Active ingredient release analysis of solid dosage forms

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The active ingredient release analysis of solid dosage forms refers to the investigation of the release of an active ingredient from solid dosage forms .

Pharmacopoeia devices

According to the European Pharmacopoeia , devices for determining the release of active ingredients from solid dosage forms are devices with the aid of which the release of active ingredients from a solid dosage form intended for ingestion, such as capsules or tablets , can be determined in vitro . They are used in quality control, but also in formulation development and for predicting the behavior of the drug in vivo .

Rotating basket

The rotating basket apparatus consists of a 1 L cylindrical vessel with a hemispherical bottom. It is usually filled with 500-900 mL of a suitable, possibly degassed test liquid (e.g. 0.1 N HCl solution or 6.8 phosphate buffer), the temperature of which is kept constant at 37 ± 0.5 ° C. The vessel lid has holes for taking samples and for inserting a thermometer. The rotating basket, which consists of a wire mesh made of an inert metal such as stainless steel or can be coated with gold, is attached to a rod that protrudes from above into the vessel and rotates at a speed usually between 50 and 150 revolutions per minute own axis rotates. The distance between the basket and the bottom of the vessel must be 25 ± 2 mm.

This device is advantageous for capsules, since the drug form is in a closed basket and cannot float on the surface. However, the wire network can be made by e.g. B. clog swelling substances, in addition, the network can ensure mechanical abrasion of the dosage form and thus influence the disintegration or the rate of dissolution. If the test item is in the middle of the basket, the movement there due to the rotation is significantly less compared to a position further on the edge, so that the reproducibility can be influenced.

Blade stirrer

The paddle stirrer apparatus consists of a 1 L cylindrical vessel with a hemispherical bottom. It is usually with 500-900 mL of a suitable, degassed test liquid, e.g. B. 0.1 N HCl solution or 6.8 phosphate - buffer filled, the temperature of which is kept constant at 37 ± 0.5 ° C. The vessel lid has holes for taking samples and, for example, inserting a thermometer. The metal or other inert, rigid material is placed at a distance of 25 ± 2 mm from the bottom of the vessel. The solid dosage form to be tested should ideally be at the bottom of the container; if it floats up, it can be weighed down with the aid of a sinking device. The stirring speed is usually between 50 and 150 revolutions per minute. The different hydrodynamic conditions in the vessel can influence the dissolution and release of the active ingredient, especially the hydrodynamically dead zone in the middle below the paddle stirrer can lead to the formation of a non-detachable cone from the tablet.

Immersing cylinder

The apparatus consists of a glass cylinder with a bottom made of wire mesh that moves evenly up and down in another glass cylinder with a flat bottom. This glass cylinder is usually filled with 300 ml of a suitable medium which, with the aid of a water bath, has a constant temperature of 37 ± 0.5 ° C. In the course of the release test, the sample cylinder can be immersed in several glass cylinders. By using different test solutions in these, the individual sections of the gastrointestinal tract can be simulated better.

Flow cell

The flow cell is located in a water bath heated to 37 ± 0.5 ° C and is connected to a pump that conveys the test liquid from a storage container at a constant speed from bottom to top through the flow cell. To ensure the most even flow possible, there are approx. 1 mm small glass beads in the lower conical part of the flow cell. On the 3 mm wide opening there is a glass bead with a diameter of 5 mm, which prevents the opening from being clogged with smaller beads. The drug form to be tested is located in a tablet holder halfway up the cylindrical part of the flow cell or on the glass beads themselves. The flow cell is closed by a filter which prevents the removal of undissolved particles with the test liquid. Standardized diameters of the cells are 12 mm and 22.6 mm.

The medium can be changed continuously, for example with regard to the pH value , but also with regard to the flow rate , in order to reflect the physiological conditions in the gastrointestinal tract. In the case of the flow cell apparatus, the flow rate is usually between 4 and 50 ml / min.

Flow cells can represent both open and closed systems, depending on whether the test liquid is returned to the storage container after flowing through the cell or not. In open systems, the dissolved active ingredient is removed from the system, which simulates the absorption of the drug in the intestine, so that sink conditions are more likely than in closed systems.

Determination of the drug release

Implementation according to the pharmacopoeia

The dosage forms are added to the respective apparatus as intended. Samples are taken from the test liquid after a specified period of time or at regular intervals. If there are several sampling times, the extracted test liquid may have to be replaced. The duration of the test and the medium depend on the dosage form.

In the case of pharmaceutical forms with delayed release of active ingredients, a change of medium from 0.1 N hydrochloric acid to a phosphate buffer with pH 6.8 is prescribed after 2 hours; this can be done with apparatus 1 and 2 by adding a buffered solution to the hydrochloric acid test liquid while changing the total volume ( Method A) or by completely replacing the test liquid (method B). In the case of apparatus 3, the media change takes place by exchanging the cylinder in which the sample cylinder is immersed. B. the reservoir of the test liquid can be exchanged.

evaluation

The samples taken are filtered if necessary and then evaluated quantitatively with regard to the active ingredient. HPLC analysis and UV spectroscopy are preferred for this purpose. For the “test for the release of active ingredients from solid dosage forms” according to the Pharmacopoeia, the proportion of the total amount of dissolved active ingredient must correspond to certain acceptance criteria after a specified time in relation to the content indicated on the label.

The data can also be used to create the release profile and the dissolution rate profile by plotting the cumulative or differential amount of active ingredient released as a function of time. By in-vitro / in-vivo correlation of the dissolution-time profiles, conclusions can be drawn about the behavior of the dosage form in vivo , which is important for the approval of generics.

literature

  • Kurt H.Bauer, Karl-Heinz Frömming, Claus Führer: Textbook of Pharmaceutical Technology: With an Introduction to Biopharmacy 8th Edition. Wissenschaftliche Verlagsgesellschaft Stuttgart 2006 pp. 224–228
  • Rudolph Voigt: Pharmaceutical technology for studies and work 10th edition Deutscher Apotheker Verlag Stuttgart, 2006, pp. 284–287
  • European Pharmacopoeia 8th Edition, Volume 1, Deutscher Apotheker Verlag Stuttgart, May 2016, Chapter 2.9.3 Active ingredient release from solid dosage forms

Individual evidence

  1. ↑ a b European Pharmacopoeia . 8th edition. tape 1 . Deutscher Apotheker Verlag, Stuttgart May 2016, 2.9.3 Release of active ingredients from solid dosage forms.
  2. ^ Rudolph Voigt: Pharmaceutical technology for study and work . 10., revised. and exp. Edition. Deutscher Apotheker Verlag Stuttgart, 2006, ISBN 978-3-7692-3511-1 , p. 285 .
  3. ^ A b Kurt H. Bauer, Karl-Heinz Frömming, Claus Führer: Textbook of Pharmaceutical Technology With an Introduction to Biopharmacy . 8th, through and updated edition. Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 2006, ISBN 978-3-8047-2222-4 , p. 225, 227 .