HK1166310B - Nalmefene hydrochloride dihydrate - Google Patents

Description

Nalmefene hydrochloride dihydrate

The present invention relates to a new non-hygroscopic form of nalmefene hydrochloride, namely nalmefene hydrochloride dihydrate, especially for oral dosage forms, and to a process for its preparation.

Background

Nalmefene is a known opioid receptor antagonist that inhibits the pharmacological effects of both administered opioid agonists and agonists endogenously produced by the opioid system. The clinical usefulness of nalmefene as an antagonist stems from its ability to rapidly (and selectively) reverse the effects of these opioid agonists, including the repression common in the central nervous system and respiratory system.

Nalmefene was originally developed for the treatment of alcohol dependence, where doses of 10-40mg administered (about 1-2 hours before drinking) have shown good results when patients think of imminent alcohol consumption (Karhuvaara et al, alcohol. clin. exp. res. (2007), vol.31 No.7. pp1179-1187). In addition, nalmefene has been studied for the treatment of other addictive disorders, such as pathological gambling and addiction to shopping. In these investigational procedures and tests, nalmefene has been used, for example, as a parental solution (Revex)^TM)。

Nalmefene is an opiate derivative that is structurally similar to the opiate antagonist naltrexone. Advantages of nalmefene over naltrexone include a longer half-life, greater oral bioavailability and no dose dependent hepatotoxicity found.

Nalmefene differs from naltrexone in that the ketone group at the 6-position of naltrexone is replaced by a methylene group (CH2), which greatly increases the binding affinity for the mu-opioid receptor. Nalmefene also has a high affinity for other opioid receptors (kappa and delta receptors) and is considered a "universal antagonist" that blocks all three receptors.

Nalmefene can be prepared according to the methods described by Hanh et al (j.med. chem., 18, 259-262(1975), Mallinckrodt (us 4,751,307) and Meltzner et al (us 4,535,157).

By using the above mentioned method, the free base of nalmefene is obtained, which can then be converted into the hydrochloride salt by using conventional methods.

According to Brittain (Analytical Profiles of Drug Substances and Excipients) (1996), Vol 24, pp.351-395), nalmefene hydrochloride can be recrystallized from water to give pure Drug Substances which inevitably contain a monohydrate crystalline phase. In this same review, the monohydrate phase of nalmefene hydrochloride is described as substantially non-hygroscopic, since it can only absorb up to 1% of extraneous moisture.

The inventors of the present invention have found that: in contrast to the literature, nalmefene hydrochloride as monohydrate is hygroscopic.

Therefore, there is a need to provide a new, stable and non-hygroscopic hydrate form of nalmefene and a method for its preparation.

Summary of The Invention

The present invention relates to nalmefene hydrochloride dihydrate in a preferred crystalline form represented by the formula.

The nalmefene hydrochloride dihydrate is non-hygroscopic.

The invention also relates to two methods for preparing nalmefene hydrochloride dihydrate:

process (I): converting nalmefene hydrochloride into nalmefene hydrochloride dihydrate by reslurrying in an aqueous solution, e.g. water, such as pure water, and

process (II): nalmefene hydrochloride is recrystallized in an aqueous solution, e.g. water, such as pure water.

The repulping process (process I) comprises the steps of:

(1) nalmefene hydrochloride (17- (cyclopropylmethyl) -4, 5-alpha-epoxy-6-methylenemorphinan-3, 14-diol hydrochloride) and an aqueous solution (e.g., water, such as pure water) are mixed,

(2) optionally heating the mixture to a temperature sufficient to cause,

(3) optionally subjecting the mixture to distillation to obtain a mixture,

(4) the mixture is stirred until conversion is complete, e.g., less than 1 hour, such as about 1 hour, e.g., at least 1 hour, and

(5) the solid formed was isolated.

The recrystallization process (process II) comprises the steps of:

(a) nalmefene hydrochloride (17- (cyclopropylmethyl) -4, 5-alpha-epoxy-6-methylenemorphinan-3, 14-diol hydrochloride) and an aqueous solution (e.g., water, such as pure water) are mixed,

(b) heating the mixture to obtain a substantially homogeneous solution,

(c) optionally distilling the mixture obtained in (b),

(d) cooling the solution obtained in step (b) or (c), followed by seeding with nalmefene hydrochloride, and

(e) the solid formed was isolated.

Another aspect of the invention (method III) is a method of recovering any unused nalmefene in methods I and II, comprising the steps of:

(i) optionally distilling the mother liquor obtained in process (I) or (II),

(ii) basifying the mother liquor obtained in step (I) or process (I) or (II),

(iii) extracting the mixture with a suitable organic solvent,

(iv) adding hydrogen chloride, and

(v) the solid formed was isolated.

