PTO/SB/08a (10-07)
`Approved for use through 10131 /2007. OMB 0651-0031
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Substitute for form 1449A/PTO
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`INFORM/'\T'°N D'3C'-OSURE
`STATEMENT BY APPLICANT
`
`(Use as many sheets as necessary)
`
`Application Number
`
`Not yet assigned
`
`Complete if Known
`
`First Named Inventor
`Art Unit
`Examiner Name
`Attorney Docket Number
`
`Andreas FISCHER
`Not yet assigned
`Not Yet assigned
`029310.58469C2
`
`Examiner
`
`‘
`
`U.S. PATENT DOCUMENTS
`Publication Date
`Name of Patentee or
`MM-DD-YYYY
`Applicant of Cited Document
`03-17-2005
`Bartholomaeus et al.
`02-05-2002
`Buschmann et al.
`
`Pages, Columns, Lines, Where
`Relevant Passages or Relevant
`Figures Appear
`
`FOREIGN PATENT DOCUMENTS
`
`Examiner
`Initials‘
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`‘
`
`.
`
`Count
`
`Foreign Patent Document
`code“ Number‘ Kind Code 5 ifknown
`W0 03/035053
`
`Publication Date
`MM-DD—YYYY
`May 1, 2003
`
`Name of Patentee or
`Applicant of Cited Document
`Bartholomaeus et al.
`
`Pages. Columns. Lines.
`Where Relevant Passages
`or Relevant Figures Appear
`corresponds to A1
`
`EF 0 693 475
`
`01-24-1996
`
`Gruenenthal GmbH
`
`corresponds to A3
`
`Examiner
`Si . natu re
`
`Date
`Con dered
`
`‘EXAMINER: Initial if reference considered. whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance and not
`considered. Include copy of this form with next communication to applicant. 1 Applicant's unique citation designation number (optional). 2 See Kinds Codes of
`USPTO Patent Documents at www.uspto.gov or MPEP 901.04. 3 Enter Office that issued the document, by the two—|etter code (WIPO Standard ST.3)_ 4 For
`Japanese patent documents, the indication of the year of the reign of the Emperor must precede the serial number of the patent document. 5 Kind of document by
`the appropriate symbols as indicated on the document under WIPO Standard ST.16 if possible. 6 Applicant is to place a check mark here it English language
`Translation is attached.
`This collection of information is required by 37 CFR 1.97 and 1.98. The information is required to obtain or retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 USC. 122 and 37 CFR 1.14. This collection is estimated to take 2 hours to complete,
`including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments
`on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent
`and Trademark Office, U.S. Department of Commerce, PO. Box 1450, Alexandria. VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS
`ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`
`If you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`RS 1002 - 000001
`
`

`
`PTO/SB/08b (10-07)
`Approved for use through 10/31/2007. OMB 0651-0031
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid OMB control number.
`
`_
`Subsmute f°' f°"" 1449B[PTO
`
`Application Number
`
`Com - Iete if Known
`Not yet assigned
`
`STATEMENT BY APPUCANT
`(Use as many sheets as necessa
`
`§',TL.".?"’““"Ve"t°'
`Examiner Name
`— Attorney Docket Number
`
`Not yet assigned
`02931 0.5846962
`
`NON PATENT LITERATURE DOCUMENTS
`
`_
`Examiner
`
`'
`
`Include name of the author (in CAPITAL LETTERS), title of the article (when appropriate), title of the item
`(book,
`magazine, journal, serial, symposium, catalog, etc.), date, page(s), volume-issue number(s), publisher, city
`
`International Preliminary Report on Patentability dated December 28, 2006, and
`PCTIISAIZ37 0Nritten Opinion of the International Searching Authorlty) (seven (7) pages).
`
`Examiner
`Si nature
`
`Date
`Con dered
`
`*EXAM|NER: Initial If reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation it not in conformance and not
`considered. Include copy of this form with next communication to applicant.
`1 Applicant's unique citation designation number (optional). 2 Applicant is to place a check mark here if English language Translation is attached.
`This collection of Information is required by 37 CFR 1.97 and 1.98. The information is required to obtain or retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 2 hours to complete,
`including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments
`on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, US. Patent
`and Trademark Office, US. Department of Commerce, P.O. Box 1450. Alexandria. VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS
`ADDRESS. SEND To: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`
`If you need assistance in completing the form, call 1-800-PTO—91.99 and select option 2.
`
`RS 1002 - 000002
`
`

