Drug Dissolution Apparatus IV USP (Flow-through-Cell)

By: Mitul Shah | Views: 16156 | Date: 28-Mar-2011

The flow-through-cell apparatus (Apparatus I is consists of a reservoir for the dis¬solution medium and a pump that force dissolution medium through the cell holding the test sample. Flow rate ranges from 4 to 16 ml/min. six samples are tested during the dissolution testing. And the medium is maintained at 370C. Apparatus I may be used for modified-release dosage forms that contain active in¬gredients having very limited solubility.

USP apparatus IV (Flow-through-Cell)

                   The flow-through-cell apparatus (Apparatus I is consists of a reservoir for the dis¬solution medium and a pump that force dissolution medium through the cell holding the test sample. Flow rate ranges from 4 to 16 ml/min. six samples are tested during the dissolution testing. And the medium is maintained at 370C. Apparatus I may be used for modified-release dosage forms that contain active in¬gredients having very limited solubility.
               
                   There are many variations of this method. Essentially, the sample is held in a fixed position while the dissolution medium is pumped through the sample holder. Thus dissolving the drug, Laminar flow of the medium is achieved by using a pulse less pump. Peristaltic or centrifugal pumps are not recommended. The flow rate is usually maintained between 10 and 100 ml/min. The dissolution medium may be fresh or recalculated. In the case of fresh medium, the dissolution rate at any moment may be obtained, whereas in the official paddle or basket method, cu¬mulative dissolution rates are monitored. A major advantage of the flow-through method is the easy maintenance of a sink condition for dissolution. A large volume of dissolution medium may also be used, and the mode of operation is easily adapted to automated equipment.

Introduction:

                         The use of flow through cells for the dissolution testing of tablets and capsules is not a new idea. Over 40 years ago a flow through method was developed in the laboratories of the United States Food and Drug Administration (FDA) and discussions with the dissolution experts from the United States Pharmacopoeia (USP) were initiated. The flow through cell used today is based on subsequent development work by Dr. F. Langenbucher and Prof. H Moeller and was incorporated as Apparatus IV in the USP, the European Pharmacopoeia and the Japanese Pharmacopoeia during the 90ies 1,2,3,4. Today the most commonly used apparatus (USP IV and I) are equipped with a paddle stirrer or a basket. The fixed solvent volume of maximal 2000 ml is kept at a temperature of 37° C. The flow through method uses an unlimited amount of solvent. There are a number of advantages compared to the apparatus I and II. Sink conditions can easily be reached with Apparatus IV. Also pH changes during the test are easily performed. The media change is performed by switching a valve from one medium to another medium. As the cell volume is only about 10 ml and a typical flow rate is 16 ml/min it only requires about one minute for a complete pH change. Sampling in stirrer methods often leads to problems. The introduction of the sampling probe can change the hydrodynamics and therefore the dissolution conditions. In addition, the sampling45 position must always be at the same point to guarantee reproducibility. In the flow through method there are no problems related to sampling. Neither manual nor automated manipulations are necessary. The sample solution is automatically filtered upon leaving the cell and can be analyzed directly or after fractioning without interference of the dissolution process.

Method                                                                                                        
                 The drug product is placed in a small volume cell with precisely defined dimensions. The dimensions along with the test method are defined in the USP chapter <724>46. A ruby ball is placed at the bottom of the cell acting as a check valve and prevents glass beads (when used) from blocking the cell channel. Two cell types are specified in the USP, the 12 mm and the 22.6 mm tablet cells including tablet holder. In the EP 447 additionally a suppository cell is described.

