Influence of X-ray Radiation as PAT Method on the Model Substances Tramadol HCl and Nifedipine Compared to the Influence of UV-Vis Radiation

Martin Vogt and Elke Sternberger-Rützel · Robert Bosch GmbH Packaging Technology, Waiblingen Manuel Birke and Christoph Jacobs · PHAST Gesellschaft für Pharmazeutische Qualitätsstandards mbH, Homburg

Corresponding Author:

Martin Vogt, Robert Bosch GmbH; Packaging Technology, Stuttgarter Str. 130, Waiblingen; e-mail: martin.vogt4@bosch.com

Summary

Bosch has recently developed an X-ray technology, which can be implemented in a capsule filling machine (GKF) or as a stand alone visual inspection control unit (KKX), fulfilling PAT purposes. This technology is applicable for 100 % check weighing, detection of foreign particles (e. g. metal), measurement of capsule conditions (length, deformation) and provides information about the filling process.

The measurement principle is based on the Lambert-Beer law. Intensity of the incident X-ray radiation is attenuated dependent on the sample passed – through distance. The absorbance A, the negative logarithm of the quotient of incident intensity and transmitted intensity, is directly proportional to the distance transmitted, which can be related to the mass of the transmitted sample.

Due to the short measurement period of the X-ray technology in the range of 250 ms to 1 s, this technique allows for 100 % inline weight control of capsules and is considered to be a non – destructive technique.

In the present study, the influence of X-ray radiation on sample stability in comparison to environmental radiation sources like daylight was investigated for Nifedipine. This API is known to undergo photodegradation to dehydronifedipine upon exposure to UV light and to the nitroso analogue of dehydronifedipine when exposed to sunlight. Additionally, the influence of radiation to Tramadol HCl was analyzed, which is known to be stable even under accelerated stress conditions in solution.

For both, Nifedipine and Tramadol, no degradation was observed if exposed to X-ray radiation for a period of 2 hours. Tramadol HCl was stable even after exposure to artificial daylight for a period of 30 minutes as expected.

Nifedipine showed increasing photodegradation over time to the main degradation products Nifedipine Impurity A (dehydronifedipine) and Nifefedipine Impurity B (nitroso analogue of dehydronifedipine) as well as to several other unknown degradation products. After 30 min exposure to artificial daylight Nifedipine showed a total degradation of 10.06 % including 0.44 % Nifedipine impurity A, 9.46 % Nifedipine impurity B and 0.16 % unknown degradation products.

1.Introduction

1.1 Preliminary consideration

With the introduction of X-ray technology as a measuring system (fig. 1) to control different parameters during production of medicinal products, the need to know the influence of X-ray on APIs (active pharmaceutical ingredients) was evident.

In order to detect and classify the potential degradation of the API based on X-ray radiation, a reference method for comparison is needed. In order to use established methods, ICH guidelines were considered as the best choice.

Therefore, the ICH guideline Q1B for photo stability testing [1] with adapted exposure times as the preferred comparison for the degradation of API by light energy was chosen.

This chapter shows, which amount of radiation energy is charged on the test samples by the different types of radiation energy:

1.1.1 Calculation of energy charged on samples, according to ICH guideline Q1B: Test1 [1]

“Use of a cool white fluorescent lamp with an output according to the D65/ID65 emission standard, defined in ISO 10977 (1993).” ICH guideline Q1B Test 1 requires a luminous exposure of Hν = 1,200,000 lx·h for the tested sample. In order to find the corresponding energy which effects the sample surface under these conditions, the following calculation was carried out. One lux-second is equal to 1 lumen-second per square-meter: 1 lx·s = 1 lm · m-2 · s Under ideal conditions one lumen of light results in 1/683 Watt, according to Figure 4: 1 lm = 1/683 W = 0.001464 W @ λ = 555 nm

Thus one lux-second can also be written as 1 lx·s = 1 lm · s · m-2 = 1/683 W · s · m-2 .

One lux-hour is consequently: 1 lx·h = 3,600 lx·s = 3,600/683 Ws · m-2 = 5.27 Ws·m-2. 1,200,000 lux-hours result accordingly in: Hν = 1,200,000 lx·h = 6,325,036.6 Ws·m-2 .

