The official compendia apparatus and method for testing dissolution, and even disintegration (
27), of SL tablets includes the use of large volumes of dissolution medium with constant agitation surrounding the tablets. These conditions do not simulate those in the SL cavity. More bio-relevant dissolution tests for SL tablets were proposed in the 1970s using methods based on
in situ concentration measurement (
28), but few advances have been reported in recent years. Due to the limited number of SL tablet formulations now commercially available, there is limited focus for dissolution testing of this dosage form. In contrast, buccal formulations have been studied extensively, leading to advances in dissolution apparatus, procedures, and techniques (
29). Although both buccal and SL formulations are intended to be administered within the oral cavity, there are significant differences in design of these formulations which in turn lead to different physicochemical and release characteristics. It is “bio-irrelevant” to apply one single apparatus and method to test the API release of two or more different dosage form categories,
i.e., oral
versus SL tablets. Instead, the guidelines of the International Pharmaceutical Federation/American Association of Pharmaceutical Sciences recommend that “different apparatus should be employed on a case-by-case basis, and the method should be specific to the dosage form category, formulation type, or even to a particular, individual product” (
30). The custom-made apparatus and the novel
in vitro method proposed here were specifically designed to evaluate the dissolution of rapidly disintegrating SL tablets.
The dissolution testing consists of two main steps: the dissolution of the dosage form when the API is released and dissolved into the medium, and the measurement of the API content in the samples. These two steps are separated by a filtration step (
15) which ensures that the sample for analysis contains only the API in solution, dissolved in the specified time period. The design of our apparatus was based on these concepts. The API was released and dissolved in the dissolution medium inside the glass funnel, and the samples were instantaneously collected at the specified time-point in the collecting tube following filtration to prevent the passage of undissolved API solid particles and to terminate dissolution.
The reusable parts that came into contact with the API including the glass funnel and the fritted glass base (Fig. ) were thoroughly cleaned between tests. Any API remaining in the dissolution apparatus was totally removed prior to the next dissolution test in order to maintain the integrity of testing.
Five washings were sufficient to remove virtually 100% of any residual E left in the fritted glass base after the filtration of either low or high concentrations of standard E solutions. Similarly, the potential problem of minimal amounts of E that might have been adsorbed to the nylon filter membrane (
31) was solved by replacing the membrane after each test to prevent carry-over to the next test. Other filter membrane materials (
32) could be evaluated for possible reduction in the adsorption of API. The recovery of API could also be improved by discarding a partial fixed volume of filtrate before analysis. This step insures that the available active adsorption sites in the filter membrane are saturated and the subsequent filtration does not further decrease the API concentration in the filtrate (
31).
The percent of drug released and dissolved increased with time from 15 to 60 s and was virtually 100% at 120 s for the representative E 40 mg SL tablet (Fig. ). The source of variability among time-points could be partially due to variability in tablet content. Since individual SL tablets had to be used for each time-point as replicates, greater variability was expected due to content variability among tablets, which were always within the USP limits. However, use of the novel in vitro method resulted in reproducible dissolution data, with a coefficient of variation of 5.6% at 60 s and 3.2% at 120 s. Time-points ≥60 s were associated with less variability than those <60 s; consequently, the 60 and 120 s intervals were selected for dissolution testing of SL tablets.
Between-days reproducibility was achieved for both the commercial tablets and the E 40 mg SL tablets under development (Fig. ). This ensured that the dissolution testing variability among different tablets within the test and among different test days resulted in acceptable consistency using the novel in vitro method.
Our custom-made apparatus required a different tablet to test dissolution at each time-point. Dissolution testing at a range of time-points is required only for modified release formulations and the demonstration of an API release profile over time (
33). This apparatus is intended to evaluate SL tablets at the single time-point recommended for SL tablet administration (
26). When assessing drug release from rapidly disintegrating SL tablets, the major objective is to ensure virtually total release of the API for absorption within 120 s or less after insertion into the SL cavity.
