U.S. patent application number 15/457191 was filed with the patent office on 2017-06-29 for crystalline form of y-aminobutyric acid analog.
The applicant listed for this patent is XenoPort, Inc.. Invention is credited to Tono Estrada, Christine Hook-Frauenfelder, Stephen P. Raillard, Uwe Zacher.
Application Number | 20170183296 15/457191 |
Document ID | / |
Family ID | 34465215 |
Filed Date | 2017-06-29 |
United States Patent
Application |
20170183296 |
Kind Code |
A1 |
Estrada; Tono ; et
al. |
June 29, 2017 |
CRYSTALLINE FORM OF y-AMINOBUTYRIC ACID ANALOG
Abstract
A crystalline form of a .gamma.-aminobutyric acid analog, and
methods of preparing same, are provided.
Inventors: |
Estrada; Tono; (Santa Clara,
CA) ; Raillard; Stephen P.; (Mountain View, CA)
; Hook-Frauenfelder; Christine; (Glis, CH) ;
Zacher; Uwe; (Brig, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XenoPort, Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
34465215 |
Appl. No.: |
15/457191 |
Filed: |
March 13, 2017 |
Related U.S. Patent Documents
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Application
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14831688 |
Aug 20, 2015 |
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15457191 |
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14206893 |
Mar 12, 2014 |
9150503 |
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14831688 |
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13164620 |
Jun 20, 2011 |
8686034 |
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14206893 |
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12897567 |
Oct 4, 2010 |
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13164620 |
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12548200 |
Aug 26, 2009 |
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12897567 |
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10966507 |
Oct 14, 2004 |
8026279 |
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12548200 |
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60511287 |
Oct 14, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 21/00 20180101; A61P 25/08 20180101; A61P 25/32 20180101; A61P
43/00 20180101; A61K 9/14 20130101; A61K 31/225 20130101; A61P
25/18 20180101; C07C 271/22 20130101; A61P 25/22 20180101; A61P
25/24 20180101; A61P 1/04 20180101; A61P 13/00 20180101; A61P 25/02
20180101; A61P 29/00 20180101; A61P 1/00 20180101; C07B 2200/13
20130101; A61P 19/00 20180101; A61P 25/20 20180101; A61P 25/28
20180101; C07C 2601/14 20170501; A61P 13/02 20180101; A61P 25/04
20180101; A61P 25/14 20180101; A61P 25/00 20180101 |
International
Class: |
C07C 271/22 20060101
C07C271/22 |
Claims
1.-8. (canceled)
9. A method for preparing crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid comprising: heating
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic in a solvent or a solvent mixture to provide a solution; and
cooling the solution to provide crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
10. The method of claim 9, wherein the solvent is selected from the
group consisting of methanol, ethanol, 1,2-propane diol, t-butanol,
n-butanol, isopropanol, acetic acid, nitromethane, acetonitrile,
dimethylsulfoxide, dimethylformamide, N-methyl pyrrolidone,
acetone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl
acetate, methyl isobutyl ketone, 1,2-dimethoxyethane,
tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, methyl t-butyl
ether, chlorobenzene, 1,4-dioxane, diethyl ether, cumene, o-xylene,
m-xylene, p-xylene, 2-ethoxyethanol, 1,2-ethandiol, ethyl formate,
2-methoxyethanol, 1-pentanol, anisole, dichloromethane, cis and
trans 1,2-dichloroethylene, chloroform, dimethylacetamide,
propylacetate and mixtures thereof.
11. The method of claim 9, wherein the solvent is a solvent
combination comprising a solvent and an anti-solvent.
12. The method of claim 11, wherein the anti-solvent is selected
from the group consisting of pentane, hexane, heptane, octane,
nonane, decane, undecane, dodecane, cis or trans decalin,
cyclohexane, methylcyclohexane and mixtures thereof.
13. The method of claim 12, wherein the solvent combination
comprises ethyl acetate and heptane and the temperature of heating
is between about 50.degree. C. and reflux.
14. The method of claim 13, wherein the temperature is about
70.degree. C.
15. The method of claim 13 or 14, wherein the concentration of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid in the ethyl acetate/heptane mixture is between about
0.18 g/mL and about 0.22 g/mL.
16. The method of claim 11, wherein the solvent is a solvent
combination comprising methyl t-butyl ether and methylcyclohexane
and the temperature of heating is in the range of between about
20.degree. C. to about 40.degree. C.
17. The method of claim 16, wherein the concentration of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid in the solvent combination is between about 0.1 g/mL
and about 0.25 g/mL.
18. The method of claim 17, wherein the solution is cooled to a
temperature between about 0.degree. C. and about 25.degree. C.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 14/831,688 filed Aug. 20, 2015 which is
continuation application of U.S. patent application Ser. No.
14/206,893, filed Mar. 12, 2014, now U.S. Pat. No. 9,150,503, which
is a continuation application of U.S. patent application Ser. No.
13/164,620, filed Jun. 20, 2011, now U.S. Pat. No. 8,686,034, which
is a continuation application of U.S. patent application Ser. No.
12/897,567, filed Oct. 4, 2010, which is a continuation application
of U.S. patent application Ser. No. 12/548,200, filed Aug. 26,
2009, which is a divisional application of U.S. patent application
Ser. No. 10/966,507, filed Oct. 14, 2004, which claims the benefit
of priority under 35 U.S.C. .sctn.119(e) to U.S. Provisional Patent
Application No. 60/511,287, filed Oct. 14, 2003, the disclosures of
which are hereby incorporated herein in their entireties.
1. FIELD
[0002] Disclosed herein is a crystalline form of an analog of
y-aminobutyric acid and methods of making the crystalline form
thereof. These analogs may be used as therapeutic agents in the
treatment of certain diseases and disorders, including, for
example, neuropathic pain and post-herpetic neuralgia.
2. BACKGROUND
[0003] In general, crystalline forms of drugs are preferred over
amorphous forms of drugs, in part, because of their superior
stability. For example, in many situations, an amorphous drug
converts to a crystalline drug form upon storage. Because amorphous
and crystalline forms of a drug typically have differing
physical/chemical properties, potencies and/or bioavailabilities,
such interconversion is undesirable for safety reasons in
pharmaceutical administration. A key characteristic of any
crystalline drug substance is the polymorphic behavior of such a
material. Polymorphs are crystals of the same molecule which have
different physical properties because the crystal lattice contains
a different arrangement of molecules. The different physical
properties exhibited by polymorphs affect important pharmaceutical
parameters such as storage, stability, compressibility, density
(important in formulation and product manufacturing) and
dissolution rates (important in determining bioavailability).
Stability differences may result from changes in chemical
reactivity (e.g., differential hydrolysis or oxidation, such that a
dosage form discolors more rapidly when comprised of one polymorph
than when comprised of another polymorph), mechanical changes
(e.g., tablets crumble on storage as a kinetically favored
crystalline form converts to thermodynamically more stable
crystalline form) or both (e.g., tablets of one polymorph are more
susceptible to breakdown at high humidity). Solubility differences
between polymorphs may, in extreme situations, result in
transitions to crystalline forms that lack potency or are toxic. In
addition, the physical properties of the crystalline form may be
important in pharmaceutical processing. For example, a particular
crystalline form may form solvates more readily or may be more
difficult to filter and wash free of impurities than other forms
(i.e., particle shape and size distribution might be different
between one crystalline form relative to other forms).