The overall energy absorbed at the sample surface can be determined with the following equation. The surface depends on the conditions within the X-ray measuring system: The examined area covered by the API is equal to the X-ray sensor dimensions of 50 x 75 mm as worst case conditions or usually smaller. A = 75 mm · 50 mm = 3,750 mm2 = 0.00375 m2 (Surface X-ray sensor) ETest1 = Hν· A = 23,718 Ws

The amount of energy, which is absorbed by the sample in ICH guideline Q1B Test 1, is 23,718 Ws on the reference-surface of A = 0.00375 m2.


1.1.2 Calculation of energy charged on samples, according to ICH guideline Q1B: Test2 [1]

“A near UV fluorescent lamp (spectral distribution λ = 320 to 400 nm), with not less than 200 W·h·m-2 “ Overall energy on surface A in test 2: ETest2 = PTest2 · A = 2,700 Ws with A = 0.00375 m2 and 1 Wh = 3,600 Ws


The amount of energy, which is absorbed by the sample in ICH guideline Q1B Test 2, is 2,700 Ws on the reference-surface of A = 0.00375 m2.

1.1.3 Calculation of energy charged on samples during X-ray exposure

In order to know the amount of energy absorbed by the samples during the exposure time by X-ray radiation, firstly the emitted radiated power of the used X-ray source is calculated (see chapter 1.1.3.1).

In a second step the aspects of radiation physics are taken under consideration, which occur during the propagation of energy-rays in free space (see chapter 1.1.3.2).

In the third step is shown, what X-ray exposure times are necessary, to charge the samples with the same amount of energy like with visible light (according to ICH guideline Q1B Test 1) or UV-light (ICH guideline Q1B Test 2), see chapter 1.1.3.3.

1.1.3.1 Calculation of the radiation power emitted by the X-ray source

The radiated power J [Watt] of the X-ray source is proportional to the atomic number Z of the anode material, to the anode-current IA and the square of the anode-voltage UA [2]: J = α · Z IA UA2 α = 10-9 V-1 Z = 74 (atomic number of Tungsten) UA = 40kV = 40,000V IA = 0.5 mA = 0.0005 A J = 10-9 V-1 · 74 · 0.0005A · (40,000V)2 = 0.0592 VA = 0.0592 W Therefore, the overall emitted radiated power of the used X-ray source is J = 0.0592 W

1.1.3.2 Free-space attenuation: Calculation of the power arriving at the sensor surface

The free space attenuation (fig. 2) describes the reduction of power density in the propagation of electromagnetic waves in free space. Ideally, free-space attenuation occurs in a vacuum, for example in space at radio links from satellites and is an important criterion to calculate the necessary transmitting power and receiver sensitivity.

If high-frequency power P is radiated by an isotropic spherical source, then the radiation is spread uniformly in all directions. Consequently, surfaces of equal power density S will form spheres around the emitter. With an increasing sphere radius r, the energy is distributed over a larger area A = 4πr2 around the emitter.


Calculation of the Intensity (power per unit area) arriving at the sensor surface, caused by X-ray radiation, based on the given equation in figure 2:with P = 0.0592 W; r = 180 mm = 0.18 m (distance of the focal-spot to the sample) S = 0.1454 W·m-2

Calculation of the power in relation to the surface area of the X-ray sensor: PDetector = S · A with A = 75 mm · 50 mm = 3,750 mm2 = 0.00375 m2 PDetector = 0.0005 W In the worst case a maximum power of PDetector = 0.5 mW arrives at the X-ray sensor surface.

Only a very small part of the arriving power is absorbed by the examined objects (σ). If all of the energy was absorbed by the product (σ), the X-ray sensor would not detect anything (fig. 3).

1.1.3.3 Calculation of X-ray exposure time

In order to be able to compare the amounts of energy out of ICH guideline Q1B Test 1 and 2 with the necessary energy caused by X-Ray to reach the same amount, a simple rule of proportion can be applied:

The X-Ray source mentioned above generates an effective power of PDetector = 0.0005 W on the sample surface A. Knowing the energies out of ICH guideline Q1B Test 1 and 2, the needed exposure times can be determined as follows:
tX-ray-Test1 = ETest1 / PDetector= 23,718 Ws / 0.0005 W = 47,436,000 s = 13,177 h = 549 d tX-ray-Test2 = ETest2 / PDetector = 2,700 Ws / 0.0005 W = 5,400,000 s = 1,500 h = 62.5 d

1.2 Results of preliminary consideration

To provide a photo stability sample with the same amount of energy comparable to X-ray radiation as in the ICH guideline Q1B Test 1, an X-ray exposure time of 549 days would be necessary. For practical reasons this time is too long and the exposure time was reduced to a maximum of 2 hours of X-ray exposure, corresponding to 30 min of artificial daylight exposure.

