Variability in Tablet Fragment Weights When Splitting Unscored Cyclobenzaprine 10 mg Tablets

doi:10.1331/1544-3191.44.5.583.Cook

Journal of the American Pharmacists Association

Volume 44, Issue 5, September–October 2004, Pages 583-586

https://doi.org/10.1331/1544-3191.44.5.583.Cook Get rights and content

ABSTRACT

Objective

To determine the weight variation and calculated dosing variability of tablet fragments upon splitting unscored cyclobenzaprine hydrochloride 10 mg tablets using two common tablet splitting devices.

Design

Comparative pharmaceutics study.

Setting

Pharmacy school laboratory.

Participants

Not applicable.

Interventions

Unscored cyclobenzaprine hydrochloride 10 mg tablets from one generic manufacturer were split with a tablet splitter or a kitchen knife by a licensed pharmacist and two doctor of pharmacy students (n = 15 tablets for each method per participant).

Main Outcome Measures

Fragment weights (FWs) were compared with the theoretical weights (TWs), which were calculated as one half of the mean weight of the tablets used in each part of the experiment; means, relative standard deviations (RSDs), and percentages of TW were also calculated.

Results

The mean weight before splitting the 45 tablets with the tablet splitter was 136.6 ± 2.1 mg (TW = 68.3 mg). The mean FW after splitting was 67.9 ± 7.9 mg. The RSD of 11.6% corresponded to a range of 69.4% to 130.2% of the TW and an estimated drug content of the split fragments between 3.47 mg and 6.51 mg. The mean weight before splitting the 45 tablets cut with a kitchen knife was 136.6 ± 2.0 mg (TW = 68.3 mg). The mean FW was 68.0 ± 15.7 mg with a RSD of 23.2%, corresponding to a range of 49.9% to 149.5% of the TW and an estimated drug content of the split fragments between 2.49 mg and 7.48 mg.

Conclusion

Tablet fragments obtained after splitting this generic cyclobenzaprine 10 mg product varied considerably in weight and estimated drug content. Accordingly, splitting cyclobenzaprine 10 mg tablets to achieve 5 mg doses could result in unpredictable dosing and therapeutic response.

Section snippets

Objective

The objective of this study was to determine the weight variation and calculated dosing variability of tablet fragments when unscored 10 mg cyclobenzaprine tablets were split with a tablet splitter or a kitchen knife. These two methods of tablet splitting were chosen because preliminary research determined that they were the methods most commonly used by respondents to split cyclobenzaprine 10 mg tablets.³

Methods

Cyclobenzaprine hydrochloride 10 mg tablets (Watson Pharmaceuticals, Corona, Calif., lot number P03D0140) were used for this study. Intercontinental Marketing Services (IMS Health) data from January 2002 to December 2003 indicated that the manufacturer of these tablets was the most common supplier of generic cyclobenzaprine 10 mg medication dispensed in the United States during this period. As with most other cyclobenzaprine tablets, these tablets were round, film coated, and unscored.⁴

Weights of

Results

Study results are presented in Table 1. Scatterplots showing the deviation of fragments from TW and the associated variation in estimated drug content for each splitting method are presented in Figure 1.

Discussion

This study was conducted to assess the variability in tablet weights and estimated drug content when unscored cyclobenzaprine 10 mg tablets were split with a tablet splitter or a common kitchen knife. Ideally, perfectly split fragments of a 10 mg tablet would weigh 100% of the TW and contain 5 mg of drug. However, this study indicates that splitting unscored, film-coated 10 mg tablets of cyclobenzaprine with either a tablet-splitting device or with a kitchen knife results in considerable variation

Limitations

The ability to generalize the results obtained in this study is limited by methodological constraints. Because the cyclobenzaprine tablets used for this study were obtained from the manufacturer of the most commonly used generic product, our findings cannot be generalized to all cyclobenzaprine products. However, like the product used in our study, most cyclobenzaprine tablets are film-coated, round, and unscored,⁴ and these are product characteristics that generally can produce problems when

Conclusion

In this study, splitting unscored cyclobenzaprine 10 mg tablets with a tablet splitter and particularly with a kitchen knife resulted in a large percentage of tablet fragments deviating from pharmaceutical and compendial standards. An implication of these findings is that variation in drug content produced when tablets are split may result in unpredictable dosing of cyclobenzaprine and a resulting variability in therapeutic response and increased risk of adverse effects. Dispensing the