`
`APPLICATION DATA SHEET
`
`APPLICATION INFORMATION
`
`Application type::
`
`Subject Matter:
`
`Titlez:
`
`Regular
`
`Utility
`
`Crystalline Forms of (-)-(1R,2R)-3-(3-
`
`dimethylamino-1-ethy|-2-
`
`methylpropyl)-phenol Hydrochloride
`
`Attorney Docket No.::
`
`0293105846902 A
`
`Request for Early Publication?::
`
`Request for Non-Publication?::
`
`Small Entity?::
`
`Petition included?::
`
`No
`
`No
`
`No
`
`No
`
`Initial — 12/10/2009
`
`RS 1002 - 000003
`
`

`
`APPLICANT INFORMATION
`
`Applicant one Authority Type::
`
`Primary Citizenship Country:
`
`Status:
`
`Given name::
`
`Family name::
`
`City of Residence:
`
`Country of Residence:
`
`Street of mailing address:
`
`City of mailing address::
`
`Inventor
`
`GERMANY
`
`Full Capacity
`
`Andreas
`
`FISCHER
`
`Huertgenwald
`
`Germany
`
`Stockberg 16a
`
`Huertgenwald
`
`Country of mailing address:
`
`Germany
`
`Postal or Zip Code of mailing address:
`
`52393
`
`Initial — 12/10/2009
`
`RS 1002 - 000004
`
`

`
`Applicant two Authority Type::
`
`Inventor
`
`Primary Citizenship Country:
`
`Status:
`
`Given name::
`
`Family name::
`
`GERMANY
`
`Full Capacity
`
`Helmut
`
`BUSCHMANN
`
`City of Residence:
`
`Esplugues de Llobregat
`
`Country of Residence:
`
`Spain
`
`Street of mailing address:
`
`Carrer Est 24
`
`City of mailing address:
`
`Esplugues de Llobregat
`
`Country of mailing address:
`
`Spain
`
`Postal or Zip Code of mailing address:
`
`E-08950
`
`Initial — 12/10/2009
`
`RS 1002 - 000005
`
`

`
`Applicant three Authority Type::
`
`Primary Citizenship Country:
`
`Status:
`
`Given name::
`
`Family name:
`
`City of Residence:
`
`Country of Residence:
`
`Street of mailing address::
`
`City of mailing address:
`
`Country of mailing address:
`
`Postal or Zip Code of mailing address::
`
`Inventor
`
`GERMANY
`
`Full Capacity
`
`Michael
`
`GRUSS
`
`Aachen
`
`Germany
`
`Krebsstrasse 61
`
`Aachen
`
`Germany
`
`52080
`
`Initial — 12/10/2009
`
`RS 1002 - 000006
`
`

`
`Applicant four Authority Type::
`
`Primary Citizenship Country:
`
`Status:
`
`Given name:
`
`Family name::
`
`City of Residence:
`
`Country of Residence:
`
`Street of mailing address::
`
`City of mailing address:
`
`Country of mailing address:
`
`Postal or Zip Code of mailing address::
`
`Inventor
`
`GERMANY
`
`Full Capacity
`
`Dagmar
`
`LISCHKE
`
`Eschweiler
`
`Germany
`
`Lohnerstrasse 4
`
`Eschweiler
`
`Germany
`
`52249
`
`initial — 12/10/2009
`
`RS 1002 - 000007
`
`

`
`CORRESPONDENCE INFORMATION
`
`Correspondence customer number:
`
`REPRESENTATIVE INFORMATION
`
`Representative customer number::
`
`DOMESTIC PRIORITY INFORMATION
`
`Application:
`
`Continuity Type::
`
`Parent Application:
`
`Parent Filing Date::
`
`This application Continuation of
`
`12/274,747
`
`November 20, 2008
`
`12/274,747 is a
`
`Continuation of
`
`11/646,232
`
`December 28, 2006
`
`11/646,232 is a
`
`Continuation of
`
`PCT/EP2005/006884 June 27, 2005
`
`FOREIGN PRIORITY INFORMATION
`
`Country:
`
`Application
`Number.::
`0401000‘-4
`
`ASSIGNEE INFORMATION
`
`Filing Date::
`
`Priority Claimed::
`
`00000004
`
`Assignee Name:
`
`Gruenenthal GmbH
`
`Street of mailing address::
`
`Zieglerstrasse 6
`
`City of mailing address::
`
`Country of Mailing Address:
`
`Aachen
`
`Germany
`
`Postal or Zip Code of mailing address:
`
`52078
`
`Initial — 1 2/1 O/2009
`
`RS 1002 - 000008
`
`

