Evaluation of Newly Designed and Traditional Punches in Manufacturing of Scored ODTs

To overcome difficulties in splitting, uneven breaking and inconsistent dosing frequently reported with scored tablets, a novel punch was proposed for the manufacturing of easy breakable tablets (EBTs). In this work, the performance of the EBT punch was investigated vs. a ridged one for traditional breakable tablets (TBTs) using a furosemide powder formulation for orally disintegrating tablets (ODTs). A Face Centered Central Composite Design was applied to investigate the influence of punch type, compaction force, tablet weight and press rotation speed on the mechanical properties of ODTs, their behavior in aqueous fluids and aptitude for splitting. Mass uniformity and adequate crushing strength, friability, water uptake, disintegration and wetting times were obtained from both TBTs and EBTs. Interestingly, more favorable splitting behavior was shown by tablets manufactured by the novel punch, in view of lower mass loss and portion mass variability after breaking. The ease of breaking, accuracy of subdivision and mass loss of ODTs were also evaluated by a volunteer (n = 20) panel test. Less difficulty was found in splitting EBTs than TBTs (p < 0.05), and a larger number of tablets were properly broken into four parts. Thus, this study proved the usefulness of the EBT punch in overcoming drawbacks associated with divisible tablets

In the last years, orally disintegrating tablets (ODTs) have attracted a great deal of attention as a dosage form suitable to increase the patient compliance. ODTs have been defined as solid dosage forms containing medicinal substances, which disintegrate rapidly, usually within a matter of seconds, when placed upon the tongue [1].

In addition to the advantages of solid oral dosage forms, due to their ability to disintegrate rapidly upon contact with the saliva, ODTs could address many patient needs, such as convenient administration for dysphagia sufferers, more commonly pediatric, geriatric, psychiatric and patients with nausea, vomiting and motion sickness complications [2]. Moreover, ODTs would facilitate dosing when there is no access to water, which often makes them the preferred alternative to conventional tablets and capsules [3]. Finally, they would allow for a prompt onset of action and, in some cases, drug absorption directly from the mouth avoiding or reducing first-pass metabolism.

ODTs can be obtained with different techniques, yielding dosage forms with different physical characteristics, especially in terms of mechanical properties [4,5]. Direct compression is the most advantageous because of the use of conventional equipment, extensive know-how and low costs [6]. However, since ODTs should be endowed with high porosity to improve water uptake and enable rapid disintegration, they commonly require to be tableted at low compaction forces. This may result in mechanical strength and friability issues, and thus in problems with their handling and the accuracy of the drug dose administered [3].

Scored ODTs would offer additional advantages in terms of dose flexibility and personalization, which may be reflected in a reduction in health care expenditure [7,8,9,10,11,12]. One or more score lines on the surface of tablets are useful to split them by hand into two, three or four portions. Otherwise, the use of a splitter, scissors or a knife could help divide the tablet into subunits.

The uneven breaking of tablets may result in inconsistent dosing and, consequently, in variable drug plasma levels that could be clinically relevant especially for drugs with a narrow therapeutic range.

The accuracy of subdivision needs to be evaluated by determining the uniformity of mass of the portions generated by splitting, according to the relevant monographs in the European Pharmacopoeia and United States Pharmacopeia. Moreover, an article in the Stimuli to Revision Process section of Pharmacopeial Forum, titled Pharmacopeial Standards for the Subdivision Characteristics of Scored Tablets, indicates that the ease of subdivision along the score lines should be considered as well as the loss of mass due to possible crumbling or detachment of small fragments associated with tablet splitting [13].

Many patients were reported to perceive scored tablets as having bad splitting behavior, which might consequently lead to non-compliance issues [14]. These negative feedbacks were mainly related to dysfunctional score lines, which lead to difficulties in subdivision. Moreover, excessive loss of mass and poor reproducibility of the portion mass after breaking were highlighted in a number of studies [12,14]. Characteristics of the tablets, such as the size, shape, hardness and presence as well as geometry of the score lines were shown to have a strong impact on the degree of difficulty encountered in breaking a tablet [11,12]. In this respect, continued improvement in the design of punches is necessary.

Recently, a newly designed ridged punch was proposed for the manufacturing of cross-scored easy breakable tablets (EBTs) [15]. The novel EBT punch was successfully employed for the preparation, starting from a number of co-processed excipients of placebo ODTs of 8 mm in diameter, which showed satisfactory mechanical properties on the one hand, and adequate water uptake as well as disintegration performance on the other.

Based on the above premises, the aim of the work was to study the performance of the novel EBT punch for the manufacturing of furosemide-containing cross-scored ODTs and to compare it with a traditional cross-scored punch (TBT).

Furosemide is a loop diuretic, used primarily for the treatment of edema in congestive heart failure, belonging to Class IV under the Biopharmaceutics Classification System (BCS) having low solubility and permeability [16,17]. It is a weakly acidic drug, mostly absorbed in the stomach and upper intestine. Moreover, it can be absorbed in the buccal cavity. For this reason, an ODT formulation could enhance its bioavailability. Since the furosemide dose is regularly adapted to the age and conditions of patients, scored tablets would provide flexibility in dosing, possibly reducing the number of product strengths on the market and overcoming stability problems related to the use of liquid formulations (e.g., suspensions and solutions).

Furosemide-containing ODTs obtained under different tableting conditions were evaluated for overall quality, with special focus on splitability. Due to the number of factors that can have an impact, Quality by Design was applied by using the Design of Experiments (DoE) methodology [18]. Moreover, a volunteer panel test was set to explore the ease of breaking as perceived by end users, the accuracy of subdivision of tablets and the relevant mass loss.

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Materials

Furosemide was kindly donated by Teknofarma (Torino, Italy), as was Prosolv^® ODT G₂ by JRS Pharma (Rettenmaier Italia, Castenedolo, Italy). Magnesium stearate was supplied by ACEF (Fiorenzuola d’Arda, Italy) and colloidal silica (Aerosil^® 200) by Evonik (Essen, Germany).

Palugan, L.; Moutaharrik, S.; Maroni, A.; Foppoli, A.A.; Melocchi, A.; Vecchio, C.; Gazzaniga, A.; Cerea, M. Evaluation of Newly Designed and Traditional Punches in Manufacturing of Scored ODTs. Pharmaceutics 2022, 14, 2054. https://doi.org/10.3390/pharmaceutics14102054

excipients formulation