U.S. patent application number 13/124027 was filed with the patent office on 2011-10-20 for co-crystals of tramadol and nsaids.
This patent application is currently assigned to LABORATORIOS DEL DR. ESTEVE, S.A.. Invention is credited to Jordi Benet Buchholz, Helmut Heinrich Buschmann, Lluis Sola Carandell, Jordi Carles Ceron Bertran, Carlos Ramon Plata Salaman, Nicolas Tesson.
Application Number | 20110257134 13/124027 |
Document ID | / |
Family ID | 40673614 |
Filed Date | 2011-10-20 |
United States Patent
Application |
20110257134 |
Kind Code |
A1 |
Buschmann; Helmut Heinrich ;
et al. |
October 20, 2011 |
CO-CRYSTALS OF TRAMADOL AND NSAIDs
Abstract
The present invention relates to co-crystals of tramadol and
co-crystal formers selected from NSAIDs, processes for preparation
of the same, their uses in pharmaceutical formulations, and for the
treatment of various disorders, including pain.
Inventors: |
Buschmann; Helmut Heinrich;
(Walheim, DE) ; Carandell; Lluis Sola; (Tarragona,
ES) ; Benet Buchholz; Jordi; (Tarragona, ES) ;
Ceron Bertran; Jordi Carles; (Tarragona, ES) ; Plata
Salaman; Carlos Ramon; (Barcelona, ES) ; Tesson;
Nicolas; (L'Hospitalet de Llobregat, ES) |
Assignee: |
LABORATORIOS DEL DR. ESTEVE,
S.A.
Barcelona
ES
|
Family ID: |
40673614 |
Appl. No.: |
13/124027 |
Filed: |
October 16, 2009 |
PCT Filed: |
October 16, 2009 |
PCT NO: |
PCT/EP2009/007451 |
371 Date: |
June 29, 2011 |
Current U.S.
Class: |
514/158 ;
514/569; 514/646 |
Current CPC
Class: |
A61K 31/192 20130101;
C07D 231/12 20130101; A61K 31/137 20130101; C07B 2200/13 20130101;
C07C 2601/14 20170501; A61P 19/02 20180101; C07C 59/64 20130101;
A61K 31/135 20130101; A61K 45/06 20130101; A61P 19/00 20180101;
A61P 43/00 20180101; A61P 21/00 20180101; C07C 217/74 20130101;
A61K 31/635 20130101; A61P 29/00 20180101; A61K 9/16 20130101; A61P
3/10 20180101; A61P 25/00 20180101; A61P 25/04 20180101; A61K
31/135 20130101; A61K 2300/00 20130101; A61K 31/192 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/158 ;
514/569; 514/646 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61P 25/04 20060101 A61P025/04; A61P 29/00 20060101
A61P029/00; A61K 31/192 20060101 A61K031/192; A61K 31/63 20060101
A61K031/63 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 17, 2008 |
EP |
08384012.4 |
Claims
1. A co-crystal comprising tramadol either as a free base or as a
physiologically acceptable salt and at least one NSAID.
2. A co-crystal according to claim 1 comprising tramadol either as
a free base or as a physiologically acceptable salt and at least
one NSAID, wherein the NSAID or at least one of the NSAIDs has at
least one functional group from the group consisting of ether,
thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate
ester, phosphate ester, thiophosphate ester, ester, thioester,
sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid,
sulfonic acid, amide, primary amine, secondary amine, ammonia,
tertiary amine, thiocyanate, cyanamide, oxime, nitrile, diazo,
organohalide, nitro, s-heterocyclic ring, thiophene, n-heterocyclic
ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide,
hydroxamic acid, imidazole, and pyridine.
3. A co-crystal according to claim 1, wherein the NSAID is chosen
in such a way that if compared to either tramadol alone, or to a
mixture of tramadol and the corresponding NSAID, as active agent/s:
the solubility of the co-crystal is increased; and/or the dose
response of the co-crystal is increased; and/or the efficacy of the
co-crystal is increased; and/or the dissolution of the co-crystal
is increased; and/or the bioavailability of the co-crystal is
increased; and/or the stability of the co-crystal is increased;
and/or the hygroscopicity of the co-crystal is decreased; and/or
the form diversity of the co-crystal is decreased; and/or the
morphology of the co-crystal is modulated.
4. The co-crystal according to claim 1, wherein the NSAID is
selected from: Acetylsalicylic Acid; Triflusal; HTB
(2-hydroxy-4-trifluoromethyl benzoic acid); Diflunisal;
Meclofenamic acid; Mefenamic acid; Niflumic acid; Flufenamic acid.
Diclofenac; Lonazolac; Acemetacin; Indomethacin; Tolmetin; Sulindac
Etodolac; Keterolac; Flurbiprofen; (RS)-Flurbiprofen;
Esflurbiprofen; Ibuprofen; (RS)-Ibuprofen; S-(+)-Ibuprofen;
Ketoprofen; (rac)-Ketoprofen R-(-)-Ketoprofen Bermoprofen;
Pelubiprofen; Tenosal; Aceneuramic acid; Pirazolac; Xinoprofen;
Flobufen; Anirolac; Zoliprofen; Bromfenac; Pemedolac; Dexpemedolac;
Bindarit; Romazarit; Naproxen; (S)--Naproxen; (R)--Naproxen;
Tiaprofenic acid; Ketorolac; Fenbufen; Fenoprofen; Flobufen;
Oxaprozin; Celecoxib, Etoricoxib, Lumiracoxib, Parecoxib,
Rofecoxib, Valdecoxib, and Cimicoxib.
5. The co-crystal according to claim 1, wherein the NSAID is
naproxen, its enantiomers or salts thereof.
6. The co-crystal according to claim 1, wherein the NSAID is
(S)-naproxen or (R)-naproxen.
7. The co-crystal according to claim 1, wherein the tramadol is
(-)-tramadol or (+)-tramadol.
8. A co-crystal according to claim 1, selected from: a co-crystal
comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen; a co-crystal
comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and (R)-naproxen; an enantiomeric
mixture of co-crystals comprising (-)-tramadol either as a free
base or as a physiologically acceptable salt and (S)-naproxen and
co-crystals comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and (R)-naproxen; a solvate
co-crystal comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen; a solvate
co-crystal comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and (R)-naproxen; and an
enantiomeric mixture of solvate co-crystals comprising (-)-tramadol
either as a free base or as a physiologically acceptable salt and
(S)-naproxen and co-crystals comprising (+)-tramadol either as a
free base or as a physiologically acceptable salt and
(R)-naproxen.
9. A co-crystal according to claim 5, wherein the molecular ratio
between the tramadol and naproxen is 1:2.
10. A co-crystal according to claim 9 comprising (-)-tramadol
either as a free base or as a physiologically acceptable salt and
(S)-naproxen or comprising (+) tramadol either as a free base or as
a physiologically acceptable salt and (R)-naproxen, or enantiomeric
mixtures of these co-crystals, characterized in that it shows a
Powder X-Ray Diffraction pattern with peaks [2.theta.] at 4.3, 8.7,
9.5, 10.2, 10.6, 11.3, 12.1, 12.7, 13.2, 13.7, 14.3, 14.6, 14.8,
15.5, 15.7, 16.0, 16.2, 17.0, 17.4, 17.9, 18.1, 18.7, 19.1, 19.4,
19.7, 20.1, 20.5, 20.8, 21.1, 21.4, 21.6 and 21.8 [.degree.], with
the 2.theta. values being obtained using copper radiation
(Cu.sub.K.alpha.1.54060 .ANG.).
11. A co-crystal according to claim 9 comprising (-)-tramadol
either as a free base or as a physiologically acceptable salt and
(S)-naproxen or comprising (+)-tramadol either as a free base or as
a physiologically acceptable salt and (R)-naproxen, or mixture of
enantiomers of these co-crystals, characterized in that it has a
monoclinic unit cell with the following dimensions: a=9.512(2)
.ANG. b=40.5736(11) .ANG. c=10.323(4) .ANG. .alpha.=90.degree.
.beta.32 96.29(1).degree. .gamma.=90.degree..
12. A co-crystal according to claim 9 comprising (-)-tramadol
either as a free base or as a physiologically acceptable salt and
(S)-naproxen or comprising (+)-tramadol either as a free base or as
a physiologically acceptable salt and (R)-naproxen, or enantiomeric
mixtures of these co-crystals, characterized in that the
endothermic sharp peak corresponding to the melting point has an
onset at 82.degree. C. to 84.degree. C.
