WO2000040601A1

WO2000040601A1 - Process for preparing a stable non-hygroscopic crystalline n-[n-[n- piperdin- 4-yl)butanoyl)- n.ethylglycyl]- (l)-aspartyl] -ss-cyclohexylalanine amide

Info

Publication number: WO2000040601A1
Application number: PCT/US1999/029969
Authority: WO
Inventors: Jean Rene Authelin; Alain Thouzery; Fabrice Mangin; Pierre Bailly
Original assignee: Aventis Pharmaceuticals Products Inc.
Priority date: 1998-12-30
Filing date: 1999-12-15
Publication date: 2000-07-13
Also published as: EP1155033A1; AU2844800A

Abstract

This invention is directed to a method converting the hygroscopic polymorph of N-[N-[N- (4-piperdin- 4-yl)butanoyl) -N-ethylglycyl] -(L)-aspartyl] -(L)-β-cyclohexylalanine amide to its stable, non-hygroscopic crystal form.

Description

PROCESS FOR PREPARING A STABLE NON-HYGROSCOPIC CRYSTALLINE N-[N-[N- PIPERDIN- 4-YL)BUTANOYL)- N.ETHYLGLYCYL]- (L)-ASPARTYL] -SS-CYCLOHEXYLALANINE AMIDE

FIELD OF THE INVENTION

This invention is directed to a process for preparing a non-hygroscopic stable crystalline polymoφh of -[ -[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexyl- alanine amide. More particularly, this invention is directed to a method of converting the hygroscopic polymorph ofN-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexyl- alanine amide to its stable, non-hygroscopic crystal form.

BACKGROUND OF INVENTION

N- N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexyl-alanine amide possesses antithrombotic activity, including the inhibition of platelet aggregation and thrombus formation in mammals, and is useful in the prevention and treatment of thrombosis associated with disease states such as myocardial infarction, stroke, peripheral arterial disease and disseminated intravascular coagulation.

The preparation ofN-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide is described in PCT Patent Application Publication Nos. WO 95/10295 and WO 98/07696 and U.S. Patent Application Ser. No. 60/061,719. The material prepared as described therein is hygroscopic and is physically unstable as it absorbs moisture. A stable, non-hygroscopic crystal form of

N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide and general conditions for converting the hygroscopic polymoφh to the non-hygroscopic crystal form under static and dynamic conditions are described in WO 98/07696. The static procedure involves exposing the hygroscopic polymorph to temperatures of from about 40 °C to about 80 °C and relative humidity (RH) of about 65% to about 80% in a non-moving vessel.

The dynamic procedure involves agitating the hygroscopic polymorph, for example by tumbling in a rapidly rotating rotary evaporation flask or by propeller agitation in a cylindrical vessel, under the humidity and temperature levels described for the static model. The temperature and humidity levels are achieved by injecting humidified air into a sealed chamber at the desired temperature or by introduction of water vapor under vacuum into a sealed chamber or into a conversion apparatus such as the heated flask of a rotary evaporator.

Conversion of hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]- (L)-β-cyclohexylalanine amide to its non-hygroscopic crystal form under the dynamic conditions described above on an industrial scale results in the formation of product which flows poorly and is electrostatic, leading to handling difficulties and material losses resulting from product clinging to the reaction vessel. The conditions of rapid rotation or vigorous agitation described above also result in undesirable granulation of the product. The product also may contain a large population of large particles or aggregates of particles which require additional manipulation, such as milling or sieving, with concomitant material losses, to prepare product suitable for formulation.

Consequently, there is an unmet need for an efficient, economical method of converting hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexyl-alanine amide to its non-hygroscopic crystal form on an industrial scale.

SUMMARY OF THE INVENTION

We discovered that heating hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)- aspartyl]-(L)-β-cyclohexylalanine amide in a reaction vessel rotating at a speed of from about 0.5 revolutions/hour to about 30 revolutions/hour prior to introduction of humidity, and continuing rotation of the reaction vessel during the form conversion tends to densify the product, narrow the particle size distribution, reduce the concentration of coarse particles and increase the flowability of the product.

