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Breaking Up Is Hard To Do
The marriage of innovative tablet design and tablet press results in a consumer-friendly solid dosage form
Dr. Allan S. Kaplan
Executive Vice President
Manufacturing & Pharmaceutical Dev.
ACCU-BREAK Pharmaceuticals, Inc.
and
Frederick J. Murray
President
KORSCH America Inc.
Pharmaceutical tablets are, in some cases, designed with a score mark on the tablet
that is intended to permit the patient or healthcare provider to split the tablet
in order to reduce the dosage. The score mark is created in the tablet during
the compression process, by a score line that is present in the tablet tooling.
The depth of the score is intended to promote the breakage of the tablet, while
still maintaining its integrity.
The presence of the score line does enhance the ability to break the tablet, however,
for drug products that require a highly accurate dosage, the methodology of manually
splitting a tablet is inadequate. In most cases, the tablet does not split evenly
at all, and the remaining tablet pieces represent different dosage levels. Many
studies have concluded that the manual splitting of tablets, with and without
tablet splitting devices, does not yield the desired results of an even split.
Peek1 et al., (2002) studied tablet splitting by “elderly patients” aged 59-70. In this study, patients were asked to break tablets with a mechanical splitter without detailed instructions. The results showed clearly that the tablets were not split evenly. For a warfarin 5 mg product, the average tablet was split into 1.9 mg and 3.1 mg pieces.
Biron2 et al, (1999) concluded that the loss of tablet mass due to crumbling and chipping during the breaking process was also significant.
McDevitt3 et al., (1998), found that 25 mg unscored hydrochlorothiazide tablets were manually split badly enough that 12.4% deviated by more than 20% from ideal weight. Seventy-seven percent (77%) of the test subjects stated that they would be willing to pay a premium for individually produced 12.5 mg tablets rather than split 25 mg unscored tablets.
Rosenberg4 et al., (2002), studied pharmacist-dispensed split tablets. They found that “tablet splitting resulted in an unacceptably high incidence of weight variation”, and recommended that “standards should be developed to ensure uniformity of split tablets.”
Teng5 et al., (2002), using a trained individual in a laboratory setting to split tablets, concluded that “the majority of the 11 drug products we tested, when assessed for their ability to be split into half-tablets of equal dose, failed a liberally interpreted USP (United States Pharmacopeia) uniformity test. The practice of dividing tablets to save costs or to improve a dosage regimen . . . is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.”
In the U.S., “managed care” insurance organizations may encourage splitting by patients of unscored tablets that may not even have symmetrical shapes. Many drug products in the US either are unscored tablets, or are provided as capsules despite being able to be produced as tablets.
Multi-Layer Tablet Developed
To solve this problem ACCU-BREAK Pharmaceuticals, Inc. developed the patent-pending
ACCU-BREAK drug delivery system. The ACCU-BREAK drug delivery system uses special
multi-layer technology to create an active ingredient layer at each end of the
tablet, separated by a tall inactive ingredient layer, which is configured with
a score line to promote breaking. The active dose in the tablet is divided into
two equal layers, which are placed at opposite ends of the tablet, and separated
by this inactive layer. Due to the overall geometry of the tablet, the score line
insures that the tablet will break through the inactive layer – which preserves
the active dosage at each end – regardless of the position or accuracy of the
break line. As such, this technology can guarantee that a split tablet will deliver
an exact dose, with no variability due to the breaking methodology. For the first
time, the patient and physician can be absolutely certain that a tablet dose may
be divided in an accurate and repeatable manner.
In addition to splitting single-drug products, the ACCU-BREAK drug delivery technology
offers an innovative opportunity to administer combination drug therapy. Combination
drug therapy permits more than one active drug to be delivered in a single tablet
or capsule. These products are known as “fixed dose” combination products, since
the patient or pharmacist has no way to separate the active products. The treatment
of hypertension is an excellent example where combination therapy is a frequently
used form of treatment. The limitation of the conventional fixed-dose combination
products is the lack of flexibility to discontinue or adjust one or the other
drug component, without obtaining a new prescription and therefore complicating
the patient’s drug regimen and risking non-compliance.
