WO2012122451A2

WO2012122451A2 - Polymorphs of maxacalcitol and process for the preparation of maxacalcitol

Info

Publication number: WO2012122451A2
Application number: PCT/US2012/028426
Authority: WO
Inventors: Anchel Schwartz; Koby Wolfman; Michal RAFILOVICH -GIVON; Oleg Radchenko
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2011-03-09
Filing date: 2012-03-09
Publication date: 2012-09-13
Also published as: JP2014514274A; WO2012122451A3

Abstract

The present invention relates to Maxacalcitol polymorphs and Maxacalcitol having low residual solvent content as well as processes for their preparation. The present invention also relates to pharmaceutical compositions containing Maxacalcitol polymorphs or Maxacalcitol having low residual solvent content and treatment methods using the pharmaceutical compositions.

Description

POLYMORPHS OF MAXACALCITOL AND PROCESS FOR THE PREPARATION

OF MAXACALCITOL

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent

Application Nos. 61/450,770 filed March 9, 2011, 61/482,477 filed May 4, 2011 and 61/487,123 filed May 17, 2011, the disclosure of which are herein incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to Maxacalcitol polymorphs; their preparation thereof and pharmaceutical compositions containing them; a process for the preparation of Maxacalcitol; and Maxacalcitol having low residual solvent content.

BACKGROUND OF THE INVENTION

[0003] Maxacalcitol, lalpha,25-dihydroxy-22-oxavitamin D3|20(S)-(3-hydroxy-3- methylbutoxy)-9, 10-secopregna-5(Z),7(E), 10(19)-trien-l alpha,3beta-diol|22-oxacalcitriol, (also named as (+)-(5Z,7_JE',20S)-20a-(3-hydroxy-3-methylbutoxy)-9,10-secopregna- 5,7,10(19)-trien-la,3p-diol; la,25-dihydroxy-22-oxavitamin D₃; 22-oxa-la,25-dihydroxy- vitamin D₃; 22-oxacalcitriol; and 22-oxa-l,25(OH)₂D₃) of the following formula:

is a vitamin D3 derivative is marketed under the trade name OXAROL by Chugai, Inc. OXAROL^® is approved for the treatment of secondary hyperparathyroidism, psoriasis, ichthyosis, and palmoplantar keratosis and is available as an injectible formulation, ointment, and emulsion lotion. [0004] JP 2002104995, and its PCT counterpart Publication No. WO2001079166, refer to vitamin D derivatives as well as for Maxacalcitol.

[0005] Publication No. WO 1990/09991 discloses a process for preparing the iso-21 derivative of Maxacalcitol. In addition, US5, 436, 401 and Organic Process Research & Development 2005, 9:278-287, disclose the preparation of Maxacalcitol.

[0006] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Maxacalcitol, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0007] Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional polymorphs of Maxacalcitol.

SUMMARY OF THE INVENTION

[0008] The invention encompasses novel solid state forms of Maxacalcitol, referred to herein as Forms A, B and C; processes for preparing the novel solid state forms of

Maxacalcitol; and formulations comprising the novel solid state forms of Maxacalcitol.

[0009] In another embodiment, the present invention encompasses the above described solid state forms of Maxacalcitol for use in the preparation of formulations.

[00010] In yet another embodiment the present invention encompasses Maxacalcitol having low residual solvent content, wherein the solvent is not ethylacetate and/or hexane. BRIEF DESCRIPTION OF THE DRAWINGS

[00011] Figure 1 provides a characteristic X-ray powder diffraction pattern of crystalline Maxacalcitol form A.

[00012] Figure 2 provides a characteristic X-ray powder diffraction pattern of crystalline Maxacalcitol form B.

[00013] Figure 3 provides a characteristic X-ray powder diffraction pattern of crystalline Maxacalcitol form C.

[00014] Figure 4 provides an FTIR spectrum of crystalline Maxacalcitol form A.

[00015] Figure 5 provides an FTIR spectrum of crystalline Maxacalcitol form C.

[00016] Figure 6 provides Microscope image of crystalline Maxacalcitol form A.

[00017] Figure 7 provides Microscope image of crystalline Maxacalcitol form C.

DETAILED DESCRIPTION OF THE INVENTION

[00018] The present invention provides solid state forms of Maxacalcitol; the preparation of these solid state forms, and pharmaceutical compositions comprising one or more of the provided solid state forms.

[00019] As used herein, the term "Room temperature" or "RT" refers to a temperature from about 20°C to about 30°C. Usually, room temperature ranges from about 20°C to about 25°C.

[00020] As used herein, the term "Overnight" or "ON" refers to a period of from about 15 to about 20 hours, typically from about 16 to about 20 hours.