The sensitivity of the novel
in vitro method to evaluate different SL tablet formulations was tested using both commercial tablets and representative E SL tablets under development (Fig. ). It was shown that Apo-ISDN SL tablets released about 1% of the label content after 60 s and not more than 2% after 120 s. The low DR% of Apo-ISDN could result from a poor SL formulation as reported previously for one of the ISDN SL products of slow and/or incomplete disintegration resulting in lack of therapeutic effectiveness (
34). The Apo-ISDN disintegration time was less than 10 s; therefore, the low DR% of Apo-ISDN was anticipated because of the low water solubility of ISDN. Subsequently, the volume of dissolution medium for Apo-ISDN was increased from 2 mL to 10 mL, a volume that is more than sufficient to dissolve the 5 mg dose of ISDN, but is still below “sink” conditions. Even in the presence of 10 mL of dissolution medium, only 8% (0.4 mg out of 5 mg) of ISDN was dissolved (Fig. ) and would theoretically be available for absorption within the SL cavity. The remaining dose is swallowed and metabolized for ongoing activity via the ISDN metabolites, isosorbide mononitrates, following oral administration. The systemic availability of ISDN after SL and oral tablets was previously reported to be similar, based on plasma levels and area under the plasma concentration
versus time curve of the ISDN metabolites (
35). The only advantage of a SL tablet of ISDN therefore seems to be the rapid disintegration and fast onset of action of the initial 8% of the dose.
The novel
in vitro method was also evaluated for its ability to discriminate among representative E 40 mg SL tablets which have similar
in vitro DTs. In previous
in vitro and
in vivo studies, E SL tablet formulations with similar DTs had different bioavailabilities (
18). Although the DT test ensures tablet breakdown into smaller particles, it does not evaluate the rate and extent of the API release, and in general, disintegration has been proved to be a poor indicator of bioavailability (
36). The dissolution assessment is a more selective
in vitro test than disintegration for predition of
in vivo behavior. For tablets showing a narrow range of DTs (11–15 s), the novel
in vitro method was sufficiently sensitive to identify a significant difference in DR% at 60 s ranging from 58% to 104% (Fig. ). For example, formulations 4, 5, and 6 showed identical DT (13 s), but the novel
in vitro method was able to detect formulation differences resulting in DR% that ranged from 69% to 96% after 60 s.
Using the official USP dissolution method, the concentrations of nitroglycerin could not be detected for Nitrostat® (nitroglycerin 0.6 mg), due to the sensitivity limit of the UV detector for a 0.6 mg in 900 mL dissolution medium (Fig. ). In 900 mL, a minimum of 50 Nitrostat® SL tablets would be required for UV detection, which is impractical. This small-volume custom-made apparatus has the advantage of detecting low dose APIs in commercial SL tablets like Nitrostat®. Using the novel in vitro method, the quantitative levels of nitroglycerin from individual tablets were obtained that could be quantified by UV analysis.
With regard to Apo-ISDN (ISDN 5 mg), a procedure for testing a pooled sample of six tablets in the same dissolution vessel was followed by using the USP dissolution apparatus 2 (Paddle;
10). This resulted in 92% of the drug being released after 20 min, which does not necessarily represent the dissolution within 120 s in 2 mL of saliva in the SL cavity. Using the novel
in vitro method, individual Apo-ISDN SL tablets were tested in replicate, and 1% of the drug was released at 60 s (Fig. ). Since only 2 mL of dissolution medium was available for Apo-ISDN in the custom-made apparatus, ISDN solubility was considered to be the rate-limiting step in this process. To provide acceptable “sink” conditions for ISDN 5 mg, at least 15 mL of saliva should be available within the SL cavity which is larger than the normal physiological secretions of saliva in 2 min.
This small-volume custom-made apparatus offers the advantage of testing dissolution in volumes of dissolution medium as low as 2 mL, similar to the volume of saliva normally secreted over 2 min (
5). After administration, the SL tablet is maintained in a relatively quiescent environment under the tongue as simulated in this apparatus. The lack of agitation of dissolution medium in our apparatus eliminates the problem of unstable hydrodynamics of small-volume dissolution apparatus, which is a major concern with USP Basket or Paddle apparatuses (
14,
37–
39).
The current design of the apparatus only permits the operation of dissolution testing at room temperature (25°C), but it could be modified to provide the testing of physiological temperatures of 37°C. However, since SL tablets are only exposed to the 2 mL of dissolution medium for ≤120 s, the increased temperature effect on drug dissolution is anticipated to be minimal.
The multi-unit apparatus (Fig. ) facilitates testing the dissolution of six SL tablets simultaneously similar to the official USP dissolution apparatus. This novel in vitro method demonstrated day-to-day reproducibility and discrimination among formulations.
1 Mutasem Rawas-Qalaji,2 F. Estelle R. Simons,3,4 and Keith J. Simons1,3
<
