WO2008074694A1

WO2008074694A1 - Crystallization of glucokinase activators

Info

Publication number: WO2008074694A1
Application number: PCT/EP2007/063715
Authority: WO
Inventors: Antonio A. Albano; Duk Soon Choi; Wantanee Phuapradit; Roumen Nikolaev Radinov; Navnit Hargovindas Shah
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2006-12-20
Filing date: 2007-12-11
Publication date: 2008-06-26

Abstract

The present invention provides novel methods for crystallizing glucokinase activators from amorphous glucokinase activators. The amorphous glucokinase activator is dissolved in a non-chemically reactive lipid solvent to form a supersaturated solution and the supersaturated solution is maintained at a temperature range from 5 °C above to 5 °C below the glass transition temperature of the amorphous glucokinase activator for a period of time until a crystal of the glucokinase activator is formed. These novel methods for preparing crystallized glucokinase activators are useful in the treatment or control of a number of diseases. Furthermore the application discloses crystallization processes in which the compounds are dissolved in Capmul or Gelocire solvents, encapsulated and stored during prolonged time periods followed by dispersing the contents of the capsules and filtering the crystals.

Description

CRYSTALLIZATION OF GLUCOKINASE ACTIVATORS

The present invention provides novel methods for crystallizing glucokinase activators from amorphous glucokinase activators. The amorphous glucokinase activator is dissolved in a non-chemically reactive lipid solvent to form a supersaturated solution and the supersaturated solution is maintained at a temperature range from 5 ⁰C above to 5 ⁰C below the glass transition temperature of the amorphous glucokinase activator for a period of time until a crystal of the glucokinase activator is formed. These novel methods for preparing crystallized glucokinase activators are useful in the treatment or control of a number of diseases.

Glucokinase activators (GK) are indicated for the treatment of type 2 diabetes mellitus and future indications impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Attempts to obtain a crystalline form of glucokinase activator during the final solvent crystallization step often result in the production of an amorphous form. Conventional solvent crystallization procedures, such as dissolving the compound in various solvents and solvent mixtures and partial concentration of the solution, stirring, heating or cooling the solution for extended periods, and addition of an antisolvent or vapor diffusion of an antisolvent into solutions of the compound in various solvents and solvent mixtures, result in producing the amorphous form. The utilization of common organic solvents in conjunction with an antisolvent, evaporation, and cooling techniques also produces the amorphous form.

Amorphous forms of active pharmaceutical ingredients present major difficulties during the development of a pharmaceutical dosage form. Drug substance issues include difficulty in chemical synthesis, purity, isolation, drying, and scalability. Drug product issues include difficulty in formulation development, clumping/ gelling during processing, storage, and variability in the impurities profile. Since therapeutically active compounds in a solid unit crystalline dosage form are preferred for oral administration, it would be useful to provide methods for obtaining a crystalline form to avoid pharmaceutical dosage form development difficulties.

The present invention provides a method for crystallizing a glucokinase activator that comprises the steps of (a) dissolving an amorphous glucokinase activator in a non- chemically reactive lipid solvent to form a supersaturated solution; and (b) maintaining the supersaturated solution at a temperature range from 5 ⁰C above to 5 ⁰C below the glass transition temperature of the amorphous glucokinase activator for a period of time until a crystal of the glucokinase activator is formed.

In another embodiment of the present invention, provided is a method for crystallizing a glucokinase activator, comprising the steps of:

a) heating Capmul^® PG-8 in a vessel to 50 ⁰C until the Gelucire^® 44/14 melts;

b) adding butyl hydroxyanisole and butyl hydroxytolulene to the vessel in step (a) with stirring until the butyl hydroxyanisole and butyl hydroxytolulene is dissolved;

c) adding amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide to the mixture in step (b) with stirring until the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N- [5-( 1 (S),2-dihydroxyethyl)-pyrazin-2-yl] -propionamide is dissolved;

d) encapsulating the mixture from step (c) into capsules having the quantitative composition set out below;

e) storing the capsules from step (d) at 40 °C/75%RH for 6 months to form crystals; and

f) extracting the crystals from the capsules by dispersing the contents of the capsules in water/ethanol (50:50) and then filtering the crystals to obtain crystalline 2(R)-(3-chloro- 4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]- propionamide .

In a further embodiment of the present invention, provided is a method for crystallizing a glucokinase activator, comprising the steps of:

a) heating Gelucire^® 44/14 in a vessel to 50 ⁰C until the Gelucire^® 44/14 melts;

c) adding amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo- cyclopentyl] -N- (pyrazin-2-yl) -propionamide to the mixture in step (b) with stirring until the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]- N-(pyrazin-2-yl)-propionamide is dissolved;

f) extracting the crystals from the capsules by dispersing the contents of the capsules in water/ethanol (50:50) and then filtering the crystals to obtain a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- [1 (R)-3-oxo-cyclopentyl] - N-(pyrazin-2-yl) -propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3- [1 (R) -3-oxo-cyclopentyl]-N-(pyrazin-2-yl) -propionamide. - A -