13. A co-crystal according to claim 9 in the form of a methanol
solvate comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and (R)-naproxen, characterized in
that it shows a Powder X-Ray Diffraction pattern with peaks
[2.theta.] at 4.1, 6.6, 9.0, 9.2, 10.4, 11.0, 11.5, 12.3, 12.5,
12.7, 13.0, 13.2, 13.8, 14.9, 15.4, 16.2, 17.2, 17.6, 18.1, 18.5,
19.1, 19.3, 19.6, 19.9, 20.1, 20.4, 20.9, 21.0, 21.5, 22.0, 22.3
and 22.6 [.degree.], with the 2.theta. values being obtained using
copper radiation (Cu.sub.K.alpha. 1.54060 .ANG.).
14. The co-crystal according to claim 1, wherein the NSAID is
celecoxib or a salt thereof.
15. A co-crystal according to claim 14, selected from: a co-crystal
comprising (rac)-tramadol either as a free base or as a
physiologically acceptable salt and celecoxib; a co-crystal
comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and celecoxib; and a co-crystal
comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and celecoxib.
16. Process for the production of a co-crystal according to claim 1
comprising the steps of: (a) dissolving or suspending tramadol
either as a free base or as a salt and an NSAID in a solvent; and
optionally heating the solution or dispersion to a temperature
above ambient temperature and below the boiling point of the
solution or dispersion; (d) optionally adding a solvent to the
solution/dispersion of (a) and mixing them; (e) cooling the mixed
solution/dispersion of step (a) or (d) to ambient temperature or
below; (f) optionally evaporating part or all of the solvent; and
(g) filtering-off the resulting co-crystals.
17. Pharmaceutical composition wherein said composition comprises a
therapeutically effective amount of the co-crystal according to
claim 1 in a physiologically acceptable medium.
18. A method for the treatment of pain comprising administering to
a subject in need thereof a therapeutically effective amount of at
least one co-crystal according to claim 1.
19. A co-crystal according to claim 2 comprising tramadol either as
a free base or as a physiologically acceptable salt and at least
one NSAID, wherein the NSAID or at least one of the NSAIDs has at
least one functional group chosen from the group consisting of
alcohol, thiol, ester, carboxylic acid, primary amine, secondary
amine, tertiary amine.
20. A co-crystal according to claim 8, wherein said solvate
co-crystals are alcohol solvate co-crystals.
21. A co-crystal according to claim 20, wherein said solvate
co-crystals are methanol solvate co-crystals.
22. A co-crystal according to claim 15, selected from a co-crystal
comprising (rac)-tramadol.HCl and celecoxib.
23. A method according to claim 18, wherein said pain is selected
from acute pain, chronic pain, neuropathic pain, severe to moderate
pain, hyperalgesia, allodynia, cancer pain, diabetic neuropathy,
diabetic peripheral neuropathy, osteoarthritis, fibromyalgia,
rheumatoid arthritis, ankylosing spondylitis, frozen shoulder and
sciatica.
24. Process for the production of a co-crystal according to claim 1
comprising the steps of: (a) dissolving or suspending an NSAID in a
solvent and optionally heating the solution or dispersion to a
temperature above ambient temperature and below the boiling point
of the solution or dispersion; (b) dissolving tramadol either as a
free base or as a salt in a solvent at the same time as, after, or
before step (a); (c) combining the solution of (b) with the
solution/dispersion of (a) and mixing them; (d) optionally adding a
solvent to the solution of (c) and mixing them; (e) cooling the
mixed solution/dispersion of step (c) or (d) to ambient temperature
or below; (f) optionally evaporating part or all of the solvent;
and (g) filtering-off the resulting co-crystals.
Description
[0001] The present invention relates to co-crystals of tramadol and
NSAIDs (Non steroidal anti-inflammatory drugs), processes for
preparation of the same and their uses as medicaments or in
pharmaceutical formulations, more particularly for the treatment of
pain.
[0002] Pain is a complex response that has been functionally
categorized into sensory, autonomic, motor, and affective
components. The sensory aspect includes information about stimulus
location and intensity while the adaptive component may be
considered to be the activation of endogenous pain modulation and
motor planning for escape responses. The affective component
appears to include evaluation of pain unpleasantness and stimulus
threat as well as negative emotions triggered by memory and context
of the painful stimulus.
[0003] In general, pain conditions can be divided into chronic and
acute. Chronic pain includes neuropathic pain and chronic
inflammatory pain, for example arthritis, or pain of unknown
origin, as fibromyalgia. Acute pain usually follows non-neural
tissue injury, for example tissue damage from surgery or
inflammation, or migraine.
[0004] There are many drugs that are known to be useful in the
treatment or management of pain.
[0005] Opioids are frequently used as analgesics in pain.
Derivatives of morphine are indicated for the treatment of moderate
to acute pain in human. The analgesic effect is obtained through
their action on morphinic receptors, preferably the p-receptors.
Among these derivatives of morphine, may be mentioned morphine,
codeine, pethidine, dextropropoxyphenemethadone, lenefopan and
others.
[0006] One of the morphinic derivatives that has shown very good
results when orally administrated, and which is extensively
marketed, is Tramadol, also available as a physiologically
acceptable salt, particularly as a chlorohydrate. Tramadol, whose
chemical name is
2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, has the
following formula:
##STR00001##
[0007] This structure shows two different chiral centers and thus
may exist in different diastereoisomers among which the tramadol is
the cis-diastereoisomer: (1R,2R), or (1S,2S), both also known as
(+)-tramadol and (-)-tramadol and both of which contribute in
different ways to its activity.
[0008] From the art it appears that this compound is neither fully
opioid-like, nor non-opioid-like. Some studies have demonstrate
that tramadol is an opioid agonist, whereas clinical experience
indicates that it lacks many of the typical side effects of opioids
agonist, for example respiratory depression, constipation or
tolerance.
[0009] Due to their drawbacks, opioids cannot always be given
repeatedly or at higher doses as analgesics to treat pain. The side
effects of opioids are known in the art including e.g. J. Jaffe in
"Goodman and Gilman's, The Pharmacological Basis of Therapeutics",
8.sup.th edition; Gilman et al.; Pergamon Press, New York, 1990,
Chapter 22, pages 522-573.
[0010] Consequently it has been proposed to combine opioids with
other drugs that are not opioid analgesic agents, in order to lower
the amount of opioids needed to produce an equivalent degree of
analgesia. Among these combinations, the association of tramadol
with nonsteroidal anti-inflammatory drugs (NSAIDs) has been
reported to be of particular interest (EP-0 546 676).
[0011] Thus it was the objective of the current invention to
provide new means of improving the properties of tramadol,
especially in regard to the treatment of pain, by providing new
drugable forms of tramadol.
[0012] Especially desirable improvements/advantages of the new
drugable form would include:
[0013] improvement of physicochemical properties in order to
facilitate the formulation, the manufacture, or to enhance the
absorption and/or the bioavailability: thus
[0014] being more active when compared to tramadol base or
hydrochloride salt; or
[0015] providing a form tramadol with a further active agent having
a beneficial pharmacological effect in itself, thus allowing for a
highly efficient dose/weight relation of the final active principle
or even
[0016] allowing the use of a lower therapeutic dose of either
tramadol and the further active agent, an NSAID, or of both;
[0017] having a synergistic effect through the combination of
tramadol and the further active agent, an NSAID, in the same new
drugable form; or further
[0018] having the bitter taste of tramadol removed or
ameliorated;
[0019] being easily obtainable, easy to manufacture or
[0020] allowing more flexibility in formulating, or facilitating
its formulation,
[0021] being highly soluble, thus allowing better dissolution
rates, especially if dissolving in an aqueous physiological
surrounding, or
[0022] improving stability of the co-crystal in comparison to the
physical mixture of Tramadol/Active Agent (an NSAID) at the same
ratio;
[0023] allowing new routes of administration; also
[0024] allowing--if necessary--to combine tramadol with a
chemically usually non-compatible active agent in the same
formulation or even in immediate contact, without having to isolate
tramadol; or finally
[0025] minimizing/reducing the side effects, especially the severe
side effects, assigned to tramadol.
[0026] Other desirable improvements/advantages of the new drugable
form would include being active in diseases or symptoms in which
current treatment is insufficient like sciatica or frozen
shoulder.
[0027] Most desirably the new drugable forms should combine more
than one, most of these advantages.
