Tablet Manufacturing: A Second Look At Magnesium Stearate as an Important Excipient in Tablets.
Q: Have you all come across the problems with magnesium stearate in tablet formulation? Do you all want to have deep understanding on issues with magnesium stearate and solutions to resolve them?
A: Yes, in the past I as a formulator had a problem of using Mg. Stearate in a tablet formulation.
Please find the problem and my solving the problem.
Case history: For the generic formulation Fosinopril Sodium Tablets under PIV ANDA application. I had the following problems and its successful resolution.
The API in its formulated product is unstable, it cyclizes to form degraded 'keto' in presence of metallic compound. Innovator drug product used nonmetallic lubricant which had a PIV challenge. It was found from the literature and also performing pre-formulation drug-excipients compatibility study at binary level, that use of magnesium stearate has the highest degradation, while use of calcium and zinc stearate has lower rate of degradation. It was found that the use of zinc stearate had the least degradation and was within regulatory allowance. Therefore, we selected zinc stearate as the lubricant for the drug product.
Following finding higher Fosinoprilat content in the formulated generic Fosinopril tablets (40 mg & 10 mg) an investigation was conducted to recommend for its improvement.
Objective: To investigate the causes of higher Fosinoprilat in the formulated generic Fosinopril tablets compared to Monopril (brand Fosinopril tablet) and suggest improvements for the Generic drug product.
Information from the Literature:
· Extended stability of the bulk drug substance, fosinopril sodium does not undergo the postulated rearrangement and degradation reactions.
· If exposed to high humidity, the ester prodrug undergoes hydrolysis to form the active moiety, [Fosinoprilat].
· In the formulation containing magnesium stearate, fosinopril degrades to form not only fosinoprilat, but also chelates of magnesium ion.
· Relative reactivities of metal ions in degradation of fosinopril in methanol at 24°C is as follows: Co(II) > Mn(II) > Mg(II) >Zn(II) > Ni(II) > Mn(III) > Cu(II) > Fe (III) > Ca(II) > Ba(II)
Patents:
Use of sodium stearyl fumarate or hydrogenated vegetable oil as lubricant in Fosinopril tablets is restricted by patent. (US Patent No.5, 006,344)
Inferences:
· Based on patent restrictions, literatures review, and some pre-formulation study zinc stearate was selected as the lubricant for the drug product.
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Masihuddin Jaigirdar
Pharmaceutics Expert (FDA & Industry Sector)
MJ Consultant
Silver Spring MD
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.MasihuddinMasihuddinMasihuddinMasihuddin
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