The invention also relates to a pharmaceutical composition comprising nalmefene hydrochloride dihydrate, the use of nalmefene hydrochloride dihydrate in medicine and in particular the use of nalmefene hydrochloride dihydrate for the treatment of alcohol dependence.

Brief Description of Drawings

Figure 1 shows the TGA thermogram of nalmefene hydrochloride dihydrate. The y-axis shows mass percent and the x-axis shows temperature (. degree. C.).

Figure 2 shows DVS experiments (drying curves) of nalmefene hydrochloride dihydrate performed at 40 ℃. The first y-axis (left) shows the change (%) relative to the anhydrous mass, the other y-axis (right) shows the Relative Humidity (RH) (%) of the target, and the x-axis shows the time in minutes. The thin line shows the change in target RH, and the thick line shows the change with respect to mass.

Figure 3 shows the X-ray powder diffraction pattern of nalmefene hydrochloride dihydrate. The y-axis represents intensity (counts) and the x-axis represents 2 θ angle (°).

Figure 4 shows the TGA thermogram of nalmefene hydrochloride monohydrate. The y-axis shows mass percent and the x-axis shows temperature (. degree. C.).

Figure 5 shows DVS experiments (drying curves) of nalmefene hydrochloride monohydrate performed at 40 ℃. The first y-axis (left) shows the change (%) relative to the anhydrous mass, the other y-axis (right) shows the Relative Humidity (RH) (%) of the target, and the x-axis shows the time in minutes. The thin line shows the change in target RH, and the thick line shows the change with respect to mass.

Figure 6 shows the X-ray powder diffraction pattern of nalmefene hydrochloride monohydrate. The y-axis represents intensity (counts) and the x-axis represents 2 θ angle (°).

Detailed Description

The present invention relates to nalmefene hydrochloride dihydrate represented by the formula.

The dihydrate form of nalmefene hydrochloride is particularly advantageous because it is non-hygroscopic. Due to this non-hygroscopic character, the physical properties can be controlled more easily. This is particularly important in the preparation of solid dosage forms, for example oral forms, including solid unit dosage forms such as tablets or chewable tablets and capsules.

As is well known in the pharmaceutical industry, the preparation of hygroscopic products necessitates the use of humidity controlled rooms for storage and the preparation process itself. In addition, the finished absorbent product must be packaged in sealed blisters (blisters) to avoid stability problems due to humidity. These disadvantages can be avoided by using nalmefene hydrochloride in the form of a non-hygroscopic dihydrate.

Nalmefene hydrochloride dihydrate is characterized by its non-hygroscopic nature and stable water content. The compound does not absorb or lose water when exposed to between 10% and 95% Relative Humidity (RH).

As shown in inventive example 1, DVS (dynamic vapor sorption) tests were conducted at 25 ℃ and 40 ℃. The results show that even at 95% RH, no water is adsorbed by nalmefene hydrochloride dihydrate. In contrast, as shown in example 2, nalmefene hydrochloride monohydrate absorbs about 2.5% of water when exposed to 95% RH and 40 ℃.

In addition, the results in example 2 show that the water content of the monohydrate form varies with ambient humidity, in contrast to the dihydrate, and at greater than 50% RH, the monohydrate form changes to a new structure with higher water content.

Therefore, an important property of nalmefene hydrochloride dihydrate is the aforementioned non-hygroscopic property. Accordingly, the present invention relates to non-hygroscopic nalmefene hydrochloride dihydrate which absorbs less than 1%, such as less than 0.5%, such as less than 0.3% moisture when exposed to 95% RH at 25 ℃.

Nalmefene hydrochloride dihydrate is a crystalline solid characterized by X-ray reflection angles of 8.99, 10.63, 15.24, 16.55 and 17.20 ° 2 θ (± 0.1 ° 2 θ) as measured using Cu ka 1 radiation and a water content of about 8 to about 9%, such as about 8.7%, whereas nalmefene hydrochloride monohydrate is a crystalline solid characterized by X-ray reflection angles of 7.39, 11.33, 11.52, 17.70 and 24.27 ° 2 θ (± 0.1 ° 2 θ) and a water content of 4 to 7%, depending on the relative humidity of the environment.

The invention also relates to the use of nalmefene hydrochloride dihydrate for the manufacture of a medicament.

In particular the present invention relates to the use of nalmefene hydrochloride dihydrate for the manufacture of a medicament comprising at least 5% (w/w), such as at least 10% (w/w), at least 30%, at least 50% (w/w), such as at least 70% (w/w), at least 90% (w/w), at least 95% (w/w), at least 99% (w/w) or 100% of nalmefene hydrochloride dihydrate, in particular for oral dosage forms, such as single unit solid dosage forms, such as tablets. Nalmefene hydrochloride dihydrate, in particular for the preparation of a medicament for the treatment of alcohol dependence.