[00021] For the purpose of clarity and as an aid in the understanding of the invention, as disclosed herein, the following terms and abbreviations are defined below:

CLP-8 or clp-8 l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(S)-formyl-9, 10- secopregna-5, 7 (E), 10(19)-triene

B-l or b-1 l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20-one-9, lO-secopregna-5, 7

(E), 10(19)-triene

B-2 or b-2 1 (s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(S)-hydroxy-9, 10- secopregna-5, 7 (E), 10(19)-triene

B-2 iso-21 or 1 (s), 3 (R)- bis(tertbutyldimethylsililoxy)- 20(R)-hydroxy-9, 10- b- iso-21 secopregna-5, 7 (E), 10(19)-triene

B-6 or b-6 1 (s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(R)-hydroxy-9, 10- secopregna-5, 7 (E), 10(19)-triene 6R and 6S-S0₂ adduct B-7 or b-7 l(s), 3(R)- bis(tertbutyldimethylsililoxy)-9, lO-secopregna-5, 7 (E),

10(19),17-tetraene 6R and 6S-S0₂ adduct.

B-8 or b-8 1 (s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(S)-hydroxy-9, 10- secopregna-5, 7 (E), 10(19)-triene 6R and 6S-S0₂ adduct.

B-3 or b-3 l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 22-oxa-25-hydroxy-9, 10- secocholesta-5(E), 7 (E), 10(19)-triene

B-4 or b-4 l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 22-oxa-25-hydroxy-9, 10- secocholesta-5(Z), 7 (E), 10(19)-triene

SCM-1 or scm-1 l-Bromomethyl-2,2-dimethyl oxirane

[00022] A crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure. Such data include, for example, powder X-ray diffractograms, FTIR spectra, and solid state NMR spectra. The skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.

[00023] A crystal form (or polymorph) may be referred to herein as substantially free of any other crystalline (or amorphous) forms. As used herein in this context, the expression "substantially free" will be understood to mean that the crystalline form contains 20% or less, 10% or less, 5%» or less, 2% or less, or 1% or less of any other form of the subject compound as measured, for example, by XRPD. Thus, polymorphs of Maxacalcitol described herein as substantially free of any other polymorphic forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject polymorphic form of Maxacalcitol. Accordingly, in some embodiments of the invention, the described polymorphs of Maxacalcitol may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more other crystal or amorphous forms of Maxacalcitol.

[00024] In certain embodiments, the described polymorphic form of Maxacalcitol may be in a composition which comprises the subject polymorphic form of crystalline Maxacalcitol and one or more other crystal or amorphous forms of Maxacalcitol in the above described amounts. In particular, the described polymorphic form of Maxacalcitol may be in a composition which contains essentially the subject polymorphic form of crystalline Maxacalcitol and one or more other crystal forms of Maxacalcitol in the above described amounts.

[00025] As used herein, PXRD measurements were obtained using Cu radiation having a wavelength of 1.541874 A.

[00026] The term "solvate," as used herein, and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount. When the solvent is present in

stoichiometric amount, the hydrate may be referred to as monohydrate, di-hydrate, tri-hydrate etc. The solvent content can be measured, for example, by GC, 'H-NMR, Karl-Fischer (KF) titration or by monitoring the weight increase during dynamic vapour sorption (DVS) test.

[00027] The term "anhydrous" as used herein, and unless stated otherwise, refers to crystalline Maxacalcitol which contains not more than 1% (w/w), preferably not more than 0.5% (w/w) of either water or organic solvents as measured by KF or TGA.

[00028] The crystalline forms of Maxacalcitol described herein have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

[00029] In one embodiment the present invention encompasses a crystalline form of Maxacalcitol, designated herein as Form A. Form A can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.4, 7.4, 12.3, 13.5 and 14.0 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern having peaks at 7.4, 19.3, 22.9, 24.9, and 32.9 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 ; an FTIR spectrum having peaks at 3391, 2927, 2873, 1635, 1448, 1368, 1221, 1147, 1057, 956, 909, 879, 800 and 751 cm^'1; an FTIR spectrum substantially as depicted in Figure 4; and combinations thereof. Maxacalcitol Form A can alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.4, 7.4, 12.3, 13.5 and 14.0 degrees 2-theta ± 0.2 degrees 2-theta and also having an additional one, two, three, four or five peaks selected from 14.9, 15.9, 17.1, 18.1, and 32.9 degrees 2-theta ± 0.2 degrees 2-theta. [00030] Maxacalcitol Form A can alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.4, 19.3, 22.9, 24.9, and 32.9 degrees 2-theta ± 0.2 degrees 2-theta and also having an additional one, two, three, four or five peaks selected from 6.4, 14.9, 15.9, 16.8 and 17.1 degrees 2-theta ± 0.2 degrees 2-theta.

