Formulation Exercise – Replication Of A Marketed Product

1. By : Debanjan Das
{DISCLAIMER: Certain details pertaining to
proprietorship of the product has been
deleted. This exercise is solely for
enhancement of knowledge-base and not
for any “for-profit” venture}
Product Formulation Exercise –
Replication of a Marketed Product

2. Marketed Product chosen:
Children’s Pedia Care®
Night
Rest Cough and Cold
Manufactured by Pharmacia
Consumer Healthcare
(Pfizer)

3. Drug Facts
Ingredients Use Quantity(100ml)
Chlorpheniramine maleate Antihistamine 20 mg
Dextromethorphan HBr Cough suppressant 150mg
Pseudoephedrine HCl Nasal decongestant 300mg
Corn Syrup Sweetener -
Glycerin Solvent, Preservative Up to 20%
Propylene Glycol Solvent, Preservative 10-25%
Sorbitol Sweetner, Vehicle 20-35%
Sodium Carboxymethylcellulose Viscosity builder 0.1-1%
Sodium Benzoate Preservative 0.02-0.5%
Citric acid 0.1-2%
FD&C Red No 40 Colorant <0.001%
Water Vehicle

4. Measured properties of marketed product
Properties of the marketed product
pH 3.5
Relative Density 1.2548
Viscosity 50.593 cps
Color Pinkish Red
Flavor Cherry

5. Chosen Lab Ingredients
Ingredients Suppliers Lot no
Chlorphenaramine maleate City Chemical, CT 99D318
Dextromethorphan HBr Sigma-Aldrich Co, MO 013K1428
Pseudoephedrine HCl Sigma-Aldrich Co, MO 11E0090
Light Corn Syrup Englewood Cliffs, NJ 33902
Glycerin, USP; 99.5% Ruger Chemical Co. Inc., NJ 1211-6
Propylene Glycol Ruger Chemical Co. Inc., NJ 782902
Sorbitol Ruger Chemical Co. Inc., NJ 1024-6
Sodium Carboxymethylcellulose,
High Viscosity, 2120 cps
Ruger Chemical Co. Inc., NJ P34488F11
Sodium Benzoate Amend Drug & Chemical Co. Inc., NJ C65138P28
Citric acid Monohydrate Sigma Chemical Co., MO 126H0140
Cherry Syrup

6. Solubility Data for drugs:
Chlorpheniramine maleate 1g in 4ml water, in 10
ml chloroform/alcohol
Dextromethorphan HBr 1g in 65 ml, freely
soluble in
alcohol/chloroform
Pseudoephedrine HCl 1g in 0.5 ml water,
3.6ml alcohol,91ml
chloroform

7. Arbitrary trial batch – first step
Ingredients Quantity (50 ml)
Chlorphenaramine maleate 10 mg
Dextromethorphan HBr --
Pseudoephedrine HCl 150 mg
Corn Syrup 8%
Glycerin 16%
Propylene Glycol 15%
Sodium Benzoate 0.3%
Sodium Carboxymethylcellulose 0.5%
Sorbitol 25%
Citric acid 0.5%
Water q.s. 50 ml
pH 3.2
Density 1.0928
Viscosity 18.468 cps

8. Initial formulation challenges
Inability to achieve desired viscosity
pH

9. Summary of adopted trial batches
Ingredients #1 #2 #3 #4 #5 #6 #7 #8
Chlorphenaramine
maleate
10mg
Dextromethorphan HBr ---
Pseudoephedrine HCl 150mg
Corn Syrup (%) 8 16 24 20 16 16 16 16
Glycerin (%) 16 10 10 10 10 4 4 4
Propylene Glycol %) 15 10 10 10 10 10 10 10
Sodium Benzoate %) 0.3 12 8 8 8 8 8 25
Sodium CMC (%) 0.5 0.4 1.0 0.5 0.4 0.4 0.4 0.4
Sorbitol(%) 25 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Citric acid(%) 0.5 0.3 0.3 0.3 0.3 0.3 0.3 0.3
Water(q.s) 50ml
pH 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4
Density 1.0928
Viscosity 18.468 cps 34.95 64.61 48.8 42.62 22.1 21.66 58.21

