INFLUENCE OF SPLITTING ON DISSOLUTION PROPERTIES OF METOPROLOL TABLETS

Th e objective of this work was to compare several profi les of dissolution data for metoprolol controlled release tablet formulations in order to identify possible changes in dissolution profi les of whole and scored tablets. Adequate design of score lines (on one or both sides) as well as the technology of preparation of tablet mixtures ensure forming a score line of adequate thickness, shape, size, curvature. According to the obtained results, this type of extended release formulation is eligible for splitting and use in therapy either as a whole or scored tablets.


Introduction
Metoprolol is a cardioselective β-blocker that is classifi ed as a class I substance according to the Biopharmaceutics Classifi cation Scheme BCS (), meaning that it is highly soluble and highly permeable. Th e drug is readily and completely absorbed throughout the whole intestinal tract (-) but is subject to extensive fi rst-pass metabolism resulting in incomplete bioavailability (about ). When administered as single oral dose, peak plasma concentrations occur after - hours. Th e drug is eliminated within  to  hours, which, depending on therapeutic intentions, makes it necessary to administer simple formulations of metoprolol up to  times daily (). Based on these properties and the well-defi ned relationship between the β-blocking eff ect and plasma drug concentration (), metoprolol is accommodated into extendedrelease (ER) formulation (,,). Metoprolol ER formulations smooth out peaks and valleys in the plasma levels and enable less frequent administration. Dosing intervals are typically reduced to once or twice per day ().
On the other hand, the ability to adjust doses to individual patients depends on the availability of multiple dose sizes and adequate dose response information. These are not always provided, so splitting of the tablets is sometimes necessary (). Tablet splitting is an accepted practice in dispensing medications. It is used when a dosage form of the required strength is not available commercially ().
The aim of this study was to establish possible influence of tablet splitting on dissolution profile of metoprolol extended release tablets.

Reagents
The used reagents were of analytical grade, unless otherwise stated. Metoprolol tartarate working standard was provided by Merck (Darmstadt, Germany). Sodium dihydrogen phosphate, disodium hydrogen phosphate were provided by Carl Roth GmbH & Co (Karlsruhe, Germany).

Drug dosage form (extended release tablets) tested
The tablets applied for this study were in the form of snap-tab-tablets. Each tablet consisted of  mg of metoprolol tartarate as an active ingredient. The tablet core consisted of eudragit RL PO/ RS PO; lactose monohydrate; magnesium stearate; maize starch; anhydrous colloidal silica. Film-coating suspension consisted of methylhydroxypropyl cellulose, polyethylene glycol , talc and titanium -dioxide (E).

Breakability test method-manual method
Th e tablet was held between the thumb and the index fi nger of each hand on either side of the score line (score line was on both sides of tablet) and without using the nail. Separation into two halves was done by breaking open the tablet at the deeper score line side ( Figure .).

Preparation of standard solutions
A standard curve of absorbance versus concentration was constructed using previously degassed solutions of metaprolol tartarate in the dissolution medium (phosphate buffer, pH= ,), ranging in concentration from , to , mg/ml. Absorbance versus concentration plot was linear over this concentration range and was used to determine percent of drug dissolved in the dissolution experiments. UV absorbance of each standard solution was measured spectrophotometrically at  nm.

