(T1530-02-09) Development of a Stable Intravenous Injectable Formulation of Highly Hydrolytic Molecule in a Co-Crystal with a Highly Hydrophobic (A1) and Highly Hydrophilic (A2) Drug Substance

Purpose: To develop an isotonic and neutral pH intravenous formulation for a co-crystal compound containing a highly hydrolytic & oxidative hydrophobic drug substance and highly hydrophilic drug substance intended for use in myocardial infarction.

Methods: A1 is highly hydrolytic, thermosensitive & oxidative molecule which immediately undergoes hydrolysis in presence of water or moisture. A1 is insoluble in water but solubilizes in other solubilizers and organic solvents. On the other hand A2 is hydrophilic molecule and is only water soluble and does not solubilize in other solvents or solubilizers. Hence to administer through intravenous route, both the drug substances should be in solution form which was difficult to achieve in a single solvent system. So, for both molecules to be available in a single solvent system, a co-solvent system approach was used where both molecules possess physical and chemical stability. As A1 is highly, hydrolytic, thermosensitive and oxidative molecule, hydrolysis of molecule was arrested by freeze drying the solution at lower temperatures which results in the cake containing water content less than 0.5%. The oxidative and thermosensitive instabilities were taken care by Nitrogen purging cum nitrogen overlaying and also controlled temperature manufacturing (2-8°C). The resultant lyophilized cake contains a hydrophobic molecule which is difficult to be reconstitutable with water or 0.9% saline before administration. So, a new reconstitution solution was also developed which upon reconstitution with the lyophilized product gives an isotonic solution with neutral pH (below which, the pharmacological action of the molecule is lost).

Results: All the physico-chemical attributes like water content, Assay of both actives, degradation products, reconstitution pH etc., were studied for bulk solution and finished product obtained after lyophilization. The water content and residual solvent content were in acceptible limits. The main challenge of hydrolytic degradation was arrested and was in control till accelerated 6M stability condition. Other important characterestics like pH and osmolality of the reconstituted solution which are important to retain the pharmacological action were also well within the desired range.

Conclusion: A stable intravenous formulation along with stable reconstitution solution was developed with desired physico-chemical characteristics suitable for IV administration and is scalable to manufacturing site.

Development Approach for Intravenous Formulation

6M Stability summary of Total Degradation products