Accordingly, this invention is directed to a method of preparing non-hygroscopic, crystalline N- [N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide comprising

(i) heating N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide under atmospheric pressure in a rotating reaction vessel, wherein the reaction vessel is rotating at a speed of from about 0.5 revolutions/hour to about 30 revolutions/hour; and (ii) converting the N-psf-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide to non-hygroscopic, crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide under conditions of temperature and relative humidity.

As discussed above, the non hygroscopic, crystal form of N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide prepared as described herein has advantageous properties which render is especially suitable for subsequent formulation. Accordingly, in another aspect, this invention is directed to the non hygroscopic, crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)- N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide prepared according to the method described herein.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide means any crystalline polymoφh of N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethyIglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide, or mixtures thereof. Preferred N-[N-[N-(4- piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-(3-cyclohexylalanine amide for use in the process described herein is the hygroscopic crystalline polymorph prepared as described in PCT Patent Application Publication Nos. WO 95/10295 and WO 98/07696 and U.S. Patent Application Ser. No. 60/061 ,719, incoφorated herein by reference. The relative humidity required for converting N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide to its non-hygroscopic crystal form is achieved by injecting humidified air into a chamber such as a humidity oven as described in WO 98/07696, or into a sealed reaction vessel such as a fluidized bed dryer, or preferably, by injecting water vapor into a reaction vessel under vacuum. Accordingly, in a preferred aspect, this invention is directed to a method of preparing non- hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspaιτyl]-(L)-β-cyclohexylalanine amide comprising:

(i) heating N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide under atmospheric pressure in a rotating reaction vessel, wherein the reaction vessel is rotating at a speed of from about 0.5 revolutions/hour to about 30 revolutions/hour; (ii) placing the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide contained in the reaction vessel under vacuum; (ii) injecting water vapor into the reaction vessel; and (iv) converting the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide to non-hygroscopic, crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide under the conditions of temperature and relative humidity.

Preferred conditions of temperature and relative humidity for the crystal form conversion are a relative humidity of about 65% to about 80% and a temperature of about 55 °C to about 100 °C. More preferred conditions of temperature and relative humidity are a relative humidity of about 75% and a temperature of about 60 °C to about 80 °C.

Relative humidity (RH) is defined as:

RH (%) = P_H2O/P\_I2O * 100

where P_H20 and P^S _H20 are the partial pressure of water and the pressure of saturated water vapor, respectively, at the temperature in question.

If nothing but water vapor is introduced into the chamber, the partial pressure of the water vapor equals the total pressure; therefore, the relative humidity can be readily controlled by regulating the total pressure in the chamber. When one operates in a vacuum, the necessary condition is that the chamber, except for the introduction of the water vapor, be completely air and water tight so that the entry of ambient air does not dilute the water vapor. In addition, the chamber must remain at constant temperature, otherwise unless the water pressure is homogeneous, the pressure of saturated vapor and also the relative humidity will change locally.

The saturating pressure and the partial pressures corresponding to relative humidities ranging from 60 to 100%> for temperatures between 55 and 65 °C are given in Table 1. For example, if the chamber is equilibrated at 159 mbar, which corresponds to 80%) RH at 60 °C, a cold point at 55 °C will cause the appearance of condensation. A cold point at 57 °C will be exposed to a RH of about 90%, so that there is a risk of product in this area deliquescing.

Table 1 Relative Humidities

The form conversion is accomplished in any reaction vessel capable of maintaining uniform temperature throughout with no cold points and no pressure gradient. Preferred reaction vessels for the form conversion are bicone dryers, such as the bicone dryers available from Italvacuum Company. Bicones from the Italvacuum Company have an internal system of knives called "crushers" designed for coarse grinding of the powder therein (analogous equipment exists in other drying systems such as Guedu dryers, Inox Maurer stirring ovens, etc.). The parts of the bicone exposed to water vapor are double-walled and insulated.