[0004] Agencies such as the United States Food and Drug
Administration closely regulate the polymorphic content of the
active component of a drug in solid dosage forms. In general, the
regulatory agency requires batch-by-batch monitoring for
polymorphic drugs if anything other than the pure,
thermodynamically preferred polymorph is marketed. Accordingly,
medical and commercial reasons favor synthesizing and marketing
solid drugs as the thermodynamically stable polymorph,
substantially free of kinetically favored polymorphs.
[0005]
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexa-
ne acetic acid, (1), a prodrug of the GABA analog gabapentin (2),
has high bioavailability as gabapentin when dosed either orally or
directly into the colon of a mammal (Gallop et al., International
Publication No. WO 02/100347). The high bioavailability makes
compound (1) a valuable component of oral dosage forms (including
sustained-release dosage forms) useful for treating or preventing
epilepsy, pain (especially, neuropathic pain and muscular and
skeletal pain), depression, anxiety, psychosis, faintness attacks,
hypokinesia, cranial disorders, neurodegenerative disorders, panic,
inflammatory disease (i.e., arthritis), insomnia, gastrointestinal
disorders, hot flashes, restless legs syndrome, urinary
incontinence or ethanol withdrawal syndrome.
##STR00001##
[0006] Compound (1), prepared as described in Gallop et al.,
International Publication No. WO 02/100347, is isolated as a glassy
solid after lyophilization from aqueous acetonitrile. The material
obtained by this process is partially or wholly amorphous and
certain alkali metal salt forms are hygroscopic. However, amorphous
solids and particularly hygroscopic solids are difficult to handle
under pharmaceutical processing conditions because of low bulk
densities and unsatisfactory flow properties. Moreover, handling of
hygroscopic solids requires special techniques and equipment to
obtain, for example, reproducible amounts of active compound or
solid formulation stability. Furthermore, drugs that are
hygroscopic must be packaged in special containers that have water
vapor barriers thus substantially increasing the cost of such
products.
[0007] Accordingly, a need exists for crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid with superior physicochemical properties that may be
used advantageously in pharmaceutical processing and pharmaceutical
compositions.
3. SUMMARY
[0008] A crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is provided that satisfies these and other needs. Also
provided are pharmaceutical compositions of a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid, methods of using the crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and pharmaceutical compositions thereof to treat or
prevent various diseases and methods of making crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
[0009] In a first aspect, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid is provided that has characteristic absorption peaks
(20) at 7.0.degree..+-.0.3.degree., 8.2.degree..+-.0.3.degree.,
10.5.degree..+-.0.3.degree., 12.8.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 16.4.degree..+-.0.3.degree.,
17.9.degree..+-.0.3.degree., 18.1.degree..+-.0.3.degree.,
18.9.degree..+-.0.3.degree., 20.9.degree..+-.0.3.degree.,
23.3.degree..+-.0.3.degree., 25.3.degree..+-.0.3.degree. and
26.6.degree..+-.0.3.degree. in an X-ray powder diffractogram.
[0010] In a second aspect, pharmaceutical compositions of the
crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohe-
xane acetic acid are provided. The pharmaceutical compositions
comprise
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid that has characteristic absorption peaks (20) at
7.0.degree..+-.0.3.degree., 8.2.degree..+-.0.3.degree.,
10.5.degree..+-.0.3.degree., 12.8.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 16.4.degree..+-.0.3.degree.,
17.9.degree..+-.0.3.degree., 18.1.degree..+-.0.3.degree.,
18.9.degree..+-.0.3.degree., 20.9.degree..+-.0.3.degree.,
23.3.degree..+-.0.3.degree., 25.3.degree..+-.0.3.degree. and
26.6.degree..+-.0.3.degree. in an X-ray powder diffractogram and a
pharmaceutically acceptable vehicle.
[0011] In a third aspect, methods for treating or preventing
epilepsy, pain (especially, neuropathic pain and muscular and
skeletal pain), depression, anxiety, psychosis, faintness attacks,
hypokinesia, cranial disorders, neurodegenerative disorders, panic,
inflammatory disease (i.e., arthritis), insomnia, gastrointestinal
disorders, hot flashes, restless legs syndrome, urinary
incontinence or ethanol withdrawal syndrome are provided. The
methods generally involve administering to a patient in need of
such treatment or prevention a therapeutically effective amount of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid that has characteristic absorption peaks (20) at
7.0.degree..+-.0.3.degree., 8.2.degree..+-.0.3.degree.,
10.5.degree..+-.0.3.degree., 12.8.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 16.4.degree..+-.0.3.degree.,
17.9.degree..+-.0.3.degree., 18.1.degree..+-.0.3.degree.,
18.9.degree..+-.0.3.degree., 20.9.degree..+-.0.3.degree.,
23.3.degree..+-.0.3.degree., 25.3.degree..+-.0.3.degree. and
26.6.degree..+-.0.3.degree. in an X-ray powder diffractogram.
[0012] In a fourth aspect, pharmaceutical compositions for treating
or preventing epilepsy, pain (especially, neuropathic pain and
muscular and skeletal pain), depression, anxiety, psychosis,
faintness attacks, hypokinesia, cranial disorders,
neurodegenerative disorders, panic, inflammatory disease (i.e.,
arthritis), insomnia, gastrointestinal disorders, hot flashes,
restless legs syndrome, urinary incontinence or ethanol withdrawal
syndrome in a patient in need of such treatment or prevention are
provided. The methods generally involve administering to a patient
in need of such treatment or prevention a therapeutically effective
amount of a pharmaceutical composition of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid that has characteristic absorption peaks (20) at
7.0.degree..+-.0.3.degree., 8.2.degree..+-.0.3.degree.,
10.5.degree..+-.0.3.degree., 12.8.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 16.4.degree..+-.0.3.degree.,
17.9.degree..+-.0.3.degree., 18.1.degree..+-.0.3.degree.,
18.9.degree..+-.0.3.degree., 20.9.degree..+-.0.3.degree.,
23.3.degree..+-.0.3.degree., 25.3.degree..+-.0.3.degree. and
26.6.degree..+-.0.3.degree. in an X-ray powder diffractogram.
[0013] In a fifth aspect, methods for making crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid that has characteristic absorption peaks (20) at
7.0.degree..+-.0.3.degree., 8.2.degree..+-.0.3.degree.,
10.5.degree..+-.0.3.degree., 12.8.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 16.4.degree..+-.0.3.degree.,
17.9.degree..+-.0.3.degree., 18.1.degree..+-.0.3.degree.,
18.9.degree..+-.0.3.degree., 20.9.degree..+-.0.3.degree.,
23.3.degree..+-.0.3.degree., 25.3.degree..+-.0.3.degree. and
26.6.degree..+-.0.3.degree. in an X-ray powder diffractogram are
provided.
4. BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1 illustrates an X-ray powder diffractogram of
crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid; and
[0015] FIG. 2 illustrates a differential scanning calorimetery
thermogram of crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
5. DETAILED DESCRIPTION
5.1 Definitions
[0016] "Pharmaceutically acceptable vehicle" refers to a diluent,
adjuvant, excipient or carrier with which
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is administered.
[0017] "Patient" includes humans. The terms "human" and "patient"
are used interchangeably herein.
[0018] "Preventing" or "prevention" refers to a reduction in risk
of acquiring a disease or disorder (i.e., causing at least one of
the clinical symptoms of the disease not to develop in a patient
that may be exposed to or predisposed to the disease but does not
yet experience or display symptoms of the disease).
[0019] "Promoiety" refers to a form of protecting group that when
used to mask a functional group within a drug molecule converts the
drug into a prodrug. Typically, the promoiety will be attached to
the drug via bond(s) that are cleaved by enzymatic or non-enzymatic
means in vivo.
[0020] "Treating" or "treatment" of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.,
arresting or reducing the development of the disease or at least
one of the clinical symptoms thereof). In another embodiment
"treating" or "treatment" refers to ameliorating at least one
physical parameter, which may not be discernible by the patient. In
yet another embodiment, "treating" or "treatment" refers to
inhibiting the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), physiologically, (e.g.,
stabilization of a physical parameter), or both. In yet another
embodiment, "treating" or "treatment" refers to delaying the onset
of the disease or disorder.
[0021] "Therapeutically effective amount" means the amount of a
compound that, when administered to a patient for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the patient to be treated.
[0022] Reference will now be made in detail to preferred
embodiments. Although preferred embodiments are described, it will
be understood that the invention is not limited to those preferred
embodiments. To the contrary, it is intended to cover alternatives,
modifications and equivalents as may be included within the spirit
and scope of the invention as defined by any claim(s) issuing
herefrom.
5.2 Crystalline Forms of
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid and Preparation Thereof
[0023] Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and methods of making crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid are disclosed in detail herein.
[0024] It should be understood that referral to
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid includes all substantially racemic mixtures, all
possible tautomeric forms of the conventional chemical structure
for this compound and all isotopically labeled derivatives of this
compound (e.g., .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.17O, .sup.18O, etc.).
[0025] The starting material (i.e.,
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid) can be made according to procedures disclosed in
Example 13 of Gallop et al., International Publication No. WO
02/100347 or Example 12 of Gallop et al., United States Provisional
Patent Application Ser. No. 60/606,637, filed Aug. 13, 2004,
entitled, "Methods for Synthesis of Acyloxyalkyl Carbamate
Prodrugs."
[0026] In one aspect, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid is provided. In some embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid has characteristic absorption peaks at
7.0.degree..+-.0.3.degree., 8.2.degree..+-.0.3.degree.,
10.5.degree..+-.0.3.degree., 12.8.degree..+-.0.3.degree.,
14.9.degree..+-.0.3.degree., 16.4.degree..+-.0.3.degree.,
17.9.degree..+-.0.3.degree., 18.1.degree..+-.0.3.degree.,
18.9.degree..+-.0.3.degree., 20.9.degree..+-.0.3.degree.,
23.3.degree..+-.0.3.degree., 25.3.degree..+-.0.3.degree. and
26.6.degree..+-.0.3.degree.. In other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid has characteristic absorption peaks at
7.0.degree..+-.0.2.degree., 8.2.degree..+-.0.2.degree.,
10.5.degree..+-.0.2.degree., 12.8.degree..+-.0.2.degree.,
14.9.degree..+-.0.2.degree., 16.4.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 18.1.degree..+-.0.2.degree.,
18.9.degree..+-.0.2.degree., 20.9.degree..+-.0.2.degree.,
23.3.degree..+-.0.2.degree., 25.3.degree..+-.0.2.degree., and
26.6.degree..+-.0.2.degree. in an X-ray powder diffractogram.
[0027] In some embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 54.degree. C. and about 78.degree.
C. In other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 58.degree. C. and about 70.degree.
C. In still other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 62.degree. C. and about 68.degree.
C. In still other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 62.degree. C. and about 66.degree.
C. In still other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 63.degree. C. and about 66.degree.
C. In still other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 64.degree. C. and about 66.degree.
C. In still other embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid melts between about 63.degree. C. and about 64.degree.
C.
[0028] In some embodiments, crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid may be prepared by first adding
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid to a solvent to form a solution or suspension. As used
herein, the terms solution and suspension are used interchangeably
and are meant to include circumstances where
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is placed in a solvent or solvent mixture regardless of
solubility. The solvent used in crystallization may be either a
homogenous solvent, a combination of solvents, or a solvent or
solvent combination in which the
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid exhibits temperature dependent solubility. In general,
solvents or solvent combinations in which
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is soluble within a first temperature range, and poorly
soluble within a second temperature range, can be advantageously
used in the methods described herein. Mixtures of a "good" solvent
and an "anti-solvent" can also be used with temperature dependent
solubilization, i.e., dissolving at elevated temperature and
crystallizing at room temperature. Examples of suitable "good"
solvents include methanol, ethanol, 1,2-propane diol, t-butanol,
n-butanol, isopropanol, acetic acid, nitromethane, acetonitrile,
dimethylsulfoxide, dimethylformamide, N-methyl pyrrolidone,
acetone, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl
acetate, methyl isobutyl ketone, 1,2-dimethoxyethane,
tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, methyl t-butyl
ether, chlorobenzene, 1,4-dioxane, diethylether, cumene, o-xylene,
m-xylene, p-xylene, 2-ethoxyethanol, 1,2-ethandiol, ethyl formate,
2-methoxyethanol, 1-pentanol, anisole, dichloromethane, cis and
trans 1,2 dichloroethylene, chloroform, dimethylacetamide,
propylacetate and mixtures thereof. Examples of suitable
"anti-solvents" include alkanes such as pentane, hexane, heptane,
octane, nonane, decane, undecane, dodecane, cis- or trans-decalin,
cyclohexane, methylcyclohexane and mixtures thereof.
[0029] Preferably, the dissolution process is carried out at
elevated temperature, up to and including the boiling point of the
solvent or solvent combination. Accordingly, in some embodiments,
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is dissolved in a solvent or solvent mixture with
heating and optionally, with shaking and stirring. The heated
solution may be kept at elevated temperature to ensure complete
dissolution of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid. The heated solution may also be filtered at elevated
temperature to remove any undissolved components.
