WO2016155681A1

WO2016155681A1 - An amorphous salt of the macrocyclic inhibitor of hepatitis c virus

Info

Publication number: WO2016155681A1
Application number: PCT/CZ2016/000031
Authority: WO
Inventors: Jan DOUBSKY; Gregor Sedmak
Original assignee: Zentiva, K.S.
Priority date: 2015-03-27
Filing date: 2016-03-24
Publication date: 2016-10-06
Also published as: CZ2015220A3

Abstract

The invention relates to an amorphous form of the potassium salt of the macrocyclic inhibitor of hepatitis C virus (HCV) of formula I and methods of its preparation, known under the corporate name TMC435 or the generic name simeprevir, which is, in the sodium salt form, the active ingredient of the drug Olysio (Johnson& Johnson) used for the treatment of hepatitis C.

Description

AN AMORPHOUS SALT OF THE MACROCYCLIC INHIBITOR OF HEPATITIS C VIRUS

Technical Field

The invention relates to an amorphous form of the potassium salt of the macrocyclic inhibitor of hepatitis C virus (HCV) of formula (I) and methods of its preparation,

known under the corporate name TMC435 or the generic name simeprevir, which is, in the sodium salt form, the active ingredient of the drug Olysio (Johnson&Johnson) used for the treatment of hepatitis C.

Disclosure of Invention

Simeprevir (I) is very poorly soluble in water. An improvement of solubility and the related bioavailability plays an important role in the development of drugs. The problem of bioavailability of a poorly soluble drug can be solved by administration of higher doses. However, this results in the necessity to prepare larger dosage forms, which may cause practical problems. It is convenient for the dosage forms to be compact and for their preparation to be as simple as possible.

If there is a poorly soluble active pharmaceutical ingredient, it is a well-known fact that its solubility can be improved by its conversion to the amorphous form. In such cases there is a rule that the more crystalline the substance is, the lower is its bioavailability and vice versa. Thus, reducing the degree of crystallinity has a favourable influence on the bioavailability. The amorphous form provides materials with interesting properties, e.g. better dissolution profiles and better solubility, compared to crystalline forms. However, amorphous forms typically exhibit a stability problem. This is because most amorphous substances get quickly transformed into a more stable crystalline form. This process is usually rapid and is influenced by a number of factors - temperature, humidity, trace quantities of crystalline materials in the surrounding environment etc. Even seemingly stable amorphous forms may, after a long time and for not quite a clear reason, get partly or completely transformed into a crystalline form. Thus, amorphous and crystalline forms exhibit different properties regarding not only the bioavailability, but also other properties, e.g. liquidity, compactness, hygroscopicity etc. Instable solid dosage forms may cause considerable fluctuation of the exact quantity, which may have a negative impact on the therapeutical effect as well as the preparation conditions. Therefore, in the development stage drugs are virtually in all cases transformed to a crystalline form, which exhibits stability during the production and storage of the dosage form. This means that very few drugs are available in the amorphous form.

The present invention brings a solid form of the compound of formula I that is stable and has favourable properties with regard to any of the following factors: bioavailability, pharmacokinetic profile (release rate, AUC etc.), formulation, storage etc.

If the potassium salt of the compound of formula I is transformed to the amorphous form, this is surprisingly stable and can be thus used for the treatment of hepatitis C. This form enables easy preparation of compact dosage forms and can be advantageously prepared e.g. by spray drying with OH.

Detailed description of the invention

The present invention relates to an amorphous form of the potassium salt of structure I and a method of its preparation.

The present invention further provides a method of preparing the potassium salt of structure I in an amorphous form, which requires: a) preparation of a mixture of the substance of formula I in a pharmaceutically acceptable non-aqueous solvent and aqueous potassium hydroxide; and

b) spray drying of the mixture of step a) in a spray drier. In one embodiment, in step a) a solution of potassium hydroxide is mixed with the respective solvent and subsequently the compound of structure I is added, best in the free form (i.e. not in the form of a salt). In one particular embodiment an aqueous solution of potassium hydroxide at a concentration of 7.5M to 12.5M is added to the solvent before the compound of structure I is added.

It is recommended to carry out the procedures of step a) under stirring. It is also recommendable to wait until the compound of structure I forms a solution before the mixture is subjected to spray drying.

In these preparation methods such pharmaceutically acceptable solvents are used that are volatile enough for use in spray drying (that have a boiling point lower than e.g. 150°C) and are able to dissolve simeprevir I. Such solvents include halogenated hydrocarbons (chloroform, preferably dichloromethane), ethers (diethyl ether, t-butyl methyl ether or tetrahydrofuran), ketones (e.g. ethyl methyl ketone, isobutyl methyl ketone) and alcohols (preferably ethanol or methanol, and aliphatic C3-C6 alcohols).

The present invention further provides a method of preparing the potassium salt of structure I in an amorphous form, which requires:

a) preparation of a suspension of the compound of structure I in a pharmaceutically acceptable non-aqueous solvent (preferably in C₁-C4 aliphatic alcohols or tetrahydrofuran) and mixing with a suitable Q-Q aliphatic potassium alkoxide

(preferably with potassium teri-butoxide, potassium methoxide, potassium ethoxide or potassium z-propoxide);

b) vacuum evaporation of the mixture of step a).

Another aspect of the present invention is the fact that the amorphous form of the potassium salt of simeprevir can be produced as the final dosage form. The final dosage form can be a tablet or capsule. A pharmaceutical formulation containing the amorphous form of the potassium salt of simeprevir typically contains the amorphous form of the potassium salt of simeprevir and one or more other auxiliary substances.

