DESC:Filed of invention:
The present invention relates to taste masked composition comprising Sulfadoxine and Pyrimethamine. The present invention further relates to process for manufacture of the taste masked composition comprising Sulfadoxine and Pyrimethamine.

Background and prior art:
The widespread emergence of chloroquine-resistant Plasmodium falciparum led to the development of an effective fixed dose formulation of two antimalarial agents, Pyrimethamine and the long-acting sulfonamide, Sulfadoxine, for prophylaxis and treatment.

Sulfadoxine is pteroate reductase inhibitor and Pyrimethamine is tetrahydrofolate reductase inhibitor. They act in synergistic manner as antimalarial drug combination. This combination is effective not only in adults but also effective in pediatric patients and further used in infants for the treatment of malaria.

In malaria-endemic regions, the young children and pregnant women are the most affected. Women are particularly vulnerable to the adverse effects of malaria during their first and second pregnancies.

In these endemic regions, strategies to control malaria during pregnancy rely on case management of malaria illness and anemia, and a package of preventive measures that consists of insecticide treated nets (ITNs) and intermittent preventive therapy (IPT) with Sulfadoxine-Pyrimethamine combination. Sulfadoxine-Pyrimethamine is the only antimalarial drug currently used for IPT during pregnancy.

This combination is approved by the United States' Food and Drug Administration for use as a treatment and preventive measure against malaria because the same is considered to be more effective in treating malaria caused by Plasmodium falciparum. Further, this combination may also be recommended for use in treatment and prophylactic measure for toxoplasmosis and Pneumocystis jiroveci pneumonia. (source: Wikipedia)

Various strengths of Sulfadoxine and Pyrimethamine immediate release tablets are available where Sulfadoxine is 500 mg and Pyrimethamine is 25 mg, with the total strength being 525 mg. Lower strength consists of Sulfadoxine 250 mg and Pyrimethamine 12.5 mg with the total strength being 262.5 mg.

Although Pyrimethamine is acceptable for children because it does not taste bitter; however, Sulfadoxine drug comes with slightly bitter taste. Since this combination is widely acceptable for its effectiveness against Plasmodium falciparum, particularly in children and pregnant woman, it is necessary to develop a taste masked formulation of this combination to be palatable so as to provide ease of administration for both pregnant women and children. The bitterness of any drug induces nausea & vomiting and therefore, the target population i.e. children and pregnant women will get benefitted from the taste masked combination of Sulfadoxine and Pyrimethamine, if made available.

However, taste masked formulation of Sulfadoxine and Pyrimethamine is not known and not available in the literature. Since this combination is effectively being administered to pediatric/pregnant patients for the treatment of malaria, the inventors have realized the need for the taste masking of the drug combination comprising Sulfadoxine and Pyrimethamine so as to improve patient compliance.

Objectives of the invention:
Accordingly, it is an objective of the present invention to provide the combination of Sulfadoxine and Pyrimethamine in a taste masked formulation to increase the palatability of the dosage form.

It is another objective of the invention to provide dosage forms such as granules, syrups, tablets in taste masked forms so as to increase the palatability and patient compliance of the bitter drug combination.

In yet another objective, the invention provides process for preparation of taste masked dosage forms of the combination of Sulfadoxine and Pyrimethamine.

Summary of the invention:
In accordance with the above objectives, the present invention provides a taste masked fixed dose combination of Sulfadoxine and Pyrimethamine which is bioequivalent to immediate release dosage form.

In another aspect, the invention provides taste masked pharmaceutical composition comprising fixed dose combination of Sulfadoxine and Pyrimethamine in various dosage forms such as granules, Dispersible Tablets, powder for oral suspension, etc.

In yet another aspect, the invention provides process for preparation of taste masked pharmaceutical composition comprising combination of Sulfadoxine and Pyrimethamine in various dosage forms such as granules, Dispersible Tablets, powder for oral suspension, etc.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a dispersible taste masked pharmaceutical composition comprising fixed dose combination of Sulfadoxine and Pyrimethamine which is bioequivalent to immediate release marketed product.
Accordingly, the invention provides a fixed dose dispersible taste masked pharmaceutical composition comprising;
a) Sulfadoxine in an amount of about 70 to 75%; b) Pyrimethamine in an amount of about 3 to 4% ; c) a taste masking polymer in an amount of about 1 % to 55% and a pharmaceutical carrier(s), wherein, the composition is bioequivalent to immediate release marketed product.