The conversion is typically accomplished over about 4 to about 36 hours, depending on the quantity ofN-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide to be converted, temperature and relative humidity. In general, conversion is slower at lower temperatures or lower relative humidity. As discussed herein, the product should be removed from humidification as soon as conversion is complete. The progress of the conversion is monitored by removing samples from the reaction vessel for analysis, for example by x-ray crystallography. We have observed a correlation between the physical properties (density, particle size, flowability) of the non-hygroscopic crystalline form of the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide prepared according to the process of this invention and the physical properties of the material prior to conversion. Thus, conversion of N-[N-[N- (4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide starting material containing large particles or aggregates of particles results in formation of the non hygroscopic crystalline product containing large particles or aggregates of particles.

Breaking up the large particles or aggregates of particles prior to conversion results in product having a similar particle size distribution. Accordingly, the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide starting material is optionally milled prior to undergoing conversion to the non-hygroscopic crystal form.

Milling or grinding refers to physically breaking up the large particles or aggregates of particles contained in the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide starting material using methods and apparatus well known in the art for particle size reduction of powders. The grinding is preferably performed on a conical-screen grinding mill such as a Quadro Comill grinding mill or C.M.A. grinding mill. In a conical-screen grinding mill, the material is forced to pass through the screen by a moving body in the shape of an anchor. Preferred screens have round holes with a diameter of about 610 μm to about 630 μm.

Grinding is also preferably performed on an oscillating mill such as a Frewitt mill with a grid of 1 mm. Rotation under humidification also tends to increase the population of large particles or aggregates of particles. These large particles or aggregates of particles can be broken up using the internal crushers of the bicone. However, the population of these large particles or aggregates is more advantageously controlled by reducing their formation by minimizing the period of rotation under humidification. rather than through use of the internal crushers. Accordingly, in a preferred aspect of this process, the conversion is accomplished with the internal crushers turned off.

The non-hygroscopic crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)- aspartyl]-(L)-β-cyclohexylalanine amide prepared as described above is optionally sieved to remove coarse particles. "Sieving" or "screening" refers to the operation of sorting particles by size. "Passes" means particles which pass through the screen and "waste" means the coarse particles which are left behind.

The coarse particles are recycled by recrystallization as described in WO 95/10295, WO 98/07696 and U.S. Patent Application Ser. No. 60/061.719 to form hygroscopic N-[N-[N-(4-piperdin-4- yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexyl-alanine amide, which is then converted to the non-hygroscopic crystal form as described above.

The foregoing may be better understood by reference to the following examples. One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects of the invention and obtain the ends and advantages mentioned, as well as those inherent therein. The compounds, compositions and methods described herein are present as representative of the preferred embodiments, or intended to be exemplary and not intended as limitations on the scope of the present invention.

Example 1

Crystalline hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide (41.54 kg) is introduced in the screw feeder and milled at a mass flow of 40 kg/hour in a conical-screen grinding mill (100 mm, 630 μm opening grid) equipped with a double screw feeder, type K-Tron, T35. The milled product is stored in Polyethylene bags.

Water vapor is generated by introducing purified water into a 50-liter stainless tank, the double walls of which are heated at 68 °C with a bank of heaters. Water vapor is transported toward the bicone through a double-walled pipe heated to 60 °C. The temperature regulation system of the pipe is the same as that of the vacuum arm (not heat-insulated in Italvacuum's standard 350-liter pilot plant). A manual control valve made it possible to control the flow rate of the water vapor. In the bicone, the vapor is guided toward the chamber through a pipe concentric with the vacuum pipe. The piping is designed to admit a vapor flow rate on the order of 5 kg/h, i.e. it permits the quantity to be added equivalent to that needed for the transformation (about 4%> of the weight, or 1.2 kg) in less than one hour.