The present invention also provides a novel crystalline polymorph Form I of 2(R) - (3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)- pyrazin-2-yl]-propionamide, and hydrates thereof; a novel crystalline polymorph Form II of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2- dihydroxyethyl)-pyrazin-2-yl] -propionamide, and hydrates thereof; and a novel crystalline polymorph of a 50:50 mixture of crystalline 2(R)-(3-chloro-4- methanesulfonyl-phenyl) -3- [1 (R) -3-oxo-cyclopentyl]-N-(pyrazin-2-yl) -propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin- 2-yl) -propionamide, and hydrates thereof,

In the following the Figures are briefly described:

Figure 1 is a diagram illustrating the crystal structure, using X-ray crystallographic analysis, of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2- dihydroxyethyl)-pyrazin-2-yl] -propionamide (Compound B, R/S) showing the numbering scheme employed.

Figure 2 is a differential scanning calorimetry (DSC) thermogram of Form I, Form

II, and the amorphous form of Compound B, R/S. The top DSC curve shows the entire thermal behavior of Form I, which converts to Form II via solid-solid transformation at 117 ⁰C, followed by melt of Form II at 143⁰C. The second to top DSC curve shows the endotherm of Form I up to 120 ⁰C (this sample was cooled to room temperature for the second heating). The third to top DSC curve shows the thermogram of Form II. The bottom DSC curve shows the thermogram of an amorphous form produced by heating the sample to above 150 ⁰C.

Figure 3 illustrates the powder X-ray diffraction pattern of both Form I (bottom pattern) of Compound B, R/S and Form II of Compound B, R/S (top pattern) exhibiting characteristic X-ray diffraction patterns.

Figure 4 is a diagram illustrating the crystal structure, using X-ray crystallographic analysis, of a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- [l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, R/R, form (b)) and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]- N-(pyrazin-2-yl)-propionamide (Compound A, S/R, form (a)).

Figure 5 is a differential scanning calorimetry (DSC) thermogram of the 50:50 isomeric mixture Compound A, R/R and Compound A, S/R which exhibits an endotherm around 165 ⁰C. The present invention thus provides a novel crystallization method that successfully crystallizes amorphous glucokinase activators. The method provides for crystallizing a glucokinase activator that comprises the steps of (a) dissolving an amorphous glucokinase activator in a non-chemically reactive lipid solvent to form a supersaturated solution; and (b) maintaining the supersaturated solution at a temperature range from 5 ⁰C above to 5 ⁰C below the glass transition temperature of the amorphous glucokinase activator for a period of time until a crystal of the glucokinase activator is formed. The discovery of crystalline forms of glucokinase activators contributes significantly to the improved quality of the active pharmaceutical ingredient (API) with respect to the impurities profiles. The novel crystalline forms of the glucokinase activators provide pharmaceutical solid dosage forms that may be manufactured reproducibly and are released in a uniform dissolution profile maximizing bioavailability and minimizing variability. The novel pharmaceutical solid dosage forms are preferably prepared in capsule dosage form to provide a relatively faster and more reproducible dissolution profile.

As used herein, the following terms have the given meanings:

The term "amorphous form" refers to compounds that lack the long-range order of molecular packing and have a tendency to gel when exposed to aqueous media because of their inherent physical properties, such as having a tendency to be plasticized by water.

The term "glass transition temperature" or "T₉" is the temperature below which molecules have little relative mobility. T₉ is usually applicable to wholly or partially amorphous phases. The glass transition temperature is the mid-point of a temperature range in which the molecules gradually become more viscous and change from being liquid to solid. The glass transition temperature is also referred to as the mid-point of a temperature range in which the molecules change from a rubbery state into a glassy state and vice versa.

The term "non-chemically reactive lipid solvent," means a solvent, which does not chemically interact with the glucokinase activators of the present invention. The solvent may or may not alter the isomeric composition of the glucokinase activator. For example, the solvent may convert a single amorphous form of a glucokinase activator into a crystalline mixture of isomers of the glucokinase activator.

The term "pharmaceutically acceptable," such as pharmaceutically acceptable carriers, excipients etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6^th Ed. 1995) at pp. 196 and 1456-1457.

The term "polymorph" refers to molecules of a compound that stack in the solid state in distinct ways. By varying the temperature of the solution and using different solvents, different polymorphs can be formed. Although identical in chemical composition, polymorphs can have very different properties. Polymorphs are distinguishable by various analytical techniques, especially X-ray powder diffraction patterns.

The term "prodrug" refers to compounds, which undergo biotransformation prior to exhibiting their pharmacological effects. The chemical modification of drugs to overcome pharmaceutical problems has also been termed "drug latentiation." Drug latentiation is the chemical modification of a biologically active compound to form a new compound, which upon in vivo enzymatic attack will liberate the parent compound. The chemical alterations of the parent compound are such that the change in physicochemical properties will affect the absorption, distribution and enzymatic metabolism. The definition of drug latentiation has also been extended to include nonenzymatic regeneration of the parent compound. Regeneration takes place as a consequence of hydrolytic, dissociative, and other reactions not necessarily enzyme mediated. The terms prodrugs, latentiated drugs, and bio-reversible derivatives are used interchangeably. By inference, latentiation implies a time lag element or time component involved in regenerating the bioactive parent molecule in vivo. The term prodrug is general in that it includes latentiated drug derivatives as well as those substances, which are converted after administration to the actual substance, which combines with receptors. The term prodrug is a generic term for agents, which undergo biotransformation prior to exhibiting their pharmacological actions.