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Tablet splitting of a narrow therapeutic range medication: Analysis of weight variability
2019, Pharmacien Hospitalier et Clinicien
Le fractionnement des comprimés est une pratique bien établie qui permet de réaliser des économies. Cependant, elle n’assure pas nécessairement l’uniformité de la masse des fractions, en particulier pour les médicaments à marge thérapeutique étroite. L’objectif de cette étude est d’analyser l’uniformité de masse des fractions issues d’un fractionnement à la main des comprimés d’acénocoumarol.
Cinq-cent-quarante comprimés ont été distribués à soixante volontaires qui ont procédé au fractionnement à la main. L’uniformité de masse a été évaluée en comparant les masses des fractions, déterminées par une balance analytique, aux masses théoriques. La précision et la répétabilité ont été estimées à l’aide de l’écart-type et du biais. La variabilité en masse a été évaluée selon les tests de la Pharmacopée européenne.
Toutes les masses moyennes des moitiés et des quarts de comprimés ont respecté les spécifications. Un total de 15 sur 60 (25 %) des masses moyennes des fractions huitièmes ont été hors normes. Les masses moyennes des différents niveaux ne différaient pas statistiquement de la valeur théorique. Les écarts-types moyens étaient respectivement de 10,4 %, 12,8 % et 27,6 % pour les moitiés, les quarts et les huitièmes de comprimé. La précision de division des huitièmes de comprimés est statistiquement inférieure à celle des moitiés ou des quarts de comprimés. La pratique des patients ne diffère pas en termes de précision de celle des infirmiers pour tous les niveaux.
Les résultats ont montré que le fractionnement à la main des comprimés d’acénocoumarol en demies ou en quarts respectait les spécifications contrairement au fractionnement au huitième, considéré comme une pratique inappropriée. La qualité de cette pratique est affectée par les propriétés intrinsèques du comprimé mais aussi par la capacité physique du manipulateur et la méthodologie. Cette pratique devrait être évitée autant que possible et doit être remplacée par l’utilisation d’une forme moins dosée surtout pour les médicaments à marge thérapeutique étroite.
Cette étude suggère que, pour les médicaments à marge thérapeutique étroite, un fractionnement approprié des comprimés entraîne une variation de masse acceptable. Cependant, la pratique inappropriée peut entraîner une forte incidence de variation de masse avec un risque potentiel élevé chez le patient. Dans le cas où une adaptation posologique minime doit être appliquée, il est fortement recommandé d’utiliser une forme de médicament moins dosée.
Tablet splitting is a well-established medical practice which allows costs saving. However, it does not necessarily ensure uniformity of mass of fractions especially for narrow therapeutic range drugs. The aim of this study is to determine the drug weight variability after acenocoumarol tablets hand-splitting.
A total of five hundred and forty tablets were provided to sixty volunteers (patients and nurses) who proceeded to the hand-splitting. Mass uniformity was assessed by comparing fractions mass, as determined by analytical balance, with theoretical mass. Accuracy and repeatability were estimated using RSD and bias. Mass variability was evaluated according to the European Pharmacopoeia tests.
No means halves or quarters mass fell outside specifications. A total of 15 of 60 (25%) means drug mass differed from sample for tablet-eighths. The means of drug mass for each type of fraction didn’t differ statistically from theoretical value. Means RSD (%) were 10.4%, 12.8% and 27.6% for halves, quarters and tablet-eighths respectively. The splitting accuracy of tablet-eighths is statistically less than the splitting accuracy of halves or quarters. The patient hand-splitting did not differ in terms of precision from nurse hand-splitting for all type of fractions.
The results showed that hand splitting of acenocoumarol tablets in half or in quarters met the specifications as opposed to splitting in eighth, considered as an inappropriate practice. The fractionation quality is affected by the intrinsic properties of the tablet but also by the physical capacity of the manipulator and the splitting methodology. This practice should be avoided as much as possible and should be replaced by the use of a less dosed form especially for narrow therapeutic range medications.
This study suggests that, for narrow therapeutic range drugs, appropriate tablet splitting resulted in an acceptable mass variation. However, inappropriate splitting may lead to high incidence of mass variation. For the use of acenocoumraol drug, solutions may be proposed such as the use of a lower dosage form of medication (1 mg tablet).
Challenges and innovations of drug delivery in older age
2018, Advanced Drug Delivery Reviews
Citation Excerpt :
When a liquid or easily swallowed dosage form is not available, other alternatives would be to take two smaller tablets than a single large tablet or to take two cut pieces from a scored tablet. Caution must be taken in cutting unscored tablets as studies have shown that the resulting doses may be highly variable varying by as much as 3 fold [474]. For improved delivery, patients’ acceptability should be considered in designing a solid oral dosage form.