[00031] The above Form A may be anhydrous. According to some embodiments, Form

A has a water content of not more than 0.5% w/w, as measured by F analysis.

[00032] The crystalline Maxacalcitol form A of the present invention has advantageous properties selected from at least one of: flowability, morphology or crystal habit, low content of residual solvents and the property that it can be easily dried.

[00033] The crystalline Maxacalcitol form A of the present invention can have a low residual solvent content, which is advantageous for an API used to prepare a formulation to be used in therapy. Particularly, crystalline Maxacalcitol form A of the present invention can have a residual solvent content from about 30 ppm to about 5000 ppm of residual solvents, or from about 30 ppm to about 2500 ppm of residual solvents, or from about 30 ppm to about 1000 ppm of residual solvents, or from about 30 ppm to about 500 ppm of residual solvents, or from about 30 ppm to about 250 ppm of residual solvents, for example from about 50 ppm to about 100 ppm of residual solvents.

[00034] According to some embodiments, Form A can have a low content of acetonitrile, for example, an acetonitrile content of less than (not including) 300ppm, or from about 30 ppm to about 200 ppm, for example, from about 50 ppm to about 100 ppm.

[00035] Further, the crystalline Maxacalcitol form A can have homogenous crystal habit and small particle size dimensions (<50μπι) directly obtained from manufacture process, as describe in Figure 6. Form A has the advantage of not requiring milling or grinding steps to reduce the particle size to a range of smaller dimensions. This can cause changes in the stability of the pressed/grinded powder material while when starting in advance with a smaller size of powder (Form A) this risk is being prevented. This has many advantages such as: higher compressibility which is very important for handling the powder, storage, safety, etc. Using homogenous powders, flowability of the powder may be improved. Processing of powders strongly depends on powder flowability.

[00036] In another embodiment the present invention encompasses a crystalline form of Maxacalcitol, designated herein as Form B. Form B can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 11.2, 13.7, 15.4, 15.8, and 17.6 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 2; and combinations thereof. Maxacalcitol Form B can alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.2, 13.7, 15.4, 15.8, and 17.6 degrees 2-theta ± 0.2 degrees 2-theta and also having additional one, two, three, four or five peaks selected from 16.6, 17.0, 18.1, 20.1, and 23.6 degrees 2-theta ± 0.2 degrees 2- theta.

[00037] In another embodiment the present invention encompasses a crystalline form of Maxacalcitol, designated herein as Form C. Form C can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 12.1, 12.5, 14.3, 16.1 and 18.0 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 3; an FTIR spectrum having peaks at 3391, 2967, 2934, 2874, 1643, 1447, 1375, 1221, 1151, 1060, 958, 895, 863, 800 and 743 cm^"1; an FTIR spectrum substantially as depicted in Figure 5; and combinations thereof. Maxacalcitol Form C can alternatively characterized by an X-ray powder diffraction pattern having peaks at 12.1, 12.5, 14.3, 16.1 and 18.0 degrees 2-theta ± 0.2 degrees 2-theta and also having an additional one, two, three, four or five peaks selected from 7.1, 10.5, 16.7, 18.7 and 19.7 degrees 2-theta ± 0.2 degrees 2-theta.

[00038] The above form C may exist as a hernihydrate- acetonitrile solvate. According to some embodiments, Form C has a water content from about 1.5% to about 2.5% (w/w) and an acetonitrile content from about 0.2% to about 1.2%. According to some embodiments,, Form C has a water content of about 2.1% (w/w), as measured by KF and/or TGA.

[00039] The crystalline Maxacalcitol Form C of the present invention has an advantage that it provides chemically pure Maxacalcitol. According to some embodiments, crystalline Maxacalcitol form C has a purity of at least about 99.4%, or about 99.7%, as measured by HPLC.

[00040] Further, the crystalline Maxacalcitol Form C has medium particle size dimensions (above 50μπι and smaller ΐ1ΐ3η100μηι) as described in Figure 7. This medium particle size can be reduced to a range of smaller dimensions.

[00041] Form C may be referred to herein as substantially free of Forms A or B, or of a mixture thereof. As used herein in this context, the expression "substantially free of Forms A, B or a mixture thereof " will be understood to mean that the crystalline Form C contains 5% or less, or 3% or less, or 2% or less of each of Forms A and/or B of the subject compound as measured, for example, by XRPD. Form A can be detected in Form C by the X-ray powder diffraction peaks at 7.4, 15.8, and 22.9 degrees 2-theta ± 0.2 degrees 2-theta. Form B can be detected in Form C by the X-ray powder diffraction peaks at 11.1, 11.8, and 17.6 degrees 2-theta ± 0.2 degrees 2-theta. [00042] The above solid state forms of Maxacalcitol can be used to prepare a pharmaceutical formulation that can be used as a medicament.