[0030] Preferably, the solution is cooled slowly to provide
crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid, which may be separated from residual solvent by
filtration and/or drying under reduced pressure. In some
embodiments, the solution is cooled between about 0.degree. C. and
about 25.degree. C. Other methods, known to those of skill in the
crystallization arts, (e.g., solvent evaporation, drowning,
chemical reaction, seeding with a small quantity of the desired
crystal form, etc.) may also be employed to provide crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
[0031] In some embodiments,
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is dissolved in heptane at a temperature between about
70.degree. C. and about reflux temperature. Preferably, the
temperature is about 70.degree. C. and the concentration of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid in heptane is between about 0.07 g/mL to about 0.08
g/mL. The solution is then cooled to room temperature to provide
crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
[0032] In other embodiments,
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid is dissolved in a mixture of heptane/ethyl acetate
(10:1 by volume) at a temperature between about 50.degree. C. and
about the reflux temperature, more preferably at a temperature of
about 70.degree. C. The concentration of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid in the heptane/ethyl acetate mixture is between about
0.18 g/mL to about 0.22 g/mL. The solution is then cooled to
between about 0.degree. C. and about 25.degree. C. to provide
crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
[0033] In yet other embodiments,
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid is dissolved in a mixture of methylcyclohexane/methyl
t-butyl ether (the volumetric ratio of methylcyclohexane-to methyl
t-butyl ether between about 5:1 to about 20:1, preferably, around
10:1) at a temperature between about 20 and about 40.degree. C. and
the concentration of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid in the methylcyclohexane/methyl t-butyl ether mixture
is between about 0.1 g/mL to about 0.25 g/mL. The solution is then
cooled to between about 0.degree. C. and about 25.degree. C. to
provide crystalline
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
5.3 Therapeutic Uses
[0034] Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
administered to a patient, preferably a human, suffering from
epilepsy, pain (especially, neuropathic pain and muscular and
skeletal pain), post-herpetic neuralgia, depression, anxiety,
psychosis, faintness attacks, hypokinesia, cranial disorders,
neurodegenerative disorders, panic, inflammatory disease (i.e.,
arthritis), insomnia, gastrointestinal disorders, hot flashes,
restless legs syndrome, urinary incontinence or ethanol withdrawal
syndrome. Further, in certain embodiments, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cycloh-
exane acetic acid and/or pharmaceutical compositions thereof are
administered to a patient, preferably a human, as a preventative
measure against various diseases or disorders. Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
administered as a preventative measure to a patient having a
predisposition for epilepsy, pain (especially, neuropathic pain and
muscular and skeletal pain), post-herpetic neuralgia, depression,
anxiety, psychosis, faintness attacks, hypokinesia, cranial
disorders, neurodegenerative disorders, panic, inflammatory disease
(i.e., arthritis), insomnia, gastrointestinal disorders, hot
flashes, restless legs syndrome, urinary incontinence or ethanol
withdrawal syndrome. Accordingly, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be used
for the prevention of one disease or disorder and concurrently
treating another (e.g., prevention of psychosis while treating
gastrointestinal disorders; prevention of neuropathic pain while
treating ethanol withdrawal syndrome).
[0035] The suitability of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof in treating
epilepsy, pain (especially, neuropathic pain and muscular and
skeletal pain), post-herpetic neuralgia, depression, anxiety,
psychosis, faintness attacks, hypokinesia, cranial disorders,
neurodegenerative disorders, panic, inflammatory disease (i.e.,
arthritis), insomnia, gastrointestinal disorders, hot flashes,
restless legs syndrome, urinary incontinence or ethanol withdrawal
syndrome may be determined by methods known in the art (e.g.,
Satzinger et al., U.S. Pat. No. 4,024,175; Satzinger et al., U.S.
Pat. No. 4,087,544; Woodruff, U.S. Pat. No. 5,084,169; Silverman et
al., U.S. Pat. No. 5,563,175; Singh, U.S. Pat. No. 6,001,876;
Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S.
Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;
Silverman et al., U.S. Pat. No. 6,117,906; Silverman, International
Publication No. WO 92/09560; Silverman et al., International
Publication No. WO 93/23383; Horwell et al., International
Publication No. WO 97/29101, Horwell et al., International
Publication No. WO 97/33858; Horwell et al., International
Publication No. WO 97/33859; Bryans et al., International
Publication No. WO 98/17627; Guglietta et al., International
Publication No. WO 99/08671; Bryans et al., International
Publication No. WO 99/21824; Bryans et al., International
Publication No. WO 99/31057; Magnus-Miller et al., International
Publication No. WO 99/37296; Bryans et al., International
Publication No. WO 99/31075; Bryans et al., International
Publication No. WO 99/61424; Pande, International Publication No.
WO 00/23067; Bellioti, International Publication No. WO 00/31020;
Bryans et al., International Publication No. WO 00/50027; and
Bryans et al., International Publication No. WO 02/00209).
Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be used
to treat or prevent epilepsy, pain (especially, neuropathic pain
and muscular and skeletal pain), post-herpetic neuralgia,
depression, anxiety, psychosis, faintness attacks, hypokinesia,
cranial disorders, neurodegenerative disorders, panic, inflammatory
disease (i.e., arthritis), insomnia, gastrointestinal disorders,
hot flashes, restless legs syndrome, urinary incontinence or
ethanol withdrawal syndrome using known procedures described in the
art (see references above).
[0036] The compound disclosed herein, may be more efficacious than
the parent drug molecule (e.g., gabapentin or other GABA analog) in
treating or preventing epilepsy, pain (especially, neuropathic pain
and muscular and skeletal pain), post-herpetic neuralgia,
depression, anxiety, psychosis, faintness attacks, hypokinesia,
cranial disorders, neurodegenerative disorders, panic, inflammatory
disease (i.e., arthritis), insomnia, gastrointestinal disorders,
hot flashes, restless legs syndrome, urinary incontinence or
ethanol withdrawal syndrome because the disclosed compound may
require less time to reach a therapeutic concentration in the
blood, i.e., the compound disclosed herein has a shorter t.sub.max
than gabapentin when taken orally. Without wishing to bound by
theory, it is believed that the compound disclosed herein is
absorbed from the gastrointestinal lumen into the blood by a
different mechanism than that by which gabapentin and other known
GABA analogs are absorbed. For example, gabapentin is believed to
be actively transporter across the gut wall by a carrier
transporter localized in the human small intestine. The gabapentin
transporter is easily saturated which means that the amount of
gabapentin absorbed into the blood is not proportional to the
amount of gabapentin that is administer orally, since once the
transport mechanism is saturated, further absorption of gabapentin
does not occur to any significant degree. In comparison to
gabapentin, the compound disclosed herein, is absorbed across the
gut wall along a greater portion of the gastrointestinal tract,
including the colon.
[0037] Because the compound disclosed herein can be formulated in
sustained release formulations which provides for sustained release
over a period of hours into the gastrointestinal tract and
particularly, release within the colon,
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may also be more efficacious than gabapentin in
treating or preventing epilepsy, pain (especially, neuropathic pain
and muscular and skeletal pain), post-herpetic neuralgia,
depression, anxiety, psychosis, faintness attacks, hypokinesia,
cranial disorders, neurodegenerative disorders, panic, inflammatory
disease (i.e., arthritis), insomnia, gastrointestinal disorders,
hot flashes, restless legs syndrome, urinary incontinence or
ethanol withdrawal syndrome. The ability of the compound disclosed
herein to be used in sustained release oral dosage forms reduces
the dosing frequency necessary for maintenance of a therapeutically
effective drug concentration in the blood.
