CRYSTALLINE (R)- 2-AMINO-3-PHENYLPROPYLCARBAMATE ACID

ADDITION SALTS

FIELD OF THE INVENTION

The present invention relates to crystalline salt forms of (R)-2-ami no-3 -phenyl propyl carbarn ate and a process for their preparation. The invention also relates to a pharmaceutical composition comprising one or more of the crystalline salt forms of (R)-2-ami no-3 -phenyl propyl carbarn ate, preferably in a predetermined and/or effective amount and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used for the treatment of various CNS disorders, in particular in the improvement of wakefulness and reduction of excessive sleepiness in patients with narcolepsy or obstructive sleep apnea.

BACKGROUND OF THE INVENTION

(R)-2-ami no-3 -phenyl propyl carbarn ate, a derivative of the amino acid phenylalanine, is a non amphetamine wake-promotor. The mechanism(s) by which (R)-2-amino-3- phenylpropylcarbamate exerts its wake-promoting effects in humans are presumed to be through its activity as a selective dopamine and norepinephrine reuptake inhibitor (DNRI). The compound was first approved in the U.S. to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The product (Sunosi™) contains (R)-2-ami no-3 -phenyl propyl carbarn ate as the hydrochloride salt, which is represented by the following chemical structure according to Formula (I)

WO 96/07637 A1 describes the synthesis of (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride (Example III) which is obtained as a white solid having a melting point in the range of 172-174 °C.

WO 2018/048871 A1 discloses two crystalline forms of (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride including an anhydrous and non-solvated form (Form A) and a solvate form, more precisely a hemihydrate form (Form B). WO 2018/133703 A1 discloses so called “Form CS1” and“Form CS2” of (R)-2-amino-3- phenylpropylcarbamate hydrochloride. However, when comparing Figure 1 and Figure 4 of WO 2018/133703 A1 with Figure 1 of WO 2018/048871 A1 it becomes apparent that Form CS1 corresponds to Form B and Form CS2 is the same as Form A of WO 2018/048871 Al .

Form A and Form B of (R)-2-ami no-3 -phenyl propyl carbamate hydrochloride both suffer from certain drawbacks. For example, according to the teaching of WO 2018/048871 Al Form A and Form B of the hydrochloride salt are unstable under certain environmental conditions and tend to interconvert to each other. While Form A (partially) converts to Form B at elevated relative humidity (WO 2018/048871 Al, paragraph [0075]), Form B is unstable under low relative humidity, at elevated temperature or when milled (WO 2018/048871 Al, paragraph [0075]) and (partially) converts back to Form A. It is these properties which render the production of a uniform pharmaceutical drug product containing Form A or Form B of (R)- 2- amino-3-phenylpropylcarbamate hydrochloride extremely challenging and demand precautious measures during manufacturing and storage.

Therefore, there remains a need for the provision of stable crystalline salt forms of (R)-2-amino- 3-phenylpropylcarbamate, which can be reliably formulated into a pharmaceutical drug product. There is also a need for the provision of a uniform pharmaceutical drug product containing a stable crystalline salt form of (R)-2-ami no-3 -phenyl propyl carbarn ate, which provides reliable safety and activity throughout shelf-life.

SUMMARY OF THE INVENTION

It was unexpectedly found by the inventors of the present invention that certain crystalline salt forms of (R)-2-amino-3-phenylpropyl carbamate possess improved physicochemical properties, in particular high stability against moisture and temperature stress. The salt forms of the present invention are anhydrous non-solvated forms and have the common advantage of being thermally stable, non-hygroscopic or only slightly hygroscopic and they preserve their crystal structure irrespective of the environmental relative humidity, for example, they are stable over the whole relative humidity range from 0 to 90%.

Abbreviations

PXRD powder X-ray diffractogram

DSC differential scanning calorimetry

RH relative humidity w-% weight percent

T _onset onset temperature

Am mass change

Definitions

In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:

As used herein the term“room temperature” refers to a temperature in the range of from 20 to 30 °C.

As used herein, the term“measured at a temperature in the range of from 20 to 30 °C” refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30 °C, i.e. at room temperature. Standard conditions can mean a temperature of about 22 °C. Typically, standard conditions can additionally mean a measurement under 20-80% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% relative humidity.

The term“reflection” with regards to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see“Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

The term“essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-Theta. Thus, a reflection that usually appears at 4.6° 2-Theta for example can appear between 4.4° and 4.8° 2-Theta, preferably between 4.5 and 4.7° 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

The crystalline (R)-2-ami no-3 -phenyl propyl carbamate acid addition salts of the present invention may be referred to herein as being characterized by a powder X-ray diffractogram "as shown in" a figure. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations, for example relating to the exact reflection and peak positions and their intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.

The term“anhydrous” as used herein refers to a compound where no water is cooperated in or accommodated by the crystal structure. An anhydrous compound may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

The term“non-solvated” as used herein refers to a compound where no organic solvent is cooperated in or accommodated by the crystal structure. A non-solvated compound may still contain residual organic solvent, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

The terms“dehydrating” or“dehydration” as used herein, describe the at least partial removal of water from the crystal structure of the host molecule.

The term“non-hygroscopic” as used herein refers to a compound showing a water uptake of less than 0.2 w-% in the sorption cycle when measured with GMS at a relative humidity in the range of from 0 to 90% RH and a temperature of (25.0 ± 0.1) °C, based on the weight of the compound.

The term“slightly-hygroscopic” as used herein refers to a compound showing a water uptake of less than 2.0 w-% and equal or greater than 0.2 w-% in the sorption cycle when measured with GMS at a relative humidity in the range of from 0 to 90% RH and a temperature of (25.0 ± 0.1) °C, based on the weight of the compound. The term“hygroscopic” as used herein refers to a compound showing a water uptake of less than 15.0 w-% and equal or greater than 2.0 w-% in the sorption cycle when measured with GMS at a relative humidity in the range of from 0 to 90% RH and a temperature of (25.0 ± 0.1) °C, based on the weight of the compound.

As used herein, the term“mother liquor” refers to the solution remaining after crystallization of a solid from said solution.

A“predetermined amount” as used herein with regard to the crystalline (R)-2-amino-3- phenylpropyl carbamate acid addition salts of the present invention refers to the initial amount of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salt used for the preparation of a pharmaceutical composition having a desired dosage strength of (R)-2-amino- 3-phenylpropylcarbamate.

The term“effective amount” as used herein with regard to the crystalline (R)-2-amino-3- phenylpropyl carbamate acid addition salts of the present invention encompasses an amount of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salt, which causes the desired therapeutic and/or prophylactic effect.

As used herein, the term“about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 2: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate maleate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up. Figure 3: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- malate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 4: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate L- alate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 5: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbamate phosphate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 6: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate phosphate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 7: illustrates a PXRD of crystalline (R)-2-amino-3-phenylpropyl carbamate L-tartrate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 8: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate L-tartrate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 9: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 10: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate formiate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 11: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 12: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate hippurate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 13: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbamate nitrate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 14: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate nitrate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 15: illustrates a PXRD of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y- axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 16: illustrates a representative DSC curve of crystalline (R)-2-amino-3- phenylpropylcarbamate tosylate according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to crystalline acid addition salts of (R)-2-amino-3- phenylpropyl carbamate with an acid selected from the group consisting of maleic acid, L-malic acid, phosphoric acid, L-tartaric acid, formic acid, hippuric acid, nitric acid, and p-toluene sulfonic acid. The skilled person will appreciate that in the crystalline acid addition salts of the present invention (R)-2-ami no-3 -phenyl propyl carbarn ate may be in protonated form (e.g. the secondary amino group is protonated) while the respective acid may be in a deprotonated form. Preferably, the crystalline acid addition salts of the present invention are characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbarn ate and acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. Even more preferably, the crystalline acid addition salts of the present invention are characterized in that they are anhydrous and non-solvated.

The crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention as defined in any one of the above described embodiments may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, differential scanning calorimetry and gravimetric moisture sorption. They may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the crystalline (R)-2-ami no-3 -phenyl propyl carbamate acid addition salts of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

Crystalline (R)-2-amino-3-phenylpropylcarbamate maleate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and maleic acid. In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate characterized by the chemical structure according to Formula (II)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate maleate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbamate and maleic acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. In one embodiment, the present invention relates to crystalline (R)-2- amino-3- phenylpropyl carbamate hydrogenmaleate.

The present invention also relates to crystalline (R)-2-amino-3-phenylpropyl carbamate maleate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(14.6 ± 0.2)°, (19.6 ± 0.2)° and (22.8 ± 0.2)°; or

(14.6 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)° and (22.8 ± 0.2)°; or

(14.6 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (22.8 ± 0.2)° and (23.5 ± 0.2)°; or

(8.6 ± 0.2)°, (14.6 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (22.8 ± 0.2)° and (23.5 ± 0.2)°; or (8.6 ± 0.2)°, (9.8 ± 0.2)°, (14.6 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (22.8 ± 0.2)° and (23.5 ± 0.2)°; or

(8.6 ± 0.2)°, (9.8 ± 0.2)°, (14.6 ± 0.2)°, (15.7 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (22.8 ± 0.2)° and (23.5 ± 0.2)°; or

(8.6 ± 0.2)°, (9.8 ± 0.2)°, (14.6 ± 0.2)°, (15.7 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (22.8 ± 0.2)°, (23.5 ± 0.2)° and (28.1 ± 0.2)°; or

(8.6 ± 0.2)°, (9.8 ± 0.2)°, (14.6 ± 0.2)°, (15.7 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (21.0 ± 0.2)°, (22.8 ± 0.2)°, (23.5 ± 0.2)° and (28.1 ± 0.2)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate maleate characterized by having a PXRD comprising reflections at 2- Theta angles of:

(14.6 ± 0.1)°, (19.6 ± 0.1)° and (22.8 ± 0.1)°; or

(14.6 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)° and (22.8 ± 0.1)°; or

(14.6 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (22.8 ± 0.1)° and (23.5 ± 0.1)°; or

(8.6 ± 0.1)°, (14.6 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (22.8 ± 0.1)° and (23.5 ± 0.1)°; or

(8.6 ± 0.1)°, (9.8 ± 0.1)°, (14.6 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (22.8 ± 0.1)° and (23.5 ±

0.1)°; or

(8.6 ± 0.1)°, (9.8 ± 0.1)°, (14.6 ± 0.1)°, (15.7 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (22.8 ± 0.1)° and (23.5 ± 0.1)°; or

(8.6 ± 0.1)°, (9.8 ± 0.1)°, (14.6 ± 0.1)°, (15.7 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (22.8 ± 0.1)°, (23.5 ± 0.1)° and (28.1 ± 0.1)°; or

(8.6 ± 0.1)°, (9.8 ± 0.1)°, (14.6 ± 0.1)°, (15.7 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (21.0 ± 0.1)°, (22.8 ± 0.1)°, (23.5 ± 0.1)° and (28.1 ± 0.1)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate characterized by having a PXRD comprising reflections at 2-Theta angles of (14.6 ± 0.2)°, (15.7 ± 0.2)°, (17.6 ± 0.2)°, (19.6 ± 0.2)°, (21.0 ± 0.2)°, (22.8 ± 0.2)°, (23.5 ± 0.2)°, (23.9 ± 0.2)°, (25.1 ± 0.2)° and (28.1 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate maleate characterized by having a PXRD comprising reflections at 2- Theta angles of (14.6 ± 0.1)°, (15.7 ± 0.1)°, (17.6 ± 0.1)°, (19.6 ± 0.1)°, (21.0 ± 0.1)°, (22.8 ± 0.1)°, (23.5 ± 0.1)°, (23.9 ± 0.1)°, (25.1 ± 0.1)° and (28.1 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

The present invention also relates to crystalline (R)-2-amino-3-phenylpropyl carbamate maleate characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (159 ± 5)°C, preferably of (159 ± 3)°C, even more preferably of (159 ± 2)°C and most preferably of (159 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-amino-3-phenylpropyl carbamate maleate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (161 ± 5)°C, preferably of (161 ± 3)°C, even more preferably of (161 ± 2)°C and most preferably of (161 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate of the present invention as defined in any one of the embodiments described above is non-solvated.

The present invention further relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 1.0 w-%, more preferably of less than 0.2 w-%, based on the weight of the crystalline (R)- 2- amino-3-phenylpropylcarbamate maleate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate of the present invention as defined in any one of the embodiments described above is non-hygroscopic. Crystalline (R)-2-amino-3-phenylpropylcarbamate L-malate

In one embodiment, the present invention relates to a crystalline salt comprising (R)- 2-amino- 3-phenylpropylcarbamate and L-malic acid.

In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- alate characterized by the chemical structure according to Formula (III)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate L- malate of the present invention is characterized by having a molar ratio of (R)-2-amino-3-phenylpropyl carbamate and L-malic acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. In one embodiment, the present invention relates to crystalline (R)-2- amino-3- phenylpropyl carbamate L-hydrogenmalate.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- malate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.5 ± 0.2)°, (14.9 ± 0.2)° and (18.0 ± 0.2)°; or

(7.5 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)° and (18.0 ± 0.2)°; or

(7.5 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)° and (22.7 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)° and (22.7 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)°, (19.7 ± 0.2)° and (22.7 ±

0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)°, (19.7 ± 0.2)°, (21.2 ± 0.2)° and (22.7 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)°, (19.7 ± 0.2)°, (21.2 ± 0.2)°, (22.7 ± 0.2)° and (24.3 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)°, (19.7 ± 0.2)°, (21.2 ± 0.2)°, (22.7 ± 0.2)°, (24.3 ± 0.2)° and (25.6 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate L-malate characterized by having a PXRD comprising reflections at 2- Theta angles of:

(7.5 ± 0.1)°, (14.9 ± 0.1)° and (18.0 ± 0.1)°; or

(7.5 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)° and (18.0 ± 0.1)°; or

(7.5 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)° and (22.7 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)° and (22.7 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)°, (19.7 ± 0.1)° and (22.7 ±