In another embodiment, the invention provides taste masked pharmaceutical composition comprising fixed dose combination of Sulfadoxine and Pyrimethamine in various dosage forms such as granules, Dispersible Tablets, powder for oral suspension, etc.

The pharmaceutical carrier(s) may be selected from the group consisting of binders, suspending agents, fillers, Lubricants, carbonate alkalizer and organic acid such as sodium carbonate and citric acid and flavours.

In one embodiment, the invention provides a composition comprising Sulfadoxine 500mg & Pyrimethamine 25 mg Dispersible Tablet. In another embodiment, the invention provides a composition comprising Sulfadoxine 250mg & Pyrimethamine 12.5 mg Dispersible Tablet.

Similarly, in another embodiment, the invention provides a composition comprising Sulfadoxine 500mg + Pyrimethamine 25 mg as dry powder for oral suspension. In additional embodiment, the invention provides composition comprising Sulfadoxine 250mg & Pyrimethamine 12.5 mg powder for oral suspension.

The inventiveness lies in the selection of polymer to mask the taste as well as in maintaining the immediate release profile that matches with the innovator's drug. The taste masked formulation of the present invention is bioequivalent to the marketed drug ‘Fansidar’ by the innovator.
The taste masked pharmaceutical composition comprising combination of Sulfadoxine and Pyrimethamine are provided in dosage forms such as granules, Dispersible Tablets, powder for oral suspension, etc.

In yet another embodiment, the invention provides process for preparation of taste masked pharmaceutical composition comprising combination of Sulfadoxine and Pyrimethamine in dosage forms such as granules, Dispersible Tablets, powder for oral suspension, etc.

The taste masking of the drug combination is obtained by the use of polymers selected from the group consisting of methyl methacrylic acid co-polymers or polyvinyl pyrollidone or carbomers and combinations thereof.

There are various Methacrylic acid copolymers available and can be used in pharmaceutical compositions for variety of applications, such as taste masking, sustained release, immediate release and to release the drug at right place and right time, protection from external influences (moisture) or odor, to increase patient compliance. These polymers are used generally for the purpose of enteric, sustained release or protective coatings of the pharmaceutical drug product.

In an embodiment, the taste masking polymers used in the invention is in the range of 1 % to 55%, preferably, 3-10%.

In another embodiment, the drugs Sulfadoxine and Pyrimethamine used in the taste masked formulation are provided in micronized form.

The particle size of Sulfadoxine in the taste masked formulation is around 5-100 microns, preferably, about 5- 15 microns.

The particle size of Pyrimethamine in the taste masked formulation is around 5-100 microns, preferably about 5 -50 microns.
The ratio of active to that of excipients in the taste masked formulation is in the range of 30% to 90%, preferably around 65-95%.

In an embodiment, the dosage forms of the invention may be prepared using dry and wet granulation methods.

Accordingly, the invention provides process for preparation of taste masked formulation of Sulfadoxine & Pyrimethamine which comprises:
a) Preparing granules of Sulfadoxine & Pyrimethamine using taste masking polymer and binder employing non-aqueous granulation or aqueous granulation; and
b) Compressing the granules into tablets or formulated as powder for suspension by addition of suitable diluents/carriers to increase the bulk.

In an embodiment, the invention provides taste masked granules of the Sulfadoxine & Pyrimethamine. These granules are prepared by using polymers selected from the group consisting of methacrylic acid polymers, or polyvinyl pyrrolidone or carbomer or combinations thereof as taste masking agent and binder such as polyvinyl pyrrolidone in an amount of 3 to 4% by employing non-aqueous granulation method, wherein non-aqueous solvent used is an alcohol like isopropyl alcohol or ethyl alcohol.

In another embodiment, the granules can also be prepared using aqueous granulation process. The granules are prepared using rapid mixer granulator, mass mixer or fluid bed processor or any suitable equipment to obtain the granules.

In a further embodiment, these taste masked granules are compressed into tablets, or formulated as powder for suspension by addition of suitable diluents to increase the bulk.
In an embodiment, a suspending agent can be added in powder for suspension like xanthum gum, carrageenan, various carboxy methyl cellulose polymers, etc. in an amount of 0.5 to 5%.