The term "supersaturated solution" refers to a solution that contains more of the dissolved material than could be dissolved by the solvent under normal circumstances. A supersaturated solution can also refer to a vapor of a compound that has a higher (partial) pressure than the vapor pressure of that compound. In the present invention, the supersaturated solution is supersaturated against a (potential) crystalline form, not against an amorphous form. Usually amorphous forms have a much higher solubility than a crystalline form. In the present case, the solution employed was undersaturated for the amorphous form but was supersaturated against the crystalline form. In this way, the amorphous form does not precipitate until it crystallizes.

The term "therapeutically effective amount" means an amount of a therapeutically effective compound, or a pharmaceutically acceptable salt thereof, which is effective to treat, prevent, alleviate or ameliorate symptoms of a disease.

The present invention provides a method for crystallizing a glucokinase activator that comprises the steps of (a) dissolving an amorphous glucokinase activator in a non- chemically reactive lipid solvent to form a supersaturated solution; and (b) maintaining the supersaturated solution at a temperature range from 5 ⁰C above to 5 ⁰C below the glass transition temperature of the amorphous glucokinase activator for a period of time until a crystal of the glucokinase activator is formed. Preferably, the crystallized glucokinase activator is provided in a pharmaceutical dosage form that is administered to a mammal, more preferably, the dosage form is administered to a human.

The amorphous forms of the glucokinase activators in the present invention may be selected from a wide variety of glucokinase activators and the pharmaceutically acceptable salts thereof. The amorphous glucokinase activators lack the long-range order of molecular packing and having a tendency to gel when exposed to aqueous media. Glucokinase activators are compounds developed for the primary indication treatment of type 2 diabetes mellitus and future indications impairing fasting glucose (IFG) and impaired glucose tolerance (IGT). Preferred glucokinase activators are 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, R/R), 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo- cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, S/R), and 2(R)-(3-chloro- 4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]- propionamide (Compound B). One preferred glucokinase activator is 2(R)-(3-chloro-4-methanesulfonyl-phenyl)- 3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, R/R):

The preparation of Compound A, R/R (amorphous) is disclosed in United States Patent No. 7,105,671, which disclosure is incorporated by reference herein. The preparation of Compound A, R/R IPA (the isopropanol solvate of Compound A) is disclosed in PCT international patent application No. PCT/EP2007/053153, which disclosure is incorporated by reference herein. Another preferred glucokinase activator is 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2- yl)-propionamide (Compound A, S/R).

Still another preferred glucokinase activator is 2(R)-(3-chloro-4-methanesulfonyl- phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide (Compound B):

The preparation of Compound B is disclosed in United States published patent application No. US 2004/0147748 Al, which disclosure is incorporated by reference herein.

The non-chemically reactive lipid solvent employed to dissolve the amorphous glucokinase activator to form a supersaturated condition preferably has suitable solubilizing properties, viscosities, and polarities and preferably does not chemically interact with the glucokinase activator. The solvent may or may not alter the isomeric composition of the glucokinase activator. For example, the solvent may convert a single amorphous form of a glucokinase activator into a crystalline mixture of isomers of the glucokinase activator. The amorphous glucokinase activator is preferably soluble in the lipid solvent at a temperature range from 5 ⁰C above to 5 ⁰C below the glass transition temperature of the amorphous glucokinase activator. The viscosity of the non-reactive lipid solvent (resistance to flow) in the supersaturated solution (prior to being subjected to forced crystallization) should be in the range from 85 to 4000 cps (centipoises) at 25 ⁰C. The polarity of the non-reactive lipid solvent (ionizability) should have a hydrophile- lipophile balance (HLB) value from 3 to 15. A more oil-soluble emulsifier shows a lower HLB value and a more water-soluble emulsifier shows a higher HLB value.

Non-limiting illustrative examples of suitable non-reactive lipid solvents include mixtures of glycerol and polyethylene glycol 1500 esters of long chain fatty acids (i.e., Gelucire^® 44/14), propylene glycol monocaprylate (i.e. Capmul^® PG-8, a propylene glycol monoester of medium chain fatty acids, mainly caprylic), and glycerol caprylates (i.e. Capmul^® MCM, a mono-diglyceride of medium chain fatty acids, mainly caprylic and capric).

Optionally, a preservative may be included in the non-reactive lipid solvent. Nonlimiting illustrative examples of preservatives include butyl hydroxyanisole (BHA) and butyl hydroxytolulene (BHT).