0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)°, (19.7 ± 0.1)°, (21.2 ± 0.1)° and (22.7 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)°, (19.7 ± 0.1)°, (21.2 ± 0.1)°, (22.7 ± 0.1)° and (24.3 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)°, (19.7 ± 0.1)°, (21.2 ± 0.1)°, (22.7 ± 0.1)°, (24.3 ± 0.1)° and (25.6 ± 0.1)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-malate characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (14.9 ± 0.2)°, (17.0 ± 0.2)°, (18.0 ± 0.2)°, (19.7 ± 0.2)°, (20.1 ± 0.2)°, (22.7 ± 0.2)°, (24.3 ± 0.2)°, (24.9 ± 0.2)° and (25.6 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate L-malate characterized by having a PXRD comprising reflections at 2- Theta angles of (7.5 ± 0.1)°, (14.9 ± 0.1)°, (17.0 ± 0.1)°, (18.0 ± 0.1)°, (19.7 ± 0.1)°, (20.1 ± 0.1)°, (22.7 ± 0.1)°, (24.3 ± 0.1)°, (24.9 ± 0.1)° and (25.6 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. The present invention also relates to crystalline (R)-2-amino-3-phenylpropylcarbamate L- malate characterized by having a PXRD essentially the same as shown in Figure 3 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbamate L-trial ate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (125 ± 5)°C, preferably of (125 ± 3)°C, even more preferably of (125 ± 2)°C and most preferably of (125 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- malate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (127 ± 5)°C, preferably of (127 ± 3)°C, even more preferably of (127 ± 2)°C and most preferably of (127 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-trial ate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbamate L-trial ate of the present invention as defined in any one of the embodiments described above is non-solvated.

The present invention further relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- malate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 1.0 w-%, based on the weight of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- malate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-trial ate of the present invention as defined in any one of the embodiments described above is slightly hygroscopic.

Crystalline (R)-2-amino-3-phenylpropylcarbamate phosphate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and phosphoric acid.

In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate characterized by the chemical structure according to Formula (IV)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbamate and phosphoric acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. In one embodiment, the present invention relates to crystalline (R)- 2-amino-3-phenylpropyl carbamate dihydrogenphosphate.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(5.5 ± 0.2)°, (16.3 ± 0.2)° and (20.8 ± 0.2)°; or

(5.5 ± 0.2)°, (16.3 ± 0.2)°, (19.2 ± 0.2)° and (20.8 ± 0.2)°; or

(5.5 ± 0.2)°, (16.3 ± 0.2)°, (19.2 ± 0.2)°, (20.8 ± 0.2)° and (22.3 ± 0.2)°; or

(5.5 ± 0.2)°, (16.3 ± 0.2)°, (19.2 ± 0.2)°, (19.8 ± 0.2)°, (20.8 ± 0.2)° and (22.3 ± 0.2)°; or

(5.5 ± 0.2)°, (11.1 ± 0.2)°, (16.3 ± 0.2)°, (19.2 ± 0.2)°, (19.8 ± 0.2)°, (20.8 ± 0.2)° and (22.3 ±

0.2)°; or

(5.5 ± 0.2)°, (11.1 ± 0.2)°, (15.2 ± 0.2)°, (16.3 ± 0.2)°, (19.2 ± 0.2)°, (19.8 ± 0.2)°, (20.8 ± 0.2)° and (22.3 ± 0.2)°; or

(5.5 ± 0.2)°, (11.1 ± 0.2)°, (15.2 ± 0.2)°, (16.3 ± 0.2)°, (17.6 ± 0.2)°, (19.2 ± 0.2)°, (19.8 ± 0.2)°, (20.8 ± 0.2)° and (22.3 ± 0.2)°; or

(5.5 ± 0.2)°, (11.1 ± 0.2)°, (12.5 ± 0.2)°, (15.2 ± 0.2)°, (16.3 ± 0.2)°, (17.6 ± 0.2)°, (19.2 ± 0.2)°, (19.8 ± 0.2)°, (20.8 ± 0.2)° and (22.3 ± 0.2)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate phosphate characterized by having a PXRD comprising reflections at 2-Theta angles of:

(5.5 ± 0.1)°, (16.3 ± 0.1)° and (20.8 ± 0.1)°; or (5.5 ± 0.1)°, (16.3 ± 0.1)°, (19.2 ± 0.1)° and (20.8 ± 0.1)°; or

(5.5 ± 0.1)°, (16.3 ± 0.1)°, (19.2 ± 0.1)°, (20.8 ± 0.1)° and (22.3 ± 0.1)°; or

(5.5 ± 0.1)°, (16.3 ± 0.1)°, (19.2 ± 0.1)°, (19.8 ± 0.1)°, (20.8 ± 0.1)° and (22.3 ± 0.1)°; or

(5.5 ± 0.1)°, (11.1 ± 0.1)°, (16.3 ± 0.1)°, (19.2 ± 0.1)°, (19.8 ± 0.1)°, (20.8 ± 0.1)° and (22.3 ±

0.1)°; or

(5.5 ± 0.1)°, (11.1 ± 0.1)°, (15.2 ± 0.1)°, (16.3 ± 0.1)°, (19.2 ± 0.1)°, (19.8 ± 0.1)°, (20.8 ± 0.1)° and (22.3 ± 0.1)°; or

(5.5 ± 0.1)°, (11.1 ± 0.1)°, (15.2 ± 0.1)°, (16.3 ± 0.1)°, (17.6 ± 0.1)°, (19.2 ± 0.1)°, (19.8 ± 0.1)°, (20.8 ± 0.1)° and (22.3 ± 0.1)°; or

(5.5 ± 0.1)°, (11.1 ± 0.1)°, (12.5 ± 0.1)°, (15.2 ± 0.1)°, (16.3 ± 0.1)°, (17.6 ± 0.1)°, (19.2 ± 0.1)°, (19.8 ± 0.1)°, (20.8 ± 0.1)° and (22.3 ± 0.1)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate characterized by having a PXRD comprising reflections at 2-Theta angles of (5.5 ± 0.2)°, (16.3 ± 0.2)°, (19.2 ± 0.2)°, (19.8 ± 0.2)°, (20.8 ± 0.2)°, (22.3 ± 0.2)°, (24.3 ± 0.2)°, (24.6 ± 0.2)°, (25.3 ± 0.2)° and (28.4 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate phosphate characterized by having a PXRD comprising reflections at 2-Theta angles of (5.5 ± 0.1)°, (16.3 ± 0.1)°, (19.2 ± 0.1)°, (19.8 ± 0.1)°, (20.8 ± 0.1)°, (22.3 ± 0.1)°, (24.3 ± 0.1)°, (24.6 ± 0.1)°, (25.3 ± 0.1)° and (28.4 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate characterized by having a PXRD essentially the same as shown in Figure 5 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (169 ± 5)°C, preferably of (169 ± 3)°C, even more preferably of (169 ± 2)°C and most preferably of (169 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbamate phosphate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (172 ± 5)°C, preferably of (172 ± 3)°C, even more preferably of (172 ± 2)°C and most preferably of (172 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-amino-3-phenylpropylcarbamate phosphate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-amino-3-phenylpropylcarbamate phosphate of the present invention as defined in any one of the embodiments described above is non-solvated.

The present invention further relates to crystalline (R)-2-amino-3-phenylpropylcarbamate phosphate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 1.0 w-%, based on the weight of the crystalline (R)-2-amino-3-phenylpropylcarbamate phosphate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-amino-3-phenylpropylcarbamate phosphate of the present invention as defined in any one of the embodiments described above is slightly hygroscopic.

