WO2008156356A1

WO2008156356A1 - Preparation of a pharmaceutically active ingredient comprising a desolventising step

Info

Publication number: WO2008156356A1
Application number: PCT/NL2008/050383
Authority: WO
Inventors: Frank Emile Wubbolts; Maaike Jacobine Esther Van Roosmalen; Martijn Van Der Kraan; Judith Elisabeth Gertruda Josephina Wijnhoven
Original assignee: Feyecon Development & Implementation B.V.
Priority date: 2007-06-19
Filing date: 2008-06-16
Publication date: 2008-12-24

Abstract

The invention relates to a method for desolventising a contaminated solid particulate composition containing: - at least 10 wt.% of a solid pharmaceutically active ingredient or of a solid intermediate product of the manufacture of a pharmaceutically active ingredient; - not more than 70 wt.% of contaminating solvent; and - optionally, up to 89 wt.% of inert carrier; said method comprising the steps of: a) contacting the contaminated solid particulate composition with a liquefied gas; b) allowing the contaminating solvent to become entrained in the liquefied gas; c) separating liquefied gas containing entrained contaminating solvent from the residual solid particulate composition; and d) removing liquefied gas from the residual solid particulate composition through evaporation; wherein all of the aforementioned steps are performed at a temperature below 100 ºC and below the critical temperature of the liquefied gas, and wherein steps a) to c) are performed at a pressure of at least 5 bar. Although the present method employs mild processing conditions, it enables essentially complete solvent removal.

Description

PREPARATION OF A PHARMACEUTICALLY ACTIVE INGREDIENT COMPRISING A DESOL VENTISING STEP

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method of preparing a pharmaceutically active ingredient, said method comprising the step of desolventising a particulate composition that contains a solid pharmaceutically active ingredient or a solid intermediate product of the manufacture of a pharmaceutically active ingredient and a contaminating solvent. More particularly, the present invention provides a method that enables virtually complete removal of contaminating solvents from the solid pharmaceutically active ingredients or from the solid intermediate product using mild processing conditions.

BACKGROUND OF THE INVENTION

Organic solvents are widely used in the manufacture of pharmaceutically active ingredients, e.g. as reaction media, crystallisation fluids, etc. Whilst the use of these solvents in the manufacturing process is clearly beneficial, it is important that these organic solvents are almost completely removed from the final product.

Residual organic solvents found in bulk pharmaceutical products or pharmaceutical intermediates are e.g. removed by drying the bulk in an oven or by heating the bulk dry on the filter. The temperature selected must be one at which the bulk drug is deemed stable. Unfortunately, some solvents, like aliphatic alcohols, can be difficult to remove to or below a pharmaceutically acceptable level even after drying under high vacuum at elevated temperatures for extended periods of time, for example several days. In addition, these prolonged drying conditions can cause instabilities in bulk drug substances. The increased pH due to loss of acids such as hydrochloric acid and hydrobromic acid from acid addition salts, as well as colour generation and crystal instability are undesirable side effects of prolonged drying. Besides organic solvents also water is sometimes used as a solvent in the manufacture of pharmaceutically active ingredients. As traces of water can adversely affect the stability of pharmaceutically active ingredients, complete water removal is often desirable, but not easily achieved. EP-A 0 412 053 describes a process for extracting residual solvent from a formed compressed article, such as a tablet, which consists of exposing that solid article to an inert phase of a fluid under supercritical or a gas under near-critical conditions, transferring a portion of the residual solvent from the solid article to the inert phase of the fluid or gas and removing the inert phase enriched with solvent from the solid article depleted of solvent. Example 3 describes the extraction of methylene chloride and methanol from coated tablets by exposing the tablets to carbon dioxide at 49 bar at 21 ⁰C for 8 hours.

Although a lot of effort is being invested to minimise the solvent content of pharmaceutical preparations, most of the pharmaceutically active ingredients that are employed in these preparations are still containing detectable amounts of organic solvents. Hence, even though the quantities of organic solvent contained in commercially available preparations are generally considered harmless, it would be advantageous if a method could be developed that enables essentially complete solvent removal from pharmaceutically active ingredients or from intermediate product of the manufacture of such pharmaceutically active ingredients. In order to be widely applicable, such a method should preferably employ relatively mild processing conditions, especially low process temperatures.