`
`Attorney Docket No. 0293l0.58469C2
`
`CI‘ stalline Forms of — — 1R 2R -3- 3-dimeth lamino-1—eth 1-2-
`meth 1 1'0
`1- henolh drochloride
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001] This application is a continuation of co-pending application no. 12/274,747,
`
`filed November 20, 2008, which in turn was a continuation of application no.
`
`11/646,232,
`
`filed December 28, 2006, now abandoned, which in turn was a
`
`continuation of International patent application no. PCT/EP2005/006884, filed
`
`June 27, 2005, which claims benefit of European patent application Serial No.
`
`04015091.4 filed June 28, 2004,
`
`the entire disclosures of which are hereby
`
`incorporated in their entirety.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates to solid crystalline forms of
`
`(-)-(1R,2R)-3-(3-
`
`dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride
`
`compounds,
`
`methods of producing these compounds, and related treatments, including use as
`
`analgesics as well as pharmaceutical compositions containing these compounds.
`
`BACKGROUND OF THE INVENTION
`
`[0003] The treatment of pain conditions is of great importance in medicine. There
`
`is currently a world—Wide need for additional pain therapy. The pressing
`
`requirement for a target—oriented treatment of pain conditions which is right for
`
`the patient, which is to be understood as the successful and satisfactory treatment
`
`of pain for the patients, is documented in the large number of scientific works
`
`which have recently and over the years appeared in the field of applied analgesics
`
`or on basic research on nociception.
`
`BRIEF SUMMARY OF THE INVENTION
`
`[0004] One object of the present invention is to provide new solid forms of (-)-
`
`(1R,2R)-3-(3-dimethylamino—1—ethyl-2-methylpropyl)—phenol hydrochloride useful
`
`in the treatment or inhibition of pain.
`
`RS 1002 - 000009
`
`

`
`[0005] US Pat. Nos. 6,248,737 and 6,344,558 as well as European Patent EP 693
`
`475 B1 disclose the substance and the synthesis of (-)-(1R,2R)-3-(3-dimethylamino-
`
`1-ethyl-2-methylpropyl)-phenol hydrochloride in example 25. As proven by X-ray
`
`diffraction the 1R,2R configuration as shown in the drawing of the structure in
`
`example 25 is correct although the configuration is reported as (-)-(1R,2S) in US
`
`6,248,737 and (-)-(1S,2S) in US 6,344,558 as well as in EP 693 475 B1.
`
`[0006]
`
`It has now been surprisingly found that (-)-(1R,2R)-3-(3-dimethylamino-1-
`
`ethyl-2-methylpropyl)-phenol hydrochloride can be produced in a reproducible
`
`manner in two different crystalline forms. The present invention provides a new
`
`form (Form A) of (—)—(1R,2R)—3—(3—dimethylamino—1—ethyl—2—methylpropyl)—pheI1o1
`
`hydrochloride which is different from the form already known (Form B) obtained
`
`by the procedure described in example 25 of US 6,248,737 and US 6,344,558 as
`
`well as EP 693 475 B1. This new Form A of (—)—(1R,2R)—3—(3—dimethylamino—1-
`
`ethyl—2—methylpropyl)—phenol hydrochloride is Very stable at ambient conditions
`
`and therefore useful for producing a pharmaceutical composition.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0007] Figure 1 shows an X-ray diffraction pattern;
`
`[0008] Figure 2 shows an infrared spectrum;
`
`[0009] Figure 3 shows a RAMAN spectrum;
`
`[0010] Figure 4 shows an X-ray diffraction pattern;
`
`[0011] Figure 5 shows an infrared spectrum;
`
`[0012] Figure 6 shows a RAMAN spectrum;
`
`[0013] Figure 7 shows an X-ray diffraction pattern;
`
`[0014] Figure 8 shows an X-ray diffraction pattern
`
`SUMMARY OF THE INVENTION
`
`[0015] The new crystalline Form A of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride can be identified by X-ray powder diffraction.
`
`The X-ray diffraction (“XRPD”) pattern is shown in Fig. 1 with the peak listing
`
`shown as Table 1.
`
`RS 1002 - 000010
`
`