[0028] This objective was achieved by providing new co-crystals of
tramadol. It was found that Tramadol was able to form Co-crystals
with NSAIDs. These co-crystals show improved properties if compared
to tramadol alone, and also good analgesic activity. The
co-crystals thus obtained have a specific stoichiometry which
depends upon the structure of each NSAID. Under the proper
circumstance this is also another advantage of these new solid
drugable forms possibly achieving some modulation of the
pharmacological effects. While APIs (Active Pharmaceutical
Ingredients) like tramadol in general have been recognized to form
crystalline polymorphs, solvates, hydrates and amorphous forms for
a number of years, there is little knowledge about which APIs will
form co-crystals. Co-crystals are a specific type of crystalline
form which provide a new avenue to modulate the API form and thus
to modulate API properties. Co-crystals contain an API and at least
one other component which crystallize together. Selection of the
other component helps determine whether a co-crystal will form and
what properties the co-crystal will have. Just as a polymorph,
solvate, hydrate or amorphous form of an API can modulate
stability, solubility, and hygroscopicity, a co-crystal can
modulate those same properties.
[0029] Thus the main object of the present invention is a
co-crystal comprising tramadol either as a free base or as a
physiologically acceptable salt and at least one NSAID.
[0030] "Drugable form (of tramadol)" as used herein is defined as
any form (salt, amorphous crystal, solution, dispersion, mixture
etc,) that tramadol might take which still can be formulated into a
pharmaceutical formulation usable as a medicament to treat a
disease or a symptom, especially pain.
[0031] "Co-Crystal" as used herein is defined as a crystalline
material comprising two or more compounds at ambient temperature
(20 to 25.degree. C., preferably 20.degree. C.), of which at least
two are held together by weak interaction, wherein at least one of
the compounds is a co-crystal former. Weak interaction is being
defined as an interaction which is neither ionic nor covalent and
includes for example: hydrogen bonds, van der Weals forces, and
.pi.-.pi. interactions. Solvates of tramadol that do not further
comprise a co-crystal former are not co-crystals according to the
present invention. The co-crystals may however, include one or more
solvate molecules in the crystalline lattice. Just for the sake of
clarity the distinction between crystalline salt and a co-crystal
has to be stressed here. An API bound to another compound forming a
salt by means of ionic interaction can be considered as one
"compound" according to the invention, but it cannot be considered
as two compounds by itself.
[0032] In scientific literature there currently is some discussion
on the proper use of the word co-crystal (see for example Desiraju,
Cryst. Eng. Comm., 2003, 5(82), 466-467 and Dunitz, Cryst. Eng.
Comm., 2003, 5(91), 506). A recent article by Zawarotko (Zwarotko,
Crystal Growth & Design, Vol. 7, No. 1, 2007, 4-9) gives a
definition of co-crystal which is in line with the definition given
above and thus also is a definition of "co-crystal" according to
this invention. According to this article "a co-crystal is a
multiple component crystal in which all components are solid under
ambient conditions when in their pure form. These components
consist of a target molecule or ion and a molecular co-crystal
former(s); when in a co-crystal, they coexist at a molecular level
within a single crystal".
[0033] "Co-crystal former" as use herein is defined as a molecule
being an active agent selected from NSAIDs, and with which tramadol
is able to form co-crystals.
[0034] "Active agents" are APIs which show a pharmaceutical effect
and thus can be identified as being pharmaceutically active. In a
more narrow sense this definition is encompassing all APIs being
marketed or under clinical trial for the treatment of diseases.
"Active agents with analgesic activity" are APIs (Active
Pharmaceutical Ingredients) which show efficacy in well-known
animal models of pain and thus can be identified as being
analgesics. In a more narrow sense this definition is encompassing
all APIs being marketed or under clinical trial for a labelling
including an indication falling under the definition of pain,
including also migraine. These indications might include acute
pain, chronic pain, neuropathic pain, hyperalgesia, allodynia or
cancer pain, including diabetic neuropathy or diabetic peripheral
neuropathy, osteoarthritis or fibromyalgia and all their subforms.
Examples of "active agents with analgesic activity" include NSAIDs
like naproxen or ibuprofen, pregabalin or tramadol and its
N-desmethyl-metabolite.
[0035] "Pain" is defined by the International Association for the
Study of Pain (IASP) as "an unpleasant sensory and emotional
experience associated with actual or potential tissue damage, or
described in terms of such damage (IASP, Classification of chronic
pain, 2.sup.nd Edition, IASP Press (2002), 210). Even though pain
is always subjective its causes or syndromes can be classified.
[0036] According to the IASP "allodynia" is defined as "a pain due
to a stimulus which does not normally provoke pain" (IASP,
Classification of chronic pain, 2.sup.nd Edition, IASP Press
(2002), 210). Even though the symptoms of allodynia are most likely
associated as symptoms of neuropathic pain this is not necessarily
the case so that there are symptoms of allodynia not connected to
neuropathic pain though rendering allodynia in some areas broader
than neuropathic pain.
[0037] The IASP further draws the following difference between
"allodynia", "hyperalgesia" and "hyperpathia" (IASP, Classification
of chronic pain, 2.sup.nd Edition, IASP Press (2002), 212):
TABLE-US-00001 Allodynia Lowered threshold Stimulus and response
mode differ Hyperalgesia Increased response Stimulus and response
rate are the same Hyperpathia Raised threshold; Stimulus and
response Increased response rate may be the same or different
[0038] According to the IASP "neuropathy" is defined as "a primary
lesion or dysfunction in the nervous system" (IASP, Classification
of chronic pain, 2.sup.nd Edition, IASP Press (2002), 211).
Neuropathic pain may have central or peripheral origin.
[0039] "Sciatica" or "sciatic neuritis is defined herein as a set
of symptoms including pain that derive from irritation of the
sciatic nerve or its roots,
[0040] "Frozen shoulder" or "adhesive capsulitis" is defined herein
as a symptom wherein the connective tissue surrounding the shoulder
joint or the shoulder capsule itself, is causing chronic pain,
becoming inflamed and stiff.
[0041] "Ankylosing spondylitis" or "Morbus Bechterew" is a chronic,
inflammatory arthritis and autoimmune disease. It mainly affects
joints in the spine and the sacroilium in the pelvis, causing
eventual fusion of the spine.
[0042] In one preferred embodiment of the co-crystal according to
the invention, the NSAID has at least one functional group from the
group consisting of ether, thioether, alcohol, thiol, aldehyde,
ketone, thioketone, nitrate ester, phosphate ester, thiophosphate
ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic
acid, phosphinic acid, sulfonic acid, amide, primary amine,
secondary amine, ammonia, tertiary amine, thiocyanate, cyanamide,
oxime, nitrile, diazo, organohalide, nitro, s-heterocyclic ring,
thiophene, n-heterocyclic ring, pyrrole, o-heterocyclic ring,
furan, epoxide, peroxide, hydroxamic acid, imidazole, and
pyridine;
[0043] preferably wherein the NSAID has at least one functional
group from the group consisting of alcohol, thiol, ester,
carboxylic acid, primary amine, secondary amine, tertiary
amine.
[0044] In another embodiment the NSAID has at least one functional
group from the group consisting of alcohol, ester, or carboxylic
acid.
[0045] In a further embodiment of the co-crystal according to the
invention, the NSAID/s is/are chosen in such a way that if compared
to either tramadol alone, or to a mixture of tramadol and the
corresponding active agent/s: [0046] the solubility of the
co-crystal is increased; and/or [0047] the dose response of the
co-crystal is increased; and/or [0048] the efficacy of the
co-crystal is increased; and/or [0049] the dissolution of the
co-crystal is increased; and/or [0050] the bioavailability of the
co-crystal is increased; and/or [0051] the stability of the
co-crystal is increased; and/or [0052] the hygroscopicity of the
co-crystal is decreased; and/or [0053] the form diversity of the
co-crystal is decreased; and/or [0054] the morphology of the
co-crystal is modulated.
[0055] "Mixture of tramadol and the corresponding active agent/s"
is defined as a mixture of the active agent or agents in question
(the NSAID/s) with tramadol which is only a physical mixture
without any coupling forces between the compounds and thus neither
includes salts nor another co-crystal.
[0056] In a further embodiment of the co-crystal according to the
invention, the molar ratio between tramadol and the NSAID is
different from 1. This might have the advantage of allowing the
development of a non-equimolar ratio between tramadol and the
active agent/s in a fixed dose with all the advantages of the
co-crystal.