In another specific embodiment, the present invention provides a crystalline polymorph Form I of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N- [5-( l(S),2-dihydroxyethyl)-pyrazin-2-yl] -propionamide, and hydrates thereof.

In still another specific embodiment, the present invention provides a crystalline polymorph Form II of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N- [5-( l(S),2-dihydroxyethyl)-pyrazin-2-yl] -propionamide, and hydrates thereof.

In still yet another specific embodiment, the present invention provides a crystalline polymorph of a 50:50 mixture of crystalline 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3- [ l(R)-3-oxo-cyclopentyl] -N-(pyrazin-2-yl)-propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[ l(R)-3-oxo-cyclopentyl] -N-(pyrazin- 2-yl)-propionamide, and hydrates thereof.

In a further embodiment, the invention provides a pharmaceutical composition comprising crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N- [5-( l(S),2-dihydroxyethyl)-pyrazin-2-yl] -propionamide and a pharmaceutically acceptable carrier.

Useful pharmaceutical acceptable carriers for the preparation of the compositions hereof, can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances, including additional active ingredients.

In yet another embodiment, provided is the use of crystalline 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]- propionamide for the preparation of a medicament for the treatment of diabetes.

In still another embodiment, the invention provides a pharmaceutical composition comprising a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- [l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide and 2(S)-(3-chloro-4- methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide and a pharmaceutically acceptable carrier.

In addition, the use of a 50:50 mixture of crystalline 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin- 2-yl)-propionamide for the preparation of a medicament for the treatment of diabetes is provided. The methods for crystallizing glucokinase activators of the present invention can be prepared according to the examples set out below. The examples are presented for purposes of demonstrating, but not limiting, the preparation of the dosage forms of this invention.

Examples

The following examples are provided to illustrate methods for preparing crystalline glucokinase activators

Example 1

In this example, crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide (Compound B, R/S) was prepared from amorphous Compound B, R/S by the following procedure.

Capmul^® PG-8 (34.990 g) was added to a jacketed vessel using water as a heating medium. The mixture was slowly heated to 50 ⁰C until the Capmul^® PG-8 was completely melted. Butyl hydroxyanisole (0.005g, BHA) and butyl hydroxytolulene (0.005g, BHT) were then added to the Capmul^® 44/14 and the mixture was mixed with a propeller mixer until the BHA and BHT were completely dissolved. Amorphous Compound B, R/S (15.0 g) was then added to the above solution and mixing was continued at high speed until the Compound B, R/S was completely dissolved. The above solution was then encapsulated using hard gelatin capsules (Size # 1) with an equivalent of 100 mg of Compound B, R/S as set out below.

The capsules were stored at 40 °C/75%RH and packaged in 4 oz high-density polyethylene (OHDP) bottles, induction sealed with a child resistant cap. After 6 months of storage at 40 °C/75%RH, the capsules were visually inspected for the formation of crystals. The crystals were extracted from the fill by dispersing the Capmul^® PG-8 in water/ethanol (50:50) and then filtering the crystals using a 0.45 micron filter. The crystals were dried in an oven at 40 ⁰C. The dried crystals were then submitted for solid- state characterization.

Solid State Characterization and Supportive Data

Figure 1 is a diagram illustrating the crystal structure, using X-ray crystallographic analysis, of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2- dihydroxyethyl)-pyrazin-2-yl]-propionamide (Compound B, R/S) showing the numbering scheme employed. The crystal structure of Compound B, R/S was determined as follows.

A colorless prism of C21H26CIN3O5S (Compound B, R/S), approximate dimensions 0.13 x 0.21 x 0.31mm³, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured at 110 K on an Xcalibur3 system equipped with a graphite monochromator and an Enhance (Mo) X-ray Source (λ = 0.71073A) operated at 2 kW power (50 kV, 40 mA). The detector was placed at a distance of 50 mm. from the crystal. The final cell constants of a = 8.9085(1 I)A, b = 10.0456(1 I)A, c = 24.943(3)A, α = 90°, β = 90°, γ = 90°, volume = 2232.1(4) A³, were obtained through a refinement of 5367 reflections to a maximum resolution of 0.74 A. The following table gives the data collection scan parameters for Compound B, R/S.

# Type Start End Width Time ω θ K φ Frames

1 phi 0.00 320.00 1.00 5.00 31.00 -22.00 31.00 320

2 omega -101.82 -6.82 1.00 5.00 -32.00 141.00 0.00 95

3 omega -83.01 43.99 1.00 5.00 -32.00 21.00 0.00 127

4 omega -105i -0.88 1.00 5.00 -32.00 -39.00 0.00 105

5 omega -73.13 34.87 1.00 5.00 -32.00 91.00 20.00 108

The frames were integrated with the Oxford Diffraction CrysAHsRED software package (CrysAHs CCD, Oxford Diffraction Ltd., Version 1.171.1 beta (release 21.07.2003 CrysAlisl71 VC++). The integration of the data using an orthorhombic cell yielded a total of 36438 reflections to a maximum θ angle of 33.43° (0.65 A resolution). The structure was solved and refined using the Bruker SHELXTL (v6.1) software package (Sheldrick, G.M. (2000). SHELXTL version 6.10. Bruker AXS Inc., Madison, Wisconsin, USA). Analysis of the data showed no negligible decay. Additional crystallographic data are given in Tables 1 and 2.

