Uniformity of single-dose dosage forms

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The test of uniformity of single-dose dosage forms is a test described in the European Pharmacopoeia (Pharmacopoea Europaea, Ph. Eur.), Which is used to determine the uniformity of dosage of divided dosage forms such as tablets . The uniformity is defined in the Ph. Eur. As "the degree of uniformity of the amount of active ingredient in a certain number of units".

Scope of the test

In general - unless otherwise stipulated - the requirements of the test apply to each individual active ingredient that a single-dose dosage form contains.

According to the Pharmacopoeia, the test specifications do not apply to suspensions , emulsions and gels in single-dose containers for dermal use unless otherwise specified . The test is not required for multivitamins and trace elements in preparations.

In most of the monographs of the European Pharmacopoeia , the test is not used for herbal drugs contained in the preparation and their preparations.

Carrying out the exam

Tablets and hard capsules must have a uniform active ingredient content.

First, it is determined whether the test for uniformity is to be carried out on the basis of the active ingredient content or the mass of the dosage form (test specification “Uniformity of content” or “Uniformity of mass”). The check of the content is always applicable in principle, the check of the mass is only permitted in some cases.

The next step is to check the active ingredient content according to the “physical state” of the drug. While solid dosage forms can be fed directly to a suitable process, liquid and semi-solid, for example, must be mixed well beforehand.

If special requirements are met, such as a relative standard deviation of the content of less than 2% and an existing approval from the licensing authority, the "uniformity of mass" may be carried out. The test of the mass is subdivided into more detail: uncoated tablets and film- coated tablets are only weighed. Capsules, on the other hand, are weighed full and empty, with the active ingredient content being determined from the difference between the masses - and the result of the content determination. While hard capsules can be easily opened and emptied, soft capsules have to be cut open and washed out with a suitable solvent .

For testing liquid and semi-solid dosage forms , the amount of product that can be removed from the container “under normal use conditions” - that is, the amount that would or could normally be removed for use, is first removed.

After the practical determination of the content or the mass, the acceptance value must be calculated. If this value corresponds to the criteria specified by the pharmacopoeia , the dosage form has passed the test.

The acceptance value AV is calculated using the formula:

into which a reference value M [%] , the mean value of the individual contents X [%] , a so-called acceptance constant k and the standard deviation s [%] are included. The reference value M is in turn dependent on the “fixed content per dose unit at the time of manufacture” T. Normally T = 100% is assumed and the reference value M is based on the measured average salary depending on the declared target salary. If the measured mean value of the individual levels is less than 98.5% of the target level, the M value is 98.5%. Should the mean value of the individual contents be greater than 101.5%, M is set at 101.5%. Otherwise M = X.

The value of the acceptance constant k takes on different values ​​depending on the test level. In the first round of the test, only 10 units of the dosage form are tested and k is 2.4. If the result does not correspond to the required acceptance value "L1", 20 additional units must be checked in a second test level. and k is 2.0

In the last step, the acceptance value is assessed by comparing it with the maximum acceptance value L1 . For all dosage forms, the test is passed if the acceptance value of the first 10 units is less than or equal to L1 (usually 15.0%).

If the acceptance value exceeds L1 , 20 more units must be checked. A new acceptance value is calculated for every 30 units. This new value must not exceed L1 . Furthermore, no individual salary outside of 

lie. L2 is a further test parameter and is 25.0 unless otherwise specified.

Special cases

In some cases, the dosage forms meet criteria that qualify them for the less time-consuming test of “uniformity of mass”. For example, soft capsules containing solutions do not need to be checked for “uniformity of content”.

In order to calculate the acceptance value in this case, the results of the weighing must be converted to information about the active ingredient content. The individual salary received is included in the calculation described above.

Differences to older test regulations

Compared to the older tests “Uniformity of the mass of single-dose dosage forms” and “Uniformity of the content of single-dose dosage forms”, the test differs in that it is based on assumptions about the statistical distribution of the quality feature to be tested - uniformity. It is therefore a parametric test, compared to the non-parametric or partially parametric older tests.

In the course of the calculation of the acceptance value, the European Pharmacopoeia stipulates that the calculated or determined individual contents should be expressed as a percentage of the stated content. In contrast to the tests of content and mass, the test also relates to the correctness of the content or the mass.

Furthermore, active ingredients below 2 mg or 2% of the total mass of the single dose are taken into account in the "Uniformity of content" test. All cans or proportions above are checked for "uniformity of mass".

In contrast to this, the “uniformity of content” test according to the “uniformity of single-dose dosage forms” can be used in all cases. In a few exceptions, the "uniformity of mass" test may be carried out. Examples are solutions in single-dose containers, solid preparations in single-dose containers without further additives, and soft capsules with solutions contained therein.

If the tested units do not comply with the test, there can be two groups of sources of error:

1. The units do not have a uniform active ingredient content. This case can be recognized by a high standard deviation s . Depending on the dosage form, different process errors can be the cause:

  • Hard capsules are filled with mixtures of active ingredients and excipients . These can be insufficiently mixed before filling, which means that some capsules contain more active ingredient than others.
  • Tablets are often produced in volume-metered presses. The tablet presses may vibrate strongly enough to compress press products with poor flow properties during the pressing process. The result is that, with the same volume, ever larger masses of pressed material get into the die of the press over time, which leads to increasingly heavy tablets with consequently higher active ingredient content.

2. The drug forms tested have a uniform content, but not the correct active ingredient content. This type of defect can be recognized by the content X clearly deviating from the specified value . The reasons for this can be varied:

  • In addition to errors in the manufacturing instructions, too low a content can cause the substance to decompose. In addition, errors occasionally occur in the determination of hydrates (etc.) if the content is correctly determined but is stated as an anhydrous substance .
  • Too high a salary is mostly due to calculation errors.

In the case of errors in this second group, the additional benefit of this newer test can be recognized; the test "uniformity of the content of single-dose dosage forms" would give a false positive result here, since the correctness is not included.

Individual evidence

  1. ↑ a b c d e f g h i j k Ph. Eur. 8th edition, 6th supplement: "2.9.40: Uniformity of single-dose dosage forms" . Deutscher Apotheker Verlag, Stuttgart 2016, ISBN 978-3-7692-6771-6 , p. 7375 ff .
  2. ↑ Ph.Eur. 8th edition, Grundwerk 2014, p. 1181 ff .: Liquid preparations for ingestion . 2014.
  3. ↑ Ph.Eur. 8th edition, Grundwerk 2014, p. 1184 ff .: Liquid preparations for cutaneous use . 2014.
  4. ↑ Ph.Eur. 8th edition, Grundwerk 2014, p. 1187 ff .: Granules . 2014.
  5. ↑ Ph.Eur. 8th edition, Grundwerk 2014, p. 1193 f .: capsules . 2014.
  6. ↑ Ph.Eur. 8th edition, Grundwerk 2014, p. 1195 f .: Chewing gum containing active ingredients . 2014.
  7. ↑ Ph.Eur. 8th edition, basic work 2014: "2.9.5: Uniformity of the mass of single-dose dosage forms" . Deutscher Apotheker Verlag, Stuttgart 2016, ISBN 978-3-7692-6771-6 , p. 410 .
  8. ↑ Ph.Eur. 8th edition, basic work 2014: "2.9.6: Uniformity of the content of single-dose dosage forms" . Deutscher Apotheker Verlag, Stuttgart 2016, ISBN 978-3-7692-6771-6 , p. 411 .
  9. ^ A b Alfred Fahr : Voigt Pharmaceutical Technology - for studies and work . 12th edition. German pharmacist publisher.