`
`[0016] The most important X—ray lines (2-theta Values) in terms of intensity
`
`characterizing Form A of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-
`
`phenol hydrochloride showing one or a combination of the following in a powder
`
`diffraction measurement when measured using Cu Ku radiation at ambient
`
`temperature are 14.5: 0.2, 18.2::O.2, 20.4::O.2, 21.7::O.2 and 25.5::O.2.
`
`[0017] To discriminate crystalline Form A of (—)—(1R,2R)—3—(3—dimethylamino—1-
`
`ethyl—2—methylpropyl)—phenol hydrochloride from Form B it is more advantageous
`
`to look at the unique peaks in the X—ray diffraction diagram, i.e. e.g. the lines with
`
`sufficient intensity at 2—theta Values, where Form B does not show lines with
`
`significant intensity. Such characteristic X—ray lines (2—theta Values) for Form A in
`
`a powder diffraction pattern when measured using CuKq radiation at ambient
`
`temperature are: 15.1::0.2, 16.0::0.2, 18.92202, 20.42202, 22.52202, 27.32202,
`
`29.3::O.2 and 30.4::O.2.
`
`[0018] Another method to identify crystalline Form A of
`
`(-)-(1R,2R)-3-(3-
`
`dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is IR-spectroscopy.
`
`The IR-Spectrum of Form A is shown as Fig. 2 with the peak listing shown in
`
`comparism to Form B as Table 2.
`
`[0019]
`
`In the IR-spectrum it is characteristic for crystalline Form A of (-)-(1R,2R)-
`
`3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
`
`to
`
`show a
`
`combination of the following IR bands: 318024 cm‘1, 297024 cm‘1, 2695::4 cm‘1 ,
`
`2115:4 cm-1 , 1698::4 cm-1, 1462:4 em-1, 1032:4 cm‘1 and/or 972:4 cm'1.
`
`[0020] RAMAN technique can also be used to identify of the crystalline Form A of
`
`(-)- (1R, 2R) - 3- (3- dimethylamino- 1 - ethyl-2-methylpropyl)-phenol
`
`hydrochloride.
`
`Especially the range between 800 cm'1 and 200 cm'1, which is shown in Fig. 3, is
`
`advantageously used also by way of RAl\/[AN microscopy.
`
`[0021] Crystal structure analysis of Form A of (—)—(1R,2R)-3-(3-dimethylamino-1-
`
`ethyl-2—methylpropyl)-phenol hydrochloride showed monoclinic crystals with the
`
`following parameters of the elemental cell (length of side and angle):
`
`a: 7.11 A
`
`b: 11.62 A
`
`c: 17.43 A
`
`I3: 95.0°.
`
`RS 1002 - 000011
`
`

`
`[0022] The elemental cell of the crystal of crystalline Form A has a volume of
`
`1434
`
`5 A3 and a calculated density of 1.20
`
`0.01 g/cm3.
`
`[0023] The invention further relates to processes for the preparation of crystalline
`
`Form
`
`A
`
`of
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride.
`
`[0024] The
`
`process
`
`starts
`
`from crystalline Form B of
`
`(-)-(1R,2R)-3-(3-
`
`dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according
`
`to US Pat. Nos. 6,248,737 or 6,344,558 or European Patent EP 693 475 B1
`
`incorporated herein by reference.
`
`[0025]
`
`In one embodiment of the process (—)—(1R,2R)-3-(3-dimethylamino—1—ethyl-2-
`
`methylpropyl)-phenol hydrochloride of crystalline Form A is produced by
`
`dissolving
`
`the
`
`(—)—(1R,2R)—3—(8—dimethylamino—1—ethyl—2—methylpropyl)—phenol
`
`hydrochloride of crystalline Form B in acetone, acetonitrile or
`
`isopropanol,
`
`optionally followed by filtering, leaving the solution to crystallize and isolating the
`
`crystals
`
`of
`
`(—)—(1R,2R)-3-(3-dimethylamino—1—ethyl-2-methylpropyl)-phenol
`
`hydrochloride of crystalline Form A preferably by filtering again.
`
`[0026]
`
`If acetone or acetonitrile is used it is preferred that during this process the
`
`temperature is kept below + 40 °C, more preferably below + 25°C, especially after
`
`filtering. It is further preferred that in this process between 5 mg and 1 mg, more
`
`preferably between 2.5 mg and 1.4 mg, especially between 2.0 mg and 1.4 mg (-)-
`
`(1R,2R)-8-(3-dimethylamino—1—ethyl-2-methylpropyl)-phenol
`
`hydrochloride
`
`is
`
`dissolved per ml solvent.
`
`[0027] The use of isopropanol is preferred,
`
`if seed crystals of (-)-(1R,2R)—3—(3—
`
`dimethylamino—1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form
`
`A are available. The isopropanol used preferably contains about 0.5 % per volume
`
`of water. The dissolution of
`
`the
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl—2—
`
`methylpropyl)-phenol hydrochloride of crystalline Form B in isopropanol
`
`is
`
`performed at temperatures above room temperature, preferably above 65°C but
`
`not exceeding 80 °C. After complete dissolution the heat is turned of and the seed
`
`crystals are added during a first cooling phase. Thereafter the resulting mixture is
`
`cooled down to S 15 °C, preferably 5 10 °C and especially 5 5 °C.
`
`RS 1002 - 000012
`
`

