were calculated at each time point for n 6 vessels. When the stationary disk system was used, the standard deviation at the later time points (20 30 min) was approximately %, Figure 3: Intrinsic dissolution of acetaminophen, USP (n 6, SD). compared with % observed when the rotating disk system was used. These differences are attributed to the mechanism of dissolution (7,8). In the case of the rotary operation, the pellet undergoes a shear-like motion over a planar solvent front, similar to USP Procedure I. In the case of the stationary disk system, a fixed body (volume) of solvent is stirred over the pellet, similar to USP Procedure II, and the enhancer dissolution cell used for semisolids (VanKel Industries). The USP method (rotating disk method) calls for a distance of 1.5 in. (3.31 cm) from the pellet surface to the bottom of the vessel. No supportive validation studies have been reported to justify this distance. The results of our distance variation study show that for either apparatus, there is no significant difference (p 0.05) in the dissolution curves when the 0.5-, 1.0-, and 1.5-in. distances were used (see Table III). On the other hand, a distance of 0.5 in. is not recommended. The tiny air bubbles developed in the rotating disk method were difficult to reach and remove. In the case of the stationary disk method, the stirring produced tiny vortices that interfered with the pellet surface and resulted in slightly larger standard deviations at each time point. The USP method does not call for a rotating or stirring speed. We observed that the rate of drug (peldesine) dissolution increased by 61 71% when the speed was increased from 50 to 100 rpm (see Table IV). One also can observe that in the rotating disk assembly, the shaft and die wobbled when the machine was operated at 100 rpm, resulting in standard devia- 50 Pharmaceutical Technology JUNE

5 tion values of 10 mg/cm 2 at the later time points. Conclusion The intrinsic dissolution rate of an API can be reasonably determined to describe the rate of dissolution of drug and to determine batch-to-batch chemical equivalency. The two apparatuses are well designed and are easy-to-use tools for obtaining meaningful answers. The two techniques discussed are useful in describing the rates of dissolution of compounds that are water and buffer soluble. Compounds that are practically insoluble in water can be tested with dissolution media containing surfactants and cosolvents. On the other hand, these dissolution procedures may be overkill for compounds that go into solution almost immediately (e.g., salt forms of weak acids and bases). Modifications to the Distek intrinsic dissolution die diameter have been considered when small amounts of drug compound must be tested (data not shown). Even though the USP method calls for a distance of 1.5 in., other distances can be used if the method can be validated and reproduced for each test compound. The same scenario would apply to the stirring speed. References 1. H.M. Abdou, Dissolution, Bioavailability and Bioequivalence (Mack Publishing, Easton, PA, 1989), pp H.M. Fares and J.L. Zatz, Measurement of Drug Release from Topical Gels Using Two Types of Apparatus, Pharm. Technol. 19 (1), (1995). 3. VanKel Intrinsic Dissolution Apparatus Operator s Manual and Reference, revision A. 4. Intrinsic Dissolution, United States Pharmacopoeia 24 and National Formulary 19, 1st Supplement (National Publishing, Philadelphia, 2000), pp H. Aronson, Correction Factor for Dissolution Profile Calculations, J. Pharm. Sci. 82 (11), 1190 (1993). 6. V.P. Shah, Y. Tsong, P. Sathe, and J. Liu, In Vitro Dissolution Profile Comparison Statistics and Analysis of the Similarity Factor, f 2, Pharm. Res. 15 (6), (1998). 7. U.V. Banakar, Pharmaceutical Dissolution Testing (Marcel Dekker, New York, 1992), pp S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, Solubility and Dissolution Testing, in Solid- State Chemistry of Drugs (SSCI, West Lafayette, IN, 2d ed., 1999), pp PT Circle/eINFO 38 Pharmaceutical Technology JUNE