In another embodiment, the invention relates to a method of treating alcohol dependence comprising administering to a patient in need thereof a therapeutically effective amount of nalmefene hydrochloride dihydrate, e.g. in the form of a pharmaceutical composition (e.g. a solid dosage form, such as an oral tablet).

The term "therapeutically effective amount" means an amount/dose of a compound or pharmaceutical composition that is sufficient to produce an effective response (i.e., a biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician) in the patient to whom it is administered. The "therapeutically effective amount" will vary depending on, inter alia, the disease and its severity and the age, weight, physical condition and responsiveness of the patient to be treated. In addition, a "therapeutically effective amount" may vary depending on whether a compound of the invention is used in combination with one or more compounds, in which case the amount of a given compound will be reduced, e.g., a sub-effective amount.

The term "distillation" refers to a process of separating a boiling liquid mixture according to its volatility. The application of vacuum (e.g., partial vacuum) is an example of such a separation method.

The term "chemical purity" is a normal meaning in the art and thus refers to the degree to which the resulting compound is contaminated with impurities. Thus, the resulting compound, which is at least 98% chemically pure, contains up to 2% impurities. Chemical purity can be determined by, for example, HPLC.

The term "quantitative analysis" refers to the effective content of a desired substance, expressed as weight to weight percent (w/w%).

The term "extraction" refers to liquid-liquid extraction, wherein the free nalmefene base is transferred from the aqueous phase to the organic phase.

The term "reslurry" refers to a process in which a crystalline material is suspended in a solvent or solvent mixture at an appropriate temperature whereby the crystalline material is partially dissolved and partially recrystallized, thereby allowing it to be converted into the desired form and/or purified.

KF means "Karl Fisher titration".

TGA refers to "thermogravimetric analysis".

DVS refers to "dynamic vapor sorption".

In the present invention, the term "substantially homogeneous solution" means a liquid mixture free of visibly insoluble material.

In the present invention, the term "seeding" means adding a small amount of crystals to initiate precipitation of the product.

Herein, the term "non-hygroscopic" means that less than 1%, such as less than 0.5%, such as less than 0.3% w/w of moisture is absorbed when exposed to 95% RH at 25 ℃.

In this context, the particle size is determined by laser diffraction using a MalvernMastersizer S instrument, which is disclosed in detail in the introduction to the experimental section.

The amount of nalmefene hydrochloride dihydrate in the pharmaceutical composition is preferably from about 10mg to about 100mg, such as from about 10mg to about 60mg, from about 10mg to about 40mg or about 20 mg.

The term "alcohol dependence" is a term commonly known to the skilled person, which is defined in the fourth revised edition of the Diagnostic and statistical manual of Mental Disorders (DSM-IVTR) (Diagnostic and statistical manual of Mental Disorders, 4th edition text review, american Mental suffering Publishing, 2000) as the presence of 3 or more of seven areas of life impairment associated with alcohol during the same 12 months. These impairments include tolerance when alcohol is terminated or inhalation is reduced, cessation of signs of syndrome, potential interference with vital functions related to consuming a significant amount of time to use alcohol and resuming use despite physical or mental problems.

The pharmaceutical composition comprising nalmefene hydrochloride dihydrate may further comprise one or more pharmaceutically acceptable carriers.

Methods for preparing solid pharmaceutical formulations are well known in the art. See, e.g., Remington: the Science and Practice of Pharmacy (pharmaceutical sciences and methods), 21st ed., Lippincott Williams & Wilkins (2005). Solid preparations, such as tablets, can be prepared by mixing the active ingredient with conventional carriers, such as adjuvants and/or diluents, and compressing the mixture in a tablet press. Non-limiting examples of adjuvants and/or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gelatine, and the like. Any other adjuvants or additives, such as colorants, fragrances, and preservatives, may also be used, provided they are compatible with the active ingredient. Accordingly, the pharmaceutical compositions of the present invention generally comprise an effective amount of nalmefene hydrochloride dihydrate and one or more pharmaceutically acceptable carriers.

The present invention contemplates that nalmefene hydrochloride dihydrate may be administered by any suitable route, e.g. orally or parenterally, and may be presented in any form suitable for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. In one embodiment, nalmefene hydrochloride dihydrate is preferably administered as a solid pharmaceutical entity, suitably a tablet or capsule.