`
`[0028] Optionally it is possible to reduce the solvent by evaporation, preferably in
`
`an evaporator under reduced pressure. Preferably the remaining volume of the
`
`solution after evaporation should not be less than 20 % of the volume at the
`
`beginning of the process. Optionally it is also possible to add active carbon to the
`
`solution originally prepared.
`
`[0029]
`
`In a preferred embodiment of
`
`the invention the
`
`(-)-(1R,2R)-3-(3-
`
`dimethylamino—1-ethyl-2-methylpropyl)—phenol hydrochloride of crystalline Form
`
`A obtained by the process described above is redesolved in acetone acetonitrile or
`
`isopropanol, preferably in the solvent already used in the first step, optionally is
`
`filtered to remove any insoluble residue and, optionally after reducing the amount
`
`of solvent by evaporation, is left to crystallize.
`
`[0030]
`
`It is preferred that in the last crystallization step the temperature is
`
`maintained at S 15 °C, more preferably S 10 °C and especially S 5 °C.
`
`[0031]
`
`In a further embodiment of the process according to the invention (-)-
`
`(1R,2R)-3-(8-dimethylamino—1—ethyl-2-methylpropyl)—phenol
`
`hydrochloride
`
`of
`
`crystalline Form A is produced in the solid state by cooling (-)-(1R,2R)—3—(3—
`
`dimethylamino—1-ethyl-2-methylpropyl)—phenol hydrochloride of crystalline Form
`
`B between 24 h and 168 h to a temperature between —4°C and —80°C. It is
`
`preferred that in this process the cooling temperature is between —10°C and —
`
`60°C, preferably between —15°C and — 50°C, especially between —25°C and -40°C
`
`and the cooling is carried out for a time between 24h and 120 h, preferably
`
`between 24h and 72 h, especially between 24 h and 48h.
`
`[0032] This invention further relates to a new Crystalline Form A of (-)-(1R,2R)—3—
`
`(3—dimethylamino-1—ethyl—2-methylpropyl)—phenol hydrochloride obtainable by
`
`dissolving
`
`(—)—(1R,2R)- 3- (8— dimethylamino— 1 —ethyl— 2 -methylpropyl)—phenol
`
`hydrochloride of Form B in acetonitrile together with active carbon, heating the
`
`solution to the boiling point, removing the active carbon by filtering, stirring the
`
`solution at a temperature below 40°C, removing insoluble residue by filtering and
`
`removing part of the solvent
`
`leaving (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride of Form A to crystallize, redissolving the
`
`crystals so obtained in acetonitrile, removing insoluble residue by filtering and
`
`RS 1002 - 000013
`
`

`
`removing part of the solvent
`
`leaving (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride of Form A to crystallize.
`
`[0033] Crystalline Form A according
`
`to
`
`the
`
`invention has
`
`the
`
`same
`
`pharmacological activity as Form B but is more stable under ambient conditions.
`
`It
`
`can be
`
`advantageously used as
`
`active
`
`ingredient
`
`in pharmaceutical
`
`compositions.
`
`[0034] Therefore the invention further relates to a pharmaceutical composition
`
`containing
`
`as
`
`active
`
`ingredient
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)—phenol hydrochloride of crystalline Form A according to the
`
`invention and at least one suitable additive and/or auxiliary substance.
`
`[0035] Such pharmaceutical composition according to the invention contains, in
`
`addition
`
`to
`
`crystalline
`
`Form A (—)—(1R,2R)—3—(3—dimethylamino—1—ethyl—2-
`
`methylpropyl)—phenol hydrochloride, one or more
`
`suitable additive and/or
`
`auxiliary substance such as for example carrier materials,
`
`fillers, solvents,
`
`diluents, coloring agents and/or binders, and may be administered as liquid
`
`medicament preparations in the form of injectable solutions, drops or juices, as
`
`semi—solid medicament preparations in the form of granules,
`
`tablets, pellets,
`
`patches, capsules, plasters or aerosols. The choice of the auxiliary substances,
`
`etc., as Well as the amounts thereof to be used depend on whether the medicament
`
`is
`
`to
`
`be
`
`administered
`
`orally,
`
`per
`
`orally,
`
`parenterally,
`
`intravenously,
`
`intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally
`
`or topically, for example to the skin, the mucous membranes or the eyes. For oral
`
`application suitable preparations are in the form of tablets, sugar-coated pills,
`
`capsules, granules, droplets, juices and syrups, while for parenteral, topical and
`
`inhalative
`
`application suitable
`
`forms
`
`are
`
`solutions,
`
`suspensions,
`
`readily
`
`reconstitutable dry preparations, as well as sprays. Form A in a depot form, in
`
`dissolved form or in a plaster, optionally with the addition of agents promoting
`
`skin
`
`penetration,
`
`are
`
`suitable
`
`percutaneous
`
`application
`
`preparations.
`
`Preparation forms that can be administered orally or percutaneously can provide
`
`for the delayed release of crystalline Form A according to the invention. In
`
`principle further active constituents known to the person skilled in the art may be
`
`added to the medicaments according to the invention.
`
`RS 1002 - 000014
`
`