Suitable fillers that can be used in the formulation are selected from the group consisting of sugars such as mannitol, lactose, monosacchharide, polysaccharides etc. that can be used in an amount of 30-90%.

The Lubricant, magnesium stearate is added in an amount of 0.5 to 5% to granules for lubrication purpose.

In an embodiment, a carbonate alkalizer and organic acid like sodium carbonate and citric acid used in an amount of 0.1 to 10.0%, are added to the granules to obtain dispersible tablet formulation.

The dispersible tablets or powder for oral suspension may be further flavoured using suitable flavours like orange flavor, vanilla, mint, chewing gum lemon and other flavors. These flavours may be added individually or in combinations.

The lubricated granules are either compressed into dispersible tablet or after suitable dilution with fillers selected from the group consisting of sugars such as mannitol, lactose, monosacchharide, polysaccharides or any other suitable filler, dispensed as powder for oral suspension.

In accordance with the invention, various strengths of Sulfadoxine and Pyrimethamine have been formulated using the said process and composition.

The powder for oral suspension provided according to the invention can be dispersed in water from 30 ml to 100 ml to provide a dosage of 525mg (500 mg Sulfadoxine and 25 mg Pyrimethamine) or 262.5 mg (250 mg Sulfadoxine or 12.5 mg Pyrimethamine) per 5 ml or 10 ml.
The tablet formulation of Sulfadoxine and Pyrimethamine dispersible tablets or orodispersible tablet is dispersed in 5-100 ml water, preferably in 5-15 ml water within 3 minutes.

The taste masked formulation according to invention wherein, the tablet formulation of the taste masked granules gives dissolution profile in pH 1.2, 4.5, and 6.8 with similarity factor f2 greater than 50 with respect to innovator’s immediate release product, which is not taste masked.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Example 1:
Sulfadoxine 500 mg+ Pyrimethamine 25 mg Dispersible Tablet
Manufacturing formula:
Sr. No Ingredients Spec. Trial - 06 (RD/160/07/15)
A) Dry mix % unit 525mg 500 Tab
1 Sulfadoxine Ph. Int. (micronized) Ph. Int. 71.43 500 250
2 Pyrimethamine Ph. Int. (micronized) Ph. Int. 3.57 25 12.5
3 Methacrylic acid copolymer BP 5.00 35 17.5
4 Mannitol BP 4.29 30 15
5 Crospovidone BP 3.57 25 12.5
B) Binder Preparation
6 citric acid anhydrous BP 1.00 7 3.5
7 PVP K 30 BP 0.57 4 2
8 IPA BP q.s. q.s. q.s.
9 Water BP q.s. q.s. q.s.
C) Pre-lubrication
10 Mannitol BP 1.43 10 5
11 Sodium bicarbonate BP 1.14 8 4
12 Sod. Saccharin BP 2.00 14 7
13 Xanthum gum BP 0.5% 3.5
13 Flavor Orange I.H.S 0.86 6 3
14 Colloidal silicon dioxide BP 0.29 2 1
15 Crospovidone BP 2.86 20 10
D) Lubrication
16 Magnesium stearate BP 2.00 14 7
100.00 700 350

Procedure for manufacturing:
1) Sifting:
Sifted Sulfadoxine ph. Int, on Vibro sifter using 20 # SS Sieve & collected separately,
Sifted and collected separately Pyrimethamine, Methacrylic acid copolymer, Mannitol 200 , Cospovidone, PVPK 30, Sodium Saccharine , Colloidal Silicon Dioxide on Vibro sifter using 40 # SS Sieve,
Sifted Magnesium stearate, citric acid anhydrous, orange flavour on Vibro sifter using 60 # SS Sieve & collected separately:
2) Dry mix:
Transferred sifted material of Sulfadoxine, Pyrimethamine, Meth acrylic acid copolymer, Mannitol, Cospovidone in RMG mixer and mixed it for 10 minutes.
2) Binder Preparation:
Added slowly PVPK 30 in water under continuous stirring for 30 minutes, till to obtain clear transparent solution.
Added citric acid in clear solution and stirred it for 10 minutes.
3) Granulation:
Binder addition quantity Time (Minutes) Impeller of RMG (Speed) Chopper of RMG
(Speed)