Another aspect of the invention relates to a method for obtaining nalmefene hydrochloride dihydrate. Nalmefene hydrochloride dihydrate is obtainable by any of the methods (I) and (II) listed below:

process (I): converting nalmefene hydrochloride into nalmefene hydrochloride dihydrate by reslurrying in an aqueous solution, e.g. water, such as pure water, and

process (II): nalmefene hydrochloride is recrystallized in an aqueous solution, e.g. water, such as pure water.

In one aspect of the invention, a repulping process (Process (I))Which comprises the following steps:

(1) nalmefene hydrochloride (17- (cyclopropylmethyl) -4, 5-alpha-epoxy-6-methylenemorphinan-3, 14-diol hydrochloride) and an aqueous solution (e.g., water, e.g., pure water) are mixed,

(2) optionally heating the mixture to a temperature sufficient to cause,

(3) optionally subjecting the mixture to distillation to obtain a mixture,

(4) stirring the mixture, and

(5) the solid formed was isolated.

In one embodiment of process (I), nalmefene hydrochloride is converted to nalmefene hydrochloride dihydrate by reslurry in an aqueous solution. In another embodiment, nalmefene hydrochloride is converted to nalmefene hydrochloride dihydrate by reslurrying in water. In yet another embodiment, nalmefene hydrochloride is converted to nalmefene hydrochloride dihydrate by reslurrying in pure water.

The ratio of the aqueous solution (e.g., water, such as pure water) used in step (1) may range from about 0.5ml to about 4ml of the aqueous solution/nalmefene hydrochloride (g), such as from about 1ml to about 2ml of the aqueous solution/nalmefene hydrochloride (g), more preferably about 1.5ml of the aqueous solution/nalmefene hydrochloride (g). The nalmefene hydrochloride used may be selected from any hydrate or solvate form of nalmefene or a mixture of hydrate and/or solvate forms with or without solvents. In one embodiment, nalmefene hydrochloride in the monohydrate form is used. In another embodiment of process (I), nalmefene hydrochloride in the form of a hydrate is used. In another embodiment, nalmefene hydrochloride in the form of a solvate is used. In yet another embodiment, nalmefene hydrochloride is used in a mixture in the form of a hydrated solvate.

In one embodiment of process (I), the solvent comprised in the hydrate and/or solvate form is selected from the group consisting of acetone, n-propanol, isopropanol, dichloromethane and water. In one embodiment, the solvent is acetone. In another embodiment, the solvent is n-propanol. In yet another embodiment, the solvent is isopropanol. In yet another embodiment, the solvent is dichloromethane. In yet another embodiment, the solvent is water.

The heating of step (2) is an optional step which may be carried out under conditions which are advantageous to increase the dissolution rate of the mixture obtained in step (b). The temperature of heating may depend on the environment. In some cases, the mixing can be effected at room temperature (20-25 ℃). It is contemplated that in one embodiment, the heating in step (2) is to about 50 ℃. In another embodiment, the heating of step (2) is 50 ℃ or less. In another embodiment, the heating of step (2) is to a temperature of from about 20 ℃ to about 40 ℃. In yet another embodiment, the heating of step (2) is to about 30 ℃.

Step (2) and step (3) may be carried out with or without stirring.

The distillation of step (3) may be carried out to remove organic solvents that may be present in the mixture. The distillation may be performed by applying a vacuum.

The stirring of step (4) may be carried out at a temperature of from about 0 ℃ to about 50 ℃, such as 45 ℃, e.g., from 20 ℃ to about 40 ℃. In one embodiment, the mixture is stirred for less than 1 hour. In another embodiment, the mixture is stirred for about 1 hour. In yet another embodiment, the mixture is stirred for at least 1 hour.

Isolation of the solid may be carried out at a temperature in the range of about 0-25 deg.C, such as 0-20 deg.C, more preferably in the range of 0-5 deg.C, in order to reduce the solubility of the product (e.g., in water) and increase the yield. The solid can be isolated by filtration and washed with a suitable solvent. The solvent of washing includes water and a water/organic solvent mixture or a pure organic solvent. Preferably water is used, in a further embodiment preferably water that has been pre-cooled. When organic solvents are used, grade 2 or 3 solvents (ICH Q3C (R4) guidelines) are preferred. In one embodiment, a 3-stage solvent is used, such as acetone and ethyl acetate. In one embodiment, acetone is used. In another embodiment, ethyl acetate is used.

The product may be dried under vacuum at less than 40 c, more preferably at a temperature in the range of 25-35 c.

The resulting compound is expected to be at least 98% chemically pure, such as at least 99%, or at least 99.5%.

