Good agreement between theoretical and experimental dissolution profiles were found when furosemide powders were dispersed by ultrasonication in a surfactant solutionfor all but the smallest of three batches of powder. The mean particle sizesfor the batches were 3, 10, and 19 mm when particle size was measured after sonication. Without sonication, the particle sizes were measured to be 108,38, and 27mm corresponding to the post sonicated measurements of 3, 10,and 19 mm, respectively. The relative order of the dissolution rates were also reversed before and after dispersion, indicating that comparing theoretical profiles with actual profiles would reveal the problem with agglomeration. For the smallest particle size batch of furosemide that did not agree well with the theoretically calculated dissolution rate, the drug particles were observed to agglomerate during dissolution, which would explain why the actual dis-solution rate was slower than predicted by the applications of trying to predict dissolution based on the Whitney theory, solubility, and drug particle size is to identify potential formulation problems, such as wetting and slow disintegration. This is accomplished by comparing the predicted dissolution profile with the actual profile of the formulation. If the actual dissolution profile of the dosage form is similar to that predicted by theory, one could reasonably conclude that the formulation was disintegrating rapidly and that the surface area of the released drug particles were well wetted. However, dissolution slower than predicted should be investigated to determine the cause. To this end, drug powder dissolution in the absence of excipients but with the judicial use of surfactants and agitation to promote wetting but not to increase solubility or reduce particle size can help establish problems with agglomeration and poor wetting. Dissolution profiles faster than expected might indicate a change in drug form, resulting in a higher solubility or an increase in drug surface area, either of which might occur due to formulation processing. The approach of using the dissolution theory described earlier to evaluatethe dispersion process for furosemide has been reported (20). Good agreementbetween theoretical and experimental dissolution profiles were found whenfurosemide powders were dispersed by ultrasonication in a surfactant solutionfor all but the smallest of three batches of powder. The mean particle sizesfor the batches were 3, 10, and 19 mm when particle size was measured aftersonication. Without sonication, the particle sizes were measured to be 108,38, and 27 mm corresponding to the post-sonicated measurements of 3, 10,and 19 mm, respectively. The relative order of the dissolution rates were alsoreversed before and after dispersion, indicating that comparing theoretical pro-files with actual profiles would reveal the problem with agglomeration. For thesmallest particle size batch of furosemide that did not agree well with thetheoretically calculated dissolution rate, the drug particles were observed to agglomerate during dissolution, which would explain why the actual dissolution rate was slower than predicted by theoryOne of the applications of trying to predict dissolution based on the Whitney theory, solubility, and drug particle size is to identify potential formulation problems, such as wetting and slow disintegration. This is accomplished by comparing the predicted dissolution profile with the actual profile of the formulation. If the actual dissolution profile of the dosage form is similar to that predicted by theory, one could reasonably conclude that the formulation was disintegrating rapidly and that the surface area of the released drug particles were well wetted. However, dissolution slower than predicted should be investigated to determine the cause. To this end, drug powder dissolution in the absence of excipients but with the judicial use of surfactants and agitation to promote wetting but not to increase solubility or reduce particle size can help establish problems with agglomeration and poor wetting. Dissolution profiles faster than expected might indicate a change in drug form, resulting in a higher solubility or an increase in drug surface area, either of which might occur due to formulation processing. The approach of using the dissolution theory described earlier to evaluatethe dispersion process for furosemide has been reported. Good agreement between theoretical and experimental dissolution profiles were found whenfurosemide powders were dispersed by ultrasonication in a surfactant solution for all but the smallest of three batches of powder. The mean particle sizesfor the batches were 3, 10, and 19 mm when particle size was measured aftersonication. Without sonication, the particle sizes were measured to be 108,38, and 27 mm corresponding to the post sonicated measurements of 3, 10,and 19 mm, respectively. The relative order of the dissolution rates were alsoreversed before and after dispersion, indicating that comparing theoretical profiles with actual profiles would reveal the problem with agglomeration. For the smallest particle size batch of furosemide that did not agree well with the theoretically calculated dissolution rate, the drug particles were observed to agglomerate during dissolution, which would explain why the actual dissolution rate was slower than predicted by theory Disintegration, wetting, and agglomeration should be understood and addressed by the formulator. If not, more variability in the in vitro/in vivo correlation is likely to result if a patient were to ingest something that might increase the wetting of a drug product that does not provide a surfactant itself. This would be analogous to adding a surfactant to the dissolution mediainstead of the formulation to achieve a desired dissolution profile. Again,theory can help the formulator identify potential dissolution problems. The ability of the theory presented herein to simulate a polydisperse powder under nonsink conditions, which has been shown in studies that carefully address wetting and dispersion, challenges the conventional wisdom of conducting dissolution under sink conditions. The following example will be based on the physical properties of digoxin, whose bioavailability has been shown clinically tobe dependent on its particle size (21). This dependency requires that drug particlesize be controlled so that dissolution and bioavailability is consistent from batch to batch of drug product. The question is whether to test dissolution under sink or non sink conditions. Hypothetically, let it be assumed that the drug particle size specificationcalls for the drug powder to have a geometric mean particle size of 10 mm and ageometric standard deviation of 2. Figure 3 compares the simulated dissolution profiles of a 1 mg dose of drug that has a solubility of 0.05 mg/mL, similar indose and solubility to digoxin. Profiles compare the simulated dissolution of a1 mg dose in 900 or 90 mL of water for drug powders with geometric meanparticle sizes of 10 and 20 mm, both with geometric standard deviations of2. In Figure 3, dissolution is expressed as mass dissolved as a function of timewith total dissolution occurring at the dose of 1 mg. The higher and lowersolid line profiles represent the dissolution of 10 and 20 mm powders, respectively, dissolving in 900 mL. The higher and lower dash line profiles representthe dissolution of 10 and 20 mm powders, respectively, dissolving in 90 mL.
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