Tenofovir Disoproxil Hemi-Fumaric Acid Co-Crystal
AssigneeUltimorphix Technologies B.V.
InventorsEvanthia Dova, Jaroslaw Marek Mazurek, Johnny Anker
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Abstract
The present invention provides a novel crystalline form of Tenofovir disoproxil fumarate (Tenofovir DF), designated Co-crystal TDFA 2:1, methods for the preparation thereof and its use in pharmaceutical applications, in particular in anti-HIV medicaments. The crystalline form TDFA 2:1 can be used in combination with other anti-HIV medicaments such as Efavirenz, Emtricitabine, Ritonavir and/or TMC114.
Claims16
A composition of tenofovir disoproxil with fumaric acid wherein the ratio of tenofovir disoproxil to fumaric acid is about 2:1 (TDFA 2:1).
Method for the preparation of co-crystal TDFA 2:1, comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising Co-crystal TDFA 2:1 by evaporation of the solvent;
- and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising Co-crystal TDFA 2:1 by cooling and/or evaporation crystallization of a saturated solution;
- and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising Co-crystal TDFA 2:1 by anti-solvent addition as in Table III;
- and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form TDFA 2:1 by slurry crystallisation and/or seed crystallisation.
Co-crystal TDFA 2:1, characterized by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four X-ray powder diffraction peaks selected from the group consisting of 7.9, 9.8, 11.0, 12.0, 13.7, 14.3, 16.1, 16.8, 18.0, 19.2, 20.4, 21.2, 21.7, 22.6, 23.4, 24.3, 25.4, 27.6, degrees two-theta+/−0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees;
- DSC with a characterizing peak at 117.0+/−2° C.
Method for the preparation of the Co-crystal TDFA 2:1 comprising the steps of dissolving Tenofovir DF in 2,2,2-trifluoroethanol, acetone, dichloromethane, nitromethane or water and crystallizing Co-crystal TDFA 2:1 by evaporation of the solvent.
Method for the preparation of the co-crystal TDFA 2:1, comprising the steps of
- dissolving or mixing tenofovir disoproxil fumarate 1:1 in a suitable solvent or mixture thereof as in Table I and crystallising Co-crystal TDFA 2:1 by evaporation of the solvent;
- and/or
- dissolving or mixing tenofovir disoproxil fumarate 1:1 in a suitable solvent or mixture thereof as in Table II and crystallising Co-crystal TDFA 2:1 by cooling and/or evaporation crystallization of a saturated solution;
- and/or
- dissolving or mixing tenofovir disoproxil fumarate 1:1 in a suitable solvent or mixture thereof as in Table III and crystallising Co-crystal TDFA 2:1 by anti-solvent addition as in Table III;
- and/or
- dissolving or mixing tenofovir disoproxil fumarate 1:1 in a suitable solvent or mixture thereof and crystallising tenofovir DF Form TDFA 2:1 by slurry crystallisation and/or seed crystallisation.
Method for the preparation of co-crystal TDFA 2:1 in a substantially pure form, comprising contacting tenofovir disoproxil fumarate 1:1 with an aqueous solvent, preferably water.
Pharmaceutical formulation comprising TDFA 2:1, which is substantially free from a solid form characterised by having an X-ray peak at 5.5 degrees two-theta+/−0.3 degrees two-theta and preferably essentially in absence of form Gilead 1.
Use of Co-crystal TDFA 2:1 essentially in absence of form Gilead 1 as a medicament.
Use of Co-crystal TDFA 2:1 essentially in absence of form Gilead 1 in the preparation of a medicament for the treatment of HIV.
Use of Co-crystal TDFA 2:1 essentially in absence of form Gilead 1 in the treatment of HIV.
Use of Co-crystal TDFA 2:1 essentially in absence of form Gilead 1 in combination with another pharmaceutical ingredient, preferably an anti HIV agent, preferably Efavirenz and/or Emtricitabine and/or TMC114.
Dependencies are inferred from the claim text.