Crystalline (R)-2-amino-3-phenylpropylcarbamate L-tartrate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and L-tartaric acid.

In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-tartrate characterized by the chemical structure according to Formula (V)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate L- tartrate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbarn ate and L-tartaric acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. In one embodiment, the present invention relates to crystalline (R)- 2- ami no-3 -phenylpropyl carb am ate L-hy drogentartrate .

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbamate L- tartrate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(6.7 ± 0.2)°, (11.1 ± 0.2)° and (17.7 ± 0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (17.7 ± 0.2)° and (21.5 ± 0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (17.7 ± 0.2)°, (21.5 ± 0.2)° and (22.3 ± 0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (17.7 ± 0.2)°, (20.3 ± 0.2)°, (21.5 ± 0.2)° and (22.3 ± 0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (17.7 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (21.5 ± 0.2)° and (22.3 ±

0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (16.2 ± 0.2)°, (17.7 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (21.5 ± 0.2)° and (22.3 ± 0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (14.4 ± 0.2)°, (16.2 ± 0.2)°, (17.7 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (21.5 ± 0.2)° and (22.3 ± 0.2)°; or

(6.7 ± 0.2)°, (11.1 ± 0.2)°, (14.4 ± 0.2)°, (16.2 ± 0.2)°, (16.9 ± 0.2)°, (17.7 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (21.5 ± 0.2)° and (22.3 ± 0.2)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate L-tartrate characterized by having a PXRD comprising reflections at 2- Theta angles of:

(6.7 ± 0.1)°, (11.1 ± 0.1)° and (17.7 ± 0.1)°; or

(6.7 ± 0.1)°, (11.1 ± 0.1)°, (17.7 ± 0.1)° and (21.5 ± 0.1)°; or

(6.7 ± 0.1)°, (11.1 ± 0.1)°, (17.7 ± 0.1)°, (21.5 ± 0.1)° and (22.3 ± 0.1)°; or

(6.7 ± 0.1)°, (11.1 ± 0.1)°, (17.7 ± 0.1)°, (20.3 ± 0.1)°, (21.5 ± 0.1)° and (22.3 ± 0.1)°; or

(6.7 ± 0.1)°, (11.1 ± 0.1)°, (17.7 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (21.5 ± 0.1)° and (22.3 ±

0.1)°; or (6.7 ± 0.1)°, (11.1 ± 0.1)°, (16.2 ± 0.1)°, (17.7 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (21.5 ± 0.1)° and (22.3 ± 0.1)°; or

(6.7 ± 0.1)°, (11.1 ± 0.1)°, (14.4 ± 0.1)°, (16.2 ± 0.1)°, (17.7 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (21.5 ± 0.1)° and (22.3 ± 0.1)°; or

(6.7 ± 0.1)°, (11.1 ± 0.1)°, (14.4 ± 0.1)°, (16.2 ± 0.1)°, (16.9 ± 0.1)°, (17.7 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (21.5 ± 0.1)° and (22.3 ± 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-tartrate characterized by having a PXRD comprising reflections at 2-Theta angles of (6.7 ± 0.2)°, (11.1 ± 0.2)°, (16.2 ± 0.2)°, (17.7 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)°, (22.3 ± 0.2)° and (22.9 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate L-tartrate characterized by having a PXRD comprising reflections at 2- Theta angles of (6.7 ± 0.1)°, (11.1 ± 0.1)°, (16.2 ± 0.1)°, (17.7 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (21.5 ± 0.1)°, (21.9 ± 0.1)°, (22.3 ± 0.1)° and (22.9 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- tartrate characterized by having a PXRD essentially the same as shown in Figure 7 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-tartrate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (188 ± 5)°C, preferably of (188 ± 3)°C, even more preferably of (188 ± 2)°C and most preferably of (188 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- tartrate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (191 ± 5)°C, preferably of (191 ± 3)°C, even more preferably of (191 ± 2)°C and most preferably of (191 ± 1)°C, when measured a heating rate of 10 K/min. Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- tartrate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-tartrate of the present invention as defined in any one of the embodiments described above is non-solvated. The present invention further relates to crystalline (R)-2-ami no-3 -phenyl propyl carbamate L- tartrate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 0.2 w-%, based on the weight of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L- tartrate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C. Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-tartrate of the present invention as defined in any one of the embodiments described above is slightly hygroscopic.

Crystalline (R)-2-amino-3-phenylpropylcarbamate formiate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and formic acid. In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate characterized by the chemical structure according to Formula (VI)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate formiate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbamate and formic acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. The present invention also relates to crystalline (T^^-amino-S-phenylpropylcarbamate formiate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.2 ± 0.2)°, (19.9 ± 0.2)° and (23.8 ± 0.2)°; or

(7.2 ± 0.2)°, (15.9 ± 0.2)°, (19.9 ± 0.2)° and (23.8 ± 0.2)°; or

(7.2 ± 0.2)°, (15.9 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)° and (23.8 ± 0.2)°; or

(7.2 ± 0.2)°, (11.2 ± 0.2)°, (15.9 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)° and (23.8 ± 0.2)°; or

(7.2 ± 0.2)°, (11.2 ± 0.2)°, (12.1 ± 0.2)°, (15.9 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)° and (23.8 ±

0.2)°; or

(7.2 ± 0.2)°, (11.2 ± 0.2)°, (12.1 ± 0.2)°, (15.9 ± 0.2)°, (17.6 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)° and (23.8 ± 0.2)°; or

(7.2 ± 0.2)°, (11.2 ± 0.2)°, (12.1 ± 0.2)°, (15.9 ± 0.2)°, (17.6 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)°, (21.7 ± 0.2)° and (23.8 ± 0.2)°; or

(7.2 ± 0.2)°, (11.2 ± 0.2)°, (12.1 ± 0.2)°, (15.9 ± 0.2)°, (17.6 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)°, (21.7 ± 0.2)°, (23.8 ± 0.2)° and (27.2 ± 0.2)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate formiate characterized by having a PXRD comprising reflections at 2- Theta angles of:

(7.2 ± 0.1)°, (19.9 ± 0.1)° and (23.8 ± 0.1)°; or

(7.2 ± 0.1)°, (15.9 ± 0.1)°, (19.9 ± 0.1)° and (23.8 ± 0.1)°; or

(7.2 ± 0.1)°, (15.9 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)° and (23.8 ± 0.1)°; or

(7.2 ± 0.1)°, (11.2 ± 0.1)°, (15.9 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)° and (23.8 ± 0.1)°; or

(7.2 ± 0.1)°, (11.2 ± 0.1)°, (12.1 ± 0.1)°, (15.9 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)° and (23.8 ±

0.1)°; or

(7.2 ± 0.1)°, (11.2 ± 0.1)°, (12.1 ± 0.1)°, (15.9 ± 0.1)°, (17.6 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)° and (23.8 ± 0.1)°; or

(7.2 ± 0.1)°, (11.2 ± 0.1)°, (12.1 ± 0.1)°, (15.9 ± 0.1)°, (17.6 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)°, (21.7 ± 0.1)° and (23.8 ± 0.1)°; or