`
`[0036] Preferred
`
`formulations
`
`for
`
`crystalline
`
`Form A (-)-(1R,2R)-3-(3-
`
`dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to the
`
`invention are presented in the PCT-application WO 03/035054 incorporated
`
`herein by reference.
`
`[0037] The amount of active constituent to be administered to the patient varies
`
`depending on the patient’s Weight, on the type of application, medical indication
`
`and severity of the condition. Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5
`
`mg/kg of crystalline Form A according to the invention are administered.
`
`[0038] Preferably, the crystalline Form A according to the invention is used for
`
`the treatment of pain or the treatment of urinary incontinence. Accordingly the
`
`invention also relates to the use of crystalline Form A according to the invention
`
`for the treatment of pain or the treatment of urinary incontinence.
`
`[0039] Additionally the invention relates to a method of treatment using a
`
`sufficient amount of crystalline Form A according to the invention for the
`
`treatment of a disease, especially pain or urinary incontinence.
`
`[0040] Certain embodiments of the present invention may be further understood
`
`by reference to the following specific examples.
`
`These examples and the
`
`terminology used herein are for the purpose of describing particular embodiments
`
`only and are not intended to be limiting.
`
`Example 1: Master Recipe for Preparation of Form A
`
`[0041] The master recipe is valid for a 50 ml scale.
`
`[0042] Provide
`
`1.9
`
`g
`
`(—)—(1R,2R)-8-(8-dimethylamino-1—ethyl—2-methylpropyl)—
`
`phenol hydrochloride prepared according to example 25 of European Patent EP
`
`693 475 B1 in a 50 ml glass round bottom vessel with a 3—blade overhead stirrer
`
`with baffles.
`
`[0043] Add 25 ml isopropanol and 0.5 % (V/v) water
`
`[0044] Stir at 800 rpm
`
`[0045] Heat to 80 °C
`
`[0046] Hold temperature while stirring for 10 minutes
`
`[0047] Cool to 65 °C
`
`RS 1002 - 000015
`
`

`
`[0048] Add 0.056 g seeds (Mean Sq. Wt. CL = 58 um2, Median No Wt. CL = 22
`
`um)
`
`[0049] Cool to 0 °C over 1 hour
`
`[0050] Filter slurry through PTFE filter column (5 um pore size)
`
`[0051] Dry solid material under slight vacuum until constant weight (approx. 24
`
`hours)
`
`[0052] Repeat the same procedure with the dry solid material obtained
`
`Example 2: Preparation of Form A [1]
`
`[0053]
`
`(—)—(1R,2R)—3—(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride was prepared according to example 25 of European Patent EP 693
`
`475 B1. 32.2 mg of the thus synthesized (—)—(1R,2R)—3—(3—dimethylamino—1—ethyl—2—
`
`methylpropyl)—phenol hydrochloride was — by slight heating up to 40°C and/or
`
`agitating on an orbital shaker for 30 min - dissolved in 20 ml acetone. Following
`
`that the solution was filtered through a nylon syringe filter having a mesh of 0.20
`
`um and the solution was left to crystallize by slow evaporation of the solvent.
`
`Crystalline Form A of
`
`(—)—(1R,2R)-3-(3-dimethylamino-1—ethyl—2-methylpropyl)—
`
`phenol hydrochloride was generated as proven by X-ray powder diffraction and by
`
`RAMAN microscopic analysis.
`
`Example 3: Preparation of Form A [2]
`
`[0054]
`
`(—)-(1R,2R)-8-(3-dimethylamino-1-ethyl—2—methylpropyl)—phenol
`
`hydrochloride was prepared according to example 25 of European Patent EP 693
`
`475 B1. 32.2 mg of the thus synthesized (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl—2—
`
`methylpropyl)-phenol hydrochloride was — if necessary by agitating for e.g. 80 min
`
`— dissolved in 20 ml acetone. Following that the solution was filtered with a nylon
`
`syringe filter having a mesh of 0.20 um and the solution was left to crystallize by
`
`slow evaporation of the solvent. In no step after and including the dissolving the
`
`temperature was allowed to rise above +25°C. Crystalline Form A of (-)-(1R,2R)-3-
`
`(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as
`
`proven by X-ray powder diffraction experiment and by RAMAN microscopic
`
`analysis.
`
`RS 1002 - 000016
`
`