5.4 Modes of Administration
[0038] Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
advantageously used in human medicine. As previously described,
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are useful
for the treatment or prevention of epilepsy, pain (especially,
neuropathic pain and muscular and skeletal pain), post-herpetic
neuralgia, depression, anxiety, psychosis, faintness attacks,
hypokinesia, cranial disorders, neurodegenerative disorders, panic,
inflammatory disease (i.e., arthritis), insomnia, gastrointestinal
disorders, hot flashes, restless legs syndrome, urinary
incontinence or ethanol withdrawal syndrome.
[0039] When used to treat or prevent the above disease or
disorders, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
administered or applied singly, or in combination with other
agents. Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may also be
administered or applied singly or in combination with other
pharmaceutically active agents, including other GABA analogs.
[0040] Methods of treatment and prophylaxis are provided by
administration to a patient of a therapeutically effective amount
of a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof. The patient
may be an animal, is more preferably, a mammal, and most
preferably, a human.
[0041] Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof, are
preferably administered orally. Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may also be
administered by any other convenient route, for example, by
infusion or bolus injection, by absorption through epithelial or
mucocutaneous linings (e.g., oral mucosa, rectal and intestinal
mucosa, etc.). Administration can be systemic or local. Various
delivery systems are known, (e.g., encapsulation in liposomes,
microparticles, microcapsules, capsules, etc.) that can be used to
administer crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof. Methods of
administration include, but are not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, epidural, oral, sublingual, intranasal, intracerebral,
intravaginal, transdermal, rectally, by inhalation, or topically,
particularly to the ears, nose, eyes or skin.
[0042] In some embodiments, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof can be
delivered via sustained release systems, preferably, oral sustained
release systems. In one embodiment, a pump may be used (Langer,
supra; Sefton, 1987, CRC Crit Ref Biomed. Eng. 14:201; Saudek et
al., 1989, N. Engl. J. Med. 321:574).
[0043] In other embodiments, polymeric materials can be used
("Medical Applications of Controlled Release," Langer and Wise
(eds.), CRC Pres., Boca Raton, Fla. (1974); "Controlled Drug
Bioavailability," Drug Product Design and Performance, Smolen and
Ball (eds.), Wiley, New York (1984); Langer et al., 1983, J.
Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al.,
1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351;
Howard et al., 1989, J. Neurosurg. 71:105). In still other
embodiments, polymeric materials are used for oral sustained
release delivery. Polymers include, for example, sodium
carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and hydroxyethylcellulose (preferably,
hydroxypropylmethylcellulose). Other cellulose ethers have been
described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984,
5(3) 1-9). Factors affecting drug release are well known to the
skilled artisan and have been described in the art (Bamba et al.,
Int. J. Pharm. 1979, 2, 307).
[0044] In other embodiments, enteric-coated preparations can be
used for oral sustained release administration. Coating materials
include, for example, polymers with a pH-dependent solubility
(i.e., pH-controlled release), polymers with a slow or pH-dependent
rate of swelling, dissolution or erosion (i.e., time-controlled
release), polymers that are degraded by enzymes (i.e.,
enzyme-controlled release) and polymers that form firm layers that
are destroyed by an increase in pressure (i.e., pressure-controlled
release).
[0045] In still other embodiments, osmotic delivery systems are
used for oral sustained release administration (Verma et al., Drug
Dev. Ind. Pharm. 2000, 26:695-708). In some embodiments, OROS.TM.
osmotic devices are used for oral sustained release delivery
devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes et al.,
U.S. Pat. No. 3,916,899).
[0046] In yet other embodiments, a controlled-release system can be
placed in proximity of the target of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof, thus
requiring only a fraction of the systemic dose (e.g., Goodson, in
"Medical Applications of Controlled Release," supra, vol. 2, pp.
115-138 (1984)). Other controlled-release systems discussed in
Langer, 1990, Science 249:1527-1533 may also be used.
[0047] Crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof preferably,
provide gabapentin upon in vivo administration to a patient. While
not wishing to bound by theory, the promoiety of crystalline forms
of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
cleaved either chemically and/or enzymatically. One or more enzymes
present in the stomach, intestinal lumen, intestinal tissue, blood,
liver, brain or any other suitable tissue of a mammal may cleave
the promoiety of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof. The
mechanism of cleavage is not important. Preferably, gabapentin
formed by cleavage of promoieties from the crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof does not
contain substantial quantities of .gamma.-lactam contaminant
(preferably, less than 0.5% by weight, more preferably, less than
0.2% by weight, most preferably less than 0.1% by weight) which is
formed by intramolecular cyclization of the .gamma. amino group
with the carboxyl functionality. The extent of lactam formation
from crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
assessed using standard in vitro analytical methods.
[0048] While not wishing to bound by theory, the promoiety of
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cycloh-
exane acetic acid and/or pharmaceutical compositions thereof may be
cleaved prior to absorption by the gastrointestinal tract (e.g.,
within the stomach or intestinal lumen) and/or after absorption by
the gastrointestinal tract (e.g., in intestinal tissue, blood,
liver or other suitable tissue of a mammal). If the promoiety of
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof is cleaved
prior to absorption by the gastrointestinal tract, gabapentin may
be absorbed into the systemic circulation conventionally (e.g., via
the large neutral amino acid transporter located in the small
intestine). If the promoiety of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are cleaved
after absorption by the gastrointestinal tract, this GABA analog
prodrug may be absorbed into the systemic circulation either by
passive diffusion, active transport or by both passive and active
processes.
[0049] If the promoiety of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof is cleaved
after absorption by the gastrointestinal tract, this GABA analog
prodrug may have the opportunity to be absorbed into the systemic
circulation from the large intestine. In this situation,
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
preferably administered as sustained release systems. In some
embodiments, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
delivered by oral sustained release administration. Preferably, in
these embodiments, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
administered twice per day (more preferably, once per day).
5.5 Pharmaceutical Compositions
[0050] The present pharmaceutical compositions contain a
therapeutically effective amount of a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid together with a suitable amount of a pharmaceutically
acceptable vehicle, so as to provide the form for proper
administration to a patient. When administered to a patient,
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and pharmaceutically acceptable vehicles are preferably
sterile. Water is a preferred vehicle when a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is administered intravenously. Saline solutions and
aqueous dextrose and glycerol solutions can also be employed as
liquid vehicles, particularly for injectable solutions. Suitable
pharmaceutical vehicles also include excipients such as starch,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried skim milk, glycerol, propylene, glycol, water,
ethanol, etc. The present compositions, if desired, can also
contain minor amounts of wetting or emulsifying agents or pH
buffering agents. In addition, auxiliary, stabilizing, thickening,
lubricating and coloring agents may be used.
[0051] In some embodiments, the pharmaceutical compositions of
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cycloh-
exane acetic acid are free of lactam side products formed by
intramolecular cyclization. In other embodiments, the
pharmaceutical compositions of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid are stable to extended storage (preferably, greater
than one year) without substantial lactam formation (preferably,
less than 0.5% lactam by weight, more preferably, less than 0.2%
lactam by weight, most preferably, less than 0.1% lactam by
weight).
[0052] Pharmaceutical compositions comprising crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may be manufactured by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or lyophilizing processes. Pharmaceutical
compositions may be formulated in conventional manner using one or
more physiologically acceptable carriers, diluents, excipients or
auxiliaries, which facilitate processing of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid into preparations which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration
chosen.
