Short-term storage stability ofTriple IT solution
Matthias D’Hondt1, Elien Vangheluwe1, Nadia Lemeire1, Tiene Bauters2, Brigitte
Pelfrene2, Johan Vandenbroucke2, Hugo Robays2, and Bart De Spiegeleer1,*
1 DruQuaR (Drug Quality and Registration) group, Faculty of Pharmaceutical Sciences and 2 Ghent University Hospital, Ghent University, Harelbekestraat 72, B-9000 Ghent,
Belgium (*[email protected])
2011-211b
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Triple Intrathecal (IT) chemotherapy:
• Cytarabine (CB): pyrimidine antitumor agent
• Methotrexate (MT): synthetic inhibitor
of dihydrofolate reductase
vomiting, fever, paraplegia, meningoencephalopathy
• corticosteroid: reduces complications
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Hydrocortisone: benzylalcohol (preservative)
Methylprednisolone (21)-sodium succinate (Solu-Medrol®):no preservative
Yet, no in-use stability data available:
logistics and cost issues
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Determination of short-term (in-use) storage stability of Triple IT solution (ex tempore prepared):
(0.385 %m/V CB, 0.154 %m/V MT, 0.051 %m/V MP(21)-SS)
Evaluation of influences:
- Storage temperature- Photometric conditions- Packaging- Batch to batch variability
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Batch
3 different batches
Packaging material
1. Syringe system (PhaSeal®)
2. Brown glass vial
3. Brown glass vial filled with needles
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Temperature stability
time points (n=6): 0, 4, 8, 24, 32, 48 hrs.
3 batches, 3 packaging materials (all protected from light)
Temperature (°C) Relative humidity (%)
5 50
25 60
40 75
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
Controlled conditions
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Photometric stability
- Triple IT solution quartz cuvette (25°C / 60 % R.H.)
UV light – 2 days
VIS light – 8 days
- (Light protected) control samples
2 batches, in duplo
ICH Q1B compliant (light energy)
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Fused-core HPLC method
Column (+ guard column) Halo C18 (4.6×150 mm; 2.7 µm)
Column / sample temp. 30°C / 15°C
Mobile phase A: 0.1% V/V glacial acetic acid in H2OB: 0.1% V/V glacial acetic acid in ACN
Gradient programTime (min)
015
%A9010
%B1090
Flow rate 1 ml/min
Injection volume 10 µl
Detection DAD UV @ 240 nm (MP(21)-SS) @ 280 nm (MT and CB)
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
T0hrs. Triple IT
240 nm
280 nm
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Temperature stability – Global results
Triple IT Comp. Degradation Impurity formed Mass balance 1
CB - - 100.39 – 101.31%
MT - - 99.43 – 100.97%
MP(21)-SS 2 stat. significant RRT: 0.88 and 0.90 99.49 – 100.40% 2
Reporting threshold: 0.5%1 relative to T0 hrs.; 95% CI2 Including formed impurities, assuming RRF 1
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
MP(21)-SS degradation kinetics:
assuming (and confirmed) 1st order to determine k
Arrhenius regression:
0.00305000000000001 0.00325000000000001 0.00345000000000001 0.00365000000000001
-7.5
-7
-6.5
-6
-5.5
-5
-4.5
-4
f(x) = − 5472.56704299358 x + 13.1701428843253R² = 0.968557109009822
1/T (K-1)
ln k
Ea: 45.5 kJ/mol(95% CI: 41.6 - 49.4 kJ/mol)
A: 524×103 h-1
(95% CI: 107×103 - 2571×103 h-1)
ln k = ln A – Ea/RT
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Identification MP(21)-SS related degradants (ESI-MS)
RRT: 0.88 RRT: 0.90[M+H+]+ [M+H+]+
[2M+H+]+[2M+H+]+
Methylprednisolone Methylprednisolone (17)-succinate
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Batch / packaging material influence on MP(21)-SS degradation
MLR: k batch and packaging material (Temp.
constant)
No stat. sign. (95%) batch / packaging influence
Syr 5°C Syr 25°c Syr 40°C Gl 5°C Gl 25°C Gl 40°C Gl+N 40°C
00.20.40.60.8
11.21.41.6
Batch 1
Batch 2
Batch 3
k (×
10-2
h-1
)
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Photometric stability – Global results
Triple IT Comp. Degradation (%) 1 Impurity formed Mass balance 1
CBUV - - 101.29
VIS 3.80 RRT 1.12 99.47
MTUV 32.46 - 66.92
VIS 100.00 RRT 0.85; 1.05 28.09
MP(21)-SS 2UV - RRT 0.88; 0.90 98.62
VIS - RRT 0.88; 0.90 90.84
Reporting threshold: 0.5%1 Decrease of API, relative to light protected control samples2 Including formed impurities, assuming RRF=1
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Photometric stability – MTdegradation
MT: single compound vs Triple IT mixture
Triple IT solution
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Stability protocol
Results
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Conclusion
0 20 40 60 80 100 120 140 160 180 200
-6
-5
-4
-3
-2
-1
0f(x) = − 0.0252189106582489 xf(x) = − 0.00867469502360543 xf(x) = − 0.107183115418421 x + 0.0541481840581015R² = 0.954331617986911f(x) = − 0.0766560166501102 x + 0.120880473120384R² = 0.963697247158426
MT single UVLinear (MT single UV)MT single VISLinear (MT single VIS)Triple IT UVLinear (Triple IT UV)Triple IT VISLinear (Triple IT VIS)
Time (hrs)
ln(A
ssay
Tx
/ As
say
T0)
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Related impurities specifications (Ph. Eur.) of MP(21)-SS
MP: 0.5%
MP(17)-SS: 0.5%
Risk: MP (lower solubility) precipitation
Risk: min. (31%
degradation)
Conclusion: some consistent and controlled (MP + MP(17)-SS) degradation
of MP(21)-SS is allowed in FPP (DP) Triple IT (3%).
In API Solu-Medrol® FDP (Triple IT) higher, e.g. 1%
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
∑impurities < 1%
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
Predicted MP(21)-SS degr. in function of storage condition and time
60 180 360 720 1440 28800.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
Refrigerator (5°C)
Time (min)
Pred
icted
MP(
21)-S
S de
grad
ation
(%)
15 30 60 90 120 14400.00
0.20
0.40
0.60
0.80
1.00
1.20
Room temp. (25°C)
Time (min)
5 10 15 300.00
0.10
0.20
0.30
0.40
0.50
0.60Body temp. (37°C)
Time (min)
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Related impurities specifications (Ph. Eur.) of MT API
0.2% (= IT): H, I
0.3%: (B, E)
0.5% (= QT): C
3%: (F)
6 unspecified 0.05%
∑impurities < 0.5% (excl. imp. B, E and C)
Conclusion:
no significant MT degradation is allowed Triple IT: total imp. <0.5%
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion
6 specified
BGFW - DruQuaR, Fac. Pharm. Sciences, Ghent University
Proposed storage conditions:Storage:
Max. 12 hour refrigerator 1.8% MP(21)-SS degradation
Before administration
Max. 30 min heating cycle (37°C) 0.6% MP(21)-SS degradation
During administration / transport
Max. 2 hours administration (25°C) 1.1% MP(21)-SS degradation
All light protected no MT degradation
Triple IT solution
Objective
Stability protocol
Results
Discussion
Conclusion