But How Do You Manufacture It?
The design of the ACCU-BREAK tablet format presented significant challenges with
regard to suitable tablet press technology. First, the desire to separate two
active layers by an inactive, breakable layer required at least a three-layer
tablet press. Second, the thickness of the inactive layer – relative to the overall
height of the tablet, would require an extremely deep filling depth capability
for this middle layer, which exceeded the current design of any conventional tablet
press. Finally, the filling depth of the final layer would require an extreme
level of flexibility – more than what existed in any tri-layer tablet press.
In addition to the unique geometry of the ACCU-BREAK tablet design, the tablet
press would have to provide extremely accurate layer weight control, to insure
that the active component at each end of the tablet would meet the required weight
specification.
And last but not least, the press must have the ability to prevent cross contamination
between the layers. Simply stated, the drug layers must contain only drug and
the inactive layers, only inactive ingredients.
A solution was found in the KORSCH TRP900 Multi-Layer Tablet Press. One of the
press’s greatest benefits for this challenging dosage form was that it can produce
a five-layer tablet. In addition, the use of a special tool design permits deep
filling depths for each layer, which offers extreme flexibility with regard to
the layer weights and overall tablet design. In general, for split dose applications,
the press is operated as follows:
Layer #1: Active Drug (50% dose)
Layer #2 Inactive Layer
Layer #3 Inactive Layer
Layer #4 Inactive Layer
Layer #5 Active Drug (50% dose)
For combination products, the configuration is as follows:
Layer #1 Active Drug #1
Layer #2 Inactive Layer
Layer #3 Inactive Layer
Layer #4 Inactive Layer
Layer #5 Active Drug #2
The deeper fill depth of the TRP900 permits the ACCU-BREAK tablet design to be
optimized by using multiple stages to fill the large inactive segment, which interposes
the active drug layers. Press force control is used to control the weight of each
layer, and a single-tablet rejection capability permits individual tablets to
be rejected at production speed.
The result is a process that can insure extremely accurate layer weight control, with no cross contamination between layers. The size and shape of the tablet can be configured to accommodate the required dosage, and there is flexibility to use single, or multiple drug components in the tablet design.
The press also has the capability to be configured for Wash-in-Place (WIP) and high-containment technology, which provides the additional flexibility to apply the ACCU-BREAK™ drug delivery platform to potent compounds.
ACCU-BREAK™ technology, in combination with the KORSCH TRP900 Multi-Layer, represents
innovative and cutting edge technology, and is an example of a perfect match between
innovative process and equipment technology.
Author Contacts:
Dr. Allan S. Kaplan, 954-236-7351 or a.kaplan@accubreak.com; Frederick J. Murray,
508-238-9080 or fred.murray@korschamerica.com
Footnotes:
1Peek, B.T., Al-Achi, A., and Coombs, S.J. “Accuracy of Tablet Splitting
by Elderly Patients.” The Journal of the American Medical Association 288 No.4
(2002):139-145. 2Biron, C., Liczner, P., Hansel, S. and Schved, J.F.,
“Oral Anticoagulant Drugs: Do Not Cut Tablets in Quarters.” Thromb Haemost 1201
(1999). 3McDevitt, J.T., Gurst, A.H. and Chen, Y. “Accuracy of Tablet
Splitting.” Pharmacotherapy 18 No.1 (1998):193-197. 4Rosenberg, J.M.,
Nathan, J.P. and Plakogiannis, F. “Weight Variability of Pharmacist-Dispensed
Split Tablets.” Journal of American Pharmaceutical Association 42 No.2 (2002):200-205.
5Teng, J., Song, C.K., Williams, R.L. and Polli, J.E. “Lack of Medication
Dose Uniformity in Commonly Split Tablets.” Journal of American Pharmaceutical
Association 42 No. 2 (2002):195-199.
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