[0057] NSAIDs have analgesic activity in a number of pain symptoms,
with acetyl salicylic acid known under its trademark
aspirin--despite being more than 100 years old--being an
outstandingly used pharmaceutical. Besides Aspirin other NSAIDs
(and COX--INHIBITORS) whose use generally is also centered on
anti-inflammatory action like Ibuprofen, naproxen or diclofenac are
among the worldwide most frequently applied pharmaceutical
compounds. The basis of their activity is inhibition of
cyclooxygenase (COX), one of the two activities of prostaglandin
endoperoxide synthase (PGHS). It is a key enzyme in the
prostaglandin pathway. Preferred NSAIDs, are those with a
carboxylic acid function. Preferred examples include salicylates,
anthranilates, arylacetic acids/arylalkanoic acids, and
arylpropionic acids.
[0058] It is debated in literature whether
paracetamol/acetaminophen is to be considered an NSAID. Thus--in an
embodiment of this invention--paracetamol/acetaminophen is not
considered an NSAID and is therefore excluded/disclaimed from the
(list of) NSAIDs (Co-crystal formers) according to this
invention.
[0059] In a further embodiment of the co-crystal according to the
invention, the NSAID is selected from: [0060] Acetylsalicylic Acid;
[0061] Triflusal; [0062] HTB (2-hydroxy-4-trifluoromethyl benzoic
acid); [0063] Diflunisal; [0064] Meclofenamic acid; [0065]
Mefenamic acid; [0066] Niflumic acid; [0067] Flufenamic acid;
[0068] Diclofenac; [0069] Lonazolac; [0070] Acemetacin; [0071]
Indomethacin; [0072] Tolmetin; [0073] Sulindac; [0074] Etodolac;
[0075] Keterolac; [0076] Flurbiprofen; [0077] (RS)-Flurbiprofen;
[0078] Esflurbiprofen; [0079] Ibuprofen; [0080] (RS)-Ibuprofen;
[0081] S-(+)-Ibuprofen; [0082] Ketoprofen; [0083] (rac)-Ketoprofen;
[0084] R-(-)-Ketoprofen; [0085] Bermoprofen; [0086] Pelubiprofen;
[0087] Tenosal; [0088] Aceneuramic acid; [0089] Pirazolac; [0090]
Xinoprofen; [0091] Flobufen; [0092] Anirolac; [0093] Zoliprofen;
[0094] Bromfenac; [0095] Pemedolac; [0096] Dexpemedolac; [0097]
Bindarit; [0098] Romazarit; [0099] Naproxen; [0100] (S)--Naproxen;
[0101] (R)--Naproxen; [0102] Tiaprofenic acid; [0103] Ketorolac;
[0104] Fenbufen; [0105] Fenoprofen; [0106] Flobufen; or [0107]
Oxaprozin.
[0108] In general all of these NSAIDs which have at least one
stereogenic center are to be understood as being included herein in
their racemic form or as diastereoisomers or enantiomers or
mixtures thereof.
[0109] In a further embodiment the NSAID is a Coxib, a selective
COX-2 inhibitor. Therefore, another preferred embodiment of the
invention is a pharmaceutical compound comprising Tramadol and at
least one COX-inhibitor selected from an NSAID being a Coxib.
Examples of Coxibs are: celecoxib, etoricoxib, lumiracoxib,
parecoxib, rofecoxib, valdecoxib, and cimicoxib.
[0110] Thus, especially preferred is a pharmaceutical compound
comprising tramadol and celecoxib, preferably a pharmaceutical
compound comprising (rac)-tramadol.HCl and celecoxib.
[0111] In a further embodiment of the co-crystal according to the
invention, the NSAID is selected from: [0112] Acetylsalicylic Acid;
[0113] Triflusal; [0114] HTB (2-hydroxy-4-trifluoromethyl benzoic
acid); [0115] Diflunisal; [0116] Meclofenamic acid; [0117]
Mefenamic acid; [0118] Niflumic acid; [0119] Flufenamic acid;
[0120] Diclofenac; [0121] Lonazolac; [0122] Acemetacin; [0123]
Indomethacin; [0124] Tolmetin; [0125] Sulindac; [0126] Etodolac;
[0127] Keterolac; [0128] Flurbiprofen; [0129] (RS)-Flurbiprofen;
[0130] Esflurbiprofen; [0131] Ibuprofen; [0132] (RS)-Ibuprofen;
[0133] S-(+)-Ibuprofen; [0134] Ketoprofen; [0135] (rac)-Ketoprofen;
[0136] R-(-)-Ketoprofen; [0137] Bermoprofen; [0138] Pelubiprofen;
[0139] Tenosal; [0140] Aceneuramic acid; [0141] Pirazolac; [0142]
Xinoprofen; [0143] Flobufen; [0144] Anirolac; [0145] Zoliprofen;
[0146] Bromfenac; [0147] Pemedolac; [0148] Dexpemedolac; [0149]
Bindarit; [0150] Romazarit; [0151] Naproxen; [0152] (S)--Naproxen;
[0153] (R)--Naproxen; [0154] Tiaprofenic acid; [0155] Ketorolac;
[0156] Fenbufen; [0157] Fenoprofen; [0158] Flobufen; or [0159]
Oxaprozin; or [0160] Celecoxib, [0161] Etoricoxib, [0162]
Lumiracoxib, [0163] Parecoxib, [0164] Rofecoxib, [0165] Valdecoxib,
or [0166] Cimicoxib.
[0167] The term "salt" is to be understood as meaning any form of
tramadol or the NSAID according to the invention in which this
assumes an ionic form or is charged and is coupled with a
counter-ion (a cation or anion) or is in solution. By this are also
to be understood complexes of tramadol or the NSAID with other
molecules and ions, in particular complexes which are complexed via
ionic interactions. This also includes physiologically acceptable
salt.
[0168] The term "solvate" according to this invention is to be
understood as meaning any form of the tramadol or NSAID in which
the compound has attached to it via non-covalent binding another
molecule (most likely a polar solvent) especially including
hydrates and alcohol solvates, e.g. methanol solvate.
[0169] A highly interesting NSAID to be the co-crystal former with
tramadol is the marketed drug naproxen. The chemical name of its
(S)-enantiomer, the marketed (S)-naproxen, is
(S)-(6-methoxy-2-naphtyl)propionic acid, and which is also
described as a physiologically acceptable salt. It has an empirical
formula of C.sub.14H.sub.14O.sub.3, an Mp of 153.degree. C. and a
pKa of 4.2.
##STR00002##
[0170] The (R)-enantiomer, the (R)-naproxen, whose chemical name is
(R)-(6-methoxy-2-naphtyl)propionic acid, having the same formula of
C.sub.14H.sub.14O.sub.3, Mp of 153.degree. C. and pKa of 4.2, shows
the following formula.
##STR00003##
[0171] Thus, another very preferred aspect of the invention relates
to a co-crystal according to the invention, wherein the NSAID is
naproxen, its enantiomers or salts thereof. Especially it refers to
a co-crystal according to the invention, wherein the NSAID is
(S)-naproxen or (R)-naproxen.
[0172] Another embodiment of the invention relates to a co-crystal
according to the invention, wherein the tramadol is (-)-tramadol or
(+)-tramadol.
[0173] As illustrated in more detail below tramadol and especially
its enantiomers (+)-tramadol and (-)-tramadol form co-crystals with
naproxen, especially with (S)-naproxen and (R)-naproxen. Generally
co-crystals obtained have a specific stoichiometry which depends
upon the structure of each co-crystal forming NSAID. In this
specific case of the co-crystal between tramadol and naproxen being
the co-crystal former the molecular ratio between tramadol and
naproxen is 1 to 2.
[0174] In a further preferred embodiment of the invention,
co-crystal according to the invention, is selected from [0175] a
co-crystal comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen; [0176] a
co-crystal comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and (R)-naproxen; [0177] a mixture
of enantiomers of co-crystals comprising (-)-tramadol either as a
free base or as a physiologically acceptable salt and (S)-naproxen
and co-crystals comprising (+)-tramadol either as a free base or as
a physiologically acceptable salt and (R)-naproxen; [0178] any of
the co-crystals above being solvate co-crystals, preferably being
alcohol solvate co-crystals, most preferably being methanol solvate
co-crystals.
[0179] In a highly preferred embodiment of these selected
co-crystals, the molecular ratio between the tramadol and naproxen
is 1:2.