To provide a photo stability sample with the same amount of energy comparable to X-ray radiation as in the ICH guideline Q1B Test 2, an X-ray exposure time of 62.5 days would be necessary. Again, the maximum exposure of 2 h was chosen. Since the standard exposure time during X-ray measurements is less than one minute, usually below 1 s, no significant degradation of the API is expected. Furthermore, the compliance of X-ray radiation with valid legal pharmaceutical regulations concerning dosage of X-ray for medication was confirmed (see chapter 3.3).

2.Materials and Methods

2.1 Experimental Design

Samples of the solid drug substances Nifedipine and Tramadol HCl were stressed by X-ray radiation and by artificial daylight. The exposed surface and the thickness of drug substance layer was normalized by usage of similar sample containers of violet glass with an inner diameter of 32 mm and by similar weight sample of 300 mg/container assuring complete coverage of the container bottom.

X-ray exposure of samples was performed at Robert Bosch GmbH, Waiblingen. All other tests were performed at PHAST GmbH. To evaluate the contribution of transport and environmental condition during measurement, a control sample that was only transported and handled like the other samples but not exposed to X-ray radiation was included in the study. For evaluation of thermal degradation during artificial daylight exposure a dark control sample was stressed for the maximum exposure time. Impurity amounts determined in these control samples were subtracted from the amounts of the corresponding impurity observed in the X-ray and artificial daylight stressed sample, respectively.

Table 1

Exposure times for artificial daylight.
Radiation sourceExposure times
Artificial daylight5 min, 10 min, 15 min, 20 min, 30 min

Table 2

Exposure times for X-ray radiation.
Radiation sourceExposure times
X-ray0.5 s, 1 s, 10 s, 1 min, 10 min, 1h, 2 h

All samples were prepared in triplicate.

2.2 Sample aliquotation

Sample aliquotation was performed under exclusion of daylight in a dark laboratory equipped with yellow light.

Fig. 5: Procedure to prove the compliance to legal requirements (Source: Robert Bosch GmbH).

Fig. 6: Measured dose-rates according to acceleration voltage (Source: Robert Bosch GmbH).

Approximately 300 mg of the drug substance was accurately weighed in a sample container of violet glass and sealed with a black screw stopper.

42 aliquots were individually prepared for both Nifedipine and Tramadol HCl.

2.3 Photostability testing

Samples of the solid drug substances Nifedipine and Tramadol HCl were exposed directly to an artificial daylight fluorescent lamp combining visible and UV outputs, producing an output of 48,000 Lux, similar to the D65/ID65 emission standard. The samples were exposed in the glass container. The screw stopper was removed immediately before exposure and containers were covered with a quartz glass plate. After exposure, the sample container was closed with the stopper.

Table 3

Measured dose-rates according to acceleration voltage.
Dose-measurement within the direct X-ray beam
Parameters
X-ray tube: Oxford Apogee 60 kV
Dose rate meter: Automess 6150 AD
Anode current: 0.1 mA
Distance of the focal spot to the sensor: 422 mm
Acceleration voltage [kV]Dose-rate [mSv/h] (additional absorption: none)Dose-rate [mSv/h] (additional absorption:
2 mm PEEK)
300.130.13
350.750.72
402.452.31
455.775.43
488.688.09

Table 4

Photodegradation of Nifedipine, mean values (n=3), corrected for dark control.
Time [min]Unknown degradation products [%]Known impurities [%]
123456AB
5< 0.01< 0.01< 0.01< 0.01< 0.01< 0.010.051.62
10< 0.010.010.01< 0.01< 0.01< 0.010.102.32
150.010.010.020.010.010.010.183.89
200.010.020.020.020.010.010.255.24
300.020.030.030.030.020.030.449.46
dark control< 0.01< 0.01< 0.01< 0.01< 0.01< 0.01< 0.010.01

To evaluate the contribution of thermally induced change to the total observed change, protected samples, wrapped in aluminum foil, were placed alongside the authentic sample as dark control for the maximal exposure time of 30 min. The exposure times for photostability testing are summarized in Table 1.

