Vitamin D content uniformity in pharmaceutical dosage forms
View Patent ↗New dosage forms of vitamin D and calcium carbonate having improved content uniformity are described. The improvements are realized through modifications to the formulation, the raw material specifications, and the process of manufacture.
1. A method of manufacturing calcium carbonate/vitamin D tablets comprising:
forming a premix comprising a mixture of vitamin D granulation and silicon dioxide;
adding a calcium carbonate granulation to said premix to form a first vitamin D/calcium carbonate granulation mixture, wherein the calcium carbonate granulation has a median particle size within ±40% of the vitamin D granulation;
mixing and sieving the first vitamin D/calcium carbonate granulation mixture to form a sieved first vitamin D/calcium carbonate granulation mixture;
blending the first vitamin D/calcium carbonate granulation mixture in a V blender to form a blended first vitamin D/calcium carbonate granulation mixture;
dividing the blended first vitamin D/calcium carbonate granulation mixture into four equal portions and adding calcium carbonate to each portion to form a second vitamin D/calcium carbonate granulation mixture;
blending the second vitamin D/calcium carbonate granulation mixture in a V blender; and,
forming tablets from a composition comprising the second vitamin D/calcium carbonate granulation mixture.
2. The method of claim 1 , wherein said premix of vitamin D and silicon dioxide is in a mass ratio of about 25:9 vitamin D:silicon dioxide.
3. The method of claim 1 , wherein said first mixture is in a mass ratio of about 1000:25:9 calcium carbonate:vitamin D:silicon dioxide.
4. The method of claim 1 , wherein said step of mixing and sieving comprises sieving through a US 20 Mesh sieve.
5. The method of claim 1 , wherein said step of blending the second mixture in a V blender comprises blending for about 2 minutes.
6. The method of claim 1 , wherein said step of dividing the first mixture into four equal portions and adding calcium carbonate comprises adding 2.0 kg of calcium carbonate.
7. The method of claim 1 , further comprising the step of milling and sieving said calcium carbonate granulation and said vitamin D granulation to produce said calcium carbonate and vitamin D granulations having median particle sizes within ±40% of one another.
8. The method of claim 7 , wherein said median particle sizes are within ±25% of one another.
9. The method of claim 7 , wherein said median particle sizes are within ±15% of one another.
10. The method of claim 1 , further comprising the step of milling and sieving said calcium carbonate granulation to have a D 20 value of less than 110 microns.
11. The method of claim 1 , further comprising the step of milling and sieving said calcium carbonate granulation to have a D 16 value of less than 95 microns.
12. A method of manufacturing calcium carbonate/vitamin D tablets comprising:
forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide and another layer of calcium carbonate, wherein the calcium carbonate has a median particle size within ±40% of the vitamin D;
sieving and blending the premix to form a first vitamin D/calcium carbonate granulation mixture;
adding calcium carbonate to said first vitamin D/calcium carbonate granulation mixture such that there is a layer of calcium carbonate granulation, a layer of said first granulation mixture, and another layer of calcium carbonate, to form a second vitamin D/calcium carbonate granulation mixture;
sieving and blending the second vitamin D/calcium carbonate granulation mixture; and,
forming tablets from a composition comprising the second vitamin D/calcium carbonate granulation mixture.
13. The method of claim 12 , wherein one or both of said steps of sieving and blending the premix and sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a V blender.
14. The method of claim 13 , wherein said step of sieving and blending the premix comprises blending with a V blender comprises blending for about 8 minutes.
15. The method of claim 13 , wherein said step of sieving and blending the second vitamin D/calcium carbonate granulation mixture comprises blending with a V blender comprises blending for about 50 minutes.
16. The method of claim 12 , wherein said step of forming a premix comprising a layer of calcium carbonate, a layer of vitamin D/silicon dioxide and another layer of calcium carbonate comprises adding two layers of about 500 kg each of calcium carbonate.
17. The method of claim 12 , wherein said first mixture is in a mass ratio of about 1600:20:7 calcium carbonate:vitamin D:silicon dioxide.