[0180] In a preferred embodiment of a co-crystal with a molecular
ratio between the tramadol and naproxen of 1:2 according to the
invention comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen or comprising
(+)-tramadol either as a free base or as a physiologically
acceptable salt and (R)-naproxen, or mixture of enantiomers of
these co-crystals, the co-crystal shows a Powder X-Ray Diffraction
pattern with peaks [20] at 4.3, 8.7, 9.5, 10.2, 10.6, 11.3, 12.1,
12.7, 13.2, 13.7, 14.3, 14.6, 14.8, 15.5, 15.7, 16.0, 16.2, 17.0,
17.4, 17.9, 18.1, 18.7, 19.1, 19.4, 19.7, 20.1, 20.5, 20.8, 21.1,
21.4, 21.6 and 21.8 [.degree.].
[0181] The 2.theta. values were obtained using copper radiation
(Cu.sub.K.alpha.1 1.54060 .ANG.).
[0182] In a preferred embodiment of a co-crystal with a molecular
ratio between the tramadol and naproxen of 1:2 according to the
invention comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen or comprising
(+)-tramadol either as a free base or as a physiologically
acceptable salt and (R)-naproxen, or mixture of enantiomers of
these co-crystals, the co-crystal shows a Fourier Transform Infra
Red pattern with absorption bands at 3247, 2942, 1699, 1633, 1605,
1583, 1485, 1380, 1271, 1223, 1160, 1029, 851, 789 and 704
cm.sup.-1.
[0183] In a preferred embodiment of a co-crystal with a molecular
ratio between the tramadol and naproxen of 1:2 according to the
invention comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen or comprising
(+)-tramadol either as a free base or as a physiologically
acceptable salt and (R)-naproxen, or enantiomeric mixtures of these
co-crystals, the co-crystal has a monoclinic unit cell with the
following dimensions: [0184] a=9.512(2) .ANG. [0185] b=40.5736(11)
.ANG. [0186] c=10.323(4) .ANG. [0187] .alpha.=90.degree. [0188]
.beta.=96.29(1).degree. [0189] .gamma.=90.degree..
[0190] In a preferred embodiment of a co-crystal with a molecular
ratio between the tramadol and naproxen of 1:2 according to the
invention comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and (S)-naproxen or comprising
(+)-tramadol either as a free base or as a physiologically
acceptable salt and (R)-naproxen, or enantiomeric mixtures of these
co-crystals, the endothermic sharp peak of the co-crystal
corresponding to the melting point has an onset at 82.degree.
C.
[0191] In another preferred embodiment of a co-crystal with a
molecular ratio between the tramadol and naproxen of 1:2 according
to the invention comprising (-)-tramadol either as a free base or
as a physiologically acceptable salt and (S)-naproxen or comprising
(+)-tramadol either as a free base or as a physiologically
acceptable salt and (R)-naproxen, or enantiomeric mixtures of these
co-crystals, the endothermic sharp peak of the co-crystal
corresponding to the melting point has an onset at 82.degree. C. to
84.degree. C.
[0192] In another preferred embodiment a co-crystal with a
molecular ratio between the tramadol and naproxen of 1:2 according
to the invention comprising (+)-tramadol either as a free base or
as a physiologically acceptable salt and (R)-naproxen is in the
form of a methanol solvate.
[0193] In a preferred embodiment of a co-crystal with a molecular
ratio between the tramadol and naproxen of 1:2 according to the
invention in the form of a methanol solvate comprising (+)-tramadol
either as a free base or as a physiologically acceptable salt and
(R)-naproxen, the co-crystal shows a Powder X-Ray Diffraction
pattern with peaks [2.theta.] at 4.1, 6.6, 9.0, 9.2, 10.4, 11.0,
11.5, 12.3, 12.5, 12.7, 13.0, 13.2, 13.8, 14.9, 15.4, 16.2, 17.2,
17.6, 18.1, 18.5, 19.1, 19.3, 19.6, 19.9, 20.1, 20.4, 20.9, 21.0,
21.5, 22.0, 22.3 and 22.6 [.degree.].
[0194] The 2.theta. values were obtained using copper radiation
(Cu.sub.K.alpha.1 1.54060 .ANG.).
[0195] In another preferred embodiment of a co-crystal with a
molecular ratio between the tramadol and naproxen of 1:2 according
to the invention in the form of a methanol solvate comprising
(+)-tramadol either as a free base or as a physiologically
acceptable salt and (R)-naproxen, the co-crystal shows a Fourier
Transform Infra Red pattern with absorption bands at 3523, 3151,
2928, 2861, 2465, 1706, 1632, 1603, 1567, 1485, 1461, 1445, 1417,
1388 and 1362 cm.sup.-1.
[0196] As illustrated in more detail below tramadol forms
co-crystals with (S)-naproxen. Generally co-crystals obtained have
a specific stoichiometry which depends upon the structure of each
co-crystal former. In this specific case of the co-crystal with
(S)-naproxen being the NSAID the molecular ratio between Tramadol
and (S)-naproxen is 1 to 2.
[0197] Highly interesting NSAID to be the co-crystal formers with
tramadol are the Coxibs. The most important of these is the
marketed drug celecoxib. Its chemical name is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-pyrazol-1-yl]benzenesulfonamide-
. It has an empirical formula of
C.sub.17H.sub.14F.sub.3N.sub.3O.sub.2S.
##STR00004##
[0198] In a further embodiment of the co-crystal according to the
invention, the NSAID is selected from: [0199] Celecoxib, [0200]
Etoricoxib, [0201] Lumiracoxib, [0202] Parecoxib, [0203] Rofecoxib,
[0204] Valdecoxib, or [0205] Cimicoxib.
[0206] Another very preferred aspect of the invention relates to a
co-crystal according to the invention, wherein the NSAID is
celecoxib or salts thereof.
[0207] As illustrated in more detail below tramadol--and especially
the racemate--forms co-crystals with celecoxib. Generally
co-crystals obtained have a specific stoichiometry which depends
upon the structure of each co-crystal forming NSAID. In this
specific case of the co-crystal between (rac)-tramadol and
celecoxib being the co-crystal former the molecular ratio between
tramadol and celecoxib is 1 to 1.
[0208] In a further preferred embodiment of the invention,
co-crystal according to the invention, is selected from [0209] a
co-crystal comprising (rac)-tramadol either as a free base or as a
physiologically acceptable salt and celecoxib; [0210] a co-crystal
comprising (+)-tramadol either as a free base or as a
physiologically acceptable salt and celecoxib; [0211] a co-crystal
comprising (-)-tramadol either as a free base or as a
physiologically acceptable salt and celecoxib; or preferably [0212]
a co-crystal comprising (rac)-tramadol.HCl (the hydrochloride salt
of tramadol) and celecoxib.
[0213] In a highly preferred embodiment of these selected
co-crystals, the molecular ratio between the (rac)-tramadol.HCl and
celecoxib is 1:1.
[0214] In a preferred embodiment of a co-crystal with a molecular
ratio between (rac)-tramadol.HCl and celecoxib of 1:1 according to
the invention, the co-crystal shows a Powder X-Ray Diffraction
pattern with peaks [2.theta.] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9,
14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5,
21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2,
26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3,
31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2 [.degree.].
[0215] The 2.theta. values were obtained using copper radiation
(Cu.sub.K.alpha.1 1.54060 .ANG.).
[0216] In a preferred embodiment of a co-crystal with a molecular
ratio between (rac)-tramadol.HCl and celecoxib of 1:1 according to
the invention, the co-crystal shows a Fourier Transform Infra Red
pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0
(m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m),
1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6
(s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5
(m) 625.9 (m) cm.sup.-1.
[0217] In a preferred embodiment of a co-crystal with a molecular
ratio between (rac)-tramadol.HCl and celecoxib of 1:1 according to
the invention, the co-crystal has an orthorhombic unit cell with
the following dimensions:
[0218] a=11.0323(7).ANG.
[0219] b=18.1095(12).ANG.
[0220] c=17.3206(12).ANG.
[0221] In a preferred embodiment of a co-crystal with a molecular
ratio between (rac)-tramadol.HCl and celecoxib of 1:1 according to
the invention, the endothermic sharp peak of the co-crystal
corresponding to the melting point has an onset at 164.degree.
C.