Approx. 50 % 1 SLOW OFF
RAKE THE CONTENTS USING A CLEAN SS PADDLE
Added remaining 50 % 1 SLOW OFF
RAKE THE CONTENTS USING A CLEAN SS PADDLE
If required, Added Purified Water USP 1 SLOW OFF
RAKE THE CONTENTS USING A CLEAN SS PADDLE
Kneeding 1 SLOW SLOW
RAKE THE CONTENTS USING A CLEAN SS PADDLE
Discharge --- SLOW SLOW

4) Drying:
Dried the granules of stage no 3 at 65 °C till LOD is achieved between 1.5 % - 2.5 % w/w.
5) Milling:
Milled the dried granules through 1.0 mm screen using Multimill with knives forward at medium speed.
6) Blending:
Added Mannitol DC, Sodium bicarbonate, Sodium saccharine, flavour orange, colloidal silicon dioxide in milled granules of stage 5 in octagonal blender and blended the mixture for 10 minutes.
7) Lubrication:
Lubricated the blended granules of stage no 6 for 3 minutes in octagonal blender with magnesium stearate, and compressed into tablets.
Disintegration Time (minutes): NMT- 3 Minutes
Example 2:

Sulfadoxine 500mg + Pyrimethamine 25 mg/ 5ml and Sulfadoxine 250 mg and Pyrimethamine 12.5 mg/5ml powder for oral suspension
Manufacturing Formula:

Sr.No Ingredients Spec. Trial - 06 (RD/160/07/15)
A) Dry mix % unit 525/5ml 262.5/ml
1 Sulfadoxine Ph. Int. (micronized) Ph. Int. 71.43 500 250
2 Pyrimethamine Ph. Int. (micronized) Ph. Int. 3.57 25 12.5
3 Methacrylic acid copolymer BP 5.00 35 17.5
4 Mannitol BP 4.29 30 15
5 Crospovidone BP 3.57 25 12.5
B) Binder Preparation
6 citric acid anhydrous BP 1.00 7 3.5
7 PVP K 30 BP 0.57 4 2
8 IPA BP q.s. q.s. q.s.
9 Water BP q.s. q.s. q.s.
C) Prelubrication
10 Mannitol BP 1.43 32 5
13 Flavor Orange I.H.S 0.86 6 3
14 Colloidal silicon dioxide BP 0.29 2 1
15 Crospovidone BP 2.86 20 10
D) Lubrication
16 Magnesium stearate BP 2.00 14 7
100.00 700 350

1) Sifting:
Sifted Sulfadoxine ph. Int on Vibro sifter using 20 # SS Sieve & collected separately,
Sifted and & collected separately Pyrimethamine, Methacrylic acid copolymer, Mannitol 200, Cospovidone, PVPK 30, Sodium Saccharine, Colloidal Silicon Dioxide, on Vibro sifter using 40 # SS Sieve
Sifted Magnesium Stearate, citric acid anhydrous, orange flavour on Vibro sifter using 60 # SS Sieve & collected separately.
2) Dry mix:
Transferred sifted material of Sulfadoxine, Pyrimethamine , Meth acrylic acid copolymer, Mannitol, Cospovidone in RMG mixer and mixed it for 10 minutes.
2 ) Binder Preparation:
Added slowly PVPK 30 in water under continuous stirring for 30 minutes till to obtain clear transparent solution.
Added citric acid in clear solution and stirred it for 10 minutes.
3 ) Granulation:
Binder addition quantity Time (Minutes) Impeller of RMG (Speed) Chopper of RMG
(Speed)

Approx. 50 % 1 SLOW OFF
RAKE THE CONTENTS USING A CLEAN SS PADDLE
Add remaining 50 % 1 SLOW OFF
RAKE THE CONTENTS USING A CLEAN SS PADDLE
If required, Added Purified Water USP 1 SLOW OFF
RAKE THE CONTENTS USING A CLEAN SS PADDLE
Kneeding 1 SLOW SLOW
RAKE THE CONTENTS USING A CLEAN SS PADDLE
Discharge --- SLOW SLOW

4) Drying:
Dry the granules of stage no 3 at 65 °C till LOD is achieved between 1.5 % - 2.5 % w/w.
5) Milling:
Milled the dried granules through 1.0 mm screen using Multimill with knives forward at medium speed.
6) Blending:
Added Mannitol DC, Sodium saccharine, flavour orange, colloidal silicon dioxide and xanthum gum in milled granules of stage 5 in octagonal blender and blend it for 10 minutes.
7) Lubrication:
Lubricated the blended granules of stage no 6 for 3 minutes in octagonal blender with magnesium stearate, and filled in bottles. The granule batch size can be adjusted to get 30 x 0.700g = 21 g/ 30 ml or proportionately for 60, 100, 50 ml or any other volume sizes.