Dissolution test conditions and analysis procedure
Th e dissolution test of metoprolol extended release tablets (n=), was performed using USP apparatus , Van Kel VK  dissolution tester, at a stirring speed of  rpm (Van Kel, Cary, NC, USA). Th e dissolution apparatus was maintained at  o C throughout the experiment. Th e test was carried in phosphate buff er solution, pH=,. Prior to use, the dissolution medium was deareated in the ultrasonic bath and warmed up to  o C, fi ltered using a , μm membrane fi lter (Sartorious GmbH, Goettingen, Germany) and transferred to dissolution vessel. Th e analysis was initiated once the medium cooled to  o C.
Dissolution samples in the amount of  ml were withdrawn at the following intervals (after , , , , ,  and  minutes). Correction for volume was calculated mathematically, considering that withdrawn samples were not supplemented with an equal volume of fresh dissolution fl uid to maintain a constant total volume.
Th ese samples were also fi ltered using a , μm membrane fi lter (Sartorious GmbH, Goettingen, Germany). Th e dissolution apparatus was connected with UV/VIS spectrophotometer Shimadzu  (Shimadzu, Kyoto, Japan). Determination of dissolution rates for the active ingredient in fi lm tablets was carried out according to the previously described spectrophotometric method. All the dissolution tests were performed in triplicate.

Applied method to compare dissolution profi les
In this study, as model-independent approaches (, ), two fi t factors that compare the dissolution profi les of a pair of drug products were applied to the dissolution data. Th ese fi t factors directly compare the diff erence between percent of drug dissolved per unit of time for the tested product and the reference. Th e fi t factors are denoted f (diff erence factor), and f (similarity factor) () and are defi ned by Eqs. () and (): where n is the number of dissolution sample time points, and R t and T t are individual or mean percent dissolved at each time point, t, for the reference and test dissolution profiles, respectively (, ).
Th e similarity factor fi ts the result between  and . When the test and reference profiles completely coincide the value is  and tends to  as the dissimilarity increases. This method is more adequate to dissolution profile comparisons when more than three or four dissolution time points are available. Eq. () can only be applied if the average diff erence between R and T is less than . If this difference is higher than  normalisation of the data is required (). Th is similarity factor has been adopted by the Center for Drug Evaluation and Research (FDA) and by Human Medicines Evaluation Unit of The European Agency for the Evaluation of Medicinal Products (EMEA), as a criterion for the assessment of the similarity between two in vitro dissolution profi les and is included in the ''Guidance on Immediate Release Solid Oral Dosage Forms; Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence Documentation'' (), commonly called SUPAC IR, and in the ''Note For Guidance on Quality of Modifi ed Release Products: A. Oral Dosage Forms; B. Transdermal Dosage Forms; Section I (Quality)'' (). Similarity factor ( f ) as defi ned by FDA and EMEA is a logarithmic reciprocal square root transformation of one plus the mean squared (the average sum of squares) diff erences of drug percent dissolved between the tested product and the reference.
Th is equation diff ers from the one proposed by Moore and Flanner in the weight factor and in the fact that it uses percent dissolution values. In order to consider the similar dissolution profi les, the f values should be close to  and values f should be close to . In general, f values lower than  (-) and f values higher than  (-) indicate similarity of dissolution profi les. FDA and EMEA suggest that two dissolution profi les are declared similar if f is between  and . In addition, it requests the sponsor uses the similarity factor to compare the dissolution treatment eff ect in the presence of at least  individual dosage units.

Results and Discussion
The results of dissolution analysis are summarized in Table , and Figure , which show the fraction of the dissolved drug as a function of time.
Also, the results of f and f analysis are summarized in Table ,  and  and indicate similarity of dissolution profi les TABLE 1. Fraction of the dissolved drug as a function of time from the whole tablets (1x200 mg), 1/2 tablets (1x100 mg) and halved tablets (2x100 mg)  (Table ).

Conclusion
Integrity changes of the analysed tablets during tablet splitting (halved vs. whole tablets) showed greater infl uence on the results obtained than the diff erence in declared content ( mg vs.  mg). Adequate design of score lines (on one or both sides) as well as the technology of preparation of tablet mixture ensures forming a score line of adequate thickness, shape, size, curvature. Th is line would minimize the contact area at splitting position and represents an important criterion in the design of products with extended release which would be appropriate in the therapy as a whole or halved tablets (dosage forms). According to the results obtained, this formulation is eligible for splitting and may be used in therapy either as a whole or scored tablets.