WO2012131707A2

WO2012131707A2 - Novel crystalline form of bortezomib, process for the preparation and pharmaceutical composition thereof

Info

Publication number: WO2012131707A2
Application number: PCT/IN2012/000196
Authority: WO
Inventors: Srivardhana Rao JAMJANAM; Venkata Ramakrishna Murthy MOTURU; Venkata Lakshmi Narasimha Rao Dammalapati; Seeta Ramanjaneyulu Gorantla
Original assignee: Laurus Labs Private Limited
Priority date: 2011-03-28
Filing date: 2012-03-23
Publication date: 2012-10-04
Also published as: WO2012131707A3

Abstract

The present invention provides a novel crystalline form AL of bortezomib and a process for its preparation. The present invention also provides a pharmaceutical composition using the novel crystalline form AL of bortezomib.

Description

NOVEL CRYSTALLINE FORM OF BORTEZOMIB, PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF

PRIORITY

This application claims the benefit under Indian Provisional Application No. 957/CHE/201 1 filed March 28, 2011 and entitled "Novel crystalline form of bortezomib, process for the preparation and pharmaceutical composition thereof ", the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION The present invention generally relates to a novel crystalline form of bortezomib, processes for its preparation and a pharmaceutical composition containing the same.

BACKGROUND OF THE INVENTION

Bortezomib [CAS Registry Number: 179324-69-7], monomeric boronic acid, also known as [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinyl- carbonyl) amino] propyl] amino] butyl] boronic acid [C₁9H₂₅BN₄0₄], is represented by the structure of Formula I:

Bortezomib is a modified dipeptidyl boronic acid acts to inhibit proteasome and has been indicated for use in treating mantle cell lymphoma and multiple myeloma. Bortezomib is available in the market under the brand name VELCADE™ in the form of intravenous injection. Each vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Bortezomib exists as the trimeric boroxine in the solid state; when exposed to water, the boroxine hydrolyzes to the monomeric boronic acid.

U.S. Patent No. 5,780,454 ("the '454 patent") discloses peptidyl boronic acid and its ester compounds such as bortezomib. The '454 patent further discloses a process for the preparation of bortezomib, its anti-neoplastic activity and its use in pharmaceutical product. U.S. Patent No. 6,713,446 ("the '446 patent") discloses lyophilized formulation of bortezomib esters. The '446 patent further discloses bortezomib prepared by the process as described in the '454 patent is white amorphous powder and is unstable at 2°C - 8°C over a period of longer than 3 to 6 months.

PCT publication WO 2008/075376 ("the '376 publication") discloses two crystalline polymorphic forms of bortezomib such as Form I and Form II and process for its preparation. The crystalline Form I and Form II are characterized by XRPD, IR patterns and DSC thermograms.

PCT publication WO 2009/036281 ("the '281 publication") discloses two crystalline polymorphic forms of bortezomib such as Form A and Form B and process for its preparation. Form A of bortezomib is prepared by using mixture of solvent methanol and diluent water. Form B of bortezomib is prepared by using solvents mixture(s) of toluene, ethyl acetate, and methylene chloride. The '281 publication further discloses Form A has moisture content up to about 5% by weight and Form B has up to about 3% by weight.

PCT publication WO 2011/099018 ("the '018 publication") discloses crystalline Form HI of bortezomib characterized by XRPD peaks at about 6.8, 13.2, 18.2, 19.1 and 19.5 ± 0.2° 2Θ and process for its preparation. The '018 publication further discloses processes for preparation of amorphous bortezomib.

PCT publication WO 201 1/107912 ("the '912 publication") discloses two crystalline polymorphic forms of bortezomib such as Form Al and Form A2 and process for its preparation. The crystalline Form Al was characterized by XRPD peaks at about 7.14, 8.51, 10.14, 12.20, 13.22, 14.57, 15.87, 16.71, 18.36, 18.91, 19.51, 21.35 and 25.34 ± 0.2° 2Θ and DSC melting thermogram between about 195°C and 205°C. The crystalline Form A2 was characterized by XRPD peaks at about 6.88, 7.20, 8.52, 10.06, 10.66, 12.19, 13.27, 14.64, 15.99, 16.55, 18.35, 19.05, 19.53, 21.39, 25.43 and 26.42 ± 0.2° 2Θ and DSC melting thermogram between about 170°C and 185°C and about 195°C and 210°C.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.

The discovery of new forms of active pharmaceutical ingredients ("APIs") provides opportunities to improve the performance characteristics, the solubility, stability, fiowability, tractability and compressibility of drug substances and the safety and efficacy of drug products of a pharmaceutical product. Such discoveries enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Hence, there remains a need for novel form of bortezomib.