`
`Example 4: Preparation of Form A 13)
`
`[0055]
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride was prepared according to example 25 of European Patent EP 693
`
`475 B1. 350 mg of the thus synthesized (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride were dissolved in 50 ml acetonitrile in a 250
`
`ml flask. The mixture was stirred for 1.5 h on a water bath heated to 37°C :: 1°C.
`
`Any insoluble residue was removed by filtering. Of the clear solution 35 ml was
`
`removed on a rotation evaporator at 70-80 mbar and a temperature of the water
`
`bath of 30°C :: 1°C. The precipitated solid compound was filtered by vacuum.
`
`Crystalline Form A of
`
`(—)—(1R,2R)—3—(3—dimethylamino—1—ethyl—2—methylpropyl)—
`
`phenol hydrochloride was generated as proven by X-ray powder diffraction and by
`
`RAMAN microscopic analysis.
`
`Example 5: Preparation of FormA 14]
`
`[0056]
`
`(—)-(1R,2R)-3-(3-dimethylamino-1-ethyl—2—methylpropyl)—phenol
`
`hydrochloride was prepared according to example 25 of European Patent EP 693
`
`475
`
`B1.
`
`The
`
`thus
`
`synthesized
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl—2—
`
`methylpropyl)-phenol hydrochloride was stored for 72 h at — 40°C. Crystalline
`
`Form
`
`A
`
`of
`
`(—)—(1R,2R)-3-(3-dimethylamino—1—ethyl-2-methylpropyl)-phenol
`
`hydrochloride was generated as proven by X-ray powder diffraction and by
`
`RAMAN microscopic analysis.
`
`Exam le 6: Pre aration of FormA 5
`
`OH
`
`,
`HC1
`N/
`
`Rccrystalization in
`Acctonirrilc
`
`I
`
`Mo1.\Vt.: 257,80
`C1“H3“C1N0
`
`[|\]/
`5
`C14I124C1NO
`Mo]. w:_: 257,80
`
`[0057]
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride was prepared according to example 25 of European Patent EP 693
`
`475 B1. 370 mg of the thus synthesized (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride were added to 40 ml acetonitrile and 100 mg
`
`RS 1002 - 000017
`
`

`
`active carbon in a 100 ml flask and heated to the boiling point. The active carbon
`
`was filtered off from the hot solution by means of a paper filter and the filtrate
`
`concentrated to a volume of approx. 10 ml in a rotation evaporator at 150 i 10
`
`mbar and 50°C. The solution was slowly rotated for 80 minutes at
`
`room
`
`temperature. Following that the solution was allowed to stand for 30 minutes at
`
`room temperature and than for 1 hour at 4°C. The Crystals are filtered by vacuum
`
`through a glass filter (276 mg yield).
`
`[0058] 266 mg of these Crystals were dissolved at room temperature in 45 ml
`
`acetonitrile, insoluble residues were removed by filtration and the solution was
`
`rotated for 1.5 h at 35-40°C at atmospheric pressure in a rotation evaporator.
`
`Than the solution was concentrated at 50°C and 150 i 10 mbar to a volume of
`
`approx. 10 ml and then slowly rotated for 80 minutes at room temperature.
`
`Following that the flask was allowed to stand for 12 h at 4°C.
`
`[0059] The precipitated solid is filtered by vacuum through a glass filter and dried
`
`in the air.
`
`[0060] Yield:
`
`[0061] 151 mg (40.8% of
`
`the theory in relation to used educt), white
`
`microcrystalline solid form
`
`Example 7: Preparation of Form B [1]
`
`[0062]
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride was prepared according to example 25 of European Patent EP 693
`
`475 B1. Crystalline Form B of
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder
`
`diffraction and by RAMAN microscopic analysis.
`
`Example 8: Preparation of Form B [2]
`
`[0063]
`
`(—)-(1R,2R)-3-(3-dimethylamino-1-ethyl—2—methylpropyl)—phenol
`
`hydrochloride prepared according to one of the examples 1 to 5 was milled for at
`
`least 20 min. Then it was kept at 130°C in an oven for 80 min. Crystalline Form B
`
`of
`
`(—)—(1R,2R)-8-(8-dimethylamino-1—ethyl—2-methylpropyl)-phenol hydrochloride
`
`was generated as proven by X-ray powder diffraction and by RAMAN microscopic
`
`analysis.
`
`RS 1002 - 000018
`
`