[00043] The present invention further encompasses 1) a pharmaceutical composition comprising one or more of the above described crystalline forms and at least one

pharmaceutically acceptable excipient; 2) the use of any one or combination of the above described crystalline forms in the manufacture of a pharmaceutical composition, and 3) a method of treating secondary hyperparathyroidism, psoriasis, ichthyosis and palmoplantar keratosis. The pharmaceutical composition can be useful for preparing a medicament. The present invention also provides at least one of the above described crystalline forms for use as a medicament.

[00044] In yet another embodiment the present invention encompasses Maxacalcitol having a low residual solvent content, wherein the residual solvent does not comprise ethyl acetate and/or hexane. According to some embodiments, Maxacalcitol of the invention contains from about 30 ppm to about 5000 ppm of residual solvents, or from about 30 ppm to about 2500 ppm of residual solvents, or from about 30 ppm to about 1000 ppm of residual solvents, or from about 30 ppm to about 500 ppm of residual solvents, or from about 30 ppm to about 250 ppm of residual solvents, for example from about 50 ppm to about 100 ppm of residual solvents, wherein the solvent does not comprise ethyl acetate and/or hexane.

According to some embodiments, the Maxacalcitol of the present invention has a low content of acetonitrile, for example, an acetonitrile content of less than (not including) 300ppm, or from about 30ppm to about 200ppm, or, from about 50ppm to about lOOppm. The

maxacalcitol containing low residual solvents can be used to prepare a formulation as describe above.

[00045] The present invention also offers a process for the preparation of Maxacalcitol.



The above process comprises: a) oxidizing l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(S)- formyl-9, lO-secopregna-5, 7 (E), 10(19)-triene of formula CLP-8:

CLP-8

to obtain l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20-one-9, lO-secopregna-5, 7 (E), 10(19)- triene of formula bl :

b) reducing the compound of formula bl to obtain an isomeric mixture comprising l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(S)-hydroxy-9, lO-secopregna-5, 7 (E), 10(19)-triene of formula b2:

b₂

and its isomer l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(R)-hydroxy-9, lO-secopregna-5, 7 (E), 10(19)-triene of formula of b2-iso 21:

b₂-lso 21

c) reacting the compound of formula b2 with l-bromomethyl-2,2-dimethyl oxirane of the following formula:

to obtain l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 22-oxa-25-hydroxy-9, 10-secocholesta- 5(E), 7 (E), 10(19)-triene of formula b3:

b₃

d) Irradiating the compound of formula b3 by UV to obtain the compound l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 22-oxa-25-hydroxy-9, 10-secocholesta-5(Z), 7 (E), 10(19)- triene of formula b4:

and e) removing the protecting groups on the compound of formula b4 to obtain maxacalcitol. The irradiation of step d) can be done for example by exposure to UV source.

Preferably, the UV source can provide an irradiation having a wavelength of above 450 nm.

Further, the compound of formula b2, can be recycled from its isomer, l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(R)-hydroxy-9, 10-secopregna-5, 7 (E), 10(19)-triene of formula of b2-iso 21 :

b₂-lso 21 for example by: a) protecting the compound of formula b2-iso21, for example, by using a sulfonyl protecting group to obtain l(s), 3(R)- bis(tert-butyldimethylsililoxy)- 20(R)- hydroxy-9, 10-secopregna-5, 7 (E) 6S-S0₂ adduct of formula b6:

b₆

b) Dehydrating the compound of formula b6 to obtain l(s), 3(R)- bis(tertbutyldimethylsilyl- oxy)-9, 10-secopregna-5, 7 (E), 10(19),17-tetraene 6R and 6S-S0₂ adduct of formula b7:

8426 c) Hydration of the double bond in position 17 of the compound of formula b7 to obtain l(s), 3(R)- bis(tertbutyldimethylsililoxy)- 20(S)-hydroxy-9, 10-secopregna-5, 7 (E), 10(19)-triene 6R and 6S-S0₂ adduct of formula

b₈

[00047] and d) de-protecting the compound of formula b8 to obtain the compound of formula b2.

[00048] Typically, the recycled compound of formula b2 can be combined with the obtained compound of formula b2, obtained by reducing the compound of formula bl, to provide one source of the compound of formula b2 to be used as a starting material for the preparation of the formula b3 compound.