[0222] Another embodiment of the present invention relates to a
process for the production of a co-crystal according to the
invention as described above comprising the steps of: [0223] (a)
dissolving or suspending an NSAID in a solvent; optionally heating
the solution or dispersion to a temperature above ambient
temperature and below the boiling point of the solution or
dispersion; [0224] (b) dissolving together with, or after, or
before step (a) tramadol either as a free base or as a salt in a
solvent, [0225] (c) adding the solution of (b) to the solution of
(a) and mixing them; [0226] (d) cooling the mixed
solution/dispersion of step (c) to ambient temperature; [0227] (e)
optionally evaporating part or all of the solvent; and [0228] (f)
filtering-off the resulting co-crystals.
[0229] Another embodiment of the present invention relates to a
process for the production of a co-crystal according to the
invention as described above comprising the steps of: [0230] (a)
dissolving or suspending an NSAID in a solvent; optionally heating
the solution or dispersion to a temperature above ambient
temperature and below the boiling point of the solution or
dispersion; [0231] (b) dissolving together with, or after, or
before step (a) tramadol either as a free base or as a salt in a
solvent, optionally combined with step (a) by dissolving tramadol
already together with the NSAID in step (a) [0232] (c) optionally
adding the solution of (b) to the solution of (a) and mixing them;
[0233] (d) optionally adding a solvent to the solution of (a), (b)
or (c) and mixing them; [0234] (e) cooling the mixed
solution/dispersion of step (a), (b), (c) or (d) to ambient
temperature or below; [0235] (f) optionally evaporating part or all
of the solvent; and [0236] (g) filtering-off the resulting
co-crystals.
[0237] "Ambient temperature" is defined here as a temperature
between 20 and 25.degree. C., preferably being 20.degree. C.
[0238] The solvents usable in these processes include water or
organic solvents, preferably solvents selected from acetone,
isobutyl acetate, acetonitrile, ethyl acetate, 2-butanol,
dimethylcarbonate, chlorobenzene, butylether, diisopropylether,
dimethylformamide, ethanol, water, hexane (also cyclohexane),
isopropanol, methyl ethyl ketone (also methyl isobutyl-ketone),
methanol, methyl t-butyl ether, 3-pentanone, toluene and
1,1,1-trichloroethane, most preferably including alcohols, like
ethanol. It is preferable--but not necessary--that the solvents in
steps (a) and (c) are identical.
[0239] The molecular ratio between tramadol and the NSAID lies
between 4:1 to 1:4, preferably from 3:1 to 1:3 and more preferably
from 1:1 to 1:2.
[0240] Preferably the tramadol-solution in step (b) has a
concentration of between 3M and 0.01 M.
[0241] The parts of the co-crystal according to the invention are
well-known drugs with analgesic properties sometimes used for a
long time worldwide. Due to this a further object of the present
invention is a medicament comprising a co-crystal according to the
invention.
[0242] Thus the invention also concerns a medicament comprising at
least one co-crystal according to the invention as described above
and optionally one or more pharmaceutically acceptable
excipients.
[0243] The invention also relates to a pharmaceutical composition
that comprises a therapeutically effective amount of the co-crystal
according to the invention in a physiologically acceptable
medium.
[0244] The association of two active principles in the same crystal
exhibits several advantages. Being linked, they often behave as a
single chemical entity, thus facilitating the treatments,
formulation, dosage etc. In addition to that, with both tramadol
and the NSAIDs being active analgesics these co-crystals are highly
useful in the treatment of pain, especially also not losing any
activity/weight by the addition of pharmacologically useless
counterions as in salts with no API. In addition the two active
principles are complementing each other in the treatment especially
of pain, but possibly also of various other diseases or symptoms.
Thus, the co-crystals according to the invention do combine a high
number of advantages over the state of the art.
[0245] Another advantage is that the association of two active
principles into one unique species seems to allow for a better
Pharmacokinetic/Pharmacodynamic (PKPD) including also a better
penetration of the blood-brain barrier, which helps in the
treatment of pain.
[0246] In general, in most embodiments in which the co-crystals of
tramadol are used (e.g. for the treatment of pain etc.), these
co-crystals would be formulated into a convenient pharmaceutical
formulation or a medicament. Accordingly, a desirable advantage of
a co-crystal of tramadol, would show improved pharmaceutical
properties and features, especially when compared to the free base
or tramadol hydrochloride.
[0247] Thus, the co-crystal of tramadol according to the invention,
should desirably show at least one, preferably more, of the
following features: [0248] to have a very small particle size, e.g.
from 300 .mu.m or lower; or [0249] to be and/or remain essentially
free of agglomerates; or [0250] to be less or not very hygroscopic;
or [0251] to help in formulating controlled release or immediate
release formulations; or [0252] to have a high chemical stability;
or
[0253] if given to a patient [0254] to decrease the inter- and
intra-subject variability in blood levels; or [0255] to show a good
absorption rate (e.g. increases in plasma levels or AUC); or [0256]
to show a high maximum plasma concentration (e.g. C.sub.max); or
[0257] to show decreased time to peak drug concentrations in plasma
(t.sub.max); or [0258] to show changes in half life of the compound
(t.sub.1/2), in whichever direction this change is preferably
directed.
[0259] The medicament or pharmaceutical compositions according to
the present invention may be in any form suitable for the
application to humans and/or animals, preferably humans including
infants, children and adults and can be produced by standard
procedures known to those skilled in the art. The medicament of the
present invention may for example be administered parenterally,
including intramuscular, intraperitoneal, or intravenous injection,
transmucosal or sublingual application; or orally, including
administration as tablets, pellets, granules, capsules, lozenges,
aqueous or oily solutions, suspensions, emulsions, sprays or as
reconstituted dry powdered form with a liquid medium.
[0260] Typically, the medicaments according to the present
invention may contain 1-60% by weight of one or more of the
co-crystals as defined herein and 40-99% by weight of one or more
auxiliary substances (additives/excipients).
[0261] The compositions of the present invention may also be
administered topically or via a suppository.
[0262] The daily dosage for humans and animals may vary depending
on factors that have their basis in the respective species or other
factors, such as age, sex, weight or degree of illness and so
forth. The daily dosage for humans preferably is in the range of 5
to 500 milligrams of tramadol to be administered during one or
several intakes per day.
[0263] A further aspect of the invention relates to the use of
co-crystal according to the invention as described above for the
treatment of pain, preferably acute pain, chronic pain, neuropathic
pain, hyperalgesia, allodynia or cancer pain, including diabetic
neuropathy or osteoarthritis or fibromyalgia. A further aspect of
the invention relates to the use of co-crystal according to the
invention as described above for the treatment of pain, preferably
acute pain, chronic pain, neuropathic pain, severe to moderate
pain, hyperalgesia, allodynia or cancer pain, including diabetic
neuropathy, osteoarthritis, fibromyalgia; rheumatoid arthritis,
ankylosing spondylitis, frozen shoulder or sciatica. Preferably
these uses are provided for in form of a medicament or a
pharmaceutical composition according to the invention as described
above.
[0264] Another object of the current invention is a method of
treatment of pain, preferably acute pain, chronic pain, neuropathic
pain, hyperalgesia, allodynia or cancer pain, including diabetic
neuropathy or osteoarthritis or fibromyalgia, by providing to a
patient in need thereof a sufficient amount of a co-crystal
according to the invention as described above. Preferably the
co-crystal according to the invention is provided in
physiologically suitable form like e.g. in form of a medicament or
a pharmaceutical composition according to the invention as
described above.
[0265] The present invention is illustrated below with the help of
the following figures and examples. These illustrations are given
solely by way of example and do not limit the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0266] FIG. 1: Powder X-Ray diffraction pattern of
(-)-tramadol-(S)-naproxen 1:2 co-crystal.
[0267] FIG. 2: DSC analysis of (-)-tramadol-(S)-naproxen 1:2
co-crystal.
[0268] FIG. 3: TG analysis of (-)-tramadol-(S)-naproxen 1:2
co-crystal.
[0269] FIG. 4: Structure of the unit cell of the
(-)-tramadol-(S)-naproxen 1:2 co-crystal obtained by SCXRD analysis
showing four molecules of (S)-naproxen and two molecules of
(-)-tramadol.
[0270] FIG. 5: Powder X-Ray diffraction pattern of the
(+)-tramadol-(R)-naproxen 1:2 methanol solvate co-crystal.
[0271] FIG. 6: DSC analysis of (+)-tramadol-(R)-naproxen 1:2
methanol solvate co-crystal.
[0272] FIG. 7: TG analysis of the (+)-tramadol-(R)-naproxen 1:2
methanol solvate co-crystal.
