Manufacturing of stable tablet containing rosuvastatin can not be accomplished only by using pH adjuvant compounds. Presence of inorganic salts of multivalent metals is also required to prevent the formation of lactone and oxidation decomposition products. Stability of statin also can be obtained by adding amino sugars (e.g. N-methyl-glucoseamine). The advantage of the amino sugars versus inorganic alkali-earth metal salts is that they do not irritate the mucosa in the intestines, but of course tht prize is higher.

In the pharmaceutical composition inorganic salts of multivalent metals (Ca, Mg, Zn, Al, Fe and the combinations thereof) are used as stabilizing additives such as aluminum, magnesium metasilicate, tribasic calcium phosphate, tribasic magnesium phosphate and tribasic aluminum phosphate. The marketed (under Crestor trade name) pharmaceutical composition contains tribasic calcium phosphate as stabilizing agent.

It is known from the literature that from among HMG-CoA reductase inhibitor, lipid-lowering drugs several compounds are sensitive to the properties of the micro-environment of the composition, in fact to light, to heat and humidity.

Other alternative, mannitol based granulate, in which the active ingredient statins are dissolved in NaOH solution and are added together with the granulating solution to the pharmaceutical dosage form.
In delayed-release pharmaceutical compositions containing statins as active ingredients, in which the release of the active ingredient in the stomach and the lactone formation under acidic conditions are prevented by special gel structure and enterically coated dosage form.

During our experiments surprisingly it was found, that a stable pharmaceutical composition can be produced by using magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminum hydroxide as pharmaceutical excipients.

Formula of Rosuvastatin Tablet
There are many stabilizing agents can be used such as : Tribasic calcium phosphate, Magnesium hydroxide, Calcium acetate, Trometamol, Calcium gluconate, Calcium glycerophosphate, Magnesium acetate, and Aluminum hydroxide.

The formula used as experiments:
  • Rosuvastatin Calcium 6.93 6.93 6.93 6.93 6.93 6.93 6.93 6.93 (Active ingredient)
  • Crospovidone 5% (Disintegrant)
  • Lactose 45% (Diluent)
  • Microcrystalline cellulose 102 17% (Diluent)
  • Stabilizing agent 25% : Tribasic calcium phosphate/Magnesium hydroxide/ Calcium acetate/ Trometamol/Calcium gluconate/Calcium glycerophosphate/Magnesium acetate/Aluminum hydroxide
  • Magnesium stearate 1% (Lubricant)
The active ingredient and the excipients were sieved, the active ingredient, one of the above stabilizing additives, the diluent and the disintegrant were blended. Then the lubricant was added to the inner phase, the mixture was blended and compressed to tablets.

From those options, preferably used magnesium hydroxide and/or calcium acetate as stabilizing additive. The result of stability experiments at 75° C. for 7 days total degradation Lactone is similar to Crestor. More Detail :
Total degradation Lactone Example/stabilizer product (%) product (%)
  • tribasic calcium phosphate 0.5 0.3
  • magnesium hydroxide 0.3 0.2
  • calcium acetate 0.1 0.1
  • trometamol >30 16.6
  • calcium gluconate 0.7 0.4
  • calcium glycerophosphate 0.2 0.1
  • magnesium acetate >30 26.0
  • aluminum hydroxide 1.2 0.5
 According to the results magnesium acetate and trometamol used in equal amounts are not suitable for stabilizing the pharmaceutical dosage form containing amorphous rosuvastatin calcium.

Crestor Tablet excipients
Tablet core :
  • Lactose monohydrate
  • Microcrystalline cellulose
  • Calcium phosphate
  • Crospovidone
  • Magnesium stearate
Tablet coat
  • Lactose monohydrate
  • Hypromellose
  • Triacetin
  • Titanium dioxide (E171)
  • Ferric oxide, yellow (E172) (5 mg tablet)
  • Ferric oxide, red (E172) (10 mg, 20 mg and 40 mg tablets) 
 Manufacturing and Formula Option of Rosuvastatin Tablet
Option 1 (w/w%)
  • Rosuvastatin calcium 6.93
  • Lactose 58.00
  • Microcrystalline cellulose 28.74
  • Magnesium hydroxide 5.00
  • Crospovidone 0.33
  • Magnesium stearate 1.00

Option 2 (w/w%)
  • Rosuvastatin calcium 6.93
  • Lactose 55.00
  • Microcrystalline cellulose 27.07
  • Calcium acetate 5.00
  • Crospovidone 5.00
  • Magnesium stearate 1.00 
 Option 3 (w/w%)
  • Rosuvastatin calcium 6.93
  • Lactose 54.00
  • Microcrystalline cellulose 26.57
  • Magnesium hydroxide 5.00
  • Crospovidone 5.00
  • Povidone 1.50
  • Magnesium stearate 1.00 
 Option 4 (w/w%)
  • Rosuvastatin calcium 6.93
  • Lactose 55.55
  • Microcrystalline cellulose 29.02
  • Magnesium hydroxide 2.50
  • Calcium acetate 2.50
  • Crospovidone 2.50
  • Magnesium stearate 1.00 

Manufacturing Steps:
  1. The excipients are sieved.
  2. Blending in container blender: The active ingredient and the excipients of the inner phase (lactose, microcrystalline cellulose, magnesium hydroxide and/or calcium acetate, crospovidone and in case of need povidone) are blended in the homogenization equipment with 20 rpm (rotation/minute) stirring speed for 5 minutes. Then the excipient of the external phase, magnesium stearate, is added to the powder mixture and the powder mixture is blended in the container blender with 20 rpm stirring speed for 2 minutes.
  3. Compress it with rotary tablet machine, suitable with the specifications.
  4. Coating tablet : easiest way is using an aqueous solution of Opadry II White, 85F18422. The amount of the coating is 3% of that of the individual corpuses.