The one or more other auxiliary substances used for the preparation of a pharmaceutical formulation containing the amorphous form of the potassium salt of simeprevir typically comprises at least one filler. Suitable fillers can be e.g. water-soluble fillers soluble or water- insoluble fillers such as monosaccharides, oligosaccharides and sugar alcohols, e.g. glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, rafEnose, isomalt, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitoi and lactitol. compressible sugar, microcrystalline cellulose, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate and their mixtures. Lactose monohydrate and mannitol are preferred.

One or more other auxiliary substances used for the preparation of a pharmaceutical formulation containing the amorphous form of the potassium salt of simeprevir typically comprises at least one surfactant. A suitable surfactant can be e.g. anionic, cationic, ampholytic and non-ionic surfactants, e.g. sodium lauryl sulphate, cetrimide, N-dodecyl-N,N- dimethyl-betaine, polysorbates (e.g. Tweens®), poloxamers and their mixtures. Sodium lauryl sulphate and poloxamers are preferred. One or more other auxiliary substances used for the preparation of a pharmaceutical formulation containing the amorphous form of the potassium salt of simeprevir typically comprises at least one lubricant and or glidant A suitable lubricant and glidant can be e.g. magnesium stearate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures. Magnesium stearate and colloidal silicon dioxide are especially preferred.

One or more other auxiliary substances used for the preparation of a pharmaceutical formulation containing the amorphous form of the potassium salt of simeprevir typically comprises at least one disintegrant A suitable disintegrant can be e.g. sodium croscarmellose, pregelatinized starch, crospovidone, hydroxypropyl starch, sodium starch glycolate, low substituted hydroxypropyl cellulose and their mixtures. Sodium glycolate and sodium croscarmellose are especially preferred. For the preparation of a pharmaceutical formulation containing the amorphous form of the potassium salt of simeprevir other auxiliary substances can be used as well. Suitable other auxiliary substances are, inter alia, binders, coatings, colorants, flavourings and similar substances.

Examples

The presented examples are intended to illustrate the present invention. Example 1: Preparation of the potassium salt of simeprevir in an amorphous form

Potassium tert-butoxide (0.74 g) was added to a stirred suspension of simeprevir I (4.5 g) in 45 ml of THF. The reaction mixture was stirred at the room temperature for 3 h, then it was filtered and evaporated in vacuum until dry. The potassium salt of simeprevir in an amorphous form was obtained in the yield of 93%.

Example 2: Preparation of the potassium salt of simeprevir in an amorphous form

A 10M solution of sodium hydroxide, obtained by dissolving 0.34 g in 6 ml of distilled water, was added to dichloromethane (45 ml) under vigorous stirring. Simeprevir I (4.5 g) was added to the mixture produced this way under moderate stirring and the stirring continued until the mixture was visibly clarified. This mixture was subjected to standard spray drying. The obtained product was subsequently finally dried in a vacuum drier. An amorphous potassium salt was obtained in the yield of 95%.

Example 3: Preparation of the potassium salt of simeprevir in an amorphous form

Potassium tert-butoxide (0.74 g) was added to a stirred suspension of simeprevir I (4.5 g) in 75 ml of MeOH. The reaction mixture was stirred at the room temperature for 4 h, then it was filtered and evaporated in vacuum until dry. The potassium salt of simeprevir I in an amorphous form was prepared in the yield of 91%. Example 4: Preparation of capsules or tablets containing the amorphous form of the potassium salt of simeprevir

The amorphous form of the potassium salt of simeprevir together with fillers, surfactants and disintegrants was compacted with the use of a roll compactor into the form of dry granules. The dry granules were sieved on a sieve with the mesh size of 1.0 mm. Magnesium stearate was admixed to the obtained granules for the purpose of preparing a mixture for capsuling / tabletting. The obtained mixture was processed into capsules or tabletted in a high-speed rotary tabletting machine.

Claims

C L A I M S

1. The potassium salt of simeprevir of formula I:

in a solid amorphous form.

2. The potassium salt according to claim 1, obtainable by spray drying.

3. A method of preparing an amorphous form of the potassium salt according to claim 1, characterized in that:

a) a mixture of the potassium salt of formula I is prepared in a pharmaceutically acceptable non-aqueous solvent and in aqueous potassium hydroxide; and b) the mixture of step a) is dried by spray drying in a spray drier.

4. The method according to claim 3, characterized in that in step a) an aqueous solution of potassium hydroxide is mixed with a non-aqueous solvent and subsequently the potassium salt of formula I is added.

5. The method according to any one of claims 3 to 4, characterized in that the nonaqueous solvent is a halogenated hydrocarbon.

6. The method according to claims 3 to 5, characterized in that the solvent is dichloromethane and the concentration of the aqueous solution of potassium hydroxide is in the range of 7.5M to 12.5M.

7. Use of the potassium salt of simeprevir according to claim 1 with one or more auxiliary substances for the preparation of a pharmaceutical formulation.

8. A pharmaceutical formulation containing the potassium salt of simeprevir according to claim 1, characterized in that it is in the form of tablets or capsules.

9. The potassium salt of simeprevir according to claim 1 for use as a therapeutical.

10. The potassium salt of simeprevir according to claim 1 for use for the treatment of hepatitis C.

11. The potassium salt of simeprevir according to claim 1 for use as an inhibitor of hepatitis C virus.