Table 1

Sample and crystal data for Compound B, R/S.

Identification code Compound B, R/S Chemical formula C₂IH₂₆ClN₃O₅S

Empirical formula C₂IH₂₆ClN₃O₅S

Formula weight 467.96

Temperature HO K

Wavelength 0.71073 A Crystal size 0.30923 x 0.21124 x 0.12673 mm

Crystal habit colorless prism

Crystal system Orthorhombic

Space group P2i2i2i

Unit cell dimensions a = 8.9085(11) A α= 90° b = 10.0456(11) A β= 90° c = 24.943(3) A λ = 90°

Volume 2232.1(4) A³ Z 4

Density (calculated) 1.392 Mg/m³ Absorption coefficient 0.30275 mm^{" 1} F(OOO) 984 Table 2

Data collection and structure refinement for Compound B, R/S.

Diffractometer Xcalibur3

Radiation source Enhance (Mo) X-ray Source, Mo Ka Generator power 2 kW (50 kV, 40 mA)

Detector distance 50

Data collection method phi and omega scans

Theta range for data collection 4.37 to 33.43° Index ranges -11 ≤ h < 13, -15 < k ≤ 15, -37 ≤ I < 37 Reflections collected 36438

Independent reflections 8170 [R(int) = 0.0281]

Coverage of independent reflections 96.0 %

Variation in check reflections n/a

Absorption correction Numerical Max. and min. transmission 0.92994 and 0.87861

Structure solution technique Direct Methods Structure solution program Sheldrick, G.M. (2000). SHELXTL vό.10. Refinement technique Full-matrix least-squares on F²

Refinement program Sheldrick, G.M. (2000). SHELXTL vό.10. Function minimized Σ W(FQ² - Fc²)²

Data / restraints / parameters 8170 / 0 / 338 Goodness-of-fit on F² 1.082

Δ/σ max 0.001 Final R indices(*)

6141data; I>2s (I) Rl = 0.0502, wR2 = 0.1274

all data Rl = 0.0646, wR2 = 0.1347

Weighting scheme w = l/[σ ²(F₀ ²) +[(0.0805P) ² +0.0000P]

where P = [MAX(F ₀ ² ,0) + 2F_C ² ]/ 3

Absolute structure parameter -0.03(5)

Largest diff. peak and hole 0.921 and -0.553 eA^~3

R.M.S. deviation from the mean 0.070 eA^~3

R = Σ |F₀ - FcI / ∑ |F₀| & wR2 = Σ w(F₀ ² - F_c ²)² / Σ (F₀ ² )²

From the X-ray crystallographic analysis, the following parameters for Compound B, R/S were determined: atomic coordinates and equivalent isotropicatomic displacement parameters (A²); bond lengths (A); bond angles (A); torsion angles (A); anisotropic atomic displacement parameters (A²); hydrogen atom coordinates and isotropic atomic displacement parameters (A²). This data was employed in determining the crystal structure of Compound B, R/S set out in Figure 3.

Thermal Properties of Compound B, R/S

A thermogram of Form I of Compound B, R/S exhibited a first endotherm around 117 ⁰C, followed by a shallow and broad exothermic event, and a second endotherm around 143 ⁰C. It was found that the first endotherm of Compound B, R/S was due to phase transformation of Form I to Form II of Compound B, R/S , and the second endotherm was due to melting of Form II into an amorphous form. A heating cycle study showed that Form I of Compound B, R/S undergoes polymorphic transformation around 117 ⁰C to Form II of Compound B, R/S. Once Form II was melted, the compound solidified to an amorphous form of Compound B, R/S, showing a glass transition temperature of 79 ⁰C.

Figure 2 is a differential scanning calorimetry (DSC) thermogram of Form I, Form II, and the amorphous form of Compound B, R/S. The top DSC curve shows the entire thermal behavior of Form I, which converts to Form II via solid-solid transformation at 117 ⁰C, followed by melt of Form II at 143⁰C. The second to top DSC curve shows the endotherm of Form I up to 120 ⁰C (this sample was cooled to room temperature for the second heating). The third to top DSC curve shows the thermogram of Form II. The bottom DSC curve shows the thermogram of an amorphous form produced by heating the sample to above 150 ⁰C.

Figure 3 illustrates the powder X-ray diffraction pattern of both Form I (bottom patter) of Compound B, R/S and Form II of Compound B, R/S (top pattern) exhibiting characteristic X-ray diffraction patterns.

