# US 2009/0270352 A1 · Tenofovir Disoproxil Hemi-Fumaric Acid Co-Crystal

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- Number: US 2009/0270352 A1
- Document ID: US20090270352A1
- Status: Published application
- Kind: A1
- Application number: 12/301,872
- Filed: 2008-05-21
- Published: 2009-10-29
- Earliest claimed: 2007-05-22
- Assignees: Ultimorphix Technologies B.V.
- Inventors: Evanthia Dova; Jaroslaw Marek Mazurek; Johnny Anker
- Web page: https://patentgrep.com/patent/US20090270352A1

## CPC

- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 31/18: for HIV
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A composition of tenofovir disoproxil with fumaric acid wherein the ratio of tenofovir disoproxil to fumaric acid is about 2:1 (TDFA 2:1).

### Claim 2 (depends on 1)

composition according to claim 1, which is a co-crystal.

### Claim 3 (depends on 1)

Co-crystal TDFA 2:1 according to claim 1, wherein the co-crystal is a co-crystal at temperatures between at 120 K and room temperature.

### Claim 4 (depends on 2)

Co-crystal TDFA 2:1 according to claim 2, characterised by one or more of:
a XRPD pattern substantially as set out in Table 1 and/or FIG. 1A;
a DSC substantially as set out in FIG. 1B;
a TGA substantially as set out in FIG. 1C;
a single crystal structure substantially as set out in FIG. 1E.

### Claim 5 (depends on 2)

Co-crystal TDFA 2:1 according to claim 2 in a substantially pure form.

### Claim 6

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.

### Claim 7

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.

### Claim 8

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.

### Claim 9

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.

### Claim 10 (depends on 9)

Method according to claim 9 wherein the solvent is an aqueous solvent, preferably water.

### Claim 11

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.

### Claim 12

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.

### Claim 13

Use of Co-crystal TDFA 2:1 essentially in absence of form Gilead 1 as a medicament.

### Claim 14

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.

### Claim 15

Use of Co-crystal TDFA 2:1 essentially in absence of form Gilead 1 in the treatment of HIV.

### Claim 16

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.