Example 3:
a) Physical specification of Sulfadoxine (500mg) and Pyrimethamine(25mg) dispersible tablets
Parameter Specification
Description White to off-white coloured, circular flat
bevelled edges, uncoated tablets having
"525" debossed on one side and plain on
other side
Average Weight (mg) 720.0 mg±5%
(Limit: 684.10 mg to 756.00 mg)
Diameter (mm) 13.00mm 13.00mm±0.3mm
(limit :12.70mm to13.30mm)
Thickness (mm) 4.80mm±0.3 mm
(Limit : 4.50mm to5.10mm)
Friability (%) NMT 1.0% w/w
Disintegration Time (minutes) NMT- 3 Minutes

b) Physical specification of Sulfadoxine (250mg) and Pyrimethamine(12.5mg) dispersible tablets
Parameter Specification
Description White to off-white coloured, round biconvex,uncoated tablets having break line on one side and plain on other side
Average Weight (mg) 360.0 mg±5%
Between 342.00mg to 378.00mg
Diameter (mm) 13.00mm 10.30mm±0.2mm
(limit :10.10mm to10.50mm)
Thickness (mm) 4.80mm±0.3 mm
Limit: 4.50 mm to 5.10 mm
Friability (%) NMT 1.0% w/w
Disintegration Time (minutes) NMT- 3 Minutes

Example 4:
Taste evaluation:
Taste evaluation of the Sulfadoxine(250mg) and Pyrimethamine(12.5mg) dispersible tablet has been conducted on 15 human volunteers(male 8 and female 7) for the evaluation of taste, flavor, bitterness, mouth feel, and after taste on a scale of 1 to 5. The overall rating for taste and flavor is reported to be very god to good. The overall rating for bitterness, mouth feel and after taste is reported to be moderate to acceptable.

Similarly, taste evaluation of the Sulfadoxine (500mg) and Pyrimethamine (25mg) dispersible tablet has been conducted on 15 human volunteers(male 8 and female 7) for the evaluation of taste, flavor, bitterness, mouth feel, and after taste on a scale of 1 to 5. The overall rating for taste and flavor is reported to be very good to good. The overall rating for bitterness, mouth feel and after taste is reported to be moderate to acceptable.

As is evident from the above data, the object of the provision of taste masked dispersible tablets of Sulfadoxine and Pyrimethamine is successfully achieved with the use of Methacrylic acid copolymer.

Example 5:
Stability data
Different batches of the dispersible tablets prepared in accordance with the invention are subjected to accelerated degradation and long term studies for 3 months at various temperature and moisture conditions, like 40?C/75RH; 25?C/65RH and 30?C /65RH and found that the product complies with the specification for 3 months at accelerated and long term study period.
The stability data is shown in below tables.

TEST PARAMETERS

Appear
ance

DT RS TEST Dissolution Assay Remark
Sulfaniilamide Hydroxy impurity N-acetyl impurity
(HMPS) MCPSA DCMP Any other impurity Total Impurity Sulfa Pyri Sulfa Pyri
Spec * NMT 3 Minutes NMT 0.5% NMT 0.5% NMT
0.5% NMT 0.13% NMT 0.13% NMT
0.13% NMT
1% NLT 80.0% in 30 minutes 90.0% to 110.0%
Initial Complies 1 min 32 sec ND 0.15% 0.08% 0.07% ND 0.05% 0.37% 94.12% to 99.22% 89.99% to 97.18% 101.9% 100.9% Passed
(40±2°C I 75±5% RH ) Accelerated Condition
1 M Complies 1 min 52 sec ND 0.15% 0.07% 0.07% ND 0.05% 0.35% 94.6% to 100.2% 95.5% to 100.3% 99.4% 98.2% Passed
3 Month Complies 1 min 42 sec ND 0.19% 0.10% 0.08% 0.03% 0.08% 0.70% 88.6% to 94.2% 95.6 to 102.5% 98.2% 95.8% Passed
25°±2°C I 60±5% RH) Long Term Condition
3 Month Complies 1 min 40 sec ND 0.18% 0.10% 0.08% 0.04% 0.09% 0.71% 97.5% to 102.9% 96.3% to 101.5% 99.9% 97.3% Passed
(30°±2°C / 75±5% RH) Long Term Condition
3 Month Complies 1 min 44 sec ND 0.18% 0.10% 0.08% 0.04% 0.08% 0.71% 98.7% to 101.3% 96.8% to 101.5% 98.7% 96.5% Passed
(30°±2°C / 65±5% RH) Long Term Condition
3 Month Complies 1 min 45 sec ND 0.18% 0.10% 0.08% 0.03% 0.08% 0.67% 98.4% to 102.4% 94.3% to 101.4% 99.9% 97.3% Passed
*White to off-white coloured, round biconvex, uncoated tablets having break line on one side and plain on other side.
Spec: Specification, ND: Not Detected, NA: Not Applicable, NMT: Not More Than, NL T: Not Less Than, DT: Disintegration Time, RS: Related Substance, RH; Relative Humidity.
Table 1:
Stability data of Sulfadoxine (250mg) and Pyrimethamine (12.5mg) dispersible tablets in blister pack (10 tablets)