A piston pump is used for media delivery with usual flow rates from 1.5 to 50ml/min and a 10.The pulse rate remains constantpulse rate of 120 independent of the selected flow rate. The latter is determined by the stroke length of the piston. The cell type and the flow rate are the two most important method parameters. Typically, an unlimited volume of the medium is pumped through the cells and is filtered after leaving the cell via the filter head. The filter material can be selected from a wide range of available types. The release rate of the drug product depends on the flow rate of the medium and therefore a constant flow is essential. The flow rate of the medium during the test must be constant even if filter resistance is increasing. The pump design must therefore be able to handle a range of filter types, maintain a sinusoidal flow profile and a constant flow rate. In addition, the material has to be inert to prevent absorption of drug. Studies also showed that a sinusoidal flow profile with a pulsation of 120 + 10 pulses per minute is optimal22 and it became a USP requirement1. The piston pump fulfills all of these requirements and has proven to be both precise and while peristaltic pumps can be used in special cases like testing of implants. De aeration of the test media is essential to ensure that no bubbles are formed. There are a number of test variations associated to air bubbles:
 
In an open system with a constant flow of new medium, the elute is collected in the off-line mode in a fraction collector and then analyzed afterwards in a spectrophotometer or by HPLC. The results obtained are the differential release rates, see figure 4, and can easily be converted into cumulative values.

Figure:- Flow through cell
 

Open and closed system With the flow-through method the system can be set in two ways. Either as an open or as a closed system.

(a) Open system:
                            The open system has a configuration where fresh medium is pumped through the cell and the fractions are collected. This set up enables that the dissolution test is always performed at the best possible sink conditions. Every 30 to 60 minutes fractions are collected which results in rather high fraction volumes. A typical flow rate of 16 ml/min with a 30 min fraction interval results in a fraction volume of 480ml. This is not very practicable for the laboratory and therefore a volume splitting device (splitter) is used. The splitter manages a three way valve time controlled from collection to waste. Typically only 10% of the eluate would be collected which results in 48 ml fractions. Also pH changes are easily performed. To perform pH changes a medium selector is required which switches a seven channel valve from medium one to medium two. It is recommended to use an open system configuration for poorly soluble drugs or when pH changes have to be performed. Also formulation variances of highly soluble drugs can be tested and differences at the beginning of the dissolution process are better detectable than with the USP I and II method.
 

(b) Closed system:
                             The closed system is a configuration in which medium is pumped in circle and not replaced by fresh medium. The eluate48 is collected in a beaker which is stirred with a magnetic stirrer. Samples are taken from the beaker or readings on-line with spectrophotometer to measure the cumulated concentration of drug whereas in an open system the released drug over a time period is measured.
  
               The closed system is a configuration which is similar to the stirrer methods as the volume is limited and the released drug is cumulating over time. This configuration is used for drug products having a very low dosage strength and essentially it can be performed with very small volumes. Typical examples are implants. The question of an in vivo/in vitro correlation is always extensively discussed. General valid statements cannot easily be done. On the other hand, the flow through method with constant feeding of fresh medium is sometimes better related to in vivo conditions than the stirrer method with fixed solvent volumes. In addition the pH changes allow designing an in-vitro test under in-vivo conditions. Questions pertaining49 to this problem are widely discussed in specified literature. One publication discussed various conditions for a "Bio relevant Dissolution Test with the Flow-Through Apparatus V.
Experimental Conditions
There are two different types of the medium flow through the cells, laminar and turbulent flow. A laminar flow is characterized by fluid particles moving in parallel to each other in flow direction. A turbulent flow is a type of flow regime characterized by the rapid movement of fluid particles in all direction within the flow direction. Laminar flow is mainly used however turbulent flow is preferable for implant testing or products that require agitation.
 
Qualification:
                     Besides the physical dimensions of the cells the flow rate and the temperature are the most important test parameter which can influence the test. It is recommended to check the flow rate before the test if the system was not used for some time and always after a test run to calculate the accurate release rate. The flow rate can be measured by metering the pump volume and measuring the volume versus time. The cells are made of polycarbonate and there is very little potential of variability of the geometry.
Here are parameters which are usually validated:
 
                   Currently no official USP calibrator tablets for USP IV method are available. In the USP project team 5, Dissolution Calibrators, discussions are ongoing for a calibrator tablet for USP 4. Some laboratories use in house calibrator tablets.
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