(7.2 ± 0.1)°, (11.2 ± 0.1)°, (12.1 ± 0.1)°, (15.9 ± 0.1)°, (17.6 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)°, (21.7 ± 0.1)°, (23.8 ± 0.1)° and (27.2 ± 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate characterized by having a PXRD comprising reflections at 2-Theta angles of (7.2 ± 0.2)°, (15.9 ± 0.2)°, (16.2 ± 0.2)°, (18.7 ± 0.2)°, (19.0 ± 0.2)°, (19.9 ± 0.2)°, (20.0 ± 0.2)°, (21.7 ± 0.2)°, (23.8 ± 0.2)° and (27.2 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate formiate characterized by having a PXRD comprising reflections at 2- Theta angles of (7.2 ± 0.1)°, (15.9 ± 0.1)°, (16.2 ± 0.1)°, (18.7 ± 0.1)°, (19.0 ± 0.1)°, (19.9 ± 0.1)°, (20.0 ± 0.1)°, (21.7 ± 0.1)°, (23.8 ± 0.1)° and (27.2 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate characterized by having a PXRD essentially the same as shown in Figure 9 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (152 ± 5)°C, preferably of (152 ± 3)°C, even more preferably of (152 ± 2)°C and most preferably of (152 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (153 ± 5)°C, preferably of (153 ± 3)°C, even more preferably of (153 ± 2)°C and most preferably of (153 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbamate formiate of the present invention as defined in any one of the embodiments described above is non-solvated. The present invention further relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate characterized by showing a mass change of not less than 2.0 w-%, preferably less than 0.1 w-%, based on the weight of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate of the present invention as defined in any one of the embodiments described above is slightly hygroscopic.

Crystalline (R)-2-amino-3-phenylpropylcarbamate hippurate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and hippuric acid.

In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate characterized by the chemical structure according to Formula (VII)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate hippurate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbamate and hippuric acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(5.2 ± 0.2)°, (15.6 ± 0.2)° and (18.8 ± 0.2)°; or

(5.2 ± 0.2)°, (15.6 ± 0.2)°, (18.8 ± 0.2)° and (20.8 ± 0.2)°; or

(5.2 ± 0.2)°, (15.6 ± 0.2)°, (18.8 ± 0.2)°, (20.8 ± 0.2)° and (21.1 ± 0.2)°; or

(5.2 ± 0.2)°, (15.6 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (20.8 ± 0.2)° and (21.1 ± 0.2)°; or (5.2 ± 0.2)°, (15.6 ± 0.2)°, (16.3 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (20.8 ± 0.2)° and (21.1 ± 0.2)°; or

(5.2 ± 0.2)°, (15.6 ± 0.2)°, (16.3 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (20.8 ± 0.2)°, (21.1 ± 0.2)° and (28.0 ± 0.2)°; or

(5.2 ± 0.2)°, (15.6 ± 0.2)°, (16.3 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (20.8 ± 0.2)°, (21.1 ± 0.2)°, (26.9 ± 0.2)° and (28.8 ± 0.2)°; or

(5.2 ± 0.2)°, (15.6 ± 0.2)°, (16.3 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (20.8 ± 0.2)°, (21.1 ± 0.2)°, (26.9 ± 0.2)° and (28.0 ± 0.2)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate hippurate characterized by having a PXRD comprising reflections at 2- Theta angles of:

(5.2 ± 0.1)°, (15.6 ± 0.1)° and (18.8 ± 0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (18.8 ± 0.1)° and (20.8 ± 0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (18.8 ± 0.1)°, (20.8 ± 0.1)° and (21.1 ± 0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (20.8 ± 0.1)° and (21.1 ± 0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (16.3 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (20.8 ± 0.1)° and (21.1 ±

0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (16.3 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (20.8 ± 0.1)°, (21.1 ± 0.1)° and (28.0 ± 0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (16.3 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (20.8 ± 0.1)°, (21.1 ± 0.1)°, (26.9 ± 0.1)° and (28.8 ± 0.1)°; or

(5.2 ± 0.1)°, (15.6 ± 0.1)°, (16.3 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (20.8 ± 0.1)°, (21.1 ± 0.1)°, (26.9 ± 0.1)° and (28.0 ± 0.1)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate characterized by having a PXRD comprising reflections at 2-Theta angles of (5.2 ± 0.2)°, (15.6 ± 0.2)°, (16.3 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (20.8 ± 0.2)°, (21.1 ± 0.2)°, (26.9 ± 0.2)° and (28.0 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. Alternatively, the present invention relates to crystalline (R)- 2-amino-3- phenylpropyl carbamate hippurate characterized by having a PXRD comprising reflections at 2- Theta angles of (5.2 ± 0.1)°, (15.6 ± 0.1)°, (16.3 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (20.8 ± 0.1)°, (21.1 ± 0.1)°, (26.9 ± 0.1)° and (28.0 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate characterized by having a PXRD essentially the same as shown in Figure 11 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (159 ± 5)°C, preferably of (159 ± 3)°C, even more preferably of (159 ± 2)°C and most preferably of (159 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (162 ± 5)°C, preferably of (162 ± 3)°C, even more preferably of (162 ± 2)°C and most preferably of (162 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate of the present invention as defined in any one of the embodiments described above is non-solvated.

The present invention further relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 1.0 w-%, based on the weight of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate of the present invention as defined in any one of the embodiments described above is slightly hygroscopic. Crystalline (R)-2-amino-3-phenylpropylcarbamate nitrate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and nitric acid.

In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate characterized by the chemical structure according to Formula (VIII)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate nitrate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbamate and nitric acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.0 ± 0.2)°, (13.1 ± 0.2)° and (17.8 ± 0.2)°; or

(7.0 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)° and (17.8 ± 0.2)°; or

(7.0 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)° and (22.5 ± 0.2)°; or

(6.3 ± 0.2)°, (7.0 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)° and (22.5 ± 0.2)°; or

(6.3 ± 0.2)°, (7.0 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)° and (22.5 ±

0.2)°; or

(6.3 ± 0.2)°, (7.0 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)°, (18.9 ± 0.2)° and (22.5 ± 0.2)°; or

(6.3 ± 0.2)°, (7.0 ± 0.2)°, (12.1 ± 0.2)°, (12.6 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)°, (18.9 ± 0.2)° and (22.5 ± 0.2)°; or

(6.3 ± 0.2)°, (7.0 ± 0.2)°, (12.1 ± 0.2)°, (12.6 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)°, (18.9 ± 0.2)°, (21.7 ± 0.2)° and (22.5 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropylcarbamate nitrate characterized by having a PXRD comprising reflections at 2- Theta angles of:

(7.0 ± 0.1)°, (13.1 ± 0.1)° and (17.8 ± 0.1)°; or

(7.0 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)° and (17.8 ± 0.1)°; or

(7.0 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)° and (22.5 ± 0.1)°; or

(6.3 ± 0.1)°, (7.0 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)° and (22.5 ± 0.1)°; or

(6.3 ± 0.1)°, (7.0 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)° and (22.5 ±

0.1)°; or

(6.3 ± 0.1)°, (7.0 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)°, (18.9 ± 0.1)° and (22.5 ± 0.1)°; or

(6.3 ± 0.1)°, (7.0 ± 0.1)°, (12.1 ± 0.1)°, (12.6 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)°, (18.9 ± 0.1)° and (22.5 ± 0.1)°; or