[0053] The present pharmaceutical compositions can take the form of
solutions, suspensions, emulsion, tablets, pills, pellets,
capsules, capsules containing liquids, powders, sustained-release
formulations, suppositories, emulsions, aerosols, sprays,
suspensions, or any other form suitable for use. In some
embodiments, the pharmaceutically acceptable vehicle is a capsule
(e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Other examples
of suitable pharmaceutical vehicles have been described in the art
(see Remington's Pharmaceutical Sciences, Philadelphia College of
Pharmacy and Science, 19th Edition, 1995). Compositions of
crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid are preferably formulated for oral delivery,
particularly for oral sustained release administration.
[0054] Pharmaceutical compositions for oral delivery may be in the
form of tablets, lozenges, aqueous or oily suspensions, granules,
powders, emulsions, capsules, syrups, or elixirs, for example.
Orally administered compositions may contain one or more optional
agents, for example, sweetening agents such as fructose, aspartame
or saccharin, flavoring agents such as peppermint, oil of
wintergreen or cherry coloring agents and preserving agents, to
provide a pharmaceutically palatable preparation. Moreover, where
in tablet or pill form, the pharmaceutical compositions may be
coated to delay disintegration and absorption in the
gastrointestinal tract, thereby providing a sustained action over
an extended period of time. Selectively permeable membranes
surrounding an osmotically active driving compound are also
suitable for orally administering the compounds and compositions
disclosed herein. In these later platforms, fluid from the
environment surrounding the capsule is imbibed by the driving
compound, which swells to displace the agent or agent composition
through an aperture. These delivery platforms can provide an
essentially zero order delivery profile as opposed to the spiked
profiles of immediate release formulations. A time delay material
such as glycerol monostearate or glycerol stearate may also be
used. Oral compositions can include standard vehicles such as
mannitol, lactose, starch, magnesium stearate, sodium saccharine,
cellulose, magnesium carbonate, etc. Such vehicles are preferably
of pharmaceutical grade.
[0055] For oral liquid preparations such as, for example,
suspensions, elixirs and solutions, suitable carriers, excipients
or diluents include water, saline, alkyleneglycols (e.g., propylene
glycol), polyalkylene glycols (e.g., polyethylene glycol) oils,
alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g.,
acetate, citrate, ascorbate at between about 5 mM to about 50 mM),
etc. Additionally, flavoring agents, preservatives, coloring
agents, bile salts, acylcarnitines and the like may be added.
[0056] Pharmaceutical compositions for administration via other
routes may also be contemplated. For buccal administration, the
compositions may take the form of tablets, lozenges, etc.
formulated in conventional manner. Liquid drug formulations
suitable for use with nebulizers and liquid spray devices and EHD
aerosol devices will typically include a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane
acetic acid with a pharmaceutically acceptable vehicle. Preferably,
the pharmaceutically acceptable vehicle is a liquid such as
alcohol, water, polyethylene glycol or perfluorocarbon. Optionally,
another material may be added to alter the aerosol properties of
the solution or suspension of the compounds disclosed herein.
Preferably, this material is liquid such as an alcohol, glycol,
polyglycol or a fatty acid. Other methods of formulating liquid
drug solutions or suspension suitable for use in aerosol devices
are known to those of skill in the art (see, e.g., Biesalski, U.S.
Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611). A
crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may also be formulated in rectal or vaginal
compositions such as suppositories or retention enemas, e.g.,
containing conventional suppository bases such as cocoa butter or
other glycerides. In addition to the formulations described
previously, a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may also be formulated as a depot preparation. Such
long acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may be formulated with suitable polymeric or
hydrophobic materials (for example, as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0057] In some embodiments, a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is formulated as a pure active agent. In other
embodiments, a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is formulated as a mixture with other crystalline forms
of
-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid.
5.6 Dosages
[0058] A crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof, will
generally be used in an amount effective to achieve the intended
purpose. For use to treat or prevent diseases or disorders such as
epilepsy, pain (especially, neuropathic pain and muscular and
skeletal pain), depression, anxiety, psychosis, faintness attacks,
hypokinesia, cranial disorders, neurodegenerative disorders, panic,
inflammatory disease (i.e., arthritis), insomnia, gastrointestinal
disorders, hot flashes, restless legs syndrome, urinary
incontinence or ethanol withdrawal syndrome the crystalline forms
of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
administered or applied in a therapeutically effective amount.
[0059] The amount of a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof that will be
effective in the treatment of a particular disorder or condition
disclosed herein will depend on the nature of the disorder or
condition, and can be determined by standard clinical techniques
known in the art as previously described. In addition, in vitro or
in vivo assays may optionally be employed to help identify optimal
dosage ranges. The amount of a crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof administered
will, of course, be dependent on, among other factors, the subject
being treated, the weight of the subject, the severity of the
affliction, the manner of administration and the judgment of the
prescribing physician.
[0060] For example, the dosage may be delivered in a pharmaceutical
composition by a single administration, by multiple applications or
controlled release. In some embodiments, the crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
delivered by oral sustained release administration. Preferably, in
these embodiments, the crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
administered twice per day (more preferably, once per day). Dosing
may be repeated intermittently, may be provided alone or in
combination with other drugs and may continue as long as required
for effective treatment of the disease state or disorder.
[0061] In some embodiments, the dose of the crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
adjusted to provide between about 500 mg/day and about 7000 mg/day
of prodrug (equivalent to about 260 mg/day and about 3600 mg/day of
gabapentin). Dosage ranges may be readily determined by methods
known to the skilled artisan.
[0062] The crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof are
preferably assayed in vitro and in vivo, for the desired
therapeutic or prophylactic activity, prior to use in humans.
Preferably, a therapeutically effective dose of a crystalline forms
of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof described
herein will provide therapeutic benefit without causing substantial
toxicity. Toxicity of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof may be
determined using standard pharmaceutical procedures and may be
readily ascertained by the skilled artisan. The dose ratio between
toxic and therapeutic effect is the therapeutic index. The dosage
of crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof described
herein will preferably be within a range of circulating
concentrations that include an effective dose with little or no
toxicity.
5.7 Combination Therapy
[0063] In certain embodiments, crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof can be used
in combination therapy with at least one other therapeutic agent.
The crystalline forms of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and/or pharmaceutical compositions thereof and the
other therapeutic agent can act additively or, more preferably,
synergistically. In some embodiments, a pharmaceutical composition
comprising a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is administered concurrently with the administration of
another therapeutic agent, which can be part of the same
pharmaceutical composition as the crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid or a different pharmaceutical composition. In other
embodiments, a pharmaceutical composition comprising a crystalline
form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid is administered prior or subsequent to administration
of another therapeutic agent. For example, a crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid may be administered in combination with an amorphous
form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid, another crystalline form of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid, gabapentin or pregabalin.
6. EXAMPLES
[0064] The following examples describe in detail the preparation of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid and a crystalline form thereof. 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.
[0065] In the examples below, the following abbreviations have the
following meanings. If an abbreviation is not defined, the
generally accepted meaning applies.