Table 2
Stability data of Sulfadoxine (500mg) and Pyrimethamine (25mg) dispersible tablets in blister pack(10 tablets)

TEST PARAMETERS

Appear
ance

DT RS TEST Dissolution Assay Remark
Sulfaniilamide Hydroxy impurity N-acetyl impurity
(HMPS) MCPSA DCMP Any other impurity Total Impurity Sulfa Pyri Sulfa Pyri
Spec * NMT 3 Minutes NMT 0.5% NMT 0.5% NMT
0.5% NMT 0.13% NMT 0.13% NMT
0.13% NMT
1.0% NLT 80.0% in 30 minutes 90.0% to 110.0%
Initial Complies 1min 30 sec ND 0.17% 0.09% 0.08% 0.03% 0.05% 0.45% 91.2% to 93.0% 95.7% to 97.5% 98.2% 98.9% Passed
(40±2°C I 75±5% RH ) Accelerated Condition
1 M Complies 1 min 38 sec ND 0.15% 0.08% 0.07% ND 0.05% 0.36% 87.3% to 93.2% 94.1% to 97.9% 102.4% 102.6% Passed
3 M Complies 1 min 48 sec ND 0.15% 0.08% 0.07% ND 0.08% 0.39% 85.0% to 88.9% 95.2% to 99.7% 99.4% 99.9% Passed
(25°±2°C I 60±5% RH) Long Term Condition
3 M Complies 1min 42 sec ND 0.15% 0.08% 0.07% ND 0.08% 0.39% 88.0% to 95.0% 91.4% to 96.5% 99.2% 99.5% Passed
(30°±2°C / 75±5% RH) Long Term Condition
3 M Complies 1min 44 sec ND 0.15% 0.08% 0.07% ND 0.08% 0.39% 85.9% to 90.6% 91.8% to 93.4% 97.1% 97.7% Passed
(30°±2°C / 65±5% RH) Long Term Condition
3 M Complies 1min 42 sec ND 0.15% 0.08% 0.07% ND 0.08% 0.39% 87.2% to 90.9% 92.9% to 95.7% 99.9% 98.8% Passed
*White to off-white coloured, circular flat bevelled edges, uncoated tablets having ‘525’ debossed on one side and plain on other side.
Spec: Specification, ND: Not Detected, NA: Not Applicable, NMT: Not More Than, NL T: Not Less Than, DT: Disintegration Time, RS: Related Substance, RH; Relative Humidity.