[00049] Having described the invention with reference to certain preferred

embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Analytical techniques

X-ray powder diffraction:

XRD diffraction measurement was performed on X-Ray powder diffractometer

PanAnalytical X'pert Pro powder diffractometer: CuKa radiation; λ = 1.541874 A;

X'Celerator detector active length (2 theta) = 2.122 mm; at laboratory temperature 22-25 °C; zero-background sample-holders. The scanning parameters were: range: 4-40 degrees 2Θ; scan mode: continuous scan; step size: 0.0167 deg. and scan rate: 3 deg/min. 2 028426

FT-IR spectroscopy

Data was collected using a Perkin-Elmer Spectrum One Spectrometer, at 4 cm^"1 resolution with 16 scans, in the range of 4000-400 cm^"1. Sample was analyzed in KBr pellet. The spectrum was recorded using an empty cell as a background.

KF analysis

Equipment

Metrohm 831 KF Coulometer with Metrohm 832 KF Thermoprep, using a temperature 105 °C

Analysis parameters

Sample weight: ca. 50 mg

TGA analysis

Equipment

Mettler Toledo TGA/DSC 1.

Scanning parameters

Heating between 25-250 °C.

Heating rate: 10°C/min.

Purging with 40 ml/min N2 flow.

Sample weight: ca. 10 mg.

Crucible: 150 xL alumina Crucible with standard aluminum lid.

** Equipment

Mettler Toledo STAR SW 9.20.

Scannins parameters

Heating between 25 -300°C.

Heating rate: 10°C/min.

Purging with 50 ml/min N2 flow.

Sample weight: ca. 3-10 mg. Crucible: 100 μΐ alumina Crucible with standard aluminum lid.

EXAMPLES

Example 1: Preparation of Maxacalcitol a) Synthesis of B

CLP-8

Procedure:

l(s), 3(R)- Bis(tertbutyldimethylsililoxy)- 20(S)-formyl-9, lO-secopregna-5, 7 (E), 10(19)-triene(CLP-8) (100 g) was added to dimethylformamide (DMF) with stirring.

Air flow was bubbled through the solution and diazabicyclooctane (DABCO) was added, followed by addition of Cu(OAc)₂ and bipiridyl .The resulting solution was warmed to a temperature of 40±3°C and stirred at this temperature for 18±3 hours.

The reaction progress was checked by TLC. When the reaction was completed (CLP- 8<1%), ethyl acetate and water were added and the mixture stirred for a few minutes and allowed to separate. The aqueous phase (lower) was washed with ethyl acetate.

The combined organic phases were washed with brine, dried over Na₂S0₄

(anhydrous), and filtered.

Evaporation under reduced pressure at a temperature of 40±3 °C, gave crude B-l, (110-120 g) as a white semi-solid. 8426 b) Synthesis of B-2

b₂-lso 21

Procedure:

B-l (115 g) was dissolved in diisopropyl ether and NaB¾ was added followed by addition of ethanol. The solution was warmed to a temperature of 60±3°C and stirred at this temperature for 4 hours. The reaction progress was checked by TLC. When the reaction was completed (B-1<1%), the reaction mixture was filtered through a Buchner funnel. To the filtrate, water was added and the mixture was evaporated to dryness under reduced pressure at a temperature of 40±3°C.

Ethyl acetate and water were added and the mixture stirred for a few minutes and allowed to separate. The organic phase was washed with brine, dried over Na₂S0₄

(anhydrous), and filtered. Evaporation under reduced pressure at a temperature of 40±3 °C, gave 110-130 g crude B-2.

Column Purification:

The crude product was purified on a chromatographic column using silica gel with mixtures of 0¾0₂ in hexane.

to get 18-22 g of B-2 as a white solid and 55-65 g of iso-21 B-2 as a white solid . 6 c) Synthesis of B-6:

b₂-lso 21

Procedure:

B-2 (60 g) was dissolved in CH₂C1₂ and water was added.

S0₂ flow was bubbled through the stirred solution, for 60±10 min.

The reaction progress was checked by TLC. When the reaction was completed (B-2 <5%), the phases were allowed to separate. The aqueous phase (upper) was washed with CH₂C1₂.

To the combined organic phases, nitrogen was bubbled through, with stirring at room temperature for about 5 min. Then, the solution was dried over Na₂S0₄ (anhydrous) and NaHC03 and filtered. Evaporation under reduced pressure at a temperature 35±3 °C, gave 62-70 g crude B-6. d) Synthesis of B-7

Procedure:

B-6 crude (66 g) was dissolved in pyridine and the solution was cooled

to 0±3 °C. Then, POCl₃ was slowly added. The reaction mixture was warmed to 22±3 °C and stirred at 22±3 °C for 18±2 h. The reaction progress was checked by TLC. When the reaction was completed (B-6 <5%), cold ethyl acetate and ice were added and the mixture stirred for a few min. and allowed to separate. The organic phase (upper) was washed with 32% HCl, to reach pH=3 and the phases were allowed to separate. The aqueous phase (lower) was washed with ethyl acetate. The combined organic phases were washed with IN HCl, then with 10% solution of NaHC0₃ and finally with brine, dried over Na2S04 (anhydrous) and filtered. Evaporation under reduced pressure at a temperature of 40±3 °C, gave 62-70 g crude B-7. e) Synthesis of B-8:

