1. THE FORMULATION OF FUROSEMIDE DISPERSIBLE TABLETS FOR USE IN PEDIATRICS

2. Abwova Veronica Vugutsa B. Pharm
Author & supervisors
Author
Abwova Veronica Vugutsa B. Pharm
Supervisors
Prof. K. A. M Kuria
Dr. P. Mbeo

3. 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

4. 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

5. 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

6. 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

7. 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-20AHT-from Japan
The equipment used was from the school of pharmacy departments of pharmaceutics and pharmacy practice and the department of pharmaceutical chemistry

8. 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

9. 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 :
sodium starch glycollate with cross povidone, sodium starch glycollate with cross carmellose and cross povidone with cross carmelose

10. 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

11. 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 4
Appearance
Elegant tablet consistent in appearance 5
Identity
Positive for Furosemide 6
Assay
90-110% 7
Weight uniformity
Meets USP standards 8
Content uniformity 9
Disintegration
Not more than 3min 10
Dissolution
Not less than 80% released within 60minutes

12. Results
Data from previous formulation studies was obtained and summarised as below
Chemical name: 4-chloro-N-Furfuryl-5-Sulphamoylanthranilic acid
Pharmacological class- Loop diuretic
Solubility: mg/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 n-octanol / water reported as 2.29
Data from compatibility studies showed Furosemide to be compatible with all the excipients picked for the formulations

13. 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

14. Results-physical tests
UNIFORMITY OF WEIGHTS
BATCH NUMBER 1 2 3
Number of tablets 20
Average weight (mg)
0.501
0.479
0.502
STD Deviation
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
% deviation from projected weight
0.2%
4.2%
0.4%
Calculated API content
100.2%
95.8%
100.4%
Formulated dispersible tablets
TABLET HARDNESS
BATCH NMBER 1 2 3
Number of tablets 10
Average hardness
6.3
5.9
6.4
STD Deviation
2.2
0.639
1.3
TABLET FRIABILITY
BATCH NUMBER 1 2 3
% FRIABILITY
0.98
2.6
0.9

15. Results-physical tests
Pictures of disintegrating tablets
Disintegration time(seconds)
Batch 1 2 3
Average disintegration time (seconds) 62
137 69
Standard deviation
4.082
14.024
10.206

16. Results-Analytical tests
ASSAY RESULTS
BATCH 1
BATCH 3
AVERAGE %CONTENT
100.99
108.81
STD DEVIATION
0.217
0.999
DISSOLUTION RESULTS
BATCH 1
BATCH 3
AVERAGE DISSOLUTION (%)
95%
82%
STD DEVIATION
15.3
13.4

17. 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

18. 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 formulation after dispersion.