We choose 30 min as the maximum duration for radiation in order to have a certain compatibility between the different sources of energy. Due to the fact that 1,2 mio lux h or 200 Watt h/m2, according to the guideline [1], are given off after 25 h with this lamp with 48,000 lux, a duration of 62.5 days with X-ray exposure would have been necessary (see 1.1.3). In order to reduce this time for pragmatic reasons and to compare it with realistic X-ray radiation times, the radiation in artificial light was defined as a maximum of 30 min.

2.4 X-ray radiation stability testing

Samples of the solid drug substances Nifedipine and Tramadol HCl were exposed directly to an X-ray tube with a power of 0.0592 Watt (tungsten anode, anode voltage 40 KV, current 0.5 mA).

The exposure times for X-ray stability testing are summarized in Table 2.

The given exposure times were chosen in order to simulate the standard process time (< 1s) and to create degradation kinetics (up to 2 h) with a worst case scenario.

2.5 Test methods for purity determination

2.5.1 Test method for related substances of Nifedipine

Determination of related substances was performed analog to the Ph. Eur. 7.3 monograph for Nifedipine [7]. The parameters of the test method were adapted for composition of the mobile phase and injection volume to assure suitable peak separation. To protect them from daylight, all solutions were prepared in amber glass flasks in a lab equipped with yellow light.

As a stationary phase Phenomenex Luna C18, 150 x 4.6, 5 µm was used, while methanol/0.03 % sulfuric acid (60:40v/v) was used as a mobile phase. 2 µL of each sample were injected. Runs were performed with 1 mL/min flow rate. Detection was performed at 235 nm. Impurities A and B were quantified using Ph.Eur. chemical reference standards (CRS) for these impurities. Other impurities are quantified against Nifedipine CRS.

2.5.2 Test method for related substances of Tramadol HCl

Determination of related substances was performed analog to the Ph. Eur. 7.3 monograph for Tramadol hydrochloride [8] with adapted injection volume.

To protect them from daylight, all solutions were prepared in amber glass flasks in a lab equipped with yellow light. As a stationary phase, Phenomenex Luna C8, 250 x4.0, 5 µm was used, while acetonitrile/0.2 % trifluric acid (295:705 v/v) was used as a mobile phase. 10 µL of each sample were injected. Runs were performed with 1 mL/min flow rate. Detection was performed at 270 nm. Impuritiy A was identified using Ph.Eur. chemical reference standards (CRS). All impurities are quantified against Tramadol CRS.

3.Results

3.1 Results Nifedipine

3.1.1 Results after exposure to X-ray radiation

Nifedipine was stable if exposed to X-ray radiation for 2 hours as a worst case condition. Consequently, it was stable in all other shorter radiated samples as well. The dark control sample of Nifedipine and all stressed samples contained 0.01 % Nifedipine impurity B and 0.03 % of an unknown degradation product at a retention time of 3.6 min, which is within the specification limit of ≤ 0.1 % for both impurities. Thus, impurity B and the unknown degradation product at retention time 3.6 min were not formed during X-ray exposure and can be disregarded as a by-product.

No further degradation products exceeding the disregarding limit of 0.01 % were observed after exposure to X-ray radiation for 2 hours. Overlay chromatograms are shown in Figure 7, a zoomed view is given in Figure 8.

3.1.2 Results after exposure to artificial daylight

Nifedipine was not stable if exposed to artificial daylight for 30 minutes. The dark control sample of Nifedipine and all further stressed samples contained 0.03 % of an unknown degradation product at a retention time of 3.6 min, which is within the specification limit of ≤ 0.1 %. Thus, the unknown degradation product at retention time 3.6 min was not formed during artificial daylight exposure and can be disregarded as a by-product. Additionally, the dark control sample contained 0.01 % Nifedipine impurity B. This amount was subtracted from the amount of Nifedipine impurity B found in the stressed samples.

Nifedepine showed increased photodegradation over the exposure time. Already after 5 minutes of exposure, Nifedipine impurity B, the main degradation product upon exposure to sun light, was formed to 1.62 % which is above the specification limit of ≤ 0.1 %. Additionally, Nifedipine impurity A, also a main degradation product upon exposure to UV-light, was formed to 0.05 % which is within the specified limits of ≤ 0.1 %.