A new polymorphic form of the bortezomib has now been discovered and has been designated as crystalline Form AL. The main object of the present invention is to provide novel crystalline form of bortezomib, which is more stable over the time and reproducible and so, are very useful during their pharmaceutical modifications.

Another object of the present invention relates to the processes for the preparation of novel crystalline form of bortezomib.

Yet another object of the present invention relates to a pharmaceutical composition comprising novel crystalline form of bortezomib. SUMMARY OF THE INVENTION

In accordance with the illustrated objectives, the invention encompasses novel crystalline form of bortezomib.

In accordance with one embodiment, the present invention provides novel crystalline form of bortezomib, hereinafter designated as crystalline Form AL.

In accordance with a second embodiment, the present invention provides crystalline Form AL of bortezomib characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 2.

In accordance with a third embodiment, the present invention provides crystalline Form AL of bortezomib, characterized by one or more X-Ray diffraction (XRD) peaks at about 6.0, 8.5, 12.2, 13.3, 14.1, 17.3, 18.8, 19, 19.6, 20, 21.6, 22.4, 23.2, 24.2, 24.6, 26, 26.8 and 27.3° ± 0.2° 2Θ.

In accordance with a fourth embodiment, the present invention provides crystalline Form AL of bortezomib having water content from about 5% to about 14% by weight.

In accordance with a fifth embodiment, the present invention provides crystalline Form AL of bortezomib having water content from about 7% to about 10% by weight.

In accordance with a sixth embodiment, the present invention provides crystalline Form AL of bortezomib having thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.

In accordance with a seventh embodiment, the present invention provides crystalline Form AL of bortezomib characterized by infrared absorption (IR) spectrum substantially in accordance with Figure 4.

In accordance with an eighth embodiment, the present invention provides process for preparing crystalline Form AL of bortezomib, comprising the steps of:

a) mixing bortezomib with water to obtain a slurry mixture,

b) slurrying the resultant mixture at ambient temperature,

c) isolating the bortezomib.

In accordance with a ninth embodiment, the present invention provides crystalline form AL of bortezomib free of its diastereomeric impurities and having a purity of greater than about 99.5% by HPLC.

In accordance with a tenth embodiment, the present invention provides crystalline form AL of bortezomib having less than about 0.1 % by HPLC of (R,R)-diastereomer by HPLC.

In accordance with an eleventh embodiment, the present invention provides a pharmaceutical composition comprising bortezomib prepared by the process of the present invention and at one or more pharmaceutically acceptable excipients. BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention. Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of bortezomib as obtained in Example - 1. Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Form AL of bortezomib as obtained in Example - 2. Figure 3 is the characteristic thermo gravimetric analysis (TGA) curve of crystalline Form AL of bortezomib as obtained in Example - 2.

Figure 4 is the characteristic infrared absorption (IR) spectrum of crystalline Form AL of bortezomib as obtained in Example - 2.

Figure 5 is the stability study table for crystalline polymorph Form AL of bortezomib. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel crystalline form of bortezomib and process for its preparation. Crystal forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. It is desirable to investigate all solid state forms of a drug, including all crystal/polymorphic forms, and to determine the stability, dissolution and flow properties of each crystal/polymorphic form. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Set, 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

The term "water content" refers to the content of water based upon the Loss on Drying method (the "LOD" method) as described in Pharmacopeial Forum, Vol. 24, No. 1 , p. 5438 (January-February 1998), the Karl Fisher assay for determining water content or thermo gravimetric analysis (TGA).

Thermogravimetry analysis (TGA) is a measure of the thermally induced weight loss of a material as a function of the applied temperature. TGA is restricted to transitions that involve either a gain or a loss of mass, and it is most commonly used to study desolvation processes and compound decomposition. Karl Fisher analysis, which is well known in the art, is also used to determine the quantity of water in a sample, for example Karl Fisher Coulometric technique.

As used herein the term "slurry" refers to a suspension of insoluble particles or slightly soluble particles in an aqueous or organic (non-aqueous) liquid, without complete dissolution of the solid.

In one embodiment, the present invention is directed to a novel crystalline form of bortezomib, designated as crystalline polymorph Form AL. The crystalline Form AL of bortezomib may be characterized by, for example, X-ray powder diffraction pattern and/or melting point. The powder XRPD spectrum for crystalline Form AL is presented in Figure 2. The X-Ray powder diffraction can be measured by an X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 40kV, 30 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50°26; step width=0.032° and scan speed=3°/minute.