The vacuum system contains first a cyclone topped with a bag filter followed by a safety gauntlet, then a condenser cooled to 5 °C with a cooling battery. The condenser is efficient enough to condense almost all the vapor. The vacuum is ensured by a pump with a liquid ring. The vacuum is regulated by aspirating air at the level of the vacuum pump. A pressure probe is placed in the aspiration arm of the vacuum. A RH probe, also located in the aspiration arm, makes it possible to confirm the data indicated by the pressure probe. During operation, the operator confirms that the pressure data and data from the RH probe agree by using a table of equivalents. The vacuum is broken by adding filtered nitrogen. To prevent a countercurrent of nitrogen from returning dust deposited in the arm of the dryer to the tank, nitrogen is introduced through the same pipe as the water vapor. Water vapor can be substituted for nitrogen by turning the valve.

The milled product is placed in a bicone dryer (Italvacuum, 350 L). The jacket of the bicone has been previously heated to 60 °C. The product is heated to 57 °C in the bicone (rotation 0.5 rpm) over 65 minutes. The bicone is then put carefully under vacuum (60 mbar) in 10 minutes. Vapor coming from the boiler is introduced in the bicone. The pressure is increased up to 150mbar within 35 minutes.

Rotation is maintained during 1.5 hours, after which the bicone is rotated during 5 minutes each hour.

The pressure is maintained at 150mbar (+/- lmbar) for 26 hours.

After this period, vapor introduction is stopped, the pressure is decreased to 70 mbar and the bicone is purged with nitrogen. A sample is taken and conversion to the non hygroscopic crystal form is confirmed by X-Ray (in process control). The pressure is then increased to atmospheric pressure, the bicone is emptied, and the product is sieved (200 millimeter diameter 10 mm openings). The fine fraction is packaged in polyethylene bags and drums.

Yield: 39.15 kg (94.5 %) (including samples taken for analysis). Large particles (> 10 mm in diameter): 0.54 kg (can be recycled by recrystallization in B form). Lost product: 1.73 kg (4.2%).

Example 2

Crystalline hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide (68.68 kg) is introduced in the screw feeder and milled at a mass flow of 51.6 kg/hour in a conical-screen grinding mill (200 mm, 630 μm opening grid) equipped with a double screw feeder, type K-Tron, T35. The milled product falls directly into the bicone. Water vapor is generated as described above by introducing purified water into a 150-liter stainless tank, the double walls of which are heated at 65 °C with a bank of heaters. The jacket of the pipe between the boiler and the bicone is heated at 60 °C.

The milled product is placed in a bicone dryer (Italvacuum, 600 L). The jacket of the bicone has been previously heated to 61 °C. The product is heated to 59 °C in the bicone (rotation 0.3 φm) over 165 minutes. The rotation speed is decreased to 0.17 φm and the bicone is put carefully under vacuum (44 mbar) in 20 minutes. Vapor coming from the boiler is introduced in the bicone and the pressure is increased up to 153 mbar within 25 minutes. Rotation is maintained for 40 minutes, then the bicone is rotated during 6 minutes each 2 hours. The pressure is maintained at 154mbar (+/- lmbar) for 27.5 hours.

After this period, vapor introduction is stopped, the pressure is decreased to 49 mbar and the bicone is purged with nitrogen. The pressure is increased up to atmospheric pressure. A sample is taken and conversion to the non hygroscopic crystal form is confirmed by X-Ray (in process control). The bicone is emptied in a moving container and sieved (700 millimeter diameter, 2 mm opening). The fine fraction is packaged in polyethylene bags and drums. Some product adhering to the bicone wall is recovered and packaged separately. Total recovered material 68.81 kg.

Yield: 60.18 kg (87.5%) (including several samples taken for analysis). Large particles (more than 2 mm in diameter): 4.52 kg. Material adhering to the bicone wall: 1.1 1 kg. Lost product: 3.00 kg (4.4%). Large particles and the recovered material adhering to the bicone wall is recycled by recrystallization as the hygroscopic polymoφh.

Example 3

Crystalline hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide (181 kg) is milled on a frewitt mill (1 mm grid) at a flow of 60 kg/h.

