A DISSOLUTION TEST METHOD FOR SOLID STEROIDAL PHARMACEUTICAL FORMULATIONS

Abstract: The invention provides for a method of determining the dissolution rate of a steroid from its solid pharmaceutical formulation. Said method comprises: adding a steroidal formulation to a paddle assembly containing an aqueous solution of polysorbate 20, where the concentration of polysorbate 20 is about 0.025 to about 0.15 % weight/volume and the temperature of the assembly is about 37 DEG C; removing aliquots and measuring the percentage of steroid in each aliquot.

Description: A DISSOLUTION TEST METHOD FOR SOLID STEROIDAL PHARMACEUTICAL FORMULATIONS FIELD OF THE INVENTION The present invention relates to a method for measuring the dissolution rate of a solid steroidal pharmaceutical formulation. More particularly, the invention relates to a method for determining the dissolution rate of the steroids, norgestimate and ethinyl estradiol from tablet formulations. BACKGROUND A pharmaceutical agent is useless if it cannot be delivered to a biological system at a controlled rate sufficient to elicit and maintain a physiological effect for a desired period of time. Therefore is it imperative to the quality control of drug substances that a pharmaceutical manufacturer reproducibly and reliably test the rate at which a drug substance is released from its formulation. The rate at which a drug is released from capsules or tablets to liquid media can be established by in vitro dissolution testing. In this type of test, solid formulations are added to a liquid medium and over time samples are withdrawn then analyzed for the percentage of dissolved drug substance. Studies have shown that in vitro dissolution rates are directly related to efficacy and bioavailability of many pharmaceutical formulations. Due to these results, drug manufacturers routinely use dissolution testing to assure the lot to lot consistency of their product. The major component of dissolution medium is water, but often other components are added to increase the comparability of the in vitro dissolution test with a biological system. Aqueous HCI, alcohols and surfactants (polysorbate 80) have been added to dissolution media for this purpose. In the case of steroidal formulations, in vitro dissolution tests have used isopropanol and water as the dissolution medium. However, for such formulations, these tests have not satisfactorily replicated gastric conditions and have not proven sufficient to reproducibly discern between pharmaceutical formulations whose steroidal dissolution rates decline over time. The object of the present invention is to measure the dissolution rate of steroids from their pharmaceutical formulations in a reproducible manner. Where said method distinguishes variations in dissolution behavior between different batches of formulations. SUMMARY OF THE INVENTION The invention provides for a method of determining the dissolution rate of a steroid from its solid pharmaceutical formulation. Said method comprises: adding a steroidal formulation to a paddle assembly containing an aqueous solution of polysorbate 20, where the concentration of polysorbate 20 is about 0.025 to about 0.15% weight/volume and the temperature of the assembly is about 37 °C; removing aliquots and measuring the percentage of steroid dissolved in each aliquot. DETAILED DESCRIPTION OF THE INVENTION The precision and accuracy of dissolution testing is dependent upon strict observance of subtle parameters and controls. (Remington's Pharmaceutical Sciences). The present invention finds that the dissolution medium is critical and controls the composition of the medium, namely the type of water, the surfactant and the solution's concentration. In addition, to the aforementioned factors, the method of preparing the dissolution medium (premixing time) can be critical with some surfactants. The surfactant employed is polysorbate 20, a partially esterified cyclic derivative of sorbitol, a natural sugar. The surfactant's most popular use is in the preparation of pharmaceutical formulations it may have other uses. Polysorbate 20 is commercially available from a number of suppliers and due to the surfactant's susceptibility to degradation over time, USP (23/NF 18) has published standards for determining the suitability of the surfactant. However the published values (hydroxyl, saponification, water, residue on ignition, arsenic, heavy metals and acid content values) do not guarantee suitability of polysorbate 20 for this dissolution test. ( See Donbrow, M. et al Journal of Pharmaceutical Sciences, 67, 12, pgs. 1676-81 1978). Although polysorbate 20 produced