After 30 minutes exposure to artificial daylight Nifedipine impurity A and B further increased to 0.44 % and 9.46 %, respectively, and additional six other impurities were formed. The results of Nifedipine photodegradation are summarized in Table 4, a graphical presentation for known impurities A and B is given in Figure 9 and for unknown degradation products in Figure 10. Overlay chromatograms are shown in Figure 7, a zoomed view is given in Figure 8.

3.2 Results Tramadol

3.2.1 Results after exposure to X-ray radiation

Tramadol HCl was stable if exposed to X-ray radiation for 2 hours. The dark control sample of Tramadol HCl and all stressed samples contained 0.04 % Tramadol impurity A, which is within the specification limit of ≤ 0.2 %. Thus, impurity A was not formed during X-ray exposure and can be disregarded as a by-product.

No further degradation products exceeding the disregarding limit of 0.02 % were observed after exposure to X-ray radiation for 2 hours. Overlay chromatograms are shown in Figure 11, a zoomed view is given in Figure 12.

3.2.2 Results after exposure to artificial daylight

Tramadol HCl was stable if exposed to artificial daylight for 30 minutes. The dark control sample of Tramadol HCl and all stressed samples contained 0.04 % Tramadol impurity A, which is within the specification limit of ≤ 0.2 %. Thus, impurity A was not formed during X-ray exposure and can be disregarded as a by-product.

No further degradation products exceeding the disregarding limit of 0.02 % were observed after exposure to X-ray radiation for 30 minutes. Overlay chromatograms are shown in Figure 11, a zoomed view is given in Figure 12.

3.3 Proof of compliance to legal requirements

In order to prove that the radiation dose for the examined pharmaceuticals is below the valid limit of 0.1 Gray as given in AmRadV [8], a dose-measurement within the direct X-ray beam was realized.

The standard X-ray tube was positioned at a distance of 422 mm to a dose rate meter (type “Automess 6150AD”) in previous tests. Table 3 shows the dose-rates according to the acceleration voltage of the X-ray tube.

In order to obtain the correlation of the results shown above to the conditions of the capsule measurement within the equipment in the production, worst case parameters are used for a comparative calculation.

The distance between the focal spot and the analyzed object in the machine is 180 mm. Considering the inverse square law (see chapter 1.1.3.2), the dose rate increases as follows: Ix = I0 · (422 mm/180 mm)2 = I0 · 5.5 The anode-current during the measurement is 5 times larger (0.5 mA instead of 0.1 mA) than in the dose-rate measurement:
Ix = I0 · 5 · 5.5 = I0 · 27.5 The largest high voltage used during a capsule scan is limited to 40 kV, because a larger high voltage would overexpose the X-ray image. The dose rate for the mentioned parameters results in: Ix = 2.31 mSv/h · 27.5 = 63.5 mSv/h Result: Even an X-ray exposure time of 60 min does not exceed the accepted dose-limit of 0.1 Gray = 0.1 Sv = 100 mSv.

Considering that the exposure time during the measurement is usually not larger than one second, the dose which is absorbed by the object is smaller than 1/5000 of the current dose-rate limit: = 100 mSv / (63.5 mSv/h / 3600 s/h) = 100 mSv / 0.01764 mSv/s = 5569 s. Additionally, this result is a theoretical value, which would be applicable, if all of the radiation would be absorbed by the capsule. In practice the capsules then would appear as a completely black area at the sensor. The fact is that the capsule area is only very slightly darker than the areas with no absorption. This leads to the conclusion, that only a very small amount of radiation is really absorbed by the capsules and thus may influence the API (see Figure 3, chapter 1.1.3.2). The major part of the beam passes through the capsules and is finally absorbed by the X-ray sensor and the shielding – with no influence to the pharmaceuticals.

As a summary, the amount of X-ray radiation that is absorbed by the analyzed medicinal products does not exceed the valid dose-limits.

4.Conclusions

As known from literature, Nifedipine is very sensitive to daylight. 30 minute exposure to artificial daylight results in degradation of approx. 10 %. In contrast, no degradation occurs for Nifedipine when exposed to X-ray radiation for up to 2 hours. As deduced in the introduction, the amount of energy for X-ray radiation is not comparable to the amount of artificial light exposition in this short period of time because the energy of X-ray radiation is much lower.