In one aspect of the invention, the recrystallization process (Process (II))The method comprises the following steps:

(a) nalmefene hydrochloride (17- (cyclopropylmethyl) -4, 5-alpha-epoxy-6-methylenemorphinan-3, 14-diol hydrochloride) and an aqueous solution (e.g., water, such as pure water) are mixed,

(b) heating the mixture to obtain a substantially homogeneous solution,

(c) optionally distilling the mixture obtained in step (b),

(d) cooling the solution obtained in step (b) or (c), followed by seeding with nalmefene hydrochloride, and

(e) the solid formed was isolated.

In one embodiment of process (II), nalmefene hydrochloride is converted to nalmefene hydrochloride dihydrate by recrystallization from an aqueous solution. In another embodiment, nalmefene hydrochloride is converted to nalmefene hydrochloride dihydrate by reslurrying in water. In yet another embodiment, nalmefene hydrochloride is converted to nalmefene hydrochloride dihydrate by reslurrying in pure water.

The amount of aqueous solution (e.g., water, such as pure water) used in step (a) can range from about 0.9ml to about 4ml of aqueous solution per nalmefene hydrochloride (g), such as from about 1ml to about 2ml of aqueous solution per nalmefene hydrochloride (g), or about 1.5ml of aqueous solution per nalmefene hydrochloride (g). The nalmefene hydrochloride used may be selected from any hydrate or solvate form of nalmefene or a mixture of hydrate and/or solvate forms with or without solvents.

In one embodiment of process (II), nalmefene hydrochloride in the form of a hydrate is used. In another embodiment, nalmefene hydrochloride in the form of a solvate is used. In yet another embodiment, nalmefene hydrochloride is used in a mixture in the form of a hydrated solvate.

In one embodiment of process (II), the solvent comprised in the hydrate and/or solvate form is selected from the group consisting of acetone, n-propanol, isopropanol, dichloromethane and water. In one embodiment, the solvent is acetone. In another embodiment, the solvent is n-propanol. In yet another embodiment, the solvent is isopropanol. In yet another embodiment, the solvent is dichloromethane. In yet another embodiment, the solvent is water.

The suspension may be heated until a substantially homogeneous solution, i.e. a solution, is obtained. The heating of step (b) may be performed to achieve a temperature of about 50 ℃ to about 100 ℃, such as about 50 ℃ to about 90 ℃ or about 70 ℃ to about 85 ℃.

A partial vacuum may then be applied to remove traces of organic volatiles (if present) in step (c).

Optionally filtering (e.g., through a 0.65 μm cartridge) the solution obtained in step (b) or step (c) to remove foreign matter prior to performing step (d).

In step (d), the solution may be cooled to a temperature between 40 ℃ and about 50 ℃ and then seeded. In one embodiment of the invention, the inoculation is carried out at a temperature between 40 ℃ and 50 ℃. The inoculation is carried out by using nalmefene hydrochloride dihydrate crystals. In one embodiment of the invention, the nalmefene seeding material may be obtained by the above repulping method (I).

The amount of seed crystals added in step (d) may be about 1/2000(w/w) nalmefene hydrochloride seed/nalmefene hydrochloride added in step (a), such as about 1/1000(w/w) seed or 1/200 nalmefene hydrochloride seed/nalmefene hydrochloride added in step (a).

Suitable cooling ramps, such as rapid cooling ramps, and suitable agitation, such as vigorous agitation, discourage further growth of the crystals that have formed and help provide a product with a well-defined, fine and relatively small particle size. The cooling from the inoculation temperature to the isolation temperature may be completed within a few hours and more preferably within 1 hour. Thus, the inoculated mixture obtained in step (d) may be further cooled, such as by flash cooling, which cooling comprises the steps of:

(d') further cooling the mixture to a temperature of about 0-5 deg.C, e.g., for a period of about 45 minutes or more, and

(d ") the mixture is then maintained at a temperature of about 0-5 ℃ for a period of, for example, about 45 minutes or more, after which the solid formed is separated according to step (e).

Isolating the solid formed in step (e). Isolation of the solid may be carried out at a temperature in the range of about 0-20 c, more preferably in the range of 0-5 c, in order to reduce the solubility of the product in water and thereby increase the yield. The solid can be isolated by filtration and washed with a suitable solvent. The solvent of washing includes water and a water/organic solvent mixture or a pure organic solvent. In one embodiment, the solvent of washing is selected from acetone and water. In one embodiment, acetone is used. In another embodiment, a mixture of acetone and water is used. In yet another embodiment, water is used. In another embodiment, the water used is pre-cooled water. When washing with organic solvents, grade 2 or 3 solvents (ICH Q3C (R4) guidelines) are preferred, with grade 3 solvents such as acetone and ethyl acetate being more preferred. In one embodiment, ethyl acetate is used.