[0066] Atm=atmosphere
[0067] Boc=tert-butyloxycarbonyl
[0068] Cbz=carbobenzyloxy
[0069] DCC=dicyclohexylcarbodiimide
[0070] DMAP=4-N,N-dimethylaminopyridine
[0071] DMF=N, N-dimethylformamide
[0072] DMSO=dimethylsulfoxide
[0073] Fmoc=9-fluorenylmethyloxycarbonyl
[0074] g=gram
[0075] h=hour
[0076] HPLC=high pressure liquid chromatography
[0077] L=liter
[0078] LC/MS=liquid chromatography/mass spectroscopy
[0079] M=molar
[0080] min=minute
[0081] mL=milliliter
[0082] mmol=millimoles
[0083] NHS=N-hydroxysuccinimide
[0084] THF=tetrahydrofuran
[0085] TFA=trifluoroacetic acid
[0086] TLC=thin layer chromatography
[0087] TMS=trimethylsilyl
[0088] .mu.L=microliter
[0089] .mu.M=micromolar
[0090] v/v=volume to volume
6.1 Example 1:
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid via Trimethylsilyl Ester Intermediate
Step A:
1-{[(.alpha.-Chloroethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid
[0091] In a 5-liter, 3-neck, round bottom flask containing
dichloromethane (1.6 L) is added gabapentin (120.4 g, 0.704 mol)
followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane
(178 mL, 1.40 mol) is slowly added while maintaining the reaction
temperature below 15.degree. C. and the resulting suspension is
stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol)
is then added slowly while maintaining the temperature below
15.degree. C. After the addition is complete, additional
triethylamine (88 mL, 0.63 mol) is added and the resulting
suspension is stirred at room temperature for 30 min. The resulting
silyl ester is converted via acidic work-up to the corresponding
acid by washing the reaction mixture with water (2.times.1 L),
followed by 1N HCl (2.times.2 L) then brine (2.times.500 mL). After
drying over anhydrous sodium sulfate and removal of the solvent in
vacuo, the crude product (190 g) is obtained as an orange oil and
used in Step B without further purification. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 1.41-1.57 (m, 10H), 1.78 (d, 3H),
2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).
Step B:
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohex-
ane Acetic Acid
[0092] To a 3-liter, 3-neck, round bottom flask is added isobutyric
acid (254 g, 2.9 mol) followed by triethylamine (395 ml, 2.84 mol).
The reaction mixture is cooled to room temperature and a solution
of crude acid from the above reaction step (190 g, 0.69 mol) in
dichloromethane (80 mL) is added in a controlled fashion while
maintaining the temperature below 30.degree. C. The resulting pale
yellow solution is stirred overnight. The reaction mixture is then
diluted with one volume of dichloromethane and washed with water
(6.times.500 mL), aqueous potassium bicarbonate (3.times.500 mL),
and brine (2.times.500 mL). After drying over anhydrous sodium
sulfate, removal of the solvent in vacuo affords the crude product
as a dark red oil (87 g). A portion (35 g) of this product is
loaded onto an 800 g Biotage.TM. normal phase silica gel flash
column and eluted with 40% diethyl ether in hexane (6 L), which
after removal of the solvent in vacuo affords the product as a
colorless oil (13.5 g). This is repeated with a second 35 g portion
of crude product yielding a further 13.5 g of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid. A sample of the product (25 g) is recrystallized by
dissolution in heptane (325 mL) at 70.degree. C., followed by slow
cooling to room temperature. The white crystalline product (23 g)
is isolated by filtration. Melting point: 63-64.degree. C.
6.2 Example 2:
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid via Allyl Ester Intermediate
Step A: Allyl 1-Aminomethyl-1-Cyclohexane Acetate Hydrochloride
[0093] A dry 3 L, three-neck, round-bottomed flash fitted with a
magnetic stirring bar and a 500 mL pressure-equalizing addition
funnel is flushed with nitrogen gas. The flask is charged with
gabapentin (171 g, 1.0 mol) and allyl alcohol (1 L, 852 g, 14.6
mol) and the entire mixture is cooled to 0.degree. C. in an
ice-water bath. Thionyl chloride (225 mL, 360 g, 3.0 mol) is added
dropwise over a period of 1 h to the stirred solution. The reaction
mixture is allowed to stir at room temperature for 16 h, then is
diluted with ethyl ether (2 L) and cooled to 0.degree. C. while
stirring. After several minutes white crystals form, which are
collected by filtration. The crude product is recrystallized from a
1/3 (v/v) mixture of ethanol and ethyl ether (2 L) to give the
product as a white solid (220 g 88%). m.p.: 138-142.degree. C.
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 1.36-1.54 (m, 10H), 2.57
(s, 2H), 3.05 (s, 2H), 4.61 (d, J=6 Hz, 2H), 5.22 (dd, J.sub.1=10.4
Hz, J.sub.2=1.2 Hz, 1H), 5.33 (dd, J.sub.1=17.2 Hz, J.sub.2=1.4 Hz,
1H), 5.90-6.00 (m, 1H). MS (ESI) m/z 212.0 (M-Cl).sup.-.
Step B: Allyl
1-{[(.alpha.-Chloroethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetate
[0094] To a solution of the above hydrochloride salt (220 g, 0.89
mol) in dichloromethane (1 L) is slowly added 1-chloroethyl
chloroformate (101.7 mL, 132.3 g, 0.92 mol). The reaction mixture
is cooled to 0.degree. C. and 4-methylmorpholine (205 mL, 188.9 g,
1.87 mol) is slowly added over a period of 1 h while maintaining a
temperature of less than 10.degree. C. The resulting turbid
solution is stirred at room temperature for 1 h. Ethanol (150 mL)
is added and the reaction mixture is stirred at room temperature
for 1 h. The reaction mixture is then diluted with ether (2.5 L),
washed with water (1 L) and brine (1 L). The organic phase is dried
over sodium sulfate and concentrated to give the title compound as
a light yellow viscous liquid (282 g, 100%). .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 1.35-1.58 (m, 10H), 1.78 (d, J=5.6
Hz, 3H), 2.32 (s, 2H), 3.22 (d, J=6.8 Hz, 2H), 4.57 (d, J=5.6 Hz,
2H), 5.25 (dd, J.sub.1=10.4 Hz, J.sub.2=1 Hz, 1H), 5.32 (dd,
J.sub.1=17.2 Hz, J.sub.2=1.6 Hz, 1H), 5.52 (br, 1H, NH), 5.90-5.94
(m, 1H), 6.54 (q, J=5.6 Hz, 1H).