Compound B, R/S Scale-Up Crystallization

A solution containing 30 g of amorphous compound Compound B, R/S, purity 98.29 area% (HPLC detection at 230 nm) and dr 97.34 : 1.71 (RS / SS), in isopropyl acetate was concentrated to a weight of 100 g. To the solution were added seeds (150 mg) of the crystalline compound and the mixture was stirred at ambient temperature for 4 h, then at 36-37 ⁰C for 16 h. A suspension of white solids obtained. The suspension was stirred at ambient temperature for another 2.5 days. Then the suspension was concentrated further by removing slowly 32 g of solvent in a stream of nitrogen and allowed to stir for another day at ambient temperature. Then the suspension was cooled briefly to -10 ⁰C and the solids were filtered, washed with 10 mL of cold (-10 ⁰C) isopropyl acetate and dried by suction on the filter to give 22.86 g of a white solid, purity 99.65 area%, dr 99.68: 0.32. The solid was dried further in a vacuum oven at 50 ⁰C / 28 in Hg for 1.5 h to give 22.72 g of a white solid, which contained 0.3 wt% isopropanol.

Example 2

In this example, a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl- phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, R/R) and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]- N-(pyrazin-2-yl)-propionamide (Compound A, S/R) was prepared from amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2- yl)-propionamide (Compound A, R/R) by the following procedure.

Gelucire^® 44/14 (34.990 g) was added to a jacketed vessel using water as a heating medium. The mixture was slowly heated to 50 ⁰C until the Gelucire^® 44/14 was completely melted. Butyl hydroxyanisole (0.005g, BHA) and butyl hydroxytolulene

(0.005g, BHT) were then added to the Gelucire^® 44/14 and the mixture was mixed with a propeller mixer until the BHA and BHT were completely dissolved. Amorphous Compound A, R/R (15.0 g) was then added to the above solution and mixing was continued at high speed until the Compound A, R/R was completely dissolved. The above solution was then encapsulated using hard gelatin capsules (Size # 1) with an equivalent of 100 mg of Compound A, R/R as set out below.

The capsules were stored at 40 °C/75%RH and packaged in 4 oz high-density polyethylene (OHDP) bottles, induction sealed with a child resistant cap. After 6 months of storage at 40775%RH, the capsules were visually inspected for the formation of crystals. The crystals were extracted from the fill by dispersing the Gelucire^® 44/14 in water/ethanol (50:50) and then filtering the crystals using a 0.45 micron filter. The crystals were dried in an oven at 40⁰C. The dried crystals were then submitted for solid- state characterization. The dried crystals were found to be a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2- yl)-propionamide (Compound A, R/R) and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)- 3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, S/R).

Solid State Characterization and Supportive Data

Figure 4 is a diagram illustrating the crystal structure, using X-ray crystallographic analysis, of a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- [l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide (Compound A, R/R, form (b)) and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]- N-(pyrazin-2-yl)-propionamide (Compound A, S/R, form (a)). The diagram shows the numbering scheme employed. The structure contains two stereoisomers, the 2S (form (a)) and 2R (form (b)) configurations. The chiral center at C 10 is R in both molecules.

Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius. Note the change in chirality at C2. The crystal structure of the 50:50 isomeric mixture Compound A, R/R and Compound A, S/R was determined as follows. A colorless block of C1₉H20CIN3O4S (50:50 isomeric mixture Compound A, R/R and Compound A, S/R), approximate dimensions 0.016 mm x 0.064 mm x 0.081 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured at 110 K on an Xcalibur3 system equipped with a graphite monochromator and an Enhance (Mo) X-ray Source (λ = 0.71073A) operated at 2 kW power (50 kV, 40 mA). The detector was placed at a distance of 50 mm. from the crystal. The final cell constants of a = 9.5555(9)A, b = 10.4576(9)A, c = 11.6925(1O)A, α = 65.527(8)°, β = 71.368(8)°, λ = 67.902(9)°, volume = 966.58(15)A³, were obtained through a global refinement of all reflections. The following table gives the data collection scan parameters for the 50:50 isomeric mixture Compound A, R/R and Compound A, S/R:

# Type Start End Width Time ω θ φ Frames

1 phi 0.00 320.00 1.00 20.00 -9.00 -30.00 21.00 320

2 omega -106.38 36.62 1.00 20.00 -30.00 -19.00 60.00 143

3 omega -103.00 4.00 1.00 20.00 -30.00 -79.00 340.00 107

4 omega -0.52 92.48 1.00 20.00 30.00 -129.00 330.00 93

5 omega -110.63 -19.63 1.00 20.00 -30.00 161.00 0.00 91

The frames were integrated with the Oxford Diffraction CrysAHsRED software package. The integration of the data using a Triclinic cell yielded a total of 17579 reflections to a maximum θ angle of 32.98° (0.65 A resolution). The structure was solved and refined using the Bruker SHELXTL (v6.1) software package. Analysis of the data showed no negligible decay. Additional crystallographic data are given in Tables 3 and 4. Table 3

Sample and crystal data for 50:50 isomeric mixture of Compound A, R/R and Compound A, S/R