The product may be dried under vacuum at less than 40 c, more preferably at a temperature in the range of 25-35 c.

The resulting compound is expected to be at least 98% chemically pure, such as at least 99% chemically pure, or at least 99.5% chemically pure.

It is further expected that nalmefene hydrochloride dihydrate obtained in process (II) above has the following particle size distribution: d90 equal to or lower than 400 μm, D50 equal to or lower than 200 μm, D10 equal to or lower than 50 μm, D90/D50 ratio equal to or lower than 2.5, wherein D "XX" (XX given as 10, 50 or 90) is defined as the following values: where the "XX percentage" (by volume) of particles have a diameter below the specified value. Thus, for D10, 10% of the particle size (by volume) has a diameter equal to or lower than 50 μm.

Recovery of nalmefene hydrochloride from mother liquor (method III)：

Nalmefene hydrochloride is highly soluble in aqueous solutions (e.g. water, e.g. pure water) and part of this material is therefore lost to the mother liquor. To recover any unused nalmefene hydrochloride in process I or II listed above, a recovery process has been developed comprising:

(i) optionally distilling the mother liquor obtained in process (I) or (II),

(ii) basifying the mother liquor obtained in step (I) or process (I) or (II),

(iii) extracting the mixture with a suitable organic solvent,

(iv) adding hydrogen chloride, and

(v) the solid formed was isolated.

(iii) the basification of step (ii) is carried out with an organic or inorganic base to a pH in the range of 8-10, such as 8-9. In an embodiment of process (III), the basification of step (ii) is carried out with ammonium hydroxide.

In the extraction step (iii), the organic solvent may be selected from: halogenated hydrocarbons, ethers, esters, ketones, more preferably dichloromethane, 2-methyl-tetrahydrofuran, ethyl acetate, 2-butanone, even more preferably dichloromethane. In one embodiment, the organic solvent is a halogenated hydrocarbon. In another embodiment, the organic solvent is an ether. In another embodiment, the organic solvent is selected from esters. In another embodiment, the organic solvent is selected from ketones. In another embodiment, the organic solvent is dichloromethane. In another embodiment, the organic solvent is 2-methyl-tetrahydrofuran. In another embodiment, the organic solvent is ethyl acetate. In another embodiment, the organic solvent is 2-butanone.

(iv) treating the organic solvent solution of nalmefene base obtained in step (iii) with hydrogen chloride to precipitate nalmefene hydrochloride.

The amount of hydrogen chloride added in step (iv) depends on different factors, such as the amount of nalmefene in the mother liquor used, and will be apparent to the skilled person. After addition of hydrochloric acid to the mixture of step (iv), the product precipitated.

The precipitated solid can be isolated as described in methods I and II.

The resulting compound is expected to be at least 98% chemically pure, such as at least 99% chemically pure, or at least 99.5% chemically pure.

Examples

Herein, chemical purity is determined by HPLC method using the following conditions:

chromatographic conditions：

In this context, the particle size is determined by LASER diffraction using a Malvern Mastersizer S instrument, which consists of a LASER transmitter (LASER-NEON-wavelength 632nm), an optical system (300F lens, range 0.5-900 μm), a suspension cell (beam length 2.4mm) and a photodiode detector.

The samples were analyzed using mineral oil (CAS 8042-47) as a spreading agent.

Example 1

1.1 preparation of dihydrate

The dihydrate was prepared as follows:

20g of crude nalmefene hydrochloride (99.26% chemical purity, 92.9% quantitative) were suspended in 24ml of water. The mixture was heated and the solid completely dissolved at 60-65 ℃. The solution was heated to 70 ℃ and held at this temperature for 15 minutes. The solution was cooled from 70 ℃ to 20 ℃ over 3 hours using a linear ramp.

Nalmefene hydrochloride was added as seed at 50 ℃. The seed crystals do not dissolve and nalmefene starts to crystallize. When the ramp cooling was terminated, the suspension was kept stirring at 20 ℃ for 2.5 days. The solid was filtered and washed with acetone (50 ml). The wet product was dried under vacuum at 40 ℃ overnight to give 13.2g nalmefene hydrochloride dihydrate (99.74% chemical purity, water content 8.54% w/w by Karl Fisher titration).

1.1b preparation of dihydrate

20g of crude nalmefene hydrochloride (97.2% chemical purity, 82.6% quantitative analysis) were suspended in 30ml of water. The mixture was heated and the solid completely dissolved at 80 ℃. The organic volatiles were removed by vacuum distillation. The solution was cooled to 50 ℃.