Step C: Allyl
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetate
[0095] To a mixture of isobutyric acid (432 mL, 391.5 g, 4.4 mol)
and 4-methylmorpholine (488 mL, 449 g, 4.4 mol) is added a solution
of the chlorocarbamate from the previous step (282 g, 0.88 mol) in
isobutyric acid (432 mL, 391.5 g, 4.4 mol). The addition occurs at
0.degree. C. over a period of 30 min. The resulting turbid solution
is stirred at room temperature for 16 h. The reaction mixture is
diluted with ether (2.5 L) and washed with water (3.times.500 mL)
followed by 10% aqueous potassium bicarbonate (6.times.500 mL) then
brine (500 mL). The organic phase is dried over sodium sulfate and
concentrated to yield the title compound as a viscous liquid (328
g, 100%). .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 1.15 (d, J=7.2
Hz, 6H), 1.35-1.58 (m, 10H), 2.31 (s, 2H), 2.51 (m, 1H), 3.19 (d,
J=5.6 Hz, 2H), 4.56 (d, J=5.6 Hz, 2H), 5.24 (dd, J.sub.1=10 Hz,
J.sub.2=1 Hz, 1H), 5.32 (dd, J.sub.1=17 Hz, J.sub.2=1.2 Hz, 1H),
5.35 (br, 1H), 5.84-5.94 (m, 1H), 6.78 (q, J=5.6 Hz, 1H). MS (ESI)
m/z 392.24 (M+H)'.
Step D: Deprotection of Allyl
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane
Acetate
[0096] To a stirred suspension of ammonium formate (112 g, 1.7 mol)
in ethanol (500 mL) is added the above allyl ester (328 g, 0.88
mol) together with 10% Pd/C (15 g) under a nitrogen atmosphere.
After 6 h, the reaction mixture is worked-up by filtering off the
catalyst. The catalyst is washed with ethanol (2.times.250 mL) and
the filtrates are combined and evaporated. The crude product is
dissolved in ether (2 L) and the organic phase is washed with 2N
HCl (2.times.2 L) to convert the ammonium salt into the acid form,
followed by washing with water (1 L) and brine (1 L). The ether
layer is dried over sodium sulfate and concentrated to give the
crude product as a viscous liquid (240 g, 82%).
Step E: Crystallization of
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-Cyclohexane
Acetic Acid
[0097] A 3 L round-bottom flask is equipped with a heating oil
bath, a nitrogen inlet adapter, an internal thermometer, an
overhead mechanical stirrer, and a reflux condenser. The flask is
flushed with nitrogen and charged with a 1/10 (v/v) mixture of
ethyl acetate/heptane (1.2 L) and the crude product from the
preceding reaction (240 g). The flask is heated until the product
dissolves, then cooled according to the following schedule:
TABLE-US-00001 Temp (.degree. C.) Time (Internal Entry (min.) temp)
Appearance Remarks 1 0 18.0 Solid in solvent Start heating oil bath
2 10 48 Turbid Slow dissolution of product 4 20 58 Clear solution
Turn off oil bath 5 25 60 Clear solution Maximum temp. reached 6 45
43 Turbid Compound crystallizing 7 60 36 Milky solution Seed with
pure ref. material 8 90 24 Solid in solution
[0098] The flask is then cooled to 4.degree. C. overnight with
stirring (cooling improves the yield). The product is filtered and
washed with heptane (2.times.100 mL), then dried under reduced
pressure (25 mm of Hg (0.033 atm)) at 30.degree. C. for 18 h to
yield
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid (185 g) as a white crystalline solid.
6.3 Example 3: X-Ray Powder Diffraction Analysis of Crystalline
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid
[0099] X-ray powder diffractograms (XRPD's) of crystalline samples
of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid produced according to Examples 1 and 2 above are
measured with a Bruker D8 Discover X-ray powder diffractometer
using Cu K.alpha. radiation. The instrument is equipped with
parallel beam optics and a two-dimensional HI-STAR area detector.
The tube voltage and amperage are set to 40 kV and 40 mA,
respectively. The collimated X-ray beam is reduced to a spot size
of about 0.5 mm in diameter. The area detector is placed 15 cm from
the center of the goniometer and the angular resolution is
approximately 0.033.degree./pixel. The detector covers a range of
35.degree. in 2-theta (20) within one frame. The angle between the
X-ray beam and the horizontal sample plate is set to 4.degree. and
the center of the area detector is set to an angle of 18.degree..
This geometry allows the measurement of 2-theta from 4.5.degree. to
39.5.degree. within one frame. Typical averaging time is 3 minutes
for each XRPD pattern collected. A corundum sample (NIST 1976) is
used to calibrate the XRPD instrument. Both samples give equivalent
diffractogram patterns, as illustrated in FIG. 1.
6.4 Example 4: Melting Point and Differential Scanning Calorimetry
Analysis of Crystalline
1-{[(.alpha.-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid
[0100] Melting points of crystalline samples of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid produced according to Examples 1 and 2 above are
measured using an Electrothermal 9200 melting point apparatus and
are determined to be 63-64.degree. C.
[0101] Differential scanning calorimetry (DSC) analysis of
crystalline samples of
1-{[(.alpha.-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane
acetic acid produced according to Examples 1 and 2 above are
measured using a Perkin Elmer Series 7 instrument, scanning from
25.degree. C. to 250.degree. C. at a scan rate of 5.degree.
C./minute. A test portion of the sample is placed in an aluminum
pan and the cap crimped to eliminate any visible seam between the
cap and the pan. An empty pan is prepared in the same manner as a
blank. The pans are placed in the Differential Scanning
calorimeter. The material is run at the appropriate temperature
program (Equilibration at Initial Temp, Isothermal, Ramp Rate,
Final Temp) to produce the thermogram shown in FIG. 2. DSC analysis
show an endothermic transition with an onset temperature of
58.3.degree. C. and a AH of 72.39 J/g. At the peak endotherm of
63-64.degree. C. the sample visibly melts.
6.5 Example 5:
{[(1-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane
Acetic Acid
[0102] To a solution of gabapentin (6.8 g, 0.04 mole) in water (40
mL) is added a solution of [(1-isobutanoyloxyethoxy)carbonyloxy]
succinimide (10 g, 0.036 mol) in acetonitrile (40 mL) over a period
of 30 minutes. The reaction is stirred at ambient temperature for 3
hours. The reaction mixture is diluted with methyl tert-butyl ether
(200 mL), washed with water (2.times.100 mL) and brine (50 mL). The
organic phase is separated, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to afford the title compound as
a white solid (12 g, quantitative).
[0103] Crystallization:
[0104] The solid compound (12 g) is suspended in methylcyclohexane:
methyl tert-butyl ether 10:1 (60 mL). The suspension is slowly
heated up to 50.degree. C. over a period of 30 minutes. The clear
solution is then allowed to cool to room temperature. The turbid
mixture is seeded with 5 mg of the title compound in crystalline
form. The mixture is further cooled to 0-4.degree. C. for 2 hours.
The solid product is filtered and washed with methylcyclohexane
(2.times.10 mL) to yield the title compound as a white crystalline
solid (10 g, 83% yield). The crystalline solid material has a
melting point of about 64-66.degree. C. as measured by open
capillary melting point determination.
[0105] Finally, it should be noted that there are alternative ways
of implementing the present invention. Accordingly, the present
embodiments are to be considered as illustrative and not
restrictive, and the invention is not to be limited to the details
given herein, but may be modified within the scope and equivalents
of any claim(s) issuing herefrom. All publications and patents
cited herein are incorporated by reference in their entirety.
* * * * *