Stable amorphous Eliglustat premix and process for the preparation thereof
The present invention relates to pharmaceutical compositions of Eliglustat. In particular the present invention relates to stable amorphous Eliglustat premix having enhanced stability and dissolution properties. The present invention also provide a stable premix composition comprising amorphous Eliglustat or a pharmaceutical acceptable salt thereof, pharmaceutical compositions comprising the premixes, and processes for preparing the same. The compositions prepared in the present invention includes sublingual or mouth dissolving tablets, and capsules of Eliglustat and/or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier.
1. A stable pharmaceutical composition of amorphous Eliglustat which comprises:
i. a stable amorphous Eliglustat premix comprising of Eliglustat or its pharmaceutically acceptable salt with at least one premixing agent, and
ii. at least one stabilizer comprising basic inorganic salts of magnesium, and
iii. optionally, at least one pharmaceutically acceptable excipient, wherein the said premix is free flowing.
2. The stable pharmaceutical composition as claimed in claim 1 , wherein the at least one premixing agent is selected from diluents, lubricants, disintegrants, glidants, and surface active agents and mixture thereof.
3. The stable pharmaceutical composition as claimed in claim 1 , wherein the at least one premixing agent is selected from the group consisting of polyvinylpyrrolidone, copovidone, polyvinyl alcohol, lactose, polyethylene glycol, polyol, sodium starch glycolate, colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, sugars, magnesium aluminometasilicate, fumed silica and combinations thereof.
4. The stable pharmaceutical composition as claimed in claim 1 , wherein the amorphous Eliglustat premix is prepared by a process comprising of:
a. dissolving a mixture of Eliglustat with suitable additive or excipient in an organic solvent and stirring it to get a clear solution;
b. adding suitable premixing agent to the solution obtained in step (a) and further stirring to get a clear solution;
c. adding second premixing agent and stabilizer to the solution obtained in step (b) and mixing thoroughly to get a uniform dispersion;
d. adding organic solvent to the solution obtained in step (c);
e. removing said organic solvent;
f. drying the mass obtained in step (e);
g. sieving the mass obtained in step (f); and
h. vacuum drying the mass of step (g) for complete solvent removal to obtain the Eliglustat premix which is free flowing.
5. The stable pharmaceutical composition as claimed in claim 4 , wherein the organic solvent in step (a) and (d) is selected from the group consisting of halogenated hydrocarbons selected from dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; alcohols selected from methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butyl alcohol; ketones selected from acetone, ethyl methyl ketone, diethyl ketone, and methyl isobutyl ketone; esters selected from ethyl acetate, n-propyl acetate, n-butyl acetate and t-butyl acetate; ethers selected from diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether and 1,4-dioxane; nitriles selected from acetonitrile and propionitrile and mixtures thereof.
6. The stable pharmaceutical composition as claimed in claim 4 , wherein the organic solvent in step (a) and (d) is alcohol selected from the group consisting of methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol and t-butyl alcohol.
7. The stable pharmaceutical composition as claimed in claim 1 , wherein the composition is a solid dosage form selected from powder, granules, capsules, tablets, films, sublingual tablets or mouth dissolving tablets and pellets.
8. The stable pharmaceutical composition as claimed in claim 1 , wherein a content of total impurities in the composition is not more than 3.0% under accelerated stability conditions for a storage period of 3, 6 or 12 months.
9. The stable pharmaceutical composition as claimed in claim 1 , wherein a content of any unknown impurities in the composition is not more than 0.2% under accelerated stability conditions for a storage period of 3, 6 or 12 months.
10. The stable pharmaceutical composition as claimed in claim 1 , wherein a content of N-oxide impurity in the composition is not more than 2.0% under accelerated stability conditions for a storage period of 3, 6 or 12 months.
11. The stable pharmaceutical composition of claim 1 , wherein said basic inorganic salts of magnesium is heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, or aluminum hydroxide-magnesium.
12. A stable sublingual tablet composition of amorphous Eliglustat which comprises:
i. a stable amorphous Eliglustat premix comprising of Eliglustat or its pharmaceutically acceptable salt with at least one premixing agent, and
ii. at least one stabilizer, and
iii. optionally, at least one pharmaceutically acceptable excipient, wherein the said premix is free flowing.