As shown in Figure 3, the thermogravimetric analysis of crystalline Form AL of bortezomib recorded on TGA Q500 V 20.8 build 34 in platinum pan with a temperature rise of about 5°C/min in the range of about 30°C to about 300°C.

In another embodiment, the present invention provides process for preparing crystalline Form AL of bortezomib, comprising the steps of: a) mixing bortezomib with water to obtain a slurry mixture,

b) slurrying the resultant mixture at ambient temperature,

c) isolating the bortezomib. The starting material bortezomib is known in the art and can be prepared by any known method, for example starting bortezomib may be synthesized as disclosed in U.S. Patent No. 7,714,159. The starting bortezomib in the slurry may be any crystalline or other form of bortezomib, including various solvates, as long as bortezomib crystalline form is produced during the process of the invention.

The water used for the slurry of the invention is preferably degassed purified water. Bortezomib may be present in any amount that will produce the bortezomib crystalline form upon the process of the present invention. Preferably, the bortezomib is present in an amount of about 1% to about 50% by weight of the water, more preferably about 1% to about 40% by weight, still more preferably about 1% to about 30% by weight, most preferably about 1% to about 10% by weight. One skilled in the art would understand that depending on the temperature during the slurry, the amount of bortezomib used may be varied.

The slurry may be carried out with the aid of suitable temperature. Typically, the slurry may be heated at a temperature of about 0°C to about 65°C, preferably at about 25°C to about 55°C. The slurry may be prepared at other suitable temperatures as long as the bortezomib crystalline form is sufficiently formed. Routine experimentation will provide the approximate range of suitable temperatures for a given amount of water and bortezomib.

The slurry is optionally stirred for a period of time needed to achieve the desired transformation, and the solid compound collected and analyzed. Typically, the stirring time may be from about 5 minutes to about 24 hours, preferably about 1 hour to about 6 hours, more preferably about 2 hours to about 4 hours. The resultant product may be collected by techniques known in the art, e.g., filtration, to obtain pure bortezomib in crystalline Form. The temperature during the filtration may range from temperature at about 20°C to about 35°C. The resulting solid can then be filtered, washed with water to provide crystals of bortezomib. The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 50°C over a period of about 6 hours to about 24 hours, preferably drying can be carried out at a temperature of about 35 °C to 40°C over a period of about 15 hours.

The bortezomib recovered using the process of the present invention is in substantially pure bortezomib crystalline Form AL. The bortezomib crystalline Form AL can be characterized by one or more techniques for example, an X-Ray diffraction (XRD) pattern substantially in accordance with Figure.2.

In another embodiment, pure bortezomib crystalline Form AL obtained by the process of the present invention is characterized by TGA curve substantially in accordance with Figure. 3 corresponding to a weight loss of about 8.5%.

The process of the present invention advantageously provide crystalline form of bortezomib in relatively high purity, e.g., a purity of greater than or equal to about 98% as measure by high performance liquid chromatography (HPLC), preferably greater than or equal to about 99%, and more preferably greater than or equal to about 99.5%. The water used for the process of the present invention is not only effecting the formation of crystals of novel crystalline form AL of bortezomib, surprisingly found that it reduces the content of (R,R) and (S,S) diastereomeric impurities of Formula II and Formula III respectively during the slurrying process of the present invention.

In another embodiment, the present invention provides pure bortezomib in crystalline Form, obtained by the process described herein, substantially free of bortezomib diastereomeric impurities of Formula II and Formula III, wherein the word "substantially free" refers to bortezomib having less than about 0.5% of Formula II or Formula III, as measured by HPLC, more preferably less than about 0.2% of Formula II or Formula III, as measured by HPLC, still more preferably less than about 0.1 % of Formula II or Formula III, as measured by HPLC.

Formula II Formula III

In another embodiment, the process of the present invention advantageously provides bortezomib having low content of organic residual solvents, which are selectively removed during the water aided slurrying process of the present invention. The present invention further provides pure bortezomib in crystalline Form AL obtained by the process described herein, having relatively low content of one or more organic volatile impurities.

