Product Profile:
In-Situ Deaeration of Dissolution Media Through a Hollow ShaftTM System
Rolf Rolli,(1) Alexander Fiechter(1) and Richard Hengst(2)
(1) SOTAX LTD., Basel, Switzerland
(2) SOTAX Corporation, Furlong, PA

email for correspondence:rolf.rolli@sotax.ch

Summary
Deaeration of dissolution media is required by the USP and therefore a standard procedure in the quality control laboratory of the pharmaceutical industry. Traditional methods using vacuum are cumbersome, time consuming and bear the risk of reaeration during dispensing of the media into the dissolution vessels.
A new in-situ method with direct deaeration in the dissolution vessels just prior to the start of the dissolution test is described. The experimental data show that the deaeration rate is much faster than traditional methods and is more complete. This new deaeration method works with a wide range of different media. The described system is a very cost effective way to deaerate.

Introduction
It's well known and documented in the literature that oxygen can influence the dissolution rate of solid dosage forms [1]. Therefore, the health authorities have taken this into consideration and require or recommend deaeration of the media. The USP 23 states "Note-Dissolved gases can cause bubbles to form, which may change the results of the test" [2]. As a deaeration method the USP recommends: "Heat the medium, while stirring gently, to about 45°C, immediately filter under vacuum using a filter having a porosity of 0.45 mm or less, with vigorous stirring under vacuum for about 5 minutes." In the Ninth Supplement, USP-NF slightly alters the method [3]. This method is cumbersome and time consuming. To overcome some of these drawbacks, automated external media preparation stations are commercially available. The USP also states that "Other validated deaeration techniques for removal of dissolved gases may be used [2]. Several authors have summarized different deaeration techniques that utilize vacuum, heating, sonication, membranes and helium [4,5]. The helium sparging method was considered expensive. According to our experience this is due to lack of a good hardware design to dispense the helium efficiently. The risk of reaeration during dispensing of the media into the dissolution vessels is another problem. Experiments in the SOTAX application lab show reaeration rates from 20% to 60 % depending on the way the media is dispensed into the dissolution vessels [6]. Other authors have studied the reaeration and found up to a 275% increase in the oxygen level after dispensing the media into the dissolution vessels [7].

We have developed an in-situ deaeration technique applying the SOTAX Hollow ShaftTM stirrers. The Hollow ShaftTM stirrers are able to dispense the helium very efficiently and deaeration of the dissolution medium is executed very quickly in the test vessels. With this system, the risk of reaeration during dispensing of the media into the dissolution vessels is eliminated. The described apparatus is also a very cost effective way to deaerate as it requires only an additional 3-way valve, connected to a helium supply, besides the standard SOTAX AT7smart automated dissolution tester equipped with the Hollow ShaftTM system.

Experimental
Apparatus
SOTAX AT7smart equipped with the SOTAX Hollow ShaftTM stirrers [8] connected to a 3-way valve and a helium source for deaeration and fraction collector or UV spectrophotometer [Figure 1]. A WTW model OXI 320 Meter [9] with an oxygen sensor type Cell Ox 325 was used to measure the % saturated oxygen content in the dissolution media before and after the deaeration with helium. The instrument was calibrated daily according to the manufacturer's directions.

The in-situ deaeration is performed through the SOTAX Hollow ShaftTM system [10] which contains a sample opening and a 0.1 mm stainless steel pre-filter [Figure 2] which disperses helium bubbles finely and is also used for sampling.

Figure 1: Dissolution Apparatus equipped for in-situ deaeration

Figure 2: Hollow Shaft deaeration and Sampling System

Preparation of dissolution media
Deionized water, 0,1N HCl and phosphate buffer pH7.4 were used in the evaluations.

Deaeration Techniques
Dissolution media is dispensed into each dissolution vessel and then in-situ deaerated on-line with helium (1bar valve pressure) through the Hollow ShaftTM.

Each medium was degassed at 37°C and 100 rpm for up to 6 minutes.

After the short deaeration period the dissolution test can start by switching a 3-way valve in the lines of the Hollow ShaftTM system. The Hollow ShaftTM system is then utilized for sampling on-line to a UV spectrophotometer or off-line to a fraction collector.