SUMMARY OF THE INVENTION

The inventors have developed a method that meets the aforementioned requirements. The inventors have found that particulate compositions containing a solid pharmaceutically active ingredient and a contaminating solvent or a solid intermediate of the manufacture of a pharmaceutically active ingredient and a contaminating solvent can be desolventised in a very effective manner by: a) contacting the contaminated solid particulate composition with a liquefied gas; b) allowing the contaminating solvent to become entrained in the liquefied gas; c) separating liquefied gas containing entrained contaminating solvent from the residual solid particulate composition; and d) removing liquefied gas from the residual solid particulate composition through evaporation; wherein all of the aforementioned steps are performed at a temperature below 100 ⁰C and below the critical temperature of the liquefied gas, and wherein steps a) to c) are performed at a pressure of at least 5 bar.

The present method offers the advantage that essentially all solvent contained in the particulate composition can be rinsed off with the help of the liquefied gas. Once the solvent has been removed, the liquefied gas can be eliminated essentially completely from the decontaminated particulate composition by flashing off the liquefied gas by reducing pressure.

Since the liquefied gas containing entrained contaminating solvent can easily be separated into gas and contaminating solvent, the present process offers the additional advantage that both the gas and the solvent can be recirculated, thus minimising the environmental impact of these processing agents.

Another advantage of the present method resides in the fact that contaminating solvent can be removed from the particulate composition within a short period of time. Furthermore, the present method offers the advantage that the energy requirement is relatively low, especially in comparison to processes that employ drying at elevated temperatures.

Finally, the present method offers the important advantage that it can be operated at low temperatures. Thus, in the present method, the risk of heat-induced degradation of the pharmaceutically active ingredient or the intermediate product is minimal. DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to a method of preparing a pharmaceutically active ingredient, said method comprising the step of desolventising a contaminated solid particulate composition containing:

- at least 10 wt.% of a solid pharmaceutically active ingredient or of a solid intermediate of the manufacture of a pharmaceutically active ingredient;

- not more than 70 wt.% of contaminating solvent; and

- optionally, up to 89 wt.% of inert carrier; said method comprising the steps of: a) contacting the contaminated solid particulate composition with a liquefied gas; b) allowing the contaminating solvent to become entrained in the liquefied gas; c) separating liquefied gas containing entrained contaminating solvent from the residual solid particulate composition; and d) removing liquefied gas from the residual solid particulate composition through evaporation; wherein all of the aforementioned steps are performed at a temperature below 100 ⁰C and below the critical temperature of the liquefied gas, and wherein steps a) to c) are performed at a pressure of at least 5 bar. The term "pharmaceutically active ingredient" as used herein refers to an ingredient that exhibits pharmacologic activity as such or that will exhibit such activity after having been metabolised or otherwise processed in vivo following administration. According to a particularly preferred embodiment, the pharmaceutically active ingredient employed in the present process is a pharmaceutically active substance. The term "liquefied gas" as used herein refers to a medium that is gaseous under ambient conditions (20 ⁰C, 1.01295 bar) and that has been rendered liquid by increasing pressure to at least 5 bar at a temperature below 100 ⁰C. The term "liquefied gas" does not encompass a gas that is in a supercritical state. According to a preferred embodiment, the liquefied gas employed in accordance with the present invention has a pressure that does not exceed 70%, more preferably does not exceed 60% and most preferably does not exceed 50% of its critical pressure and/or a temperature that lies below its critical temperature. It should be understood that in step c) of the present process the liquefied gas containing entrained contaminating solvent is separated from the residual solid particulate composition whilst still being in a liquid state.

The present method may advantageously be employed to desolventise a wide range of pharmaceutically active ingredients. Examples of pharmaceutically active ingredients that may suitably be desolventised by means of the present method include steroids, non-steroid anti- inflammatory drug substances, heterocycles, alkaloids, peptides and proteins.

The present method is particularly suitable for desolventising pharmaceutically active ingredients or intermediate products that are in an amorphous state during steps a) to c). In case the pharmaceutically active ingredient or the intermediate product is in an amorphous state the contaminating solvent can usually be removed essentially completely without much difficulty. If the pharmaceutically active ingredient or the intermediate product is in a crystalline state, it is difficult to remove solvent entrapped within the crystalline matrix.