Identification code 50:50 isomeric mixture

Compound A, R/R and Compound A, S/R

Crystallization solvents none

Crystallization method crystallization from polymer

Chemical formula Ci₉H₂₀ClN₃O₄S

Empirical formula Ci₉H₂₀ClN₃O₄S Formula weight 421.89

Temperature HO K

Wavelength 0.71073 A

Crystal size 0.08085 x 0.06425 x 0.01584 mm

Crystal habit colorless block Crystal system Triclinic

Space group Pl

Unit cell dimensions a = 9.5555(9) A α= 65.527(8)° b = 10.4576(9) A β= 71.368(8)° c = 11.6925(1O) A λ = 67.902(9)° Volume 966.58(15) A³ Z 2

Density (calculated) 1.450 Mg/m³ Absorption coefficient 0.33731 mm^{" 1} F(OOO) 440 Table 4

Data collection and structure refinement for 50:50 isomeric mixture of Compound A, R/R and Compound A, S/R

Diffractometer Xcalibur3 Radiation source Enhance (Mo) X-ray Source, Mo Ka

Generator power 2 kW (50 kV, 40 mA)

Detector distance 50

Data collection method phi and omega scans

Theta range for data collection 4.00 to 32.98° Index ranges -14 ≤ h < 14, -15 ≤ k < 15, -16 ≤ I < 17

Reflections collected 17579

Independent reflections 11508 [R(int) = 0.0337]

Coverage of independent reflections 89.0 %

Variation in check reflections n/a Absorption correction Numerical

Max. and min. transmission 0.97811 and 0.95647

Structure solution technique Direct Methods

Structure solution program Sheldrick, G.M. (2000). SHELXTL vό.10.

Refinement technique Full-matrix least-squares on F² Refinement program Sheldrick, G.M. (2000). SHELXTL vό.10.

Function minimized ∑ w(F_o ² - F_C2)2

Data / restraints / parameters 11508 / 3 / 513 Goodness-of-fit on F² 0.816 Δ^/σmax 0.343 Final R indices(*)

6523data; I>2s (I) Rl = 0.0480, wR2 = 0.0834 all data Rl = 0.0803, wR2 = 0.0906 Weighting scheme w = l/[σ ²(F_O ²) +[(0.0346P) ² +0.0000P] where P = [MAX(F _o ² ,0) + 2F_C ² ]/3 Absolute structure parameter -0.04(4) Largest diff. peak and hole 0.778 and -0.467 eA^"3 R.M.S. deviation from the mean 0.066 eA^"3

R = Σ |F_O - F_c| / ∑ |F_O| & wR2 = ∑ w(F_o ² - F_C2)2 / ∑ (F_Q2 )2

From the X-ray crystallographic analysis, the following parameters for the 50:50 isomeric mixture Compound A, R/R and Compound A, S/R were determined: atomic coordinates and equivalent isotropicatomic displacement parameters (A^); bond lengths (A); bond angles (A); torsion angles (A); anisotropic atomic displacement parameters (A^); hydrogen atom coordinates and isotropic atomic displacement parameters (A^). This data was employed in determining the crystal structure of the 50:50 isomeric mixture Compound A, R/R and Compound A, S/R set out in Figure 4.

Thermal Properties of 50:50 Isomeric Mixture of Compound A, R/R and Compound A, S/R

Figure 5 is a differential scanning calorimetry (DSC) thermogram of the 50:50 isomeric mixture Compound A, R/R and Compound A, S/R which exhibits an endo therm around 165 ⁰C.

Claims

1. A method for crystallizing a glucokinase activator that comprises the steps of:

(a) dissolving an amorphous glucokinase activator in a non-chemically reactive lipid solvent to form a supersaturated solution; and

(b) maintaining the supersaturated solution at a temperature range from

5 ⁰C above to 5 ⁰C below the glass transition temperature of the amorphous glucokinase activator for a period of time until a crystal of the glucokinase activator is formed.

2. The method according to claim 1, wherein the glucokinase activator is selected from the group consisting of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- [ l(R)-3-oxo- cyclopentyl] -N- (pyrazin-2-yl) -propionamide, 2(S)-(3-chloro-4-methanesulfonyl- phenyl)-3- [ l(R)-3-oxo-cyclopentyl] -N-(pyrazin-2-yl)-propionamide, and 2(R) -(3- chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N- [5-( l(S),2-dihydroxyethyl)-pyrazin- 2-yl] -propionamide.

3. The method according to claim 2, wherein the glucokinase activator is 2(R) -(3- chloro-4-methanesulfonyl-phenyl)-3- [ l(R)-3-oxo-cyclopentyl] -N-(pyrazin-2-yl)- propionamide.

4. The method according to claim 2, wherein the glucokinase activator is 2(S)-(3- chloro-4-methanesulfonyl-phenyl)-3- [ l(R)-3-oxo-cyclopentyl] -N-(pyrazin-2-yl)- propionamide.

5. The method according to claim 2, wherein the glucokinase activator is 2(R) -(3- chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N- [5-( l(S),2-dihydroxyethyl)-pyrazin- 2-yl] -propionamide.

6. The method according to claim 1, wherein the non-chemically reactive lipid solvent has a hydrophile-lipophile balance value from 3 to 15 and the supersaturated solution has a viscosity in the range from 85 to 4000 cps at 25 ⁰C.