[0273] FIG. 8: Powder X-Ray diffraction pattern of the
(rac)-tramadol.HCl-celecoxib 1:1 co-crystal.
[0274] FIG. 9: DSC analysis of the (rac)-tramadol.HCl-celecoxib 1:1
co-crystal.
[0275] FIG. 10: TG analysis of the (rac)-tramadol.HCl-celecoxib 1:1
co-crystal.
[0276] FIG. 11: Structure of the unit cell of the
(rac)-tramadol.HCl-celecoxib 1:1 co-crystal obtained by SCXRD
analysis showing two molecules of celecoxib and two molecules of
tramadol.
EXAMPLES
Example 1a
Process to obtain (-)-tramadol-(S)-naproxen (1:2) Co-Crystal
[0277] A solution of (S)-naproxen (2.14 g, 9.3 mmol) in 20 mL of
methanol was added in 10 minutes to a stirred solution of
(-)-tramadol (2.45 g, 9.3 mmol) in 10 mL of methanol. The resulting
solution was stirred at room temperature for 30 minutes and the
solvent was evaporated under vacuum rendering a light yellow oil.
The oil was cooled to -197.degree. C. and allowed to warm to room
temperature to give the amorphous (-)-tramadol-(S)-naproxen salt as
a white solid (4.59 g, 100%).
[0278] Procedure: The above obtained amorphous
(-)-tramadol-(S)-naproxen salt (1:1) (2.2 g, 4.46 mmol) was
suspended in 10 mL of diisopropyl ether and stirred for 7 days at
room temperature. The resulting suspension was filtered off. The
filtrate was washed with ca. 2 mL of diisopropyl ether and dried
under vacuum at 40.degree. C. (10 mm Hg) for 24 hours to give a
co-crystal of (-)-tramadol-(S)-naproxen in a 1:2 ratio as a
crystalline white solid (1.37 g, 85% yield referred to (S)-naproxen
content of the initial mixture).
Example 1b
Process to Obtain (-)-tramadol-(S)-naproxen (1:2) Co-Crystal
[0279] A solution of (-)-tramadol (0.58 g, 2.20 mmol) in 2 mL of
isopropanol was added to a stirred suspension of (S)-naproxen (1.02
g, 4.43 mmol, 2 eq) in 2 mL of isopropanol at 60.degree. C. The
resulting solution was cooled to room temperature and a third of
the solvent was evaporated. The solution was seeded with 5-10 mg of
crystalline (-)-tramadol-(S)-naproxen (1:2) co-crystal and was left
standing at room temperature for 48 hours without stirring. The
resulting suspension was filtered off, the filtrate was washed with
ca. 1 mL of isopropanol and dried under vacuum (10 mm Hg) at
60.degree. C. for 24 hours to give the co-crystal
(-)-tramadol-(S)-naproxen in a 1:2 ratio as a white solid (1.31 g,
81%).
Characterisation of the Co-Crystal:
[0280] (-)-tramadol-(S)-naproxen (1:2) co-crystal obtained
according to example 1 was fully characterised by .sup.1H-NMR,
FTIR, powder X-Ray diffraction, single crystal X-Ray diffraction,
DSC and TG (see FIGS. 1 to 4).
[0281] The optical rotation value is
[.quadrature.].sup.23.sub.D=+6.degree. (c=1.00, MeOH)
Powder X-ray Diffraction (PXRD) Pattern of a Co-Crystal of
(-)-Tramadol and (S)-Naproxen (1:2) (See FIG. 1).
[0282] Powder diffraction patterns were acquired on a D8 Advance
Series 2Theta/Theta powder diffraction system using
Cu.sub.K.alpha.-radiation in transmission geometry. The system is
equipped with a V{hacek over (A)}NTEC-1 single photon counting PSD,
a Germanium monochromator, a ninety positions auto changer sample
stage, fixed divergence slits and radial soller. Programs used:
Data collection with DIFFRAC plus XRD Commander V.2.4.1 and
evaluation with EVA V.12.0 (see FIG. 1). The peaks expressed in
angles 2.quadrature. and d-values are described in detail in table
1:
TABLE-US-00002 TABLE 1 List of selected peaks obtained by powder
X-Ray diffraction of a co-crystal of (-)-tramadol and (S)-naproxen
(1:2). Angle d-Value Relative Angle d-Value Relative 2.theta..sup.1
(.ANG.) Intensity % 2.theta..sup.1 (.ANG.) Intensity % 4.296
20.55171 8.9 16.176 5.47506 4.0 8.659 10.20397 20.0 17.033 5.20140
9.1 9.458 9.34300 36.6 17.449 5.07826 4.2 10.209 8.65740 10.4
17.882 4.95625 3.1 10.634 8.31301 12.5 18.131 4.88881 7.3 11.302
7.82251 16.4 18.700 4.74132 100.0 12.118 7.29783 9.3 19.060 4.65259
29.6 12.693 6.96824 28.2 19.407 4.57012 15.7 13.241 6.68136 9.4
19.705 4.50167 32.7 13.754 6.43322 21.3 20.115 4.41077 41.6 14.278
6.19841 2.4 20.525 4.32376 11.6 14.626 6.05175 6.3 20.795 4.26805
12.1 14.790 5.98498 7.3 21.097 4.20773 16.5 15.551 5.69362 4.3
21.409 4.14714 13.2 15.711 5.63613 4.3 21.579 4.11476 13.8 16.015
5.52985 9.6 21.855 4.06355 8.4 .sup.1The 2.theta. values were
obtained using cupper radiation (Cu.sub.K.alpha. 1.54060.ANG.)
.sup.1H-NMR Spectrum of a Co-Crystal of (-)-Tramadol and
(S)-Naproxen (1:2):
[0283] Proton nuclear magnetic resonance analyses were recorded in
deuterated methanol (MeOH-d4) in a Bruker Avance 400 Ultrashield
NMR spectrometer, equipped with a z-gradient 5 mm BBO (Broadband
Observe) probe. Spectra were acquired solving 2-10 mg of sample in
0.6 mL of deuterated solvent.
[0284] .sup.1H NMR spectrum (in d4-methanol at 400 MHz) .delta.
shows peaks at 1.47-1.96 (m, 8H), 1.51 (d, J=7 Hz, 6H), 2.17 (m,
1H), 2.55 (dd, J=2 Hz, J=13 Hz, 1H), 2.57 (s, 6H), 2.88 (dd, J=9
Hz, J=13 Hz, 1H), 3.78 (q, J=7 Hz, 2H), 3.80 (s, 3H), 3.89 (s, 6H),
6.82 (dd, J=2 Hz, J=8 Hz, 1H), 7.07 (m, 4H), 7.19 (d, J=2 Hz, 2H),
7.29 (t, J=8 Hz, 1H), 7.45 (dd, J=2 Hz, J=8 Hz, 2H), 7.70 (m,
6H).
FT-IR Spectrum of a Co-Crystal of (-)-Tramadol and (S)-Naproxen
(1:2):
[0285] The FTIR spectra (ATR) of the co-crystal of
(-)-tramadol-(S)-naproxen were recorded using a Bruker Tensor 27,
equipped with a MKII golden gate single reflection ATR system, a
mid-infrared source as the excitation source and a DTGS detector.
The spectra were acquired in 32 scans at a resolution of 4
cm.sup.-1.
[0286] The sample of (-)-tramadol-(S)-naproxen co-crystal (1:2)
shows a Fourier Transform Infra Red spectrum (ATR) with absorption
bands .nu..sub.max at 3247, 2942, 1699, 1633, 1605, 1583, 1485,
1380, 1271, 1223, 1160, 1029, 851, 789 and 704 cm.sup.-1.
DSC Analysis of a Co-Crystal of (-)-Tramadol and (S)-Naproxen (1:2)
(See FIG. 2):
[0287] DSC analyses were recorded in a Mettler Toledo DSC822e.
Samples of 1-2 mg were weighted into 40 .mu.L aluminium crucibles
with a pinhole lid, and were heated, under nitrogen (50 mL/min), at
10.degree. C./min from 30 to 300.degree. C.
[0288] The endothermic peak of the DSC analysis of
(-)-tramadol-(S)-naproxen co-crystal (1:2) corresponds to the
melting point with an onset at 82.degree. C., see FIG. 2.