A comparable result can be applied for Tramadol HCl: no degradation occurred during X-ray radiation and in this case, additionally, no degradation occurred during artificial light exposition. Tramadol HCl is a very stable compound for both sources of radiation as proven.

With this comparison of radiation of the model APIs Nifedipine and Tramadol HCl, it is proven that X-ray radiation as a PAT (Process Analytical Technology) tool does not influence the API degradation during the standard application of less than 1 second of radiation. Therefore, X-ray detection is a suitable optical inspection method without any negative influence on the medicinal product. Bosch has recently developed an X-ray technology, which can be implemented in a capsule filling machine (GKF) or as a stand alone visual inspection control unit (KKX), fulfilling PAT purposes. This technology is applicable for 100 % check weighing, detection of foreign particles (e. g. metal), measurement of capsule conditions (length, deformation) and provides information about the filling process [9].

The measurement principle is based on the Lambert-Beer law. Intensity of the incident X-ray radiation is attenuated dependent on the sample passed – through distance. The absorbance A, the negative logarithm of the quotient of incident intensity and transmitted intensity, is directly proportional to the distance transmitted, which can be related to the mass of the transmitted sample.

Due to the short measurement period of the X-ray technology in the range of 250 ms to 1 s, this technique allows for 100 % inline weight control of capsules and is considered to be a non – destructive technique.

In the present study, the influence of X-ray radiation on sample stability in comparison to environmental radiation sources like daylight was investigated for Nifedipine. This API is known to undergo photodegradation to dehydronifedipine upon exposure to UV light and to the nitroso analogue of dehydronifedipine when exposed to sunlight [10]. Additionally, the influence of radiation to Tramadol HCl was analyzed, which is known to be stable even under accelerated stress conditions in solution [11].

For both, Nifedipine and Tramadol HCl, no degradation was observed if exposed to X-ray radiation for a period of 2 hours – with a standard exposure of less than 1 s.

Tramadol was stable even after exposure to artificial daylight for a period of 30 minutes as expected.

Nifedipine showed increasing photodegradation over time to the main degradation products Nifedipine Impurity A (dehydronifedipine) and Nifefedipine Impurity B (nitroso analogue of dehydronifedipine) as well as to several other unknown degradation products. After 30 min exposure to artificial daylight Nifedipine showed a total degradation of 10.06 % including 0.44 % Nifedipine impurity A, 9.46 % Nifedipine impurity B and 0.16 % unknown degradation products.

Literatur

[1]ICH Harmonised Tripartite Guideline, “Stability Testing: Photostability Testing of New Drug Substances and Products, Q1B” Current Step 4 version, dated 6 November 1996
[2]http://e3.physik.uni-dortmund.de/~suter/Vorlesung/Medizinph ysik_06/6_Roentgendiagnostik.pdf (30.03.2012)
[3]http://hyperphysics.phy-astr.gsu.edu/hbase/forces/isq.html# c4] (30.03.2012) (modified)
[4]http://e3.physik.uni-dortmund.de/~suter/Vorlesung/Medizinph ysik_06/6_Roentgendiagnostik.pdf (30.03.2012) (modified)
[5]http://www.ecse.rpi.edu/~schubert/Light-Emitting-Diodes-dot -org/chap16/F16-07 %20V%28lambda%29 %20photopic. jpg (30.03.2012)
[6]Ph. Eur. 7.3, monograph for Nifedipine
[7]Ph. Eur. 7.3, monograph for Tramadol HCl
[8]AmRadV – Arzneimittelverordnung § 1 section 1 point 3 [http://www.gesetze-im-internet.de/amradv/index.html] (30.03.2012)
[9]Vogt, M., Beck, M., Maga, I., 100 %-Inline-Qualitätskontrolle mit X-ray-Technologie, TechnoPharm, 2011, Nr. 1, 60 – 67
[10]Grundy, J. S., Kherani, R., Foster, R. T., Photostability determination of commercially available nifedipine oral dosage formulations, J. Pharm. and Biomed. Anal., 1994, Vol. 12, No. 12, 1529 – 1535.
[11]Negro, S., et al., Stability of Tramadol and Haloperidol for continuous subcutaneous infusion at home, J. Pain and Symptom Manage., 2005, Vol. 30, No. 2, 192 – 199.
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