(6.3 ± 0.1)°, (7.0 ± 0.1)°, (12.1 ± 0.1)°, (12.6 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)°, (18.9 ± 0.1)°, (21.7 ± 0.1)° and (22.5 ± 0.1)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate characterized by having a PXRD comprising reflections at 2-Theta angles of (7.0 ± 0.2)°, (13.1 ± 0.2)°, (16.4 ± 0.2)°, (17.8 ± 0.2)°, (18.9 ± 0.2)°, (21.2 ± 0.2)°, (21.7 ± 0.2)°, (22.5 ± 0.2)°, (24.7 ± 0.2)° and (27.5 ± 0.2), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropylcarbamate nitrate characterized by having a PXRD comprising reflections at 2- Theta angles of (7.0 ± 0.1)°, (13.1 ± 0.1)°, (16.4 ± 0.1)°, (17.8 ± 0.1)°, (18.9 ± 0.1)°, (21.2 ± 0.1)°, (21.7 ± 0.1)°, (22.5 ± 0.1)°, (24.7 ± 0.1)° and (27.5 ± 0.1), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate characterized by having a PXRD essentially the same as shown in Figure 13 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (162 ± 5)°C, preferably of (162 ± 3)°C, even more preferably of (162 ± 2)°C and most preferably of (162 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (163 ± 5)°C, preferably of (163 ± 3)°C, even more preferably of (163 ± 2)°C and most preferably of (163 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbamate nitrate of the present invention as defined in any one of the embodiments described above is non-solvated.

The present invention further relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 1.0 w-%, more preferably of less than 0.1 w-%, based on the weight of the crystalline (R)-2- amino-3-phenylpropylcarbamate nitrate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate of the present invention as defined in any one of the embodiments described above is non-hygroscopic.

Crystalline (R)-2-amino-3-phenylpropylcarbamate tosylate

In one embodiment, the present invention relates to a crystalline salt comprising (R)-2-amino- 3-phenylpropylcarbamate and p-toluenesulfonic acid.

In particular, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate characterized by the chemical structure according to Formula (IX)

Preferably, crystalline (R)-2-ami no-3 -phenyl propyl carbamate tosylate of the present invention is characterized by having a molar ratio of (R)-2-ami no-3 -phenyl propyl carbamate and p- toluenesulfonic acid in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 and most preferably the molar ratio is in the range of from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate as defined in any one of the above described embodiments characterized by having a PXRD comprising reflections at 2-Theta angles of:

(4.1 ± 0.2)°, (13.1 ± 0.2)° and (19.2 ± 0.2)°; or

(4.1 ± 0.2)°, (13.1 ± 0.2)°, (18.7 ± 0.2)° and (19.2 ± 0.2)°; or

(4.1 ± 0.2)°, (13.1 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)° and (24.9 ± 0.2)°; or

(4.1 ± 0.2)°, (13.1 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)°, (20.6 ± 0.2)° and (24.9 ± 0.2)°; or

(4.1 ± 0.2)°, (8.3 ± 0.2)°, (13.1 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)°, (20.6 ± 0.2)° and (24.9 ±

0.2)°; or

(4.1 ± 0.2)°, (8.3 ± 0.2)°, (12.5 ± 0.2)°, (13.1 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)°, (20.6 ± 0.2)° and (24.9 ± 0.2)°; or

(4.1 ± 0.2)°, (8.3 ± 0.2)°, (12.5 ± 0.2)°, (13.1 ± 0.2)°, (14.9 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)°, (20.6 ± 0.2)° and (24.9 ± 0.2)°; or

(4.1 ± 0.2)°, (8.3 ± 0.2)°, (12.5 ± 0.2)°, (13.1 ± 0.2)°, (14.9 ± 0.2)°, (16.7 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)°, (20.6 ± 0.2)° and (24.9 ± 0.2)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate tosylate characterized by having a PXRD comprising reflections at 2- Theta angles of: (4.1 ± 0.1)°, (13.1 ± 0.1)° and (19.2 ± 0.1)°; or

(4.1 ± 0.1)°, (13.1 ± 0.1)°, (18.7 ± 0.1)° and (19.2 ± 0.1)°; or

(4.1 ± 0.1)°, (13.1 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)° and (24.9 ± 0.1)°; or

(4.1 ± 0.1)°, (13.1 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)°, (20.6 ± 0.1)° and (24.9 ± 0.1)°; or

(4.1 ± 0.1)°, (8.3 ± 0.1)°, (13.1 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)°, (20.6 ± 0.1)° and (24.9 ±

0.1)°; or

(4.1 ± 0.1)°, (8.3 ± 0.1)°, (12.5 ± 0.1)°, (13.1 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)°, (20.6 ± 0.1)° and (24.9 ± 0.1)°; or

(4.1 ± 0.1)°, (8.3 ± 0.1)°, (12.5 ± 0.1)°, (13.1 ± 0.1)°, (14.9 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)°, (20.6 ± 0.1)° and (24.9 ± 0.1)°; or

(4.1 ± 0.1)°, (8.3 ± 0.1)°, (12.5 ± 0.1)°, (13.1 ± 0.1)°, (14.9 ± 0.1)°, (16.7 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)°, (20.6 ± 0.1)° and (24.9 ± 0.1)°,

when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In addition, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate characterized by having a PXRD comprising reflections at 2-Theta angles of (4.1 ± 0.2)°, (13.1 ± 0.2)°, (16.7 ± 0.2)°, (17.6 ± 0.2)°, (18.7 ± 0.2)°, (19.2 ± 0.2)°, (20.6 ± 0.2)°, (20.8 ± 0.2)°, (24.3 ± 0.2)° and (24.9 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Alternatively, the present invention relates to crystalline (R)-2-amino-3- phenylpropyl carbamate tosylate characterized by having a PXRD comprising reflections at 2- Theta angles of (4.1 ± 0.1)°, (13.1 ± 0.1)°, (16.7 ± 0.1)°, (17.6 ± 0.1)°, (18.7 ± 0.1)°, (19.2 ± 0.1)°, (20.6 ± 0.1)°, (20.8 ± 0.1)°, (24.3 ± 0.1)° and (24.9 ± 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate characterized by having a PXRD essentially the same as shown in Figure 15 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

Furthermore, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (190 ± 5)°C, preferably of (190 ± 3)°C, even more preferably of (190 ± 2)°C and most preferably of (190 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (192 ± 5)°C, preferably of (192 ± 3)°C, even more preferably of (192 ± 2)°C and most preferably of (192 ± 1)°C, when measured a heating rate of 10 K/min.

Preferably, the crystalline (R)-2-amino-3-phenylpropylcarbamate tosylate of the present invention as defined in any one of the embodiments described above is anhydrous.

Even more preferably, the crystalline (R)-2-amino-3-phenylpropylcarbamate tosylate of the present invention as defined in any one of the embodiments described above is non-solvated.

The present invention further relates to crystalline (R)-2-amino-3-phenylpropylcarbamate tosylate characterized by showing a mass change of less than 2.0 w-%, preferably of less than 1.0 w-%, based on the weight of the crystalline (R)-2-amino-3-phenylpropyl carbamate tosylate, when measured with GMS during the sorption cycle at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C.

Preferably, the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate of the present invention as defined in any one of the embodiments described above is slightly hygroscopic.

