DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application, in its entirety, claims the benefit of earlier Indian provisional patent application No. 872/CHE/2014 filed on February 21, 2014.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of ritonavir crystalline form I.

BACKGROUND OF THE INVENTION

Ritonavir is an antiretroviral drug used to treat Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). It is an inhibitor of proteases, including HIV protease. It is often prescribed in combination with other HIV drugs as a pharmacokinetic inhibitor to prevent protease metabolism of the other co-prescribed drugs. Ritonavir is chemically known as 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Ritonavir has the following structural formula:

Ritonavir is marketed under the brand name NORVIR® by AbbVie, Inc. It is presently sold in a soft gelatin capsule dosage form for oral administration and is indicated for use in combination with other antiretroviral agents for the treatment of HIV infection. The combination of ritonavir and lopinavir is sold in a capsule dosage form for oral administration under the brand name KALETRA®, also marketed by AbbVie, Inc. KALETRA® is also indicated for use in combination with other antiretroviral agents for the treatment of HIV infection.

The inhibiting activity of ritonavir and advantages for use in conjunction with other antiretroviral drugs is disclosed in U.S. Patent No. 6,037,157, as well as the Physicians’ Desk Reference, pages 487-492 (56th edition, 2002), both of which are hereby incorporated by reference.

Additionally, U.S. Patent No. 5,541,206 discloses ritonavir, a process for its synthesis, and crystalline polymorphic form I of ritonavir. U.S. Patent No. 6,894,171 discloses polymorphic form of ritonavir form II, as well processes for the preparation of form II. U.S. Patent No. 7,148,359 discloses amorphous ritonavir as well as a process for the preparation of amorphous ritonavir. U.S. Patent No. 7,205,413 discloses polymorphic Form III, Form IV, and Form V of ritonavir as well as processes for the preparation of each. Each of these four patents is also hereby incorporated by reference.

There is need to provide an improved process for the preparation of stable crystalline ritonavir form I. The present disclosure provides a novel method, which is feasible for use in an industrial setting, for the preparation of pharmaceutically suitable crystalline ritonavir form I.

SUMMARY OF THE INVENTION

One aspect of the present disclosure provides an improved process for the preparation of crystalline ritonavir form I.

In one embodiment of the present invention, the process for the preparation of crystalline ritonavir form I may include the steps of suspending ritonavir in a solvent, adding a second solvent, raising the temperature of the reaction mass, optionally seeding with crystalline ritonavir form I, then quickly cooling the reaction mass to obtain crystalline form I of ritonavir.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The present discloses an improved process for the preparation of crystalline ritonavir form I.
In one embodiment of the present invention, crystalline ritonavir form I may be prepared through the following steps:
a) suspending ritonavir in a first solvent,
b) adding a second solvent,
c) heating the reaction mass,
d) cooling the reaction mass, and
e) isolating crystalline form I of ritonavir

According to the present disclosure, ritonavir is suspended in a first solvent. Within the context of the present invention, the first solvent may include a C1-5 ester moiety, and may be, for example, ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, or mixtures thereof.

According to the present disclosure, a second solvent may then be added. In some embodiments, this second solvent is a C5-9 hydrocarbon, and may be, for example, n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures thereof. In some embodiments, n-heptane has been found to a particularly useful second solvent.

Next, the temperature of the reaction mass may be raised to about 70 - 80 °C and maintained there for about 2-3 hours. The reaction mass may then be rapidly, or shock, cooled to approximately 10 - 15 °C to result in the formation of a solid. In some embodiments, transferring the reaction mass into a pre-cooled vessel at 10-15 °C is a particularly effective method for rapidly cooling the reaction mass. In some embodiments, filtering the reaction mass while transferring it into the pre-cooled vessel was found to be particularly useful in efficient production of ritonavir form I. The solid formed through such processes may then be filtered to obtain crystalline ritonavir form I.

In another embodiment of the present invention, an improved process for the preparation of crystalline ritonavir form I may be achieved by the following steps:
a) suspending ritonavir in a first solvent,
b) adding second solvent,
c) heating the reaction mass,
d) adding seed crystals,
e) cooling the reaction mass, and
f) isolating crystalline form I of ritonavir

According to this embodiment of the present disclosure, ritonavir is suspended in a first solvent. Within the context of the present invention, the first solvent is a C1-5 ester, which may be, for example, ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, or mixtures thereof. According to the present disclosure, a second solvent is then added. This second solvent is, in some embodiments, a C5-9 hydrocarbon, and may be, for example, n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures thereof. In some embodiments, n-heptane has been found to particularly useful as a second solvent.

Next, the temperature of the reaction mass is raised to about 70 - 80 °C and maintained there for about 2 - 3 hours. Seed crystals of ritonavir form I may then be added to the reaction mixture. The reaction mass may then be rapidly cooled to approximately 10 - 15 °C, at which point a solid forms. It has been found in some embodiments, that transferring the mass into a pre-cooled vessel maintained at 10 - 15 °C is particularly useful for achieving rapid cooling of the reaction mixture. In other embodiments, filtering the reaction mass while transferring into a pre-cooled reaction vessel was found to achieve particularly desirable reaction results. The obtained solid may then be filtered to obtain crystalline ritonavir form I.