Both drug delivery performance and various age-related physical, mental and physiological changes can affect drug effectiveness and safety in elderly patients. The many drug delivery systems developed over the years include recent novel transdermal, nasal, pulmonary and orally disintegrating tablets that provide consistent, precise, timely and more targeted drug delivery. Certain drug delivery systems may be associated with suboptimal outcomes in the elderly because of the nature of drug present, a lack of appreciation of the impact of age-related changes in drug absorption, distribution and clearance, the limited availability of pharmacokinetic, safety and clinical data. Polypharmacy, patient morbidity and poor adherence can also contribute to sub-optimal drug delivery systems outcomes in the elderly. The development of drug delivery systems for the elderly is a poorly realised opportunity, with each system having specific advantages and limitations. A key challenge is to provide the innovation that best meets the specific physiological, psychological and multiple drug requirements of individual elderly patients.
A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in paediatric practice
2017, International Journal of Pharmaceutics
This study sought to determine whether there is an evidence base for drug manipulation to obtain the required dose, a common feature of paediatric clinical practice. A systematic review of the data sources, PubMed, EMBASE, CINAHL, IPA and the Cochrane database of systematic reviews, was used. Studies that considered the dose accuracy of manipulated medicines of any dosage form, evidence of safety or harm, bioavailability, patient experience, tolerability, contamination and comparison of methods of manipulation were included. Case studies and letters were excluded. Fifty studies were eligible for inclusion, 49 of which involved tablets being cut, split, crushed or dispersed. The remaining one study involved the manipulation of suppositories of one drug. No eligible studies concerning manipulation of oral capsules or liquids, rectal enemas, nebuliser solutions, injections or transdermal patches were identified. Twenty four of the tablet studies considered dose accuracy using weight and/or drug content. In studies that considered weight using adapted pharmacopoeial specifications, the percentage of halved tablets meeting these specifications ranged from 30% to 100%. Eighteen studies investigated bioavailability, pharmacokinetics or clinical outcomes following manipulations which included nine delayed or modified release formulations. In each of these nine studies the entirety of the dosage form was administered. Only one of the 18 studies was identified where drugs were manipulated to obtain a proportion of the dosage form, and that proportion administered. The five studies that considered patient perception found that having to manipulate the tablets did not have a negative impact on adherence. Of the 49 studies only two studies reported investigating children. This review yielded limited evidence to support manipulation of medicines for children. The results cannot be extrapolated between dosage forms, methods of manipulation or between different brands of the same drug.
Weight and content uniformity of lorazepam half-tablets: A study of correlation of a low drug content product
2013, Saudi Pharmaceutical Journal
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This last objective is not necessarily realized if the tablet is split in two halves to administer half of the labeled dose, especially if the splitting process is not performed successfully to give two equal halves or if the drug was distributed unevenly throughout the tablet during its manufacture. Several studies have been conducted to investigate the weight uniformity of the obtained tablet halves (Kristensen et al., 1995; Zaid et al., 2010; Zaid and Ghosh, 2011; Cook et al., 2004). These studies have focused on weight uniformity because this parameter should be correlated to the uniformity of content which cannot be investigated using tools available in a pharmacy setting.
The aim of this study was to investigate the degree of correlation between the weight and the content of spilt-halves of lorazepam 2.5 mg tablets. Weight variation and drug content of lorazepam half-tablets were evaluated according to the European Pharmacopoeia tests. Only one individual mass of the 30 half tablets was outside the limits of 85–115% of the average mass, but since it was within 75–125% of the average mass, the product passed the test. Each individual content was between 85% and 115% of the average content (99.8% expressed as a percent to label claim) and within the limits of 75–125%, so the product passed the uniformity of content test. The correlation coefficient (r) between the weight and the content of split halves was found to be 0.994. The weights of split tablet halves appear to be directly correlated with their drug content even for a medication with a low drug content, thus it is recommended that pharmacists who split tablets into two halves, assure the weight uniformity of the resultant halves. Manufacturers should develop formulation and manufacturing procedures that ensure high degree of correlation between weight and content not only among the whole tablet but also among the obtained tablet halves.
The impact of ageing on the barriers to drug delivery
2012, Journal of Controlled Release
