dx.doi.org/10.14227/DT060199P16

Hollow ShaftTM Sampling Method for Dissolution Testing

Richard Hengst and Rolf Rolli, Sotax Corporation, Furlong, PA

Introduction

With the increased testing demand in the laboratories of pharmaceutical

companies, governmental institutions and contract service companies,

automation becomes an important issue. Automated procedures can guarantee a

higher throughput of samples with increased accuracy and a decreased variation

due to human interference. With pressure to reduce the average cost per analysis

automation is a viable solution. This paper compares Hollow ShaftTM sampling

versus manual sampling in apparatus 1 and 2 dissolution testing.

Background

Sampling procedures in dissolution testing apparatus generate a great interest in

the scientific community as they can influence test results significantly.

Therefore, the regulatory authorities have taken this into consideration and have

issued guidelines. The USP 23 [1] describes exactly how samples should be

taken; "Withdraw a specimen from a zone midway between the surface of the

Dissolution Medium and the top of the rotating basket or blade, not less than 1

cm from the vessel wall" (see figure 1). With the increased tendency to automate

dissolution procedures this becomes even more important. The USP 23 requires

"No part of the assembly, including the environment in which the assembly is

placed, contributes significant motion, agitation, or vibration beyond that due to

the smoothly rotating stirring element [1]. In USP apparatus 1 and 2 dissolution

tests the samples are traditionally taken with a probe placed into the vessel. The

probe adds turbulence if it remains in the liquid phase. Lift devices can be

installed to move the probes in and out of the vessel at the required sampling

times. In addition filtration with a probe sampling system may not meet the lab

requirements. To overcome these problems, the Hollow ShaftTM sampling system

was introduced several years ago and installed in numerous pharmaceutical

laboratories throughout the world (figure 2). The Hollow ShaftTM sampling

system allows for short sampling intervals, down to 20 seconds per sample and

therefore the analysis of fast release drugs is possible.

Figure 1: Pink rectangle is

the sampling zone according

to USP 23

Figure 2: Hollow Shaft

Sampling System

The scientific community represented by the International Pharmaceutical

Federation (FIP) issued new guidelines to reflect recent developments in testing,

methodology and equipment [2]. In regards to automation, the guidelines state,

"Validation of automated systems, concerning the sampling and analytical

procedure, including media preparation and test performance, has to consider

accuracy, precision and avoid contamination by any dilutions, transfers, cleaning

or sample or solvent preparation procedures." It should be proven that there is no

significant difference between data obtained with the manual dissolution

equipment and the automated system, including manipulations such as permanent

sampling probes, additional valves, hollow shaft, etc. In addition, the USP has

issued guidelines regarding automated sampling and states[3] "If automated

equipment is used for sampling and the apparatus is modified, validation of

modified apparatus is needed to show that there is no change .."

Comparisons between manual and Hollow ShaftTM sampling have already been

presented to show that no significant differences exist between the results of

samples taken manually or by means of Hollow ShaftTM [4,5]. This study presents

an extended comparison of manual (probe) sampling versus Hollow

ShaftTM sampling using semi automatic on-line and off-line systems and a fully

automated dissolution system, the SOTAX AT70. The official USP calibrator

tablets were used as the test samples. All results have been taken from dissolution

systems located in pharmaceutical labs to show a realistic comparison of

equipment in routine use at different locations around the world.

Equipment

The following equipment was used in the study:

On-line: SOTAX AT7 dissolution

tester with Hollow ShaftTM sampling

system and CY7-50 piston pump

connected to a Perkin Elmer

Lambda 20 spectrophotometer

Off-line: SOTAX AT7 dissolution

tester with Hollow ShaftTM sampling system and CY7-50 piston pump connected

to a C 613 fraction collector

Filters: Whatman GF/D 2.7 m microfiber filters

Fully automated system :

SOTAX AT70 with Hollow ShaftTM sampling system and

CY7-50 piston pump connected to a Perkin Elmer

Lambda 20 and/or to a fraction collector C 613 for

combined on/off-line operation

Filters: Gelman 0.45 m glass fiber filters

Sampling:

In all equipment, manual sampling through the SOTAX

pipette guide ensured that the manual sample was consistently taken from the

same position. The automated sampling was done through the Hollow ShaftTM.

Experimental Methods

All tests were executed according to the USP apparatus calibrator test using

current lots of USP tablets and standards.

The dissolution medium was prepared with deionized water and the specified

chemicals. The medium was deareated by helium sparging for 30 sec while

maintaining a temperature of 40C. After the test of 30 minutes the samples were

withdrawn simultaneously. All samples have been measured with a Perkin-Elmer

Lambda spectrophotometer except on the AT70 #97.1.001 where a Shimadzu

UV-1601 was used. The spectrophotometers were equipped with either 1mm or

10mm flow through cuvettes . Standard readings were done before and after the

sample measurements. The mean of both standard values was used to calculate %

dissolved.

Test conditions

Salicylic acid Prednisone

Standard:

Lot I, Weigh approx.

50mg and dissolve in

1000ml phosphate

buffer pH 7.4 +/- 0,05

(to increase solubility

1% Ethanol was

added)

Lot K, Weigh approx.

50mg and dissolve in

1000ml deionized

water (to increase

solubility 2% Ethanol

was added)

Tablets: Lot N, 300mg active

substance

Lot L, 50mg active

substance

Dissolution Medium:

900ml deaerated

phosphate buffer pH

7.40 +/- 0.05, 37.0 +/-

0.3C

900ml deaerated

water, 37.0 +/- 0.3C

Sampling Interval: 30 minutes 30 minutes

Measurement: 296nm 242nm

Paddle: 100 rpm 50 rpm

Basket: 100 rpm 100 rpm

Results

The apparatus involved in the study are described by the serial numbers. The

sampling method is coded as follows:

M: Manual

HS on-line: Hollow shaft sampling on-line with spectrophotometer (see

Equipment).

HS off-line: Hollow shaft sampling off-line with fraction collector and

subsequent measurement with spectrophotometer (see Equipment).

The % dissolved results from each vessel, the mean and the difference of manual

sampling minus hollow shaft sampling is shown in figure 3.

Figure 3.

Table 1

AT7 on-line systems

The following systems were used in the study: AT7 #96.4.162 , AT7 #96.4.145.

Table 2

AT7 off-line systems

The following systems were used in the study: AT7 #91.1.074 two studies, AT7

#91.1.056, AT7 #94.4.098, AT7 #94.4.097, AT7 #91.1.056.

Table 3

AT70 on-line and combined on/off-line

The following systems were used in the study: AT70 #97.1.001, AT70

#97.1.002, AT70 #97.1.005, AT70 #97.1.006, AT70 #97.1.007, AT70 #97.1.008

Statistical Evaluation

All data for the paddle method were combined to recalculate mean and standard

deviation to have a clear statistical comparison.

Conclusion

The data show that samples taken by means of the Hollow ShaftTM method are

comparable to the results taken by a manual method. The system of Hollow

ShaftTM sampling is fully compliant with all current FIP,USP and FDA guidelines

and is an efficient sampling method. The Hollow ShaftTM sampling system can be

utilized in a range of configurations from fully automated to on- or off-line

operation for reliable and consistent data.

References

[1] USP 23, January 1, 1995 page 1791

[2] Pharmacopeial Forum, Volume 21, Number 5, 1371-1382

[3] Pharmacopeial Forum 23 Number 6 (Nov-Dec 1997), page 5257

[4] Dissolution Technologies, Vol. 3, issue 2, May 1996, 11-15

[5] Rolf Rolli oral presentation at FIP Spring Meeting, 15th May 1997, Allschwil