7. The method according to claim 1, wherein the lipid is selected from the group consisting of mixtures of glycerol and polyethylene glycol 1500 esters of long chain fatty acids, propylene glycol monoesters of caprylic acids, and mono-diglycerides of caprylic and capric fatty acids.

8. A method for crystallizing a glucokinase activator, comprising the steps of:

(a) heating Capmul^® PG-8 in a vessel to 50⁰C until the Gelucire^® 44/14 melts;

(b) adding butyl hydroxyanisole and butyl hydroxytolulene to the vessel in step (a) with stirring until the butyl hydroxyanisole and butyl hydroxytolulene is dissolved;

(c) adding amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide to the mixture in step (b) with stirring until the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide is dissolved;

(d) encapsulating the mixture from step (c) into capsules having the quantitative composition set out below;

(e) storing the capsules from step (d) at 40°C/75%RH for 6 months to form crystals; and

(f) extracting the crystals from the capsules by dispersing the contents of the capsules in water/ethanol (50:50) and then filtering the crystals to obtain crystalline 2(R)- (3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)- pyrazin-2-yl] -propionamide.

9. A method for crystallizing a glucokinase activator, comprising the steps of:

(a) heating Gelucire^® 44/14 in a vessel to 50⁰C until the Gelucire^® 44/14 melts;

(c) adding amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo- cyclopentyl]-N-(pyrazin-2-yl)-propionamide to the mixture in step (b) with stirring until the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]- N-(pyrazin-2-yl)-propionamide is dissolved;

(f) extracting the crystals from the capsules by dispersing the contents of the capsules in water/ethanol (50:50) and then filtering the crystals to obtain a 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- [ l(R)-3-oxo-cyclopentyl] - N-(pyrazin-2-yl)-propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3- [l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide.

10. A crystalline polymorph Form I of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)- 3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide, and hydrates thereof, having a differential scanning calorimetry thermogram substantially as depicted in Figure 2.

11. A crystalline polymorph Form II of 2(R)-(3-chloro-4-methanesulfonyl- phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide, and hydrates thereof, having a differential scanning calorimetry thermogram substantially as depicted in Figure 2.

12. A crystalline polymorph Form I of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)- 3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide, and hydrates thereof, having an X-ray powder diffraction pattern substantially as depicted in Figure 3.

13. A crystalline polymorph Form II of 2(R)-(3-chloro-4-methanesulfonyl- phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide, and hydrates thereof, having an X-ray powder diffraction pattern substantially as depicted in Figure 3.

14. A crystalline polymorph of a 50:50 mixture of crystalline 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin- 2-yl)-propionamide, and hydrates thereof, having a differential scanning calorimetry thermogram substantially as depicted in Figure 5.

15. Crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide prepared by a process comprising the steps of:

(c) adding amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-

N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]-propionamide to the mixture in step (b) with stirring until the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- N- [5-( 1 (S),2-dihydroxyethyl)-pyrazin-2-yl] -propionamide is dissolved; (d) encapsulating the mixture from step (c) into capsules having the quantitative composition set out below;

(e) storing the capsules from step (d) at 40 °C/75%RH for 6 months to form crystals; and

16. A 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-

[1 (R) -3-oxo-cyclopentyl]-N-(pyrazin-2-yl) -propionamide and 2(S)-(3-chloro-4- methanesulfonyl-phenyl) -3- [1 (R) -3-oxo-cyclopentyl]-N-(pyrazin-2-yl) -propionamide prepared by a process comprising the steps of:

(a) heating Gelucire^® 44/14 in a vessel to 50 ⁰C until the Gelucire^® 44/14 melts;

(c) adding amorphous 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo- cyclopentyl] -N- (pyrazin-2-yl) -propionamide to the mixture in step (b) with stirring until the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]- N-(pyrazin-2-yl)-propionamide is dissolved;

17. A pharmaceutical composition comprising crystalline 2(R)-(3-chloro-4- methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl]- propionamide and a pharmaceutically acceptable carrier.

18. The use of crystalline 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3- cyclopentyl-N-[5-(l(S),2-dihydroxyethyl)-pyrazin-2-yl] -propionamide for the preparation of a medicament for the treatment of diabetes.

19. A pharmaceutical composition comprising a 50:50 mixture of crystalline 2(R)- (3-chloro-4-methanesulfonyl-phenyl)-3- [ l(R)-3-oxo-cyclopentyl] -N-(pyrazin-2-yl)- propionamide and 2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo- cyclopentyl]-N-(pyrazin-2-yl)-propionamide and a pharmaceutically acceptable carrier.

20. The use of 50:50 mixture of crystalline 2(R)-(3-chloro-4-methanesulfonyl- phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)-propionamide and 2(S) -(3- chloro-4-methanesulfonyl-phenyl)-3-[l(R)-3-oxo-cyclopentyl]-N-(pyrazin-2-yl)- propionamide for the preparation of a medicament for the treatment of diabetes.

21. The methods or crystalline polymorphs as described herein before.

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