The present invention provides pure bortezomib crystalline form obtained using the process of the present invention described herein, may have a residual solvent content that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

The present invention provides pure bortezomib crystalline Form AL, obtained by the process disclosed herein, having less than about 800 parts per million (ppm) C_1-4 alcohols such as methanol, ethanol, isopropanol, preferably less than about 200 ppm; less than about 500 ppm ethyl acetate, preferably less than about 100 ppm; less than about 500 ppm toluene, preferably less than about 100 ppm; less than about 500 ppm tetrahydrofuran, preferably less than about 100 ppm; less than about 500 ppm of methylene chloride, ethylene chloride or chloroform, preferably less than about 100 ppm; less than about 500 ppm of acetone, preferably less than about 100 ppm; less than about 500 ppm of n-heptane, n-hexane, methyl cyclohexane or cyclohexane, preferably less than about 200 ppm; less than about 500 ppm of diisopropyl ether or methyl tertiary butyl ether, preferably less than about 100 ppm. The present invention further provides pure bortezomib crystalline form, obtained by the process disclosed herein, having less than about 37 ppm methanol; less than 190 ppm hexane; and less than about 10 ppm acetone, ethyl acetate, methylene chloride and methyl cyclohexane. The present invention provides bortezomib crystalline form, obtained by the above process, as analyzed using the chiral high performance liquid chromatography ("Chiral HPLC") with the conditions described below:

Column : Chiralpak AD-H, (250 x 4.6) mm, 5 μπι

Elution : Isocratic

Diluent : n-heptane: isopropyl alcohol: Ethanol (80:10:10)

Flow rate : 0.6 ml/min

Detection wavelength : 270 nm

Injection volume : ΙΟμΙ,

Run time : 70 minutes

The bortezomib crystalline Form AL of the present invention have good flow- properties and are far more stable at temperature about 0° to about 30°C.

The bortezomib crystalline Form AL obtained by the process as described above have an increased stability as compared to the known amorphous form obtained as per the '454 patent. The amorphous Form described in the '454 patent is unstable at 2°C - 8°C over a period of longer than 3 to 6 months. In contrast, the process herein described arrives at a bortezomib in crystalline Form AL is stable at about -20°C to about +30°C and 65% RH. Figure 5 shows stability study table of bortezomib crystalline Form AL of the present invention.

In another embodiment, the present invention provides a pharmaceutical composition comprising bortezomib crystalline Form AL prepared by the process of the present invention and at least one pharmaceutically acceptable excipient.

Bortezomib crystalline form AL obtained as per the process of the present invention is not only stable but also well suited for use in preparing pharmaceutical formulations. The pharmaceutical formulations according to the present application include but are not limited to solid oral dosage forms such as tablets, capsules, powders and so on; liquid oral dosage forms such as solutions, dispersions, suspensions, emulsions and so on; parenteral dosage forms (including intramuscular, subcutaneous, intravenous) such as injectable dosages by solution or suspension or dispersions or sterile powders for reconstitution; transdermal delivery systems; targeted delivery systems etc.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.

EXAMPLES:

EXAMPLE 1 : Purification of bortezomib from ethyl acetate.

Bortezomib (10 gms) and ethyl acetate (140 ml) were taken into a round bottom flask. The reaction mixture was heated to about 60° and the solution was filtered through 0.45 micron filter and washed with ethyl acetate (20 ml). The combined filtrate was allowed to cool to 25-35 °C, and stirred for 1-2 hrs. Further the reaction mixture was allowed to cool 0-5°C and stirred for another 2 hrs. The precipitated solids were filtered and washed with chilled ethyl acetate (20 ml). The product was crushed in a mortar and pestle and died under vacuum at 35°- 40°C for about 12 hrs to afford 8.0 g of the title compound.

HPLC purity (chemical): 99.6%

HPLC purity (chiral): 99.7%

The XRPD is set forth in Figure- 1

EXAMPLE 2: Preparation of crystalline bortezomib Form AL (Slurry at 25° - 35°C).

Bortezomib (10 g; purity: 99.8%, (R,R)-diastereomer: 0.41%, (S,S)-diastereomer: 0.03%) and degassed water (300 ml) were taken into a round bottom flask. The resultant mass was stirred for 3 hrs at 25-35°C. Filtered the product and washed with degassed water (100 ml). The wet product was dried under vacuum at 35°- 40°C for 15 hrs to afford 9.5 gms of the title compound.

HPLC purity (chemical): 99.7%

HPLC purity (chiral): 99.8%

(R,R)- diastereomer: 0.05%

(S,S)- diastereomer: 0.02%

The XRPD is set forth in Figure-2

The TGA is set forth in Figure-3

The IR is set forth in Figure-4

Residual Solvents:

EXAMPLE 3 : Preparation of crystalline bortezomib Form AL (Slurry at 5° - 15°C)

Bortezomib (2 gms; purity: 99.8%, (R,R)-diastereomer: 0.48%, (S,S)-diastereomer: 0.03%) and degassed water (60 ml) were taken into a round bottom flask. The reaction mixture was allowed to cool to 10°C and stirred for 3 hrs at 5° - 15°C. Filtered the product and washed with degassed water (100 ml). The wet product was dried under vacuum at 35°- 40°C for 15 hrs to afford 1.98 gms of the title compound.

