Transcript the formulation of furosemide dispersible tablets for use in pediatrics

THE FORMULATION OF FUROSEMIDE
DISPERSIBLE TABLETS FOR USE IN
PEDIATRICS
Author & supervisors
Author
Abwova Veronica Vugutsa B. Pharm
Supervisors
Prof. K. A. M Kuria
Dr. P. Mbeo
Background
• Liquid formulations are the preferred formulation in
pediatric drug administration
• They Present a challenge to the formulation scientist:
need for taste masking, reduced stability and bulkiness
• WHO recommended the development of more
pediatric friendly formulations as solid dosage forms
• Most drug development companies concentrate on
adult formulation
• Clinical trials in pediatrics are very stringent hence
most companies don’t do it
Background
• Furosemide is a loop diuretic used in in both
pediatrics and adult for fluid overload in
hypertension and heart disease
• In Kenya there is no pediatric friendly
formulation registered by the PPB
• Patients get it extemporanously prepared or
those who can afford it get it specially
imported, making it quite expensive
Objectives
Specific objectives
• To come up with a target product profile for
Furosemide dispersible tablets.
• To carry out pre-formulation studies on Furosemide
• To carry out formulation optimization studies
• To carry out tabletting of Furosemide dispersible
tablets
• To test the quality of the formulated Furosemide
dispersible tablets
Significance of the study
Availability of dispersible tablets will facilitate
• Accurate dosing
• Convenient administration of solid dosage forms
to children
• Reduced bulk as opposed to liquids
• Increased shelf life compared to the
extemporaneously prepared formulations thus
reduced trips to the pharmacy
• Reduced healthcare cost
Methodology-equipment
• Sifter
• Tabletting machine - Erweka single punch automatic
tabletting machine
• Weighing balance - Shimadzu
• Friability tester - Erweka
• Electronic tablet hardness tester – Schleuniger
• Dissolution testing machine type 2
• HPLC machine – Prominence auto sampler, Sil-20AHTfrom Japan
The equipment used was from the school of pharmacy departments of
pharmaceutics and pharmacy practice and the department of pharmaceutical
chemistry
Methodology-Materials
• Furosemide
• Lactose
• Maize starch
• Sucrose
• Talc
• Magnesium stearate
• Colloidal silicon dioxide
• Sodium starch glycollate
• Croscarmellose
• Crospovidone
The materials were obtained as gift from Laboratory and
allied company
Methodology
• Setting up of the target product profile
• Data gathering from previous preformulation
studies. The molecule having been on the market
for a long time, preformulation data was
gathered from literature
• Formulation. Granulation of the lactose was
carried using starch as a binder
• The granules were divided into three and a
combination of two superdisintegrants added per
batch :
Methodology
• Part of the granules were lubricated and used
to produce dummy tablets
• The dummies were weighed and the amount
of Furosemide to be incorporated calculated
• Furosemide content per tablet was
determined based on its dosing in pediatrics
• Tableting was then carried out and the tablets
evaluated for quality using physical and
analytical tests for tablets as per the USP
Results
• The target product profile was set as
follows
QUALITY ATTRIBUTE
TARGET
CRITICALITY
1
Dosage form
Tablet
2
Potency
4mg
Critical
3
Pharmacokinetics
Immediate release tablet
Critical
4
Appearance
Elegant tablet consistent in appearance
Critical
5
Identity
Positive for Furosemide
Critical
6
Assay
90-110%
Critical
7
Weight uniformity
Meets USP standards
Critical
8
Content uniformity
Meets USP standards
Critical
9
Disintegration
Not more than 3min
Critical
10
Dissolution
Not less than 80% released within 60minutes
Critical
Results
• Data from previous formulation studies was obtained
and summarised as below
• Chemical name: 4-chloro-N-Furfuryl-5Sulphamoylanthranilic acid
• Pharmacological class- Loop diuretic
• Solubility: 0.0825mg/ml is the Aqueous solubility at
room temperature and it increases with increase in pH
• Polymorphism: 7 polymorphic forms although
polymorphism has not been reported to affect
bioavailability.
• pKa: Furosemide has a pKa value of 3.8. It is weakly
acidic.
• Partition coefficient: The partition coefficient in noctanol / water reported as 2.29
Results
• Formulation optimization:
• Two formulations, the one with the
combination of sodium starch glycollate and
crospovidone as well as that of croscarmellose
and crospovidone as superdisitergrants were
found to give good formulations.
• The formulated tablets from the two
combinations were found to comply with USP
specifications for tablets
Results-physical tests
UNIFORMITY OF WEIGHTS
Formulated dispersible tablets
BATCH NUMBER
1
2
3
Number of tablets
20
20
20
0.501
0.479
0.502
0.0078
0.0117
0.0075
% deviation of tablet with min weight
2.2
6.05
2.3
%deviation of tablet with max weight
3.8
4.38
3.7
Projected tablet weight (mg)
500
500
500
0.2%
4.2%
0.4%
100.2%
95.8%
100.4%
Average weight (mg)
STD Deviation
% deviation from projected weight
Calculated API content
BATCH NMBER
TABLET FRIABILITY
BATCH NUMBER
% FRIABILITY
TABLET HARDNESS
1
2
3
0.98
2.6
0.9
1
2
3
Number of tablets
10
10
10
Average hardness
6.3
5.9
6.4
STD Deviation
2.2
0.639
1.3
Results-physical tests
Pictures of disintegrating tablets
Disintegration time(seconds)
Batch
1
2
3
Average disintegration time
(seconds)
Standard deviation
62
137
69
4.082
14.024
10.206
Results-Analytical tests
ASSAY RESULTS
BATCH 1
AVERAGE %CONTENT
BATCH 3
100.99
108.81
0.217
0.999
STD DEVIATION
DISSOLUTION RESULTS
BATCH 1
BATCH 3
AVERAGE DISSOLUTION (%)
95%
82%
STD DEVIATION
15.3
13.4
Conclusion
• The set target profile was achieved for two of
the formulations.
• The combination of sodium starch glycollate
and crospovidone as well as that of
croscarmellose and crospovidone can be used
successfully to formulate Furosemide
dispersible tablets
Recommendations
• Stability tests should be carried out to check
for the stability over prolonged storage times
and varied conditions
• Flavoring can be done to improve the
formulations and make it child friendly
• Sweetening can also be done although this
may not be necessary since the taste is not
unpleasant
• Thickening of the formulation can also be
carried out to improve the consistency of the