Water vapor is generated as described above by introducing purified water into a 150-liter stainless tank, the double walls of which are heated at 75 °C with a bank of heaters. The jacket of the pipe between the boiler and the bicone is heated at 75 °C.

The milled product is placed in a bicone dryer (Italvacuum. 600 L). The jacket of the bicone has been previously heated to about 72°C. The product is heated to about 72 °C in the bicone (rotation 0.34 rpm) over 3 hours. The bicone is then put carefully under vacuum (231 mbar). Water vapor coming from the boiler is introduced in the bicone and the bicone is rotated at 0.34 φm for 5 hours. The rotation is then stopped and heating under vacuum is continued for an additional 8 hours. The bicone is then emptied and the material is sieved on a 2 mm sieve. Yield: 172.5 kg (96%) (including samples for analysis and research puφose). Large particles (more than 2 mm in diameter): 2.1 kg. Lost product: 6.0 kg.

Analytical Methods Screening:

Material is screened on a Chauvin vibrating screening unit equipped with a sieve and an AFNOR base 200 mm in diameter. Screens with a mesh opening of 200, 400, 630, 1000, 1600, and 2000 μm were used. 0.25%) Svloid was added to the mass to be screened, to eliminate electrostatic charges. The product was vibrated for ten minutes.

Density and Carr Index:

Carr index and density are measured following European Pharmacopoeia. A 250 ml test tube is filled with powder up to ca. 220 ml. The mass of the sample as well as the exact volume that it occupies (v 0) are determined. The test tube is placed on an Engelsmann STAV 2003 volume meter, and the volume is determined after 0, 10, 50, 100, 250, and 500 blows.

The Carr Index is equal to:

• either f_Can. = dO - dSOO Carr Index at 0 blows d500

• or I_Carr = dlO - d500 Carr Index at 10 blows d500

Physical properties

Claims

We Claim:

1. A method of preparing non-hygroscopic, crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide comprising

(i) heating N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide under atmospheric pressure in a rotating reaction vessel, wherein the reaction is rotating at a speed of from about 0.5 revolutions/hour to about 30 revolutions/hour; and (ii) converting the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide to non-hygroscopic, crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide under conditions of temperature and relative humidity.

2. The method of claim 1 wherein the converting is at a relative humidity of about 65% to about 80% and a temperature of about 55 °C to about 100 °C.

3. The method of claim 2 wherein the converting is at a relative humidity of about 75% and a temperature of about 60 °C to about 80 °C.

4. The method of claim 2 further comprising milling the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycylJ-(L)-aspartyl]-(L)-β-cyclohexylalanine amide prior to heating.

5. The method of claim 2 wherein the relative humidity is achieved by injecting water vapor into the reaction vessel under vacuum.

6. A method of preparing non-hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)- aspartyl]-(L)-β-cyclohexylalanine amide comprising

(i) heating N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide under atmospheric pressure in a rotating reaction vessel, wherein the reaction is rotating at a speed of from about 0.5 revolutions/hour to about 30 revolutions/hour; (ii) placing the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide contained in the reaction vessel under vacuum; (ii) injecting water vapor into the reaction vessel; and

(iv) converting the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β- cyclohexylalanine amide to non-hygroscopic N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)- aspartyl]-(L)-β-cyclohexylalanine amide under conditions of temperature and relative humidity.

7. The method of claim 6 wherein the converting is at a relative humidity of about 65% to about

80%) and a temperature of about 55 °C to about 100 °C.

8. The method of claim 7 wherein the converting is at a relative humidity of about 75% and a temperature of about 60 °C to about 80 °C.

9. The method of claim 8 further comprising milling the N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide prior to heating.

10. Non hygroscopic crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]- (L)-β-cyclohexylalanine amide prepared according to the method of claim 1.

1 1. Non hygroscopic crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]- (L)-ιβ-cyclohexylalanine amide prepared according to the method of claim 6.