Procedure:

B-7 crude (66 g) was dissolved in 9-BBN solution (0.5 M in THF) and the solution was warmed to 45±3 °C and stirred at 45±3 °C for 3±0.5 h. The reaction progress was checked by TLC. When the reaction was completed (B-7<5%), the reaction mixture was cooled to -10±3 °C and NaOH solution was slowly added (exothermic reaction) followed by addition of H₂0₂ solution. The reaction mixture was warmed to 22±3°C and stirred at 22±3°C for 60±5 min. Then, the reaction mixture was cooled to 10±3 °C and Na₂S₂0₃ solution was added followed by addition of ethyl acetate. The phases were allowed to separate. The organic phase (upper) was washed with water and then with brine, dried over Na₂S0₄ (anhydrous) and filtered.

Evaporation under reduced pressure, gave 80-100 g crude B-8. f) Synthesis of

Procedure:

B-8 crude (90 g) was dissolved in ethanol and NaHC0₃ was added. The reaction mixture was warmed to reflux (80±3 °C) and stirred at this temperature for 3±0.5 h. The reaction progress was checked by TLC. When the reaction was completed (B-8<5%), the reaction mixture was filtered through a Buchner funnel and the solvent was evaporated under reduced pressure at 40±3 °C, to give 70-86 g crude B-2- *.

Column Purification:

The crude product was purified on a chromatographic column using silica gel with mixtures of EtOAc in hexane,to give 35-45 g of B-2 as a white solid

g) Synthesis of B-3:

Procedure:

B-2 (40 g) was dissolved in THF and NaH was added. The reaction mixture was stirred at 22±3 °C for 5-10 min. and SCM-1 was added.

The reaction mixture was warmed stirred for 60±10 min. The reaction progress was checked by TLC. When the reaction was complete (B-2<5%), the reaction mixture was 6 cooled to 22±3 °C and L-Selectride (1M solution in THF) was added. The reaction mixture was stirred at 22±3 °C for 3±0.5 h.

The reaction progress was checked by TLC, and when the reaction was complete (B-3-i <5%), the reaction mixture was cooled to -25±3°C and 10% NaOH solution was slowly added (exothermic reaction) followed by addition of H₂0₂ solution.

The reaction mixture was then warmed to 22±3°C and stirred at 22±3°C for 60±5 min. The reaction mixture was then filtered through a Buchner funnel and ethyl acetate was added.

The phases were allowed to separate. The org. phase (upper) was washed with 30% Na₂S₂0₃ solution and then with brine, dried over Na₂S0₄ (anhydrous) and filtered. Evaporation under reduced pressure at 40±3 °C, gave 55-60 g crude B-3.

Column Purification:

The crude product was purified on a chromatographic column using silica gel with mixtures of EtOAc in hexane and then recrystallized, to give 30-40 g of B-3 as a white solid h) Synthesis of B-4:

Procedure:

B-3 (35 g) was dissolved in toluene and 9-acetyl anthracene and Et₃N were added. The reaction mixture was cooled to 0±5 °C and irradiated at this temp for 40±5 min. The reaction progress was checked by HPLC. When reaction was complete (B-3<1.5%), the reaction mixture was evaporated under reduced pressure, to give 34-40 g crude B-4. i) Synthesis ofB-5:

b₄ b₅

Procedure:

B-4 crude (37 g) was dissolved in tetrabutyl ammonium fluoride (1M solution in THF) and the reaction mixture was stirred for 18±2 h. The reaction progress was checked by TLC. When the reaction was complete (B-4<5%), the reaction mixture was evaporated under reduced pressure at 35±3 °C to provide a residue. To the residue, ethyl acetate and water were added, mixed and were allowed to separate. The aq. phase (lower) was washed with ethyl acetate. The combined org. phase was washed with brine dried over Na₂S0₄

(anhydrous), and filtered. Evaporation under reduced pressure at 30±3 °C, gave 35-45 g of crude B-5.

Column Purification:

The crude product was purified on a chromatographic column using silica gel with mixtures of acetonitrile and CH2CI2, to give 15-21g of B-5 as a white solid.

This material was further purified by two crystallizations as described below.