The benefits of the present invention are particularly pronounced in case the contaminating solvent has a normal boiling point of at least 80 ⁰C. The present method enables removal of such high boiling solvents in a single step and without utilising elevated temperatures to increase the vapour pressure of these solvents. Examples of solvents that can suitably be removed by means of the present method include NMP, decaline, DMF, DMSO, 1,4 dioxane, butanol, water, ionic liquids, ethylene glycol, xylene, chlorobenzene, dimethylacetamide, higher alkanes (e.g. C5-C12 alkanes), glycol dimethyl ether (diglym), polyethylene glycol and combinations thereof. The liquefied gas employed in the present process may or may not be combined with a co-solvent, i.e. a solvent that is liquid under ambient conditions. Typically, a co- solvent may be employed in an amount of 0-40%, preferably 0-20% by weight of the liquefied gas. Preferably, in case a co-solvent is employed, said co-solvent has a normal boiling point of less than 80 ⁰C, more preferably of less than 50 ⁰C and most preferably of less than 40 ⁰C. Most preferably, the present method does not employ co-solvent. In the present method, removal of the contaminating solvent may occur under conditions at which the contaminating solvent is in a gaseous, liquid or solid form. Preferably, the contaminating solvent is in a liquid or solid state during steps a) to c). Most preferably, the contaminating solvent is in the liquid state during steps a) to c).

The liquefied gas employed in the present process is advantageously selected from the group consisting of carbon dioxide, nitrogen oxide, ammonia, SF₆, hydro fiuorocarbons, Ci_-4 alkanes, dimethyl ether and mixtures thereof. Preferably, the liquefied gas contains at least 50 wt.%, more preferably at least 80 wt.% of carbon dioxide. Most preferably, the liquefied gas contains at least 95 wt.% of carbon dioxide.

The solid particulate composition that represents the starting material of the present method preferably contains at least 50 wt.%, preferably at least 80 wt.% of the pharmaceutically active ingredient or of the intermediate product. The remainder of the solid particulate composition comprises the contaminating solvent, and optionally inert carrier (e.g. excipient). Advantageously, the combination of the pharmaceutically active ingredient, the contaminating solvent and the optional inert carrier or the combination of the intermediate product, the contaminating solvent and the optional inert carrier together represent at least 95 wt.% of the contaminated solid particulate composition. According to another preferred embodiment, the combination of the pharmaceutically active ingredient and the contaminating solvent or the combination of the intermediate product and the contaminating solvent together represent at least 95 wt.% of the contaminated solid particulate composition. According to a further preferred embodiment the contaminated solid particulate composition has a mass weighed average particle size of at least 100 nm and not more than 5 mm. Even more preferably, the contaminated solid particulate composition has a mass weighted average particle size of at least 1 μm, more particularly of at least 50 μm. Most preferably, the contaminated solid particulate composition has a mass weighted average particle size in the range of 80-2000 μmln the present process the contacting of the contaminated solid particulate composition with the liquefied gas may occur in any way that allows the transfer of contaminating solvent from the particulate composition into the liquefied gas. According to a particularly preferred embodiment, the contacting of the contaminated solid particulate composition with the liquefied gas comprises rinsing the particulate composition with the liquefied gas.

In order to ensure that all of the particles contained in the contaminated solid particulate composition are brought into contact with the liquefied gas for a sufficiently long period of time to remove the contaminating solvent, it is preferred to ensure that during steps a) and b) the contaminated solid particulate composition is suspended in the liquefied gas. According to an even more preferred embodiment, during steps a) and b) the contaminated solid particulate composition is kept suspended in the liquefied gas by means of stirring, recirculation, gas injection, boiling, shaking, other means of mechanical action or a combination thereof. Thus, maximum transfer of the contaminating solvent into the liquefied gas may be achieved.

Effective removal of the contaminating solvent can be achieved in the present method even if the effective contact time between the contaminated solid particulate composition and the liquefied gas is not more than 30 minutes. Preferably, the contact time between the contaminated solid particulate composition and the liquefied gas is less than 15 minutes, more preferably less than 10 minutes and most preferably less than 5 minutes.

The present method offers the advantage that effective solvent removal can be achieved relatively quickly without using the very high pressures employed in extraction with supercritical or near critical fluids. Thus, the conditions employed in the present process typically meet the following requirement (P=pressure in bars and t = contact time in minutes): P x t < 3,000. More preferably the process conditions meet the requirement: P x t < 2,000; most preferably they meet the requirement: P x t < 1,000 During the contacting of the contaminated particulate composition with the liquefied gas, a fraction of the pharmaceutically active ingredient or intermediate product may be removed together with the liquefied gas. The removed fraction can easily be separated from the liquefied gas by depressurisation and may subsequently be recycled to step a. of the present method. According to a preferred embodiment, less than 10%, more preferably less than 5% and most preferably less than 3% of the pharmaceutically active ingredient or of the intermediate product is dissolved into the liquefied gas during the contacting.