TEST PARAMETERS

Appear
ance

DT RS TEST Dissolution Assay Remark
Sulfaniilamide Hydroxy impurity N-acetyl impurity
(HMPS) MCPSA DCMP Any other impurity Total Impurity Sulfa Pyri Sulfa Pyri
Spec * NMT 3 Minutes NMT 0.5% NMT 0.5% NMT
0.5% NMT 0.13% NMT 0.13% NMT
0.13% NMT
1.0% NLT 80.0% in 30 minutes 90.0% to 110.0%
Initial Complies 1 min 22 sec ND 0.15% 0.09% 0.07% ND 0.05% 0.37% 98.30% to 104.80% 98.90% to 105.20% 102.0% 98.8% Passed
(40±2°C I 75±5% RH ) Accelerated Condition
1 M Complies 1 min 51 sec ND 0.15% 0.07% 0.07% ND 0.05% 0.35% 95.9% to 98.2% 93.5% to 97.6% 97.2% 95.4% Passed
3 M Complies 1 min 56 sec ND 0.18% 0.10% 0.08% 0.04% 0.08% 0.68% 92.1% to 99.3% 90.5% to 97.9% 100.1% 94.4% Passed
(25°±2°C I 60±5% RH) Long Term Condition
3 M Complies 1 min 52 sec ND 0.19% 0.10% 0.09% 0.04% 0.08% 0.68% 94.2% to 102.3% 88.1% to 96.2% 101.5% 96.3% Passed
(30°±2°C / 75±5% RH) Long Term Condition
3 M Complies 1 min 54 sec ND 0.18% 0.10% 0.08% 0.04% 0.09% 0.68% 92.6% to 100.3% 84.4% to 93.8% 100.9% 95.5% Passed
(30°±2°C / 65±5% RH) Long Term Condition
3 M Complies 1 min 48 sec ND 0.18% 0.10% 0.08% 0.04% 0.09% 0.68% 94.0% to 98.52% 93.7% to 98.4% 98.8% 94.0% Passed
*White to off-white coloured, round biconvex, uncoated tablets having break line on one side and plain on other side.
Spec: Specification, ND: Not Detected, NA: Not Applicable, NMT: Not More Than, NL T: Not Less Than, DT: Disintegration Time, RS: Related Substance, RH; Relative Humidity.
Table 3
Stability data of Sulfadoxine(250mg) and Pyrimethamine(12.5mg) dispersible tablets in jar pack(100 tablets)
,CLAIMS:1. A fixed dose dispersible taste masked pharmaceutical composition comprising;
a) Sulfadoxine in an amount of about 70 to 75%; b) Pyrimethamine in an amount of about 3 to 4% ; c) a taste masking polymer in an amount of about 3 to 10%; and a pharmaceutical carrier(s), wherein, the composition is bioequivalent to immediate release marketed product.
2. The taste masked pharmaceutical composition according to claim 1, wherein, the taste masked polymer is selected from the group consisting of methyl methacrylic acid co-polymers or polyvinyl pyrollidone or carbomers and combinations thereof.
3. The taste masked pharmaceutical composition according to claim 1, wherein, the particle size of Sulfadoxine and Pyrimethamine in the taste masked formulation is around 5-100 microns.
4. The taste masked pharmaceutical composition according to claim 1, wherein, the particle size of Sulfadoxine in the taste masked formulation is about 5- 15 microns.
5. The taste masked pharmaceutical composition according to claim 1, wherein, the particle size of Pyrimethamine in the taste masked formulation is about 5 -50 microns.
6. The taste masked pharmaceutical composition according to claim 1, wherein, the pharmaceutical carrier(s) is selected from the group consisting of
a) binders such as polyvinyl pyrrolidone in an amount of 3 to 4%;
b) suspending agents such as xanthum gum, carrageenan, various carboxy methyl cellulose polymers in an amount of 0.5 to 5%;
c) fillers such as mannitol, sugars, , monosachharide, polysaccharides in an amount of 30-90%;
d) Lubricant such as magnesium stearate in an amount of 0.5 to 5%;
e) carbonate alkalizer and organic acid such as sodium carbonate and citric acid in an amount of 0.1 to 10.0%, and
f) flavours such as orange flavor, vanilla, mint, chewing gum lemon.
7. The taste masked pharmaceutical composition according to claim 1, wherein, the composition comprises Sulfadoxine in an amount of 500mg and Pyrimethamine in an amount of 25mg.
8. The taste masked pharmaceutical composition according to claim 1, wherein, the composition comprises Sulfadoxine in an amount of 250mg and Pyrimethamine in an amount of 12.5mg.
9. The taste masked pharmaceutical composition according to claim 1, wherein, the composition may be provided in dosage forms such as granules, Dispersible Tablets, powder for oral suspension.
10. A process for preparation of taste masked formulation of Sulfadoxine & Pyrimethamine which comprises:
a) Preparing granules of Sulfadoxine & Pyrimethamine using tastemasking polymer and binder employing non-aqueous granulation or aqueous granulation; and
b) Compressing the granules into tablets or formulated as powder for suspension by addition of suitable diluent(s)/carrier(s) to increase the bulk.