In another embodiment, the present invention relates to an improved process for the preparation of crystalline Ritonavir form I which may be carried out by the following steps:

a) suspending ritonavir in a first solvent,
b) adding second solvent,
c) heating the reaction mass,
d) cooling the reaction mass,
e) adding seed crystals, and
f) isolating crystalline form I of ritonavir

According to this embodiment of the present disclosure, ritonavir is suspended in a first solvent. Within the context of the present invention, the first solvent is a C1-5 ester, which may be, for example, ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, or mixtures thereof. According to the present disclosure, a second solvent is then added. This second solvent is, in some embodiments, a C5-9 hydrocarbon, and may be, for example, n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures thereof. In some embodiments, n-heptane has been found to particularly useful as a second solvent.

Next, the temperature of the reaction mass is raised to about 70 - 80 °C and maintained there for about 2-3 hours. The reaction mass may then be rapidly cooled to approximately 10 - 15 °C. In some embodiments, transferring the reaction mass into a pre-cooled vessel held at 10 - 15 °C was found to be particularly useful for achieving the cooling step. In some embodiments, filtering the reaction mass during the transfer of the reaction mass into a pre-cooled vessel was found to be particularly useful. Seed crystals of ritonavir form I may then be added to the reaction mixture, at which point a solid may begin to form. The obtained solid may then be filtered to obtain crystalline ritonavir form I.

Ritonavir or pharmaceutically acceptable salts thereof, prepared by the processes disclosed in the present invention may be incorporated into a pharmaceutical formulation for the treatment of HIV and/or AIDS in human patients. The pharmaceutical formulation may be an oral dosage form, for example, tablets, capsules, or oral suspensions. When formulated as a tablet, the dosage form may include such excipients as copovidone, sorbitan monolaurate, colloidal silicon dioxide, sodium stearyl fumarate, dibasic calcium phophsate (hydrated or anhydrous), and sorbitan monolaurate. The tablet may have a film coating, which may include ingredients such as hypromellose, titanium dioxide, polyvinyl alcohol, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide E172, and polysorbate 80. Capsule formulations may include excipients such as butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide. The oral suspension formulations may include excipients such as acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural & artificial flavors, natural and artificial colors, peppermint oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, citric acid, and water.

Ritonavir or pharmaceutically acceptable salts thereof, prepared by the processes disclosed in the present invention may also be administered in conjunction with other active pharmaceutical ingredients, including atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir, lopinavir, efavirenz, nevirapine, nelfinavir, maraviroc, abacavir, and zidovudine.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Examples:
Example 1: Process for the preparation of crystalline ritonavir form I
Ritonavir (100 g) was suspended in ethyl acetate (700 mL) and n-heptane (350 mL) was added. The temperature of the reaction mass was raised to 70 – 75 °C. A separate round bottom flask was cooled using a chilled water bath to a temperature of about 10 - 15 °C. The reaction mass, maintained at 70 - 75 °C, was filtered into the round bottom flask, maintained at 10 - 15 °C, using a micron filter aid and washed with ethyl acetate and n-heptane. The reaction mass was stirred for about two hours to precipitate a solid. The product was filtered and dried to obtain substantially pure crystalline ritonavir Form I.
Example 2: Process for the preparation of crystalline ritonavir form I
Ritonavir (100 g) was suspended in ethyl acetate (700 mL) and n-heptane (350 mL) was added. The temperature of the reaction mass was raised to 70 - 75 °C. A separate round bottom flask was cooled using a chilled water bath to a temperature of about 10 - 15 °C. The reaction mass, maintained at 70 - 75 °C, was filtered into the round bottom flask, maintained at 10 - 15 °C, using a micron filter aid and then washed with ethyl acetate and n-heptane. A seed crystal of ritonavir form I was added and the reaction mass was stirred for about two hours to precipitate a solid. The product was filtered and dried to obtain substantially pure crystalline ritonavir form I.

,CLAIMS:1. A process for the preparation of crystalline ritonavir form I, comprising the steps of:
a) suspending ritonavir in a first solvent to form a reaction mass;
b) adding second solvent;
c) heating the reaction mass;
d) cooling the reaction mass; and
e) isolating crystalline form I of ritonavir.

2. The process according to claim 1, further comprising the step of seeding the reaction mass with crystalline ritonavir form I, after the cooling step and before the isolating step.

3. The process according to claim 1, further comprising the step of seeding the reaction mass with crystalline ritonavir form I after the heating step and before the cooling step.

4. The process according to claim 1, wherein the first solvent is a C1-5 ester.

5. The process according to claim 4, wherein the first solvent is selected from the group consisting of ethyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, and mixtures thereof

6. The process according to claim 1, wherein the second solvent is a saturated C5-9 hydrocarbon.

7. The process according to claim 4, wherein the hydrocarbon is selected from the group consisting of n-pentane, n-hexane, cyclohexane, n-heptane, and mixtures thereof.

8. The process according to claim 1, wherein the reaction mass is heated to about 75 ± 5 °C during the heating step.

9. The process according to claim 1, wherein the reaction mass is cooled to about 10-15 °C in said cooling step.

10. The process according to claim 1, wherein the cooling step is achieved by shock cooling technique by transferring the reaction mass to a pre-cooled vessel.