Following separation of the liquefied gas from the residual particulate composition, the remainder of the liquefied gas is removed from the residual solid particulate composition by evaporation. According to a particularly preferred embodiment, evaporation of the liquefied gas in step d) is induced by reducing the pressure by not more than 10 bar. According to an even more preferred embodiment, the evaporated gas is separated from the residual particulate composition and subsequently liquefied by pressurisation, following which the liquefied gas may be reused in the present method.

In accordance with a particularly advantageous embodiment of the present invention, following separation in step c), contaminating solvent is removed from the liquefied gas containing entrained contaminating solvent and the cleaned-up liquefied gas is recirculated to step a). Preferably, the contaminating solvent is removed from the liquefied gas by depressurisation and the evaporated gas is liquefied again by pressurisation after removal of the contaminating solvent. The amplitude of the pressure fluctuations during the aforementioned depressurisation/pressurisation cycles are advantageously controlled to remain within the range 0.1-20 bar, preferably within the range of 0.1 - 10 bar.

In the present method the amount (mass) of liquefied gas that is contacted with the contaminated solid particulate composition typically exceeds the amount of the contaminated solid particulate composition by at least a factor 2. Here the amount of liquefied gas that is contacted with the particulate composition includes any recirculated liquefied gas.

The concentration of contaminating solvent in the solid particulate composition is typically reduced by at least a factor 5. In the event the contaminated solid particulate composition contains appreciable amounts of contaminating solvent, the concentration of contaminating solvent is easily reduced by at least a factor 10 or even by at least a factor 20.

According to a preferred embodiment, the contaminated solid particulate composition contains at least 3% of contaminating solvent by weight of the particulate composition. Even more preferably, the contaminated solid particulate composition contains at least 5% of contaminating solvent by weight of the particulate composition.

Typically, the amount of contaminating solvent contained in the contaminated solid particulate composition does not exceed 50 wt.%, more preferably it does not exceed

40 wt.%. Most preferably, the amount of contaminating solvent in said particulate composition does not exceed 30 wt.%.

As explained herein before, the present method offers the advantage that it enables essentially complete removal of the contaminating solvent. Accordingly, in a preferred embodiment, the desolventised solid particulate composition contains less than 0.5%, preferably less than 0.3% and most preferably less than 0.1% of contaminating solvent by weight of the pharmaceutically active ingredient or by weight of the intermediate product. The benefits of the present method may be realised using relatively mild processing conditions, especially relatively low temperatures. In a particularly preferred embodiment steps a) to d) of the present method are performed at a temperature within the range of 10-50 ⁰C. Preferably, the pressure employed during steps a) to c) is in the range of 5-100 bar, more preferably in the range of 5-40 bar. The invention is further illustrated by means of the following examples.

EXAMPLES

The experiments described in the examples were carried using the equipment and procedure described below.

Equipment

The equipment used in this experiment consisted of a 50 ml pressure chamber with a 25 mm diameter sintered metal filter of 25 μm pore size mounted in the bottom. Carbon dioxide was taken from a gas cylinder equipped with a dip-tube. The carbon dioxide was passed through a heat exchanger to cool and liquefy the gas. In this experiment the exchanger was cooled by means of spent carbon dioxide from the pressure chamber, after expansion over the discharge valve.

Procedure

A mixture of a pharmaceutically active ingredient and a contaminating solvent was placed in the pressure chamber on the filter plate and the pressure chamber was closed. With the discharge valve fully opened, the inlet valve of the pressure chamber was gently opened a little. Next the discharge valve was fully closed thus allowing the pressure in the pressure chamber to increase to the pressure in the source. Next, the inlet valve was fully opened and the discharge valve was opened slightly, thereby allowing the liquid carbon dioxide to flow gently through the pressure chamber. The carbon dioxide that expanded over valve passed through the shell side of the heat exchanger where it cooled and liquefied the carbon dioxide that entered from the source. The depressurized carbon dioxide left the heat exchanger and passed through a cyclonic separator where the gaseous carbon dioxide left through the top and liquid and contaminants were collected in the bottom.