`
`Example 9: Preparation of Form B 13)
`
`[0064]
`
`(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride prepared according to one of the examples 1 to 5 was cryogrinded
`
`for at least 15 min. Then it was kept at 125°C in a TGA for 30 min. Crystalline
`
`Form
`
`B
`
`of
`
`(-)-(1R,2R)-3-(8-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride was generated as proven by X-ray powder diffraction and by
`
`RAMAN microscopic analysis.
`
`Example 10: X-ray powder diffraction patterns of Forms A 11] and B (1)
`
`[0065] Powder Data Collection was performed with a STOE Stadi P Transmission
`
`Powder Diffractometer equipped with a curved germanium monochromator and a
`
`linear position sensitive detector. The Very carefully ground powders were
`
`prepared as flat samples. As source of the beam a copper X-ray tube with
`
`monochromatized Cu Kou (A = 1.54051 A) radiation generated at 50 kV and 30 mA
`
`was used. The 26 area for the measurement was 5° — 40°. The used step width was
`
`0.02 degrees in 2 theta. The data were collected at a temperature of 23 :: 1°.
`
`[0066] The X-ray pattern for Form A is shown in Fig. 1, the X-ray pattern for
`
`Form B in Fig. 4.
`
`[0067] The data are shown in Table 1.
`
`Table 1: Peak and Relative Intensity Listing (°20, peaks with I/I1 value of
`10 and over)
`
`1-
`
`—[
`
`EZ
`
`1
`
`Z1
`
`RS 1002 - 000019
`
`

`
`E
`
`ZZZ3
`
`Example 11: IR spectrum of Forms A and B
`
`[0068] The mid IR spectra were acquired on a Nicolet model 860 Fourier
`
`transform IR spectrophotometer equipped with a globar
`
`source, Ge/KBr
`
`beamsplitter, and deterated triglycine sulfate (DTGS) detector. A Spectra—Tech,
`
`Inc. diffuse reflectance accessory was utilized for sampling. Each spectrum
`
`represents 256 co-added scans at a spectral resolution of 4 cm-1. A background
`
`data set was then acquired with an alignment mirror in place. A single beam
`
`sample data set was then acquired. Subsequently, a Log 1/R (R=Reflectance)
`
`spectrum was acquired by rationing the two data sets against each other. The
`
`spectrophotometer was calibrated (wavelength) with polystyrene at the time of
`use.
`
`[0069] The spectrum for Form A is shown in Fig. 2. The spectrum for Form B is
`
`shown in Fig. 5.
`
`[0070] The data are shown in the following Table 2.
`
`Table 2: IR Peak Listing
`
`Peak Pos. (crn")
`
`Intensity (log
`1/R)
`
`Peak Pos. (crrfl)
`
`Intensity (log
`1/R)
`
`RS 1002 - 000020
`
`

`
`FormA
`
`FormB
`
`Peak Pos. (Cm’1)
`
`1600.9
`1281.6
`1378.3
`1219.9
`1181.2
`1503.6
`1256.5
`712.6
`879.8
`684.7
`798.7
`1313.6
`1005.1
`731.2
`1090.9
`810.2
`971.5
`842.6
`831.7
`1111.5
`1049.8
`1136.5
`461.3
`1065.8
`495.1
`542.1
`595.8
`527.9
`912.4
`1032.4
`416.9
`1698.3
`1940.5
`1870.6
`1749.4
`1801.6
`2115.5
`
`Intensity (log
`1/R)
`1.838
`1.771
`1.763
`1.754
`1.748
`1.743
`1.734
`1.725
`1.713
`1.692
`1.681
`1.673
`1.655
`1.63
`1.626
`1.622
`1.588
`1.576
`1.574
`1.55
`1.534
`1.498
`1.476
`1.457
`1.438
`1.408
`1.384
`1.327
`1.304
`>—- DJ
`1.287
`1.282
`1.279
`1.277
`1.268
`1.208
`1.061
`
`Peak Pos. (Cm'1)
`
`2682
`1940.5
`1870.7
`1801.7
`1749.5
`1598.1
`1503.2
`1451.5
`1417.2
`1396.3
`1377.1
`1353.2
`1313.2
`1280.7
`1254.8
`1217.6
`1177.5
`1154.6
`1136.4
`1111.3
`1090.3
`1065.9
`1049.9
`1004.6
`958.7
`946.6
`912.5
`877.8
`842.7
`831.4
`810.7
`795.2
`730.6
`711.7
`683.4
`595.6
`542.1
`527.7
`495.1
`464.4
`416.7
`
`Intensity (log
`1/Rt)
`2.116
`1.242
`1.246
`1.201
`1.236
`2.138
`1.755
`2.164
`1.89
`1.843
`1.864
`1.726
`1.661
`1.977
`1.973
`2.015
`1.868
`1.597
`1.43]
`1.512
`1.625
`1.425
`1.52
`1.813
`1.855
`1.735
`1.292
`1.951
`1.657
`1.664
`1.715
`1.892
`1.855
`O-B
`.
`1.917
`1.439
`1.497
`1.425
`1.663
`1.6