by a variety of manufacturers can be used, the preferred surfactant is "fresh" polysorbate 20 as described hereinafter. It has been found herein that Polysorbate 20 which was more than two years old gave variable results in dissolution tests of the same lot of steroidal formulation. Although the surfactant was not expired (manufacturer's expiration date) and met accepted USP acid values (<2.2) variable test results were a problem. When 4 year old surfactant was employed, the number of hours of premixing was inversely proportional to the percentage of dissolved steroid. For example, in dissolution tests of tablets containing norgestimate, 4 year old surfactant was used and the dissolution solution was premixed for 96 hours. At 20 min the percentage of dissolved steroid was 46.5 to 56.6%. This test was repeated using the same steroid and surfactant, but reducing the premixing time to 24 hour and gave 81.2 to 90% as the percentage of dissolved norgestimate at 20 min. However when one year old polysorbate 20 was used, the length of time that the surfactant was premixed with the water did not affect the dissolution results within a single batch. It has also been found that age alone is not the determinative factor for the suitability of polysorbate 20. Whether or not the polysorbate 20 was stored in the presence or absence of light, factors into the surfactant's usefulness for dissolution testing. Dissolution tests were run with 4 year old unprotected and light protected polysorbate 20 on single lots of steroidal formulations. These results were compared with dissolution runs with one year old polysorbate 20. The test results using the light protected material were within 4.5% of the test results obtained using one year old polysorbate. Whereas the results obtained using the unprotected material were only within 10.1% of the standard. Once again USP acid values could not be used to predict the suitability of the surfactant, for the unprotected and the light protected material were below the USP cutoff of 2.2 (2.0 and 1.7 respectively). The USP guidelines make no mention of storing the surfactant in the absence of light. The guidelines only require storage in sealed containers. Bearing all the aforementioned factors in mind, it is preferred herein to use fresh polysorbate 20: polysorbate that is less than 2 years old, which has been stored in the absence of light and has been stored under an inert atmosphere. It is possible to obtain reliable and reproducible dissolution test results using polysorbate 20 that does not meet all three criteria. However, the preferred polysorbate 20 is material that meets all three criteria. In addition to the condition of the surfactant, the type of water, temperature of the dissolution medium and concentration of the surfactant affect dissolution testing. The preferred water is helium sparged deionized water, but bottled water may be substituted. The preferred temperature of the dissolution medium is about 37 °C. However in vitro dissolution tests may be run from about 34 -42 °C. The type of paddle assembly used in the invention's in vitro test may vary, and those skilled in the art of dissolution testing may use apparatuses suitable to their needs. However a USP Paddle Assembly II (Volume 23) is the preferred assembly. With respect to concentration of surfactant, Table A illustrates that dissolution rates increase with increasing surfactant concentration. The data in this table was generated by testing a single lot of steroid with different concentrations of polysorbate 20 in the following manner. Deionized water was premixed with the sufficient polysorbate 20 to give the indicated concentration over 16 h. This solution (600 mL) was placed in each of the reaction vessels of a USP Paddle Assembly II (vol 23/18), stirred at 75 r.p.m. and equilibrated to 37 °C. A norgestimate and ethinyl estradiol formulation was added to each vessel, samples were removed at 20 min and analyzed by routine HPLC methods for the percentage of dissolved norgestimate. The first four runs used fresh polysorbate and the last run (*) used 4 year old surfactant. The data is represented as both the average % and the range of values obtained. As shown, the concentration of polysorbate 20 which give the narrowest range of values is 0.05% of fresh polysorbate 20. Therefore the preferred concentration of polysorbate 20 is 0.05%. Although the data below was obtained for norgestimate, similar results are expected for ethinyl estradiol, the other steriodal component of the formulation. TABLE A % Polysorbate 20 Average % Dissolved Range % Dissolved 0.125% 93.4 91.6-95.7 ( E 