10. Ingredients #9 #10 #1
1
#12 #13 #
1
4
#15 #16 #17 #18 #19
Chlorphenarami
ne maleate
10mg
Dextromethorph
an HBr
-- 75mg
Pseudoephedrine
HCl
150mg
Corn Syrup (%) 16 18 22 25 25 25 16 16 16 16 16
Glycerin (%) 4 4 4 4 4 4 4 4 4 4 4
Propylene
Glycol %)
10 10 10 10 10 10 10 10 10 10 10
Sodium
Benzoate
%)
16 12 10 8 8 8 20 20 20 20 20
Sodium CMC
(%)
0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.3 0.4 0.5 1.0
Sorbitol(%) 0.1 0.1 0.1 0.1 0.3 0.1 0.1 0.1 0.1 0.1 0.1
Citric acid(%) 0.3 0.3 0.3 0.3 0.5 0.3 0.3 0.3 0.3 0.3 0.3
Water(q.s) 50ml
pH 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4 3.4
Density
Viscosity 32.01 35.53 44.
8
2
47.7
1
47.71 48.12 47.
6
2
6
13.89 47.626 65.53 135.48

11. Systematic approach to arrive at the
desired viscosity
Corn syrup was tried in the first set of trials
Increasing concentrations were corn syrup were uses keeping
the other ingredients constant
A close viscosity was achieved

12. Corn Syrup (cont.)
Ingredients Quantity (50ml) Quantity
(50ml)
Quantity
(50ml)
Quantity
(50ml)
Chlorphenaramine maleate 10 mg 10 mg 10 mg 10 mg
Dextromethorphan HBr -- -- -- --
Pseudoephedrine HCl 150 mg 150 mg 150 mg 150 mg
Corn Syrup 8% 16% 24% 20%
Glycerin 10% 10% 10% 10%
Propylene Glycol 10% 10% 10% 10%
Sorbitol 25% 12% 8% 8%
Na CMC 0.4% 0.4% 0.4% 0.4%
Sodium Benzoate 0.3% 0.3% 0.3% 0.3%
Citric acid 0.5% 0.5% 0.5% 0.5%
Water q.s. 50 ml q.s. 50 ml q.s. 50 ml q.s. 50 ml
pH 3.4 3.4 3.4 3.4
Density 1.0928
1. 162 1.3721 1.241
Viscositiy 18.47 34.95 64.61 48.89

13. Graphical representation
Effect of Corn Syrup on Viscosity
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30
Concentration of Corn Syrup
Viscosityincps

14. Problems faced
Glycerin was used at a high concentration of about 10%
It has a very unpleasant taste which in high quantities makes
it unsuitable for pediatric preparations

15. Trial with glycerin
Ingredients Quantity (50 ml) Quantity(50ml)
Chlorphenaramine maleate 10 mg 10 mg
Dextromethorphan HBr -- --
Pseudoephedrine HCl 150 mg 150 mg
Corn Syrup 16% 16%
Glycerin 10% 4%
Propylene Glycol 10% 10%
Sorbitol 8% 8%
Sodium Carboxymethylcellulose 0.4% 0.4%
Sodium Benzoate 0.3% 0.3%
Citric acid 0.5% 0.5%
Water q.s. 50 ml q.s. 50 ml
pH 3.4 3.4
Density 1.2005 1.0951
Viscosity 42.62 22.12

16. Problems faced
Decreasing the glycerin concentration to 4% lead to reduced
viscosity
Other viscosity building agents were tried

17. Trials with Sorbitol
Ingredients Quantity (50 ml) Quantity (50 ml) Quantity (50 ml)
Chlorphenaramine maleate 10 mg 10 mg 10 mg
Dextromethorphan HBr -- -- --
Pseudoephedrine HCl 150 mg 150 mg 150 mg
Corn Syrup 16% 16% 16%
Glycerin 4% 4% 4%
Propylene Glycol 10% 10% 10%
Sorbitol 8% 25% 20%
Sodium
Carboxymethylcellulose
0.4% 0.4% 0.4%
Sodium Benzoate 0.3% 0.3% 0.3%
Citric acid 0.5% 0.5% 0.5%
Water q.s. 50 ml q.s. 50 ml q.s. 50 ml
pH 3.4 3.4 3.4
Density 1.093 1.293 1.221
Viscosity 21.66 58.21 47.626

18. Graphical representation
Effect of Sorbitol on Viscosity
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30
Concentration of Sorbitol
Viscosityincps

19. Problems faced
Sorbitol is synthetic and used in high proportions ( 20% ) to
attain the desired viscosity
Attempt was made to lower its concentration and to
compensate with Na CMC