Example 1

The analgesic and anti-pyretic drug 4-acetamido phenol (paracetamol) was mixed with the same amount of acetone as a contaminant. Approximately 20 ml of this slurry was poured in the pressure chamber onto the filter plate. The pressure chamber was closed and the contents of the pressure chamber were rinsed with 1 kg of carbon dioxide during 5 minutes. The paracetamol was recovered from the filter plate as a dry powder. Analysis of the rinsed paracetamol with gas chromatography showed that the level of contaminant was below 0.1 wt%.

Example 2

The analgesic and anti-pyretic drug 4-acetamido phenol (paracetamol) was mixed with the same amount of n-methyl-2-pyrrolidone (NMP). Approximately 20 ml of this slurry was poured in the pressure chamber onto the filter plate. The pressure chamber was closed and the contents of the pressure chamber were rinsed with 1 kg of carbon dioxide during 5 minutes. The paracetamol was recovered from the filter plate as a dry powder. Analysis of the rinsed paracetamol with gas chromatography showed that the level of contaminant was below 0.1 wt%.

Example 3

The analgesic and anti-pyretic drug 4-acetamido phenol (paracetamol) was mixed with the same amount of water as a contaminant. Approximately 20 ml of this slurry was poured in the pressure chamber onto the filter plate. The pressure chamber was closed and the contents of the pressure chamber were rinsed with 1 kg of carbon dioxide during 5 minutes. The paracetamol was recovered from the filter plate as a dry powder. Analysis of the rinsed paracetamol with gas chromatography showed that the level of contaminant was below 0.1 wt%. Example 4

The anti-micotic drug griseofulvin was mixed with the same amount of acetone as a contaminant. Approximately 20 ml of this slurry was poured in the pressure chamber onto the filter plate. The pressure chamber was closed and the contents of the pressure chamber were rinsed with 1 kg of carbon dioxide during 5 minutes. The griseofulvin was recovered from the filter plate as a dry powder. Analysis of the rinsed griseofulvin with gas chromatography showed that the level of contaminant was below 0.1 wt%.

Claims

1. A method of preparing a pharmarceutically active ingredient, said method comprising the step of desolventising a contaminated solid particulate composition containing:

- at least 10 wt.% of a solid pharmaceutically active ingredient or of a solid intermediate product of the manufacture of a pharmaceutically active ingredient;

- not more than 70 wt.% of contaminating solvent; and

- optionally, up to 89 wt.% of inert carrier; said method comprising the steps of: a) contacting the contaminated solid particulate composition with a liquefied gas; b) allowing the contaminating solvent to become entrained in the liquefied gas; c) separating liquefied gas containing entrained contaminating solvent from the residual solid particulate composition; and d) removing liquefied gas from the residual solid particulate composition through evaporation; wherein all of the aforementioned steps are performed at a temperature below 100 ⁰C and below the critical temperature of the liquefied gas, and wherein steps a) to c) are performed at a pressure of at least 5 bar.

2. Method according to claim 1 , wherein the contaminating solvent has a normal boiling point of at least 80 ⁰C.

3. Method according to any one of the preceding claims, wherein the liquefied gas is selected from the group consisting of carbon dioxide, nitrogen oxide, ammonia

SF₆, hydrofiuorocarbons, Ci_-4 alkanes, dimethyl ether and mixtures thereof.

4. Method according to any one of the preceding claims, wherein the contaminated solid particulate composition has a mass weighed average particle size of at least 100 nm and not more than 5 mm.

5. Method according to any one of the preceding claims, wherein the contacting of the contaminated solid particulate composition with the liquefied gas comprises rinsing the particulate composition with the liquefied gas.

6. Method according to any one of the preceding claims, wherein during steps a) and b) the contaminated solid particulate composition is suspended in the liquefied gas.

7. Method according to any one of the preceding claims, wherein the contact time between the contaminated solid particulate composition and the liquefied gas is less than 5 minutes.

8. Method according to any one of the preceding claims, wherein less than 10% of the pharmaceutically active ingredient or the intermediate is dissolved into the liquefied gas during the contacting.

9. Method according to any one of the preceding claims, wherein the contaminated solid particulate composition contains at least 3% of contaminating solvent by weight of the particulate composition.

10. Method according to any one of the preceding claims, wherein the desolventised solid particulate composition contains less than 0.5% of contaminating solvent by weight of the pharmaceutically active ingredient or the intermediate.

11. Method according to any one of the preceding claims wherein steps a) to d) are performed at a temperature within the range of 10-50 ⁰C and steps a) to c) are performed at a pressure of 5-100 bar.