Adjusting the dose in paediatric care: dispersing four different aspirin tablets and taking a proportion

Abstract

What is already known on this subject ► Children lack age-appropriate medicines, and because of this dosage forms (eg, tablets) may be manipulated by, for instance, splitting, crushing or dispersing, before a small fraction is withdrawn to obtain a prescribed dose. ► MODRIC (Manipulation of Drugs Required in Children) has provided guidelines for manipulation of tablets, and the guideline recommends that dispersion should only be performed if there is knowledge about 'solubility', 'dispersibility' or 'any special characteristics of the formulation'. ► A previous study found that manipulation through dispersion and fraction extraction of tablets containing the slightly soluble substance aspirin did not result in correct doses 22 ; however, only one tablet formulation was investigated. What this study adds ► The variation in dose accuracy and dose precision that can be encountered when aspirin tablets are dispersed and a fraction (10% or 20% of the whole tablet) is withdrawn as a paediatric dose is illustrated for four different commercially available aspirin tablets (one conventional, one chewable and two dispersible) and three different mixing procedures. ► The dose accuracy varied markedly for the different kinds of tablets, and only fractions taken from the dispersible aspirin tablets came within 20% of the intended dose. ► Fractions taken from dispersions of the conventional and chewable tablets did not reach this level of accuracy, regardless of mixing procedure. AbsTrACT Objectives When caring for children in a hospital setting, tablets are often manipulated at the ward to obtain the right dose. One example is manipulation of tablets containing the slightly water-soluble substance aspirin, used in paediatric care as an antiplatelet agent. The evidence base, however, for choosing certain tablet formulations and manipulation methods over others for extraction of proportions is lacking. The aim of this study was to investigate the effect of tablet formulation and manipulation technique on the dose accuracy and precision attained when dispersing different commercially available aspirin tablets and extracting a small proportion suitable for children. Methods The manipulation methods investigated simulated those observed in the paediatric clinic. Four tablet formulations-one chewable, one conventional and two dispersible-were dispersed in 10 mL water in a medicine measure. On (1) passive dispersion, (2) mixing by stirring with the syringe, or (3) stirring and pumping the dispersion in and out of the syringe, respectively, proportions (1 mL or 2 mL) were extracted and the doses recovered were determined using a validated UHPLC (ultra high-pressure liquid chromatography) method. results Fractions from the four different dispersed aspirin tablet formulations varied from 99% to 3% of that intended with the lowest degree of mixing, and from 96% to 34% of that intended with the highest degree of mixing. Only the dispersible tablets gave average doses within 20% of the intended dose. Conclusions Fraction extraction from d...

Comparing Two Methods of Tablet Manipulation to Adjust the Warfarin Dose in Paediatric Care

“…The finding that most of the warfarin tablet manipulations-except the splitting step-gave an acceptable recovery is in contrast to what was observed for tablets containing slightly soluble aspirin [14,25]. Comparing four types of aspirin tablets (one chewable, one conventional, and two dispersible), both accuracy and precision in the aspirin amount retrieved could be poor depending both on the tablet type chosen and the manipulation method used [14], e.g., for one 500 mg aspirin tablet only 3% of the dose intended was recovered when a full tablet was dispersed in 10 mL water and 1 mL was directly extracted as the simulated dose, and no more than 43% could be recovered using various mixing procedures. Splitting the tablet first, dispersing the half or quarter fragments in water in general improved accuracy, particularly if the fragment was dispersed directly in the oral syringe.…”

“…Regarding precision, the European Pharmacopoeia [22] states that for split tablets, no fragment should deviate more than 25% from the average (n = 30), and only one fragment should deviate with more than 15%. Formal limits with regards to tablet fractions obtained by manipulated are not known to us, but 20% deviation has been practiced previously [14,23]. In this study, these limits are used to provide context to the acceptability of the variability introduced by different manipulations; however, considerations regarding individual drug substances should be made in addition.…”

“…Splitting is the recommended method outlined in the MODRIC guideline ("Manipulation of drugs required in children") [10] but fraction extraction is a method frequently Pharmaceutics 2020, 12, 375 2 of 13 used [10]. Considerable variation may be introduced, however, both by splitting [11,12] and fraction extraction [13,14], and the variations could possibly be tied to differences in formulation. Regarding tablet splitting, Elliott et al [12] found that only three of eight investigated tablets met the European Phamacopoeia limit for tablet halves upon splitting, judged by weight, and the differences between the eight tablets investigated were considerable.…”

“…Regarding the fraction extraction method, substantial variation in the drug amount obtained by manipulation has also been demonstrated for four different tablets containing aspirin (one chewable, one conventional, and two dispersible tablets). The mean recovery of fractions varied from 34% to 96% of that intended when tablets were dispersed and a proportion (20% of a full tablet) was withdrawn [14]. As different tablets behave so differently with regards to manipulation, questions arise.…”

“…In previous studies, focusing on aspirin tablets, we hypothesized that aspirin, being "slightly soluble" in water [16], and also being available in tablets in higher doses (e.g., 75-500 mg), could cause dose inaccuracies through sedimentation in several manipulation methods [14]. Warfarin sodium is another anticoagulant drug, differing from aspirin due to its very good water solubility [16] and lower dose requirement in tablets (e.g., 2.5 mg).…”