Synthesis of taurolidine, purity profiles and polymorphs
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Publication Number
US-11738120-B1
Publication Date
2023-08-29
Expiration Date
Abstract
Improved methods for synthesizing taurolidine, improved compositions or formulations comprising taurolidine and methods for reducing an amount of impurities in taurolidine are provided herein, among other things. The taurolidine may be substantially free of impurities. The taurolidine may be a polymorph, for example, Polymorph A or Polymorph B. The composition or formulation may comprise Low-Molecular-Weight (LMW) Heparin.
Core Innovation
The disclosure provides an improved taurolidine synthesis and purification approach designed to reduce impurities and achieve a substantially impurity-free product. It identifies specific taurolidine polymorphs, including Polymorph A and Polymorph B, characterized by XRPD plots with temperature dependence.
The improved route replaces conventional conditions associated with Pd/C and succinic acid hydrogenation/condensation. It describes use of Pearlman’s catalyst (Pd(OH)2) and HCl followed by condensation using acetone/water, while contrasting with conventional use of Class 2 solvents such as toluene/hexane carryover.
The disclosure also connects the improved taurolidine quality to downstream use as part of a catheter lock solution composition for treating and reducing infection and flow reduction in blood catheters. A locking solution composition is described comprising taurolidine obtained from a specific polymorph, a biologically acceptable acid, and low concentration heparin at 50 to 2500 units per mL.
Claims Coverage
The independent claims cover four variants of a catheter locking solution composition. Across the independent claims, the inventive coverage centers on taurolidine obtained from specified XRPD-characterized polymorphs, combined with a biologically acceptable acid and low concentration heparin at 50 to 2500 units per mL.
Taurolidine polymorph sourcing by XRPD-characterized Polymorph A
Taurolidine in the locking solution is obtained from a polymorph of the taurolidine, where the polymorph is Polymorph A characterized by an X-ray powder diffraction (XRPD) plot shown in FIG. 2.
Taurolidine polymorph sourcing by XRPD-characterized Polymorph B
Taurolidine in the locking solution is obtained from a polymorph of the taurolidine, where the polymorph is Polymorph B characterized by an X-ray powder diffraction (XRPD) plot shown in FIG. 3.
Taurolidine polymorph sourcing from Polymorph A and Polymorph B
Taurolidine in the locking solution is obtained from polymorphs of the taurolidine, where the polymorphs are Polymorph A characterized by an X-ray powder diffraction (XRPD) plot shown in FIG. 2 and Polymorph B characterized by an X-ray powder diffraction (XRPD) plots shown in FIG. 3.
Taurolidine polymorph sourcing from Polymorph A or Polymorph B
Taurolidine in the locking solution is obtained from one or more polymorphs of the taurolidine, where the one or more polymorphs are selected from the group consisting of Polymorph A characterized by an X-ray powder diffraction (XRPD) plot shown in FIG. 2 and Polymorph B characterized by an X-ray powder diffraction (XRPD) plot shown in FIG. 3.
Low concentration heparin in a defined dosing range with a biologically acceptable acid
The locking solution composition includes a biologically acceptable acid and low concentration heparin in a concentration of 50 to 2500 units per mL of the composition.
Overall claim coverage ties a catheter locking solution for treating and reducing infection and flow reduction to taurolidine derived from defined XRPD-characterized polymorphs (Polymorph A, Polymorph B, both, or either). The composition further requires a biologically acceptable acid and low concentration heparin at 50 to 2500 units per mL.
Stated Advantages
Reducing impurities in taurolidine to achieve a substantially impurity-free product.
Reducing toxic residual solvents by selecting solvents used in the improved route.
Reducing byproducts/impurities, including taurultam and taurinamide.
Treating and reducing infection in blood catheters.
Treating and reducing flow reduction in blood catheters.
Documented Applications
Catheter lock solutions for treating and reducing infection and flow reduction in blood catheters using taurolidine-based compositions.
Formulation concepts for catheter lock solutions using taurolidine with citric acid/citrate buffer and optionally LMWH heparin.
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