Nalmefene hydrochloride dihydrate was added as seed at 50 ℃. The mixture was held at 50 ℃ for 3 hours and then cooled to 20 ℃. The suspension was kept under stirring at 20 ℃ for about 2.5 days. The solid was filtered and washed with acetone (20 ml). The wet product was dried under vacuum at 30 ℃ overnight to give 11.5g nalmefene hydrochloride dihydrate (99.78% chemical purity, water content 8.78% w/w by Karl Fisher titration).

1.2 Properties of dihydrate

In TGA (FIG. 1), a sample of about 10mg was heated at a rate of 10 °/min in an open pan under a stream of nitrogen. The thermogram shows a weight loss of about 8.5% at 0, beginning at room temperature and ending at 125-150 ℃.

The DVS assay was performed at 25 ℃ and 40 ℃. The curve shapes at the two temperatures are the same; the curve at 40 ℃ is shown in FIG. 2. The dihydrate is maintained at a relative humidity of 10-95%. Surface absorption at high relative humidity is less than 0.2%. At 10% RH, desorption of crystal water occurred slowly. However, the DVS-curve shows complete rehydration after drying at 0% RH, so this treatment preserves the crystal lattice.

FIG. 3 shows the use of Cu K_α1X-ray powder diffraction pattern of nalmefene hydrochloride dihydrate obtained by irradiation. The diffraction patterns were measured in reflection in the range of 5-40 ° 2 θ. Characterized by XRPD reflections at 8.99, 10.63, 15.24, 16.55 and 17.20 ° 2 Θ (± 0.1 ° 2 Θ).

Example 2

2.1a preparation of monohydrate

25g of nalmefene hydrochloride (99.24% chemical purity, 84.1% quantitative analysis) were suspended in 32ml of water. The mixture was heated to 80 ℃. The low boiling organic solvent was distilled under vacuum. The solution was cooled to 20 ℃ over 1 hour using a linear ramp. The suspension was kept under stirring for 2 hours, then cooled to 4 ℃ over 1 hour and kept under stirring at this temperature for a further 1 hour. The solid was filtered and washed with 25ml acetone. The wet solid was dried overnight under vacuum at 30 ℃ to give 13.5g nalmefene hydrochloride monohydrate (water content 4.74% w/w by Karl Fisher titration, yield 61%).

2.1b preparation of monohydrate

In a jacketed reactor, nalmefene hydrochloride (72.3g) and water (100ml) were added. The suspension was heated to 85 ℃ to give a solution. A nitrogen stream was passed. The solution was cooled to 60 ℃ over about 50 minutes and then held at that temperature for 10 minutes. The product began to precipitate at 60 ℃. The suspension was further cooled to 55 ℃ and held at 55 ℃ for 10 minutes. The suspension was cooled to 8 ℃ over about 1 hour and held at that temperature for 30 minutes before separation. The solid was filtered and washed with 83ml of acetone. The solid was dried to give 48.6g nalmefene hydrochloride monohydrate.

2.2 Properties of monohydrate

In TGA (FIG. 4), a sample of about 5mg was heated at a rate of 10 °/min in an open pan under a stream of nitrogen. The thermogram shows a weight loss of about 4% starting at room temperature and ending at 100-.

The DVS assay was performed at 25 ℃ and 40 ℃. The curve shapes at the two temperatures are the same; only the 40 ℃ curve is shown (fig. 5).

At 10% RH, the majority of the bound water was absorbed (4%). Then the weight was increased stepwise with humidity up to 4.3% at 50% RH, but suddenly increased to 6.9% at 60% RH and then again to 7.3% at 95% RH. The amounts here are given as percent weight gain relative to dry, thus corresponding to a 4.8% weight gain for the monohydrate, and a 7.2% gain for the 1.5 hydrate. The curve shows that the water content of the monohydrate is not constant but varies with the relative humidity.

FIG. 6 shows the use of Cu K_α1X-ray powder diffraction pattern of nalmefene hydrochloride monohydrate obtained by irradiation (fig. 6). The diffraction patterns were measured in reflection in the range of 5-40 ° 2 θ. Characterized by XRPD reflections at 7.39, 11.33, 11.52, 17.70 and 24.27 ° 2 θ (± 0.1 ° 2 θ).

Example 3

Preparation of nalmefene hydrochloride dihydrate

Crude nalmefene hydrochloride (7.67Kg, 93.9% for quantitative analysis) and water (8.6L) were added to a suitable reactor. The suspension was heated to 80 ℃ until the substrate (substrate) was completely dissolved. Vacuum was then applied to remove the organic solvent. The resulting solution was then filtered through a 0.65 μm cartridge and diluted with water (2.1L) to rinse the reactor and lines. The solution was cooled to 50 ℃ and 7g of nalmefene hydrochloride dihydrate seed material was added. The mixture was cooled to 0-5 ℃ over 1 hour with thorough stirring, and then kept stirring for another 1 hour. The solid was filtered and washed with acetone. The wet product was dried under vacuum at 25 ℃ to give nalmefene hydrochloride dihydrate (5.4 Kg; 73% yield) with a chemical purity of 99.89% (HPLC).