Process for the preparation of the crystalline salts of the present invention

In another aspect, the invention relates to a process for the preparation of a crystalline (R)- 2- amino-3-phenylpropylcarbamate acid addition salt with an acid selected from the group consisting of maleic acid, L-malic acid, phosphoric acid, L-tartaric acid, formic acid, hippuric acid, nitric acid and p-toluenesulfonic acid as defined in any one of the above described embodiments comprising:

(a) reacting (R)-2-ami no-3 -phenyl propyl carbarn ate and an acid selected from the group consisting of maleic acid, L-malic acid, phosphoric acid, L-tartaric acid, formic acid, hippuric acid, nitric acid and p-toluenesulfonic acid in the presence of a suitable solvent;

(b) allowing for the crystallization of the (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salt obtained in step (a);

(c) separating at least a part of the crystals obtained in step (b); (d) optionally washing the crystals obtained in step (c); and

(e) drying the crystals obtained in step (c) or (d). (R)-2-amino-3 -phenyl propyl carbarn ate may be prepared according to Example 1 herein starting from the (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride, which in turn can be prepared according to Example III of WO 96/07637 Al .

In the first step (a) of the above described process (R)-2-ami no-3 -phenyl propyl carbarn ate is reacted with the respective acid in the presence of a suitable solvent. The suitable solvent may be selected from one or more alcohol(s). Preferably, the one or more alcohol(s) is/are selected from the group consisting of methanol, ethanol, 1 -propanol and 2-propanol or any mixtures thereof. Most preferably, ethanol is used as solvent.

The molar ratio of (R)-2-ami no-3 -phenyl propyl carbarn ate and the respective acid applied in step (a) is in the range of from about 1.0: 0.8 to 1.0: 1.2, preferably of from about 1.0: 0.9 to 1.0: 1.1 or from about 1.0: 0.95 to 1.0: 1.05 such as 1.0: 1.0. Most preferably, the molar ratio of (R)-2-ami no-3 -phenyl propyl carbarn ate and the respective acid is about 1.0: 1.1.

The (R)-2-ami no-3 -phenyl propyl carbarn ate concentration in relation to the applied solvent in step (a) is in the range of from 25 - 100 g/L, most preferably of from 50 - 75 g/L.

The reaction may be carried out by first dissolving (R)-2-ami no-3 -phenyl propyl carbarn ate in the applied solvent and subsequent addition of the respective acid. The reaction may be carried out at room temperature or at elevated temperature e.g. between room temperature and reflux temperature of the applied solvent. Preferably, the temperature is selected such, that (R)- 2- amino-3-phenylpropylcarbamate and the respective acid at least partially dissolve and most preferably both components dissolve completely.

Once the reaction is complete, the (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salt is allowed to crystallize from the mother liquor. Usually, the material crystallizes gradually upon stirring. The solution may also be cooled to room temperature in order to initiate crystallization. The obtained suspension may then be further stirred until plentiful crystallization occurs e.g. for a period in the range of from 0.5 to 120 hours, preferably of from 1 to 72 hours and most preferably of from 12 to 24 hours such as 18 hours. In order to increase the yield, the suspension may be further cooled e.g. to a temperature in the range of from 0 to 10 °C, e.g. of from 2 to 8 °C. In the next step (c), at least a part of the crystals are separated from the mother liquor. Preferably, the crystals are separated from the mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.

In an optional step (d), the isolated crystals may be washed with one or more suitable solvent(s). The one or more suitable solvent(s) may be selected from one or more alcohol(s). Preferably, the one or more alcohol(s) is/are selected from the group consisting of methanol, ethanol, 1 - propanol and 2-propanol or any mixtures thereof. Most preferably, ethanol is used for washing.

Finally, the obtained crystals are dried, wherein drying may be performed at a temperature in the range of from about 20 to 80 °C, preferably of from about 20 to 60 °C , even more preferably of from about 20 to 30 °C e.g. at about room temperature. Drying may be performed at ambient pressure and/or under reduced pressure. Preferably, drying is performed applying a vacuum of about 100 mbar or less, more preferably of about 50 mbar or less for example a vacuum of about 35 mbar or less. Drying may be performed for a period in the range of from about 1 to 24 hours, preferably from about 1 to 12 hours and most preferably from about 2 to 6 hours.

Pharmaceutical compositions and medical use

In a further aspect the present invention relates to the use of the crystalline (R)-2-amino-3- phenylpropyl carbamate acid addition salts of the present invention as defined in any one of the above described embodiments for the preparation of a pharmaceutical composition.

In still a further aspect, the present invention relates to a pharmaceutical composition comprising one or more of the crystalline (R)-2-amino-3-phenylpropyl carbamate acid addition salts of the present invention as defined in any one of the above described embodiments, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition of the present invention is an oral solid dosage form, such as a tablet or a capsule. More preferably, the pharmaceutical composition of the present invention is a tablet e.g. a film-coated tablet. Most preferably, the pharmaceutical composition of the present invention is an immediate-release film-coated tablet.

The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, disintegrants, lubricants, binders, coating materials and combinations thereof. In one embodiment all of these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention.

Preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of the one or more crystalline (R)-2-amino- 3-phenylpropylcarbamate acid addition salts of the present invention as defined in any one of the above described embodiments is selected from the group consisting of 37.5 mg, 75 mg, 150 mg and 300 mg calculated as (R)-2-ami no-3 -phenyl propyl carbarn ate. Most preferably, the invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of the one or more crystalline (R)-2-amino-3- phenylpropylcarbamate acid addition salts of the present invention is 75 mg or 150 mg calculated as (R)-2-amino-3 -phenylpropylcarbamate.

The pharmaceutical composition of the present invention as defined in any one of the above described embodiments may be produced by standard manufacturing processes, which are well- known to the skilled person including e.g. blending, granulation (wet or dry granulation), tablet compression and film-coating.

The present invention also relates to the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention or a pharmaceutical composition comprising one or more of the crystalline (R)-2-amino-3 -phenylpropylcarbamate acid addition salts of the present invention as defined in any one of the above described embodiments, wherein the crystalline (R)-2-amino-3 -phenylpropylcarbamate acid addition salts of the present invention or the pharmaceutical composition comprising one or more of the crystalline (R)-2-amino-3- phenylpropyl carbamate acid addition salts of the present invention is to be administered once- daily. Preferably, the once daily dose is selected from the group consising of 37.5 mg, 75 mg and 150 mg, each dose calculated as (R)-2-ami no-3 -phenyl propyl carbarn ate. In a further aspect, the present invention relates to crystalline (R)-2-amino-3- phenylpropylcarbamate acid addition salts of the present invention or the pharmaceutical composition comprising one or more of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention as defined in any one of the above described embodiments for use as a medicament. Moreover, the present invention relates to crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention or the pharmaceutical composition comprising one or more of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention as defined in any one of the above described embodiments for use in the treatment of patients with a condition selected from the group consisting of narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit/hyperactivity disorder, restless leg syndrome, depression, bipolar disorder and obesity. In particular, the present invention relates to crystalline (R)-2-amino-3- phenylpropylcarbamate acid addition salts of the present invention or the pharmaceutical composition comprising one or more of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention as defined in any one of the above described embodiments for use in the improvement of wakefulness and reduction of excessive sleepiness in patients with narcolepsy or obstructive sleep apnea.