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In addition, since elderly patients often require lower doses than those which are commercially available, manipulation of these common solid oral dosage forms may be performed, which can have severe implications in terms of dosing errors and adverse events, resulting in poor overall therapeutic outcomes [34]. For example, cutting tablets, even using commercially available tablet cutters, can produce pieces that contain as little as 50% or up to 150% of the desired dose [35]. Furthermore, extemporaneous conversion of a solid oral dosage form into liquids – often by deconstructing tablets or capsules and dispersing the resulting powder in a suspending agent – may produce a more acceptable dosage form with greater flexibility of dose, although the resulting formulations are rarely assessed for their pharmaceutical quality and the crude suspensions that are invariably formulated can lack dose uniformity and can have absorption characteristics that differ substantially from the parent formulation [36].
Generally, we like to see ageing as a process that is happening to people older than ourselves. However the process of ageing impacts on a wide range of functions within the human body. Whilst many of the outcomes of ageing can now be delayed or reduced, age-related changes in cellular, molecular and physiological functionality of tissues and organs can also influence how drugs enter, distribute and are eliminated from the body. Therefore, the changing profile of barriers to drug delivery should be considered if we are to develop more age-appropriate medicines. Changes in the drug dissolution and absorption in older patients may require the formulation of oral delivery systems that offer enhanced retention at absorption sites to improve drug delivery. Alternatively, liquid and fast-melt dosage systems may address the need of patients who have difficulties in swallowing medication. Ageing-induced changes in the lung can also result in slower drug absorption, which is further compounded by disease factors, common in an ageing population, that reduce lung capacity. In terms of barriers to drug delivery to the eye, the main consideration is the tear film, which like other barriers to drug delivery, changes with normal ageing and can impact on the bioavailability of drugs delivery using eye drops and suspensions. In contrast, whilst the skin as a barrier changes with age, no significant difference in absorption of drugs from transdermal drug delivery is observed in different age groups. However, due to the age-related pharmacokinetic and pharmacodynamic changes, dose adaptation should still be considered for drug delivery across the skin. Overall it is clear that the increasing age demographic of most populations, presents new (or should that be older) barriers to effective drug delivery.
Oral drug delivery in personalized medicine: Unmet needs and novel approaches
2011, International Journal of Pharmaceutics
Citation Excerpt :
Usually there are no instructions how to store or to eliminate the segments. Tablet splitting devices are sometimes assumed to enable more accurate splitting, but the use of these tools does not necessarily lead to exact divided doses (Cook et al., 2004). In another study 37.3% of the segments deviated more than 10% from ideal mass when using a marketed tablet splitter (McDevitt et al., 1998).
Increasing knowledge into personalized medicine has demonstrated the need for individual dosing. Drug dosage forms are urgently needed enabling an individual therapy, especially for oral drug delivery. This review is focusing on approaches for solid and liquid oral dosage forms for individual dosing. The proposed dosage forms and devices may be distinguished into assembling and partition concepts and have been categorized regarding their applicability, costs, dose flexibility and potential benefits. Opportunities, challenges and further unmet needs are elaborated and critically discussed.
Liquid dosage forms can be accurately dosed by novel dropping tubes or oral syringes, but less precisely by dosing spoons and cups. Breaking scored tablets into fragments show major risks such as inaccurate dosing, formation of potent dust and stability issues of the residual segments. Novel approaches are proposed for solid dosage forms enabling a flexible and appropriate therapy such as various dispensers for multiparticulate drug formulations. However, most of the proposals still have to prove their applicability in practice. Promising concepts are the Solid Dosage Pen and drug-loaded oral films which can be cut in individual sections enabling freely selectable doses. Further research and development are required for novel dosage forms and medical devices appropriate for individualized therapy.

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: Disclosure: Dr. Cook is a paid consultant to McNeil Consumer & Specialty Pharmaceuticals, and Drs. M. Shah, I. Shah, and Fox are employees of that company. The authors declare no other conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria.

: Funding: Supported by a grant from McNeil Consumer & Specialty Pharmaceuticals, Fort Washington, Pa.

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ResearchVariability in Tablet Fragment Weights When Splitting Unscored Cyclobenzaprine 10 mg Tablets

ABSTRACT

Objective

Design

Setting

Participants

Interventions

Main Outcome Measures

Results

Conclusion

Section snippets

Objective

Methods

Results

Discussion

Limitations

Conclusion

Clin Ther.

J Am Pharm Assoc.

J Am Pharm Assoc.

Accuracy of tablet splitting

Pharmacotherapy.

Research
Variability in Tablet Fragment Weights When Splitting Unscored Cyclobenzaprine 10 mg Tablets