Example 2: Preparation of Maxacalcitol Form A

Maxacalcitol (5.4 g, 12.9 mmol) was dissolved in acetonitrile (CH3CN) (108 mL) by stirring in a 250 ml reactor, at 30°C for 15 min. The resulting solution was cooled to 22°C and stirred at this temperature for 2 h. Then, the solution was cooled to 10°C and stirred at this temperature for 2 h. Then, the solution was cooled to 0°C and stirred at this temperature for 2 h. Then, the solution was cooled to -18°C and stirred at this temperature for 16 h.

A solid precipitated and was collected by suction filtration and washed with cold methyl formate (at -18 °C, 50 mL). The product was dried in a vacuum oven at 28°C for 6h. The resulting powder was analyzed by XRPD to give a pattern of Maxacalcitol crystalline Form A. The residual Acetonitrile solvent content was measured at 720ppm.

Example 3: Preparation of Maxacalcitol Form A

Maxacalcitol (3.9 g, 9.3 mmol) was dissolved in diethyl ether (60 mL) by stirring in a 250 ml reactor, at 28°C for 15 min. The resulting solution was cooled to 18°C and stirred at this temperature for 0.5 h. Then, the solution was cooled to 10°C and stirred at this temperature for 1 h. Then, the solution was cooled to 0°C and stirred at this temperature for 2 h.

No crystallization was observed, so all the solvent was evaporated to dryness under reduced pressure. The obtained dry material (3.75 g) was redissolved in diethyl ether (38 mL) by stirring in 250 ml reactor at 28°C for 15 min. The resulting solution was cooled to 18°C and stirred at this temperature for 0.5 h. Then, the solution was cooled to 10°C and stirred at this temperature for 1 h. Then, the solution was cooled to 0°C and stirred at this temperature for 16 h. A solid precipitated and was collected by suction filtration and the product was dried in a vacuum oven at 35°C for 5h. The resulting powder was analyzed by XRPD to give a pattern of Maxacalcitol crystalline Form A.

Example 4: Preparation of Maxacalcitol Form B

Maxacalcitol (3.9 g, 9.3 mmol) was dissolved in methyl formate (60 mL) by stirring in a 250 ml reactor, at 22°C for 60 min. The resulting solution was cooled to 18°C and stirred at this temperature for 1.5 h. Then, the solution was cooled to 0°C and stirred at this temperature for 0.5 h. At this point, seeding was done (about 80 mg) and the solution continued stirring at 0°C for 1 h. Then, the solution was cooled to -18°C and stirred at this temperature for 2.5 h.

A solid precipitated and was collected by suction filtration, and the product was dried in a vacuum oven at 28°C for 6h. The resulting powder was analyzed by XRPD to give a pattern of Maxacalcitol crystalline Form B.

Example 5: Preparation Maxacalcitol Form C

Maxacalcitol (9.1 gr, 21.7 mmol) was dissolved in acetonitrile (182 mL) by stirring in a 250 ml reactor, at 25°C for 15 min. To the solution was added 0.9 mL water and the solution was started on a cooling program: First, it was cooled to 10°C and stirred at this temperature for 1 h. Then, the solution was cooled to 0°C and stirred at this temperature for 1 h. Then, the solution was cooled to -20°C and stirred at this temperature for 2 h.

A solid precipitated and was collected by suction filtration and was washed with cold acetonitrile (at -18 °C, 30 mL). The product was dried in a vacuum oven at 30°C for 20h.

Example 6: Preparation Maxacalcitol Form C

Maxacalcitol (9.1 gr, 21.7 mmol) was dissolved in a solution of 0.75% water in acetonitrile (225 mL) by stirring in a 250 ml reactor, at 28°C for 30 min. The solution was then started on a cooling program: First, it was cooled to 10°C during 6h, and stirred at this temperature for 1 h. Then, the solution was cooled to 0°C during 6h, and stirred at this temperature for 12 h. A solid precipitated and was collected by suction filtration and was washed with cold CH₃CN (at -18 °C, 30 mL). The product was dried in a vacuum oven at 30°C for 20h.

Example 7 : Preparation of Maxacalcitol Form A

Maxacalcitol Form C (11.1 gr) was dissolved in acetonitrile (189 mL) by stirring in a 250 ml reactor, at a temperature of 25°C for 15 min. The resulting solution was cooled to a temperature of 10°C over 3h, and stirred at this temperature for lh. Then, the solution was further cooled to a temperature of 0°C over 2h, and stirred at this temperature for lh. Then, the solution was further cooled to a temperature of -18°C over 4h, and stirred at this temperature for 8 h. A solid precipitated and was collected by suction filtration and washed with cold acetonitrile (at -18 °C, 30 mL). The product was dried in a vacuum oven at 30°C for 24h, to give 9.4 g (purity 99.75). The resulting powder was analyzed by XRPD to give a pattern of Maxacalcitol crystalline Form A. The residual Acetonitrile solvent content was measured at 75 ppm.