In another embodiment, the present invention is directed to a method of treating narcolepsy or obstructive sleep apnea, said method comprising administering crystalline (R)-2-amino-3- phenylpropylcarbamate acid addition salts of the present invention or the pharmaceutical composition comprising one or more of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention as defined in any one of the above described embodiments to a patient in need of such a treatment.

EXAMPLES

The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention.

Example 1: Preparation of (R)-2-ami no-3 -phenyl propyl carbarn ate

(R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride (10.1 g, e.g. obtained according to Example III of WO 96/07637 A) was dissolved in water (400 mL) at room temperature and aqueous NaOH (1M, 40 mL) was added. (R)-2-ami no-3 -phenyl propyl carbarn ate was extracted from the aqueous phase three times with ethyl acetate (lx 400 mL, 2x 200 mL). The organic phases were combined and dried over Na ₂ S0 ₄ . Ethyl acetate was removed on a rotary evaporator at a bath temperature of 40 °C. Subsequently, the remaining oily residue containing solid particles was dissolved in diethyl ether (100 mL) and filtrated. The solvent was removed on a rotary evaporator at a bath temperature of 40 °C. The resulting oil was then dried under vacuum (~35 mbar) at room temperature for 72 hours.

Example 2: General procedure for the preparation of the crystalline (R)-2-amino-3- phenylpropylcarbamate acid addition salts of the present invention

(R)-2-ami no-3 -phenyl propyl carbarn ate (150 mg, obtained from Example 1 hereinabove) were dissolved in ethanol (3 mL) upon heating. To the obtained solution the respective acid (1.1 mol equivalents of acid according to Table 1) was added leading to a precipitate. The obtained suspension was then stirred at 25°C for 18 hours before the crystals were collected by filtration and vacuum-dried (~35 mbar) at room temperature.

Table 1: Acids applied in general procedure of Example 2

Example 3: Powder X-ray diffraction

Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. The samples were gently ground in a mortar before measuring them, in order to minimize intensitiy differences due to preferred orientation effects. (R)-2-amino-3-phenylpropylcarbamate maleate A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate maleate according to the present invention is displayed in Figure 1 herein. The corresponding reflection list is provided in Table 2 below.

Table 2: PXRD reflections of the crystalline mealeate salt in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. (R)-2-amino-3-phenylpropylcarbamate L-malate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbamate L-trial ate according to the present invention is displayed in Figure 3 herein. The corresponding reflection list is provided in Table 3 below.

Table 3: PXRD reflections of the crystalline L-malate salt in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. (R)-2-amino-3-phenylpropylcarbamate phosphate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate phosphate according to the present invention is displayed in Figure 5 herein. The corresponding reflection list is provided in Table 4 below.

Table 4: PXRD reflections of the crystalline phosphate salt in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. (R)-2-amino-3-phenylpropylcarbamate L-tartrate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate L-tartrate according to the present invention is displayed in Figure 7 herein. The corresponding reflection list is provided in Table 5 below.

Table 5: PXRD reflections of the crystalline L-tartrate salt in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. (R)-2-amino-3-phenylpropylcarbamate formiate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate formiate according to the present invention is displayed in Figure 9 herein. The corresponding reflection list is provided in Table 6 below.

Table 6: PXRD reflections of the crystalline formiate salt in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. (R)-2-amino-3-phenylpropylcarbamate hippurate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate hippurate according to the present invention is displayed in Figure 11 herein. The corresponding reflection list is provided in Table 7 below.

Table 7: PXRD reflections of the crystalline hippurate salt in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. (R)-2-amino-3-phenylpropylcarbamate nitrate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate nitrate according to the present invention is displayed in Figure 13 herein. The corresponding reflection list is provided in Table 8 below.

Table 8: PXRD reflections of the crystalline nitrate salt in the range of from 2 to 30° 2-Theta; A typica precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.

(R)-2-amino-3-phenylpropylcarbamate tosylate

A representative diffractogram of crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate tosylate according to the present invention is displayed in Figure 15 herein. The corresponding reflection list is provided in Table 9 below.

Table 9: PXRD reflections of the crystalline tosylate salt in the range of from 2 to 30° 2-Theta; A typica precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.

Example 4: Thermal investigations by differential scanning calorimetry

DSC was performed on a Mettler Polymer DSC R instrument. The crystalline (R)-2-amino-3- phenylpropylcarbamate acid addition salts of the present invention were each heated in a 40 microliter aluminium pan with a pierced aluminium lid from 25 to 250 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.

The DSC curves of the crystalline (R)-2-ami no-3 -phenyl propyl carbarn ate acid addition salts of the present invention don’t show any dehydration/desolvation event but the first endothermic signals are rather due to melting or a solid-solid phase transition in the case of the nitrate salt. DSC investigations suggest that the salts of the present invention are anhydrous, non-solvated and stable against temperature stress.

Table 10: Summary of first thermal events observed during DSC experiments

Example 5: Gravimetric moisture sorption

Gravimetric moisture sorption was performed on an SPSx-I m moisture sorption analyzer (ProUmid, Ulm). The measurement cycles were started at ambient relative humidity (RH) of 25%. Relative humidity was then decreased to 5% in 5% steps, followed by a further decrease to 3% and to 0%. Afterwards RH was increased from 0% to 90% RH in a sorption cycle and decreased to 0 % in a desorption cycle in 5% steps. Finally the RH was increased to a relative humidity of 25% in 5% steps. The time per step was set to a minimum of 2 hours and a maximum of 6 hours. If an equilibrium condition with a constant mass of ± 0.01% within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 6 hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of 6 hours. The temperature was 25 ± 0.1 °C. Corrected values, displaying the water content of the samples, were calculated by assigning the water content determined by Karl Fischer titration after the end of the experiment to the final equilibrium point and adaption of all other points to this value. PXRD measurements were performed after the gravimetric moisture sorption experiment.

The salts of the present invention without exception showed almost no interaction with water vapour, which is indicated by only very low water uptake and lack of a hysteresis between the sorption and desorption curves. PXRD measured after the experiments confirmed that all samples preserved their initial crystal structures. Therefore, the salts of the present invention are non-hygroscopic or slightly hygroscopic and preserve their crystal structures regardless relative humidity of the envionment.

Table 11: Summary of results from GMS experiments

Comparative Example 1: Stability of the crystalline (R)-2-amino-3-phenylpropylcarbamate acid addition salts of the present invention and (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride Form A and Form B of WO 2018/048871 A1 against moisture and temperature (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride Form A and Form B of WO 2018/048871 A1 were subjected to the same test conditions as described in Example 4 (DSC experiments) and Example 5 (GMS experiments) herein above. As can be seen from the summary provided in Table 12 below, (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride Form A is hygroscopic and undergoes a (partial) crystal structure change when subjected to the gravimetric moisture sorption experiment, while (R)-2-ami no-3 -phenyl propyl carbarn ate hydrochloride Form B is thermally unstable and readily starts to dehydrate at a temperature as low as 70°C. In contrast, all salts of the present invention remained stable under the same conditions.

Table 12: Physical stability of the various (R)-2-amino-3-phcnylpropylcarbamatc acid addition salts Therefore, as shown above the crystalline (R)-2-ami no-3 -phenyl propyl carbamate acid addition salts of the present invention possess excellent stability against moisture and temperature stress.