20. Trials with Na CMC
Ingredients Quantity (50 ml) Quantity (50 ml) Quantity (50 ml) Quantity (50
ml)
Chlorphenaramine maleate 10 mg 10 mg 10 mg 10 mg
Dextromethorphan HBr -- -- -- --
Pseudoephedrine HCl 150 mg 150 mg 150 mg 150 mg
Corn Syrup 16% 16% 16% 16%
Glycerin 4% 4% 4% 4%
Propylene Glycol 10% 10% 10% 10%
Sorbitol 20% 20% 20% 20%
Sodium
Carboxymethylcellulose
0.3% 0.4% 0.5% 1.0%
Sodium Benzoate 0.3% 0.3% 0.3% 0.3%
Citric acid 0.5% 0.5% 0.5% 0.5%
Water q.s. 50 ml q.s. 50 ml q.s. 50 ml q.s. 50 ml
pH 3.4 3.4 3.4 3.4
Density 1.052 1.221 1.361 1.582
Viscosity (cps) 13.89 47.626 65.53 135.48

21. Graphical representation
Effect of NaCMC on Viscosity
0
20
40
60
80
100
120
140
160
0 0.2 0.4 0.6 0.8 1 1.2
Concentration NaCMC
Viscosityincps

22. Problems faced
Concentration of NaCMC must be fine tuned because a small
increase ( 0.1%), lead to high increase in viscosity (17.9 cps )
Dissolution of NaCMC is difficult, due to slow hydration
Hence, a stock solution ( 200 mL of 0.8% w/v) was
prepared and aliquots were used from it
Sufficient time was given for its complete hydration
Trials with increased corn syrup were tried since it is
difficult to control viscosity using Na CMC

23. Trials with increased corn syrup decreased
sorbitol conc.:
Ingredients Quantity
(50 ml)
Quantity
(50 ml)
Quantity (50 ml) Quantity
(50 ml)
Chlorphenaramine
maleate
10 mg 10 mg 10 mg 10 mg
Dextromethorphan HBr -- -- -- --
Pseudoephedrine HCl 150 mg 150 mg 150 mg 150 mg
Corn Syrup 16% 18% 22% 25%
Glycerin 4% 4% 4% 4%
Propylene Glycol 10% 10% 10% 10%
Sorbitol 16% 12% 10% 8%
Na CMC 0.4% 0.4% 0.4% 0.4%
Sodium Benzoate 0.3% 0.3% 0.3% 0.3%
Citric acid 0.5% 0.5% 0.5% 0.5%
Water q.s. 50 ml q.s. 50 ml q.s. 50 ml q.s. 50 ml
pH 3.4 3.4 3.4 3.4
Density 1.102 1.183 1.167 1.211
Viscosities 32.01 35.53 44.82 47.71

24. Optimizing pH
Sodium benzoate and citric acid was so far used in the
concentrations of 0.3% and 0.5% respectively
Attempt was made to reduce the preservative concentration
and still arrive at the desired pH

25. Effect on pH
Ingredients Quantity (50 ml) Quantity (50 ml)
Chlorphenaramine maleate 10 mg 10 mg
Dextromethorphan HBr 75mg 75mg
Pseudoephedrine HCl 150 mg 150 mg
Corn Syrup 25% 25%
Glycerin 4% 4%
Propylene Glycol 10% 10%
Sorbitol 8% 8%
Sodium Carboxymethylcellulose 0.4% 0.4%
Sodium Benzoate 0.3% 0.1%
Citric acid 0.5% 0.3%
Water q.s. 50 ml q.s. 50 ml
pH 3.4 3.4
Density 1.211 1.22
Viscosity (cps) 47.71 48.12

26. Scale up X 5
Ingredients Quantity (50 ml) Quantity (250 ml)
Chlorphenaramine maleate 10 mg 0.05g
Dextromethorphan HBr 75mg 0.75g
Pseudoephedrine HCl 150 mg 0.375g
Corn Syrup 12.5 ml 62.5 ml
Glycerin 2ml 10ml
Propylene Glycol 5ml 25ml
Sorbitol 4ml 20ml
Sodium Carboxymethylcellulose 0.4% 0.4%
Sodium Benzoate 0.05g 0.25g
Citric acid 0.15g 0.75g
Water q.s. 50 ml q.s.250 ml
pH 3.4 3.4
Density 1.22 1.321
Viscosities 47.12 53.27

27. Problems faced
Minute particulate matters seemed to adhere with the
container wall
Solubility problems occurred
Drug?
NaCMC?
Viscosity increased by a small extent
No problems with pH encountered

28. Stability studies
Studies were done in freezing temperatures at zero degree
centigrade for 5 days
The marketed formulation did not freeze but the replicated
product solidified (?)
However, once left at room temperature, it liquefied in less
than 15 mins without showing any precipitation problems

29. Conclusion
The desired viscosity and pH could be reasonably achieved
by doing the scale up which validated the lab scale formula
However, there were some solubility problems seen during
the scale up
Stability of preparation was plausible