Transcript P96_Impactul procedurilor de divizare a tabletelor asupra

The impact of tablet splitting procedures on the in-vitro performance of
prolonged-release oral formulations containing metoprolol succinate
Burcea Dragomiroiu George Traian Alexandru1, Radulescu Flavian Stefan2, Barca Maria1*, Ginghina Octav3, Cimpoieșu Adina1, Popa Daniela Elena1, Carolina Negrei4, Miron Dalia Simona5
University of Medicine and Pharmacy „Carol Davila” București
1Faculty of Pharmacy, Department of Drug Control, 6, Traian Vuia Street, 020956, Bucharest, România
2Faculty of Pharmacy, Department of Drug Industryand Pharmaceutical Biotechnologies, 6, Traian Vuia Street, 020956, Bucharest, România
3Faculty of Dental Medicine, Department of Oncological Surgery, „Sf Ioan” Hospital, 13, Vitan-Bârzești Street, 042122, Bucharest, România
4Faculty of Pharmacy, Department of Toxicology, 6, Traian Vuia Street, 020956, Bucharest, România
5Faculty of Pharmacy, Department of Pharmaceutical Physics and Informatics, 6, Traian Vuia Street, 020956, Bucharest, România
Corresponding author: [email protected]
OBJECTIVES
MATERIALS AND METHODS
The manipulation of the oral solid dosage forms prior to administration can have a
significant impact on their in-vivo performance. Particularly in the case of modified
release formulations, depending on the composition and manufacturing process,
alteration of the integrity can have a significant impact on both safety and efficacy.
Aim of the paper was to evaluate to which extent the in-vitro release process of
metoprolol succinate from prolonged release oral tablets is altered by splitting.
The protocol was applied to the reference listed drug, using different batches and
dose strengths (25-200 mg) produced in several European manufacturing sites.
The in-vitro dissolution tests were
performed
according to the USP
specific monograph for extended
release formulations (pH=6.8, 500 mL,
USP apparatus 2 at 50 rpm). The
tablets were split using a special
device and the individual fragments
were weighted.
RESULTS AND DISCUSSION
25
25
20
20
20
15
10
E100
H100
R100
S100
5
Fraction dissolved (%)
25
Fraction dissolved (%)
Fraction dissolved (%)
The in-vitro release mechanism was not altered by splitting procedures. After normalizing with the exact dose applied, the
fractions released throughout the 6 hours duration of the test and the kinetic profiles were similar. The mean differences
between the fractions released at each sampling point were lower than 5%. No dose-dumping effect was noticed. After a short
lag of 5 min or less, the tablets disintegrated, generating an uniform mass of granules agglomerated below the paddle. The
disintegration was slower and incomplete in case of the high dose strength, although this phenomenon didn’t seem to have an
impact on the in-vitro release. The irregularities in the shape and surface area of the fragments resulted by splitting generated
a higher variability of the experimental data, compared to the corresponding, whole tablets.
15
10
H50
5
120
180
240
300
360
S25
0
0
60
120
180
240
300
360
0
25
20
20
20
15
10
E100 (½)
H100 (½)
R100 (½)
S100 (½)
5
0
Fraction dissolved (%)
25
15
10
H50 (½)
5
180
240
300
360
180
240
300
360
15
10
E200 (½)
5
R50 (½)
H25 (½)
S50 (½)
S25 (½)
0
120
120
Time (min)
25
60
60
Time (min)
Fraction dissolved (%)
Fraction dissolved (%)
H25
S50
Time (min)
0
E200
5
0
60
10
R50
0
0
15
0
0
Time (min)
60
120
180
240
300
360
0
60
Time (min)
120
180
240
300
360
Time (min)
CONCLUSIONS
The release profiles proved that the performance of the prolonged release formulations of the reference listed drug is not
significantly altered by splitting procedures. Moreover, the in-vitro similarity was concluded on the evaluated dose interval.
ACKNOWLEDGEMENT
REFERENCES
This work was suported by the Sectorial Operational Programme Human
Resources (SOP HRD) 2007-2013, financed from the European Social
Fund and by the Romanian Gouvernment under the contract number
POSDRU/159/1.5/S/133377, „Program de excelență în cercetare
doctorală și postdoctorală” and by PN-II-PT-PCCA-2013-4-1903.
United States Pharmacopoeia 36 - National Formulary 31. Metoprolol Succinate Extended-Release Tablets
Mandal TK. Effect of tablet integrity on the dissolution rate of sustained-release preparations. J Clin Pharm
Ther. 1996;21(3):155-7.
Zhang YE, Schwartz JB. Effect of diluents on tablet integrity and controlled drug release. Drug Dev Ind
Pharm. 2000;26(7):761-5.