4.1 ) 0.075% 91.0 86.6-94.3 ( E 7.7) 0.05% 80.9 78.1-82.1 ( E 4.0) 0.025% 71.8 66.8-75.9 ( E 9.1 ) *0.05% 83.4 79.4-90.6 ( E 11.2) The following example is meant to illustrate the invention, not to limit it. Other embodiments will be obvious to those skilled in the art and are claimed by this invention. The identity of the compounds was confirmed by HPLC comparison with known standards. The amount of dissolved steriod was deterrmined by their HPLC area%. The polysorbate 20 used was "fresh" polysorbate as defined above. Example 1 Deionized water was sparged with helium for at least 12 min. Fresh polysorbate 20 (3.0 g; Tween ® 20) was placed in a 400 mL beaker and dissolved in sparged water (200 mL) at room temperature with the aid of mechanical stirring. The resulting solution was diluted with sparged water to 6L and stirred overnight at room temperature. A portion of the resulting solution (600 mL) was added to each vessel of a USP Paddle Assembly II (vol 23/18), the solution was stirred at 75 r.p.m. and the temperature bath of said assembly and equilibrated to 37+ 0.5 °C. Tablets containing ethinyl estradiol (EE) and norgestimate (NGM) of five lots and a control (Lot B) were dropped into the equilibrated dissolution vessels (one table per vessel and 12 vessels/lot). Samples (10 mL) were taken at 15, 20 and 30 min. Said samples were analyzed for their % of dissolved steroids by HPLC and reported (TABLE B) as the average % dissolved and the range % dissolved. The individual lots correspond to tablets containing NGM/EE mg, in the following proportions: A= 0.215/0.035 mg, B= 0.250/0.035 mg, C= 0.180/0.035 mg, D=0.250/0.035 mg, E= 0.180/0.035 mg, F= 0.215/0.035 mg. TABLE B

Claims: What is claimed is: 1. A method of measuring the dissolution rate of a solid steroidal pharmaceutical formulation, comprising: 1 ) adding said formulation to a paddle assembly containing an aqueous solution of polysorbate 20, where the concentration of polysorbate 20 is about 0.025% to about 0.15% weight/volume, the temperature of the assembly is about 37 °C; 2) removing aliquots and 3) measuring the percentage of steroid contained therein. 2. The method of claim 1 wherein the concentration of polysorbate 20 is about 0.025% to about 0.1 %. 3. The method of claim 1 wherein the solid steroidal pharmaceutical formulation contains norgestimate. 4. The method of claim 1 wherein the solid steroidal pharmaceutical formulation contains ethinyl estradiol. 5. The method of claim 1 wherein the polysorbate 20 is fresh polysorbate 20. 6. A method of measuring the dissolution rate of a solid steroidal pharmaceutical formulation, comprising: 1 ) adding said formulation to a paddle assembly containing an aqueous solution of fresh polysorbate 20, where the concentration of fresh polysorbate 20 is about 0.025% to about 0.10% weight/volume, the temperature of the assembly is about 37 °C; 2) removing aliquots and 3) measuring the percentage of steroid contained therein. 7. The method of claim 6 wherein the concentration of fresh polysorbate 20 is about 0.025% to about 0.06%. 8. The method of claim 7 wherein the solid steriodal pharmaceutical formulation contains norgestimate. 9. The method of claim 7 wherein the solid steriodal pharmaceutical formulation contains ethinyl estradiol. 10. A method of measuring the dissolution rate of a solid steroidal pharmaceutical formulation containing norgestimate, comprising: 1 ) adding said formulation to a paddle assembly containing an aqueous solution of polysorbate 20, where the concentration of polysorbate 20 is about 0.04% to about 0.06% weight/volume, the temperature of the assembly is about 37 °C; 2) removing aliquots and 3) measuring the percentage of steroid contained therein. 11. The method of claim 10 wherein the concentration of polysorbate 20 is about 0.05%. 12. A method of measuring the dissolution rate of a solid steroidal pharmaceutical formulation containing ethinyl estradiol, comprising: 1 ) adding said formulation to a paddle assembly containing an aqueous solution of polysorbate 20, where the concentration of polysorbate 20 is about 0.04% to about 0.06% weight/volume, the temperature of the assembly is about 37 °C; 2) removing aliquots and 3) measuring the percentage of steroid contained therein. 13. The method of claim 12 wherein the concentration of polysorbate 20 is about 0.05%.

Inventors: CORBO MICHAEL, DEGHETTO PAUL KEVIN, SCHULTZ THOMAS WILLIAM, CORBO, MICHAEL, DEGHETTO, PAUL, KEVIN, SCHULTZ, THOMAS, WILLIAM
Applicants: ORTHO PHARMA CORP, ORTHO PHARMACEUTICAL CORPORATION
Application year: 1997
Main classification: G01N33
IPC codes: A61K9, G01N13, G01N33