HPLC purity (chiral): 99.88%

(R,Pv)- diastereomer: 0.04%

(S,S)- diastereomer: BDL

The XRPD is set forth in Figure-2

The TGA is set forth in Figure-3

The IR is set forth in Figure-4

EXAMPLE 4: Preparation of crystalline bortezomib Form AL (Slurry at 45° - 55°C)

Bortezomib (2 gms; purity: 99.5%, (R,R)-diastereomer: 0.48%, (S,S)-diastereomer: 0.03%)) and degassed water (60 ml) were taken into a round bottom flask. The reaction mixture was heated to 50°C and stirred for 3 hrs at 45° - 55°C. The reaction mixture was allowed to cool to 25°C to 35°C, filtered the product and washed with degassed water (100 ml). The wet product was dried under vacuum at 35°- 40°C for 15 hrs to afford 1.92 gms of the title compound.

HPLC purity (chiral): 99.87%

(R,R)- diastereomer: 0.03%

(S.S)- diastereomer: BDL

The XRPD is set forth in Figure-2

The TGA is set forth in Figure-3

The IR is set forth in Figure-4

EXAMPLE 5 : Stability of crystalline bortezomib Form AL according to the invention.

Bortezomib polymorph Form AL (Example 2) was packed in transparent low density polyethylene bag filled with nitrogen and strip sealed, then the sealed bag again placed in another low density polyethylene bag containing Silica gel pillow pack and strip sealed followed by placed in a Triple Laminated Sunlight barrier finally the packed samples were stored in HDPE container. The HDPE container was loaded to the stability chambers at 5°C to 30°C/65%RH stability testing condition.

The results of stability studies are set forth in Figure 5. EXPERIMENTAL DATA:

The moisture content as measured by the Karl Fisher coulometric technique using 831 KF coulometer and 860 KF Thermoprep for three batches of crystalline Form AL of bortezomib of the present invention is set forth below in Table I.

Table I:

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

We Claim:

Claim 1. Crystalline form AL of bortezomib characterized by a powder X-ray diffraction pattern substantially in accordance with Figure 2.

Claim 2. Crystalline form AL of bortezomib characterized by a powder X-ray diffraction pattern comprising one or more characteristic peaks at about 6.0, 8.5, 12.2, 13.3, 14.1, 17.3, 18.8, 19, 19.6, 20, 21.6, 22.4, 23.2, 24.2, 24.6, 26, 26.8 and 27.3° ± 0.2° 2Θ.

Claim 3. The crystalline form AL of bortezomib of claim 2, further characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.

Claim 4. The crystalline form AL of bortezomib of claim 2, further comprising having a water content from about 7% to about 10% by weight.

Claim 5. The crystalline form AL of bortezomib of claim 2, further comprising having a water content of about 8.5% by weight.

Claim 6. The crystalline form AL of bortezomib of claim 2, further characterized by infrared absorption (IR) spectrum substantially in accordance with Figure 4.

Claim 7. A process for preparation of crystalline form AL of bortezomib, wherein the process comprises: a) mixing bortezomib with water to obtain a slurry mixture,

b) slurrying the resultant mixture at ambient temperature,

c) isolating the bortezomib.

Claim 8. The process of claim 7, wherein the bortezomib is present in the in the slurry is range of about 1% to about 50% by weight of the water.

Claim 9. The process of claim 7, wherein the slurry is carried out at a temperature of about 0°C to about 65°C.

Claim 10. The process of claim 7, wherein the slurry is carried out at a temperature of about 25°C to about 55°C.

Claim 1 1. The process of claim 7, wherein the period of slurry is from about 5 minutes to about 24 hours.

Claim 12. The process of claim 7, wherein the period of slurry is from about 2 minutes to about 4 hours.

Claim 13. The process of claim 7, wherein the crystalline form AL of bortezomib having purity level greater than about 99.5% by HPLC and contain less than 0.1% by HPLC of (R,R)-diastereomer.

Claim 14. Crystalline form AL of bortezomib having less than about 0.1% by HPLC of (R,R)-diastereomer.

Claim 15. The compound of claim 14, wherein the crystalline form AL of bortezomib having less than about 0.05% by HPLC of (R,R)-diastereomer.

Claim 16. A pharmaceutical composition comprising the crystalline form AL of bortezomib according to any of claims 1 - 15, together with one or more pharmaceutically acceptable excipients.