Results
With each medium two tests were made and the oxygen level was measured from start to 6 minutes. The mean and standard deviation was calculated for each medium, deionized water, 0.1N HCI and phosphate buffer pH7.4, (Tables 1-3, respectively).The mean % saturated oxygen contents are plotted for each medium (Figures 1-3).

Table 1: Deionized water
% saturated oxygen content
	vessel #		start	30 sec	1min	1.5min	2min	4min	6min
		1	91.5	53.5	35	24	17.5	4	3
	Test 1	4	91	53.5	34.5	24	18	4.5	3
		7	91	54	34.5	24	18	4	3
		1	93	54	35.5	24.5	18	5	3
	Test 2	4	92	53.5	36	25	17.5	5.5	3.5
		7	93	54	35.5	25.5	19	5	3.5
	mean		91.9	53.8	35.2	24.5	18	4.7	3.2
	std. dev.		0.917	0.274	0.606	0.632	0.548	0.606	0.258

Table 2: 0.1N HCl
% saturated oxygen content
	vessel #		start	30sec	1min	1.5min	2min	4min	6min
		1	97	61	38	26	18.5	5	3.5
	Test 1	4	98	62.5	38.5	26	17.5	5.5	3
		7	97	61.5	38.5	27	18	5	3.5
		1	97.5	62	38.5	27.5	18	5	2.5
	Test 2	4	98.5	62	38	26.5	17.5	5.5	3.5
		7	98	61.5	38	26	18.5	5	3
	mean		97.7	61.8	38.3	26.5	18	5.2	3.2
	std. dev.		0.6055	0.5244	0.2739	0.6325	0.4472	0.2582	0.4082

Table 3: Phosphate buffer pH 7.4
% saturated oxygen content
	vessel #		start	30sec	1min	1.5min	2min	4min	6min
		1	98	62	38	27	18.5	5	3.5
	Test 1	4	98.5	61.5	39	27.5	18	4.5	3
		7	99	63	39	27	19	5	3
		1	99.5	63.5	38.5	27.5	18.5	5	3
	Test 2	4	99	63	38.5	27.5	18.5	5.5	3.5
		7	99	63	38	28	19	5	3
	mean		98.8	62.7	38.5	27.4	18.6	5	3.2
	std. dev.		0.5164	0.7528	0.4472	0.3764	0.3764	0.3162	0.2582

Figures 1-3. Top row Figures 1 and 2. Bottom row, Figure 3.

Conclusions
The data show that in-situ deaeration through the Hollow ShaftTM is a fast method which can be applied with different dissolution media. The consumption of helium is very low and takes only one minute to fulfill USP requirements. In comparison it may require up to one hour labor to do it manually. Also, the risk of reaeration during dispensing is eliminated. The in-situ deaeration through the Hollow ShaftTM can be utilized in a range of configurations from on- or off-line systems and all the components are commercially available.

References
[1] Hanson, W.A. , Handbook of Dissolution Testing, 2nd Edition, Revised, Aster Publishing Corporation, Eugene, Oregon, 1991
[2] USP 24, January 1, 2000 page 1943
[3] Ninth Supplement, USP-NF , 4661
[4] Griffith, M.E., Curley, T.E., Martin, G.P., Consideration in Choosing a Deaeration Technique for Dissolution Media. Dissolution Technologies, Vol. 4, issue 1, February 1997, 16-17
[5] Qureshi, S.A., McGilveray, I.J., I. J. Drug Dev. Ind. Pharm. 21, (8) 905 (1995)
[6] Fiechter, A, Internal Communication, 15.7.(1999)
[7] Diebold, S.M., Dressman, J.B., De- and Reaeration of Aqueous Media for Dissolution Testing. Pharm. Ind. 60, 354-359 (1998)
[8] SOTAX AG Basel, Switzerland
[9] WTW AG, Uznach, Switzerland
[10] SOTAX AG, Basel, Switzerland

Correspondence:
Rolf Rolli
Sotax Ltd Basel
CH-4123 Allschwil 1 Switzerland
Phone +41-61-487 54 54 Fax +41-61-482 13 31
email: rolf.rolli@sotax.ch