Example 8: Preparation of Maxacalcitol Form A

Maxacalcitol Form C (16 gr) was dissolved in acetonitrile (288 mL) by stirring in a 500 ml reactor, at a temperature of 25°C for 15 min. The resulting solution was cooled to a temperature of 10°C over 3h, and stirred at this temperature for lh. Then, the solution was further cooled to a temperature of 0°C over 2h, and stirred at this temperature for lh. Then, the solution was further cooled to a temperature of -18°C over 4h, and stirred at this temperature for 8h. A solid precipitated and was collected by suction filtration and washed with cold acetonitrile (at -18 °C, 50 mL). The product was dried in a vacuum oven at 30°C for 24h, to give 12.2 g (purity 99.86). The resulting powder was analyzed by XRPD to give a pattern of Maxacalcitol crystalline Form A. Acetonitrile residual solvent content was 33 ppm.

Claims

What is claimed is:

1. Crystalline Maxacalcitol Form A, characterized by data selected from: an X- ray powder diffraction pattern having peaks at 6.4, 7.4, 12.3, 13.5 and 14.0 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern having peaks at 7.4, 19.3, 22.9, 24.9, and 32.9 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern

substantially as depicted in Figure 1; an FTIR spectrum having peaks at 3391, 2927, 2873, 1635, 1448, 1368, 1221, 1147, 1057, 956, 909, 879, 800 and 751 cm^-1; an FTIR spectrum substantially as depicted in Figure 4; and combinations thereof.

2. The crystalline Maxacalcitol Form A of claim 1, wherein said form is anhydrous.

3. The crystalline Maxacalcitol Form A of claim 1 , characterized by an X-ray powder diffraction pattern having peaks at 6.4, 7.4, 12.3, 13.5, and 14.0 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Maxacalcitol Form A of claim 3, further characterized by an X-ray powder diffraction pattern having one, two, three, four or five peaks selected from

14.9, 15.9, 17.1, 18.1, and 32.9 degrees 2-theta± 0.2 degrees 2-theta.

5. The crystalline Maxacalcitol Form A of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 7.4, 19.3, 22.9, 24.9, and 32.9 degrees 2-theta ± 0.2 degrees 2-theta.

6. The crystalline Maxacalcitol Form A of claim 5, further characterized by an X-ray powder diffraction pattern having one, two, three, four or five peaks selected from 6.4, 14.9, 15.9, 16.8 and 17.1 degrees 2-theta ± 0.2 degrees 2-theta.

7. Crystalline Maxacalcitol Form C, characterized by data selected from: an X- ray powder diffraction pattern having peaks at 12.1, 12.5, 14.3, 16.1 and 18.0 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 3; an FTIR spectrum having peaks at 3391, 2967, 2934, 2874, 1643, 1447, 1375, 1221, 1151, 1060, 958, 895, 863, 800 and 743 cm^"1; an FTIR spectrum substantially as depicted in Figure 5; and combinations thereof.

8. The crystalline Maxacalcitol Form C of claim 7, wherein said form is a hemihydrate-acetonitrile solvate.

9. Maxacalcitol having low residual solvent content, wherein the residual solvent does not comprise ethyl acetate or hexane.

10. The Maxacalcitol of claim 9, wherein the residual solvent is acetonitrile.

11. The Maxacalcitol of claim 10, wherein the acetonitrile content is less than 300ppm.

12. The Maxacalcitol of claim 9, wherein said Maxacalcitol is crystalline form A characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.4, 7.4, 12.3, 13.5 and 14.0 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern having peaks at 7.4, 19.3, 22.9, 24.9 and 32.9 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 ; an FTIR spectrum having peaks at 3391, 2927, 2873, 1635, 1448, 1368, 1221, 1147, 1057, 956, 909, 879, 800 and 751 cm^"1; an FTIR spectrum substantially as depicted in Figure 4; and combinations thereof.

13. The Crystalline Maxacalcitol or Maxacalcitol according to any one of claims 1 to 12 for use in the manufacture of a pharmaceutical composition.

14. A pharmaceutical composition comprising the Maxacalcitol Form A according to any one of claims 1 to 3 and at least one pharmaceutically acceptable excipient.

15. A method of treating secondary hype arathyroidism, psoriasis, ichthyosis or palmoplantar keratosis comprising administering a pharmaceutical composition according to claim 14.

16. The Crystalline Maxacalcitol or Maxacalcitol according to any one of claims 1 to 12 for use in the manufacture of a pharmaceutical composition for treating a patient suffering from secondary hyperparathyroidism, psoriasis, ichthyosis or palmoplantar keratosis.