The particle size of the nalmefene hydrochloride dihydrate was determined by laser diffraction using a Malvern Mastersizer S instrument. The particle size distribution is given in the table below:

D10	D50	D90
			14μm	122μm	287μm

example 4

Recovery of nalmefene hydrochloride

The mother liquor obtained in example 3 was concentrated in vacuo. Ammonium hydroxide was added to a pH of 8-9. The mixture was extracted with dichloromethane at a temperature of 30-35 ℃. The organic phase was separated and cooled to 25 ℃. Concentrated hydrochloric acid was added and the product was then precipitated. The solid was filtered and washed with dichloromethane to give 1.35Kg of nalmefene hydrochloride with a chemical purity of 98.9% which was converted to the dihydrate using the method described in example 3.

Example 5

Conversion of nalmefene hydrochloride to nalmefene hydrochloride dihydrate by reslurry

50g nalmefene hydrochloride (mixture of monohydrate, acetone solvate and dihydrate) was suspended in 50ml water at room temperature. Vacuum was applied for 1 hour to remove acetone. The suspension was stirred for a further 2 hours at room temperature. The solid was filtered and dried under vacuum at 30 ℃ to give 39.9g of pure nalmefene hydrochloride dihydrate (water content 8.76% w/w as determined by Karl Fisher titration).

Example 6

Conversion of nalmefene hydrochloride to nalmefene hydrochloride dihydrate by reslurry

3.6g nalmefene hydrochloride monohydrate were suspended in 5ml water at room temperature. The suspension was stirred at room temperature. After 1.5 hours, the dihydrate conversion was complete.

Claims (1)

1. A compound represented by the formula:

。

2. the compound of claim 1, wherein the compound is in a crystalline form, wherein the crystalline form of the compound is characterized by the use of Cu K_α1The 2 theta values of the X-ray powder diffraction pattern of the radiation have peaks at 8.99, 10.63, 15.24, 16.55 and 17.20, as shown in figure 3.

3. The compound of claim 1 or 2, which is non-hygroscopic such that less than 1% w/w of water is absorbed upon exposure to 95% RH at 25 ℃.

4. The compound of claim 3, wherein less than 0.5% w/w of moisture is absorbed by the compound upon exposure to 95% RH at 25 ℃.

5. The compound of claim 3, wherein less than 0.3% w/w of moisture is absorbed by the compound upon exposure to 95% RH at 25 ℃.

6. A compound according to claim 1 or 2 wherein the water content is 8% to 9% at a relative humidity of 10% to 95%.

7. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 6.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises at least 5% w/w nalmefene hydrochloride dihydrate.

9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises at least 10% w/w nalmefene hydrochloride dihydrate.

10. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises at least 30% w/w nalmefene hydrochloride dihydrate.

11. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises at least 50% w/w nalmefene hydrochloride dihydrate.

12. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises nalmefene hydrochloride dihydrate in an amount of at least 70% w/w.

13. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises nalmefene hydrochloride dihydrate in an amount of at least 90% w/w.

14. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises nalmefene hydrochloride dihydrate in an amount of at least 95% w/w.

15. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises at least 99% w/w nalmefene hydrochloride dihydrate.

16. The pharmaceutical composition of any one of claims 7-15, further comprising one or more pharmaceutically acceptable carriers.

17. The pharmaceutical composition according to any one of claims 7 to 15 for oral administration in a solid dosage form.

18. The pharmaceutical composition according to any one of claims 7 to 15 for oral administration, which is a tablet.

19. A pharmaceutical composition according to any one of claims 7 to 15 comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6.

20. A pharmaceutical composition according to any one of claims 7 to 15 comprising a compound according to any one of claims 1 to 6 in an amount of from 10mg to 100 mg.

21. A pharmaceutical composition according to any one of claims 7 to 15 comprising a compound according to any one of claims 1 to 6 in an amount of from 10mg to 60 mg.

22. A pharmaceutical composition according to any one of claims 7 to 15 comprising a compound according to any one of claims 1 to 6 in an amount of from 10mg to 40 mg.

23. A pharmaceutical composition according to any one of claims 7 to 15 comprising a compound according to any one of claims 1 to 6 in an amount of 20 mg.

24. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of alcohol dependence.

25. A pharmaceutical composition according to any one of claims 7 to 15 for use in the treatment of alcohol dependence.