TG Analysis of a Co-Crystal of (-)-Tramadol and (S)-Naproxen (1:2)
(See FIG. 3):
[0289] Thermogravimetric analyses were recorded in a Mettler Toledo
SDTA851e. Samples of 3-4 mg were weighted into 40 .mu.L aluminium
crucibles with a pinhole lid, and heated at 10.degree. C./min from
30 to 500.degree. C., under nitrogen (80 mL/min).
[0290] The TG analysis of the (-)-tramadol-(S)-naproxen co-crystal
(1:2) according to the invention does not show weight loss at
temperatures below the melting point (see FIG. 3).
Single Crystal XRD Analysis of a Single Crystal of a Co-Crystal of
(-)-Tramadol and (S)-Naproxen (1:2) (See FIG. 4):
[0291] The crystal structure was determined from single crystal
X-ray diffraction data. The measured crystal obtained from the
preparation according to example 1 was selected using a Zeiss
stereomicroscope using polarized light and prepared under inert
conditions immersed in perfluoropolyether as protecting oil for
manipulation. Crystal structure determination was carried out using
a Bruker-Nonius diffractometer equipped with a APPEX 2 4K CCD area
detector, a FR591 rotating anode with Mo.sub.K.alpha. radiation,
Montel mirrors as monochromator and a Kryoflex low temperature
device (T=100 K). Fullsphere data collection omega and phi scans.
Programs used: Data collection Apex2 V. 1.0-22 (Bruker-Nonius
2004), data reduction Saint+Version 6.22 (Bruker-Nonius 2001) and
absorption correction SADABS V. 2.10 (2003). Crystal structure
solution was achieved using direct methods as implemented in
SHELXTL Version 6.10 (Sheldrick, Universtitat Gottingen (Germany),
2000) and visualized using XP program. Missing atoms were
subsequently located from difference Fourier synthesis and added to
the atom list. Least-squares refinement on F.sub.0.sup.2 using all
measured intensities was carried out using the program SHELXTL
Version 6.10 (Sheldrick, Universtitat Gottingen (Germany), 2000).
All non hydrogen atoms were refined including anisotropic
displacement parameters. In FIG. 4 the structure of the co-crystal
is shown. Crystal data and structure refinement for
(-)-tramadol-(S)-naproxen (1:2) co-crystal is given in the
following table 2.
TABLE-US-00003 TABLE 2 Most relevant structural data of the SCXRD
analysis of a co- crystal of (-)-tramadol-(S)-naproxen (1:2).
Crystal system Monoclinic Space group: P2.sub.1 A (.ANG.) 9.512(2)
B (.ANG.) 40.5736(11) C (.ANG.) 10.323(4) .alpha. (.degree.) 90
.beta. (.degree.) 96.29(1) .gamma. (.degree.) 90 Z 2 Volume
(.ANG..sup.3) 3959.9(16)
Example 2
(+)-tramadol-(R)-naproxen (1:2) Co-Crystal
Process to Obtain (+)-Tramadol-(R)-Naproxen (1:2) Co-Crystal:
[0292] A solution of (R)-naproxen (751 mg, 3.26 mmol) in 4 mL of
methanol was added to a solution of (+)-tramadol (430 mg, 1.63
mmol) in 1 mL of methanol. The mixture was stirred for 30 minutes
and the solvent was evaporated under vacuum rendering an oil, which
solidified by cooling to -197.degree. C. The resulting solid was
suspended in 10 mL of diisopropyl ether and stirred for 7 days at
room temperature. The resulting suspension was filtered off. The
filtrate was washed with 5 mL of diisopropyl ether and dried under
vacuum at 40.degree. C. (10 mm Hg) for 16 hours to give a
co-crystal of (+)-tramadol-(R)-naproxen in a 1:2 ratio as a
crystalline white solid (620 mg, 53%).
Characterisation of the Co-Crystal:
[0293] (+)-tramadol-(R)-naproxen (1:2) co-crystal obtained
according to example 2 was fully characterised by .sup.1H-NMR,
FTIR, powder X-Ray diffraction, DSC and TG.
[0294] All the data obtained were identical to the data obtained
for its enantiomer (-)-tramadol-(S)-naproxen (1:2) co-crystal of
Example 1, the only difference being the optical rotation vaule of
[.quadrature.].sup.23.sub.D=-7.degree. (c=1.00, MeOH) and DSC
(10.degree. C./min): endothermic peak corresponding to the melting
point with an onset at 84.degree. C.
Example 3
(+)-tramadol-(R)-naproxen (1:2) methanol Solvate Co-Crystal
Process to Obtain (+)-Tramadol-(R)-Naproxen (1:2) Methanol Solvate
Co-Crystal:
[0295] A solution of (R)-naproxen (925 mg, 4.02 mmol) in 3 mL of
methanol was added to a solution of (+)-tramadol (530 mg, 2.01
mmol) in 1 mL of methanol. The mixture was stirred for 10 minutes
and about half of the solvent was evaporated. The resulting
solution was left standing at room temperature and after 24 hours a
solid had formed. The solid was filtered off, the filtrate was
washed with 2 mL of methanol and dried under vacuum (10 mm Hg) for
4 hours to give the methanol solvate of the 1:2 co-crystal of
(+)-tramadol-(R)-naproxen as crystalline white needles (610 mg,
42%).
Characterisation of the Co-Crystal:
[0296] (+)-tramadol-(R)-naproxen (1:2) methanol solvate co-crystal
obtained according to example 3 was fully characterised by
.sup.1H-NMR, FTIR, powder X-Ray diffraction, DSC and TG (see FIGS.
5 to 8).
[0297] The optical rotation value is
[.alpha.].sup.23.sub.D=-5.degree. (c=1.00, MeOH).
Powder X-ray Diffraction (PXRD) Pattern of a
(+)-Tramadol-(R)-Naproxen Methanol Solvate (1:2) Co-Crystal (See
FIG. 5):
[0298] Powder diffraction patterns were acquired on a D8 Advance
Series 2Theta/Theta powder diffraction system using
Cu.sub.K.alpha.-radiation in transmission geometry. The system is
equipped with a V{hacek over (A)}NTEC-1 single photon counting PSD,
a Germanium monochromator, a ninety positions auto changer sample
stage, fixed divergence slits and radial soller. Programs used:
Data collection with DIFFRAC plus XRD Commander V.2.4.1 and
evaluation with EVA V.12.0 (see FIG. 5). The peaks expressed in
angles 2.theta. and d-values are described in detail in table
3:
TABLE-US-00004 TABLE 3 List of selected peaks obtained by powder
X-Ray diffraction of (+)-tramadol-(R)-naproxen methanol solvate
(1:2) co-crystal. Angle Relative Angle Relative 2.theta..sup.1
d-Value (.ANG.) Intensity % 2.theta..sup.1 d-Value (.ANG.)
Intensity % 4.118 21.44081 12.1 17.204 5.15004 19.0 6.606 13.37037
1.4 17.610 5.03216 10.4 9.002 9.81544 3.7 18.124 4.89075 100.0
9.190 9.61534 3.2 18.499 4.79232 30.4 10.447 8.46109 49.5 19.080
4.64786 55.8 11.043 8.00578 39.3 19.352 4.58308 12.5 11.547 7.65723
2.5 19.643 4.51573 9.8 12.266 7.21033 7.8 19.898 4.45840 12.6
12.498 7.07682 8.9 20.074 4.41971 9.0 12.671 6.98047 4.1 20.424
4.34491 8.3 13.041 6.78342 4.6 20.881 4.25078 45.4 13.191 6.70672
5.3 21.035 4.22003 28.5 13.778 6.42196 6.0 21.552 4.11988 36.9
14.907 5.93807 19.4 22.023 4.03290 13.3 15.384 5.75499 6.6 22.263
3.98986 33.4 16.195 5.46846 6.3 22.580 3.93462 7.6 .sup.1The
2.theta. values were obtained using cupper radiation
(Cu.sub.K.alpha. 1.54060.ANG.)
.sup.1H-NMR Spectrum of a (+)-Tramadol-(R)-Naproxen Methanol
Solvate (1:2) Co-Crystal:
[0299] Proton nuclear magnetic resonance analyses were recorded in
deuterated methanol (MeOH-d4) in a Bruker Avance 400 Ultrashield
NMR spectrometer, equipped with a z-gradient 5 mm BBO (Broadband
Observe) probe. Spectra were acquired solving 2-10 mg of sample in
0.6 mL of deuterated solvent. .sup.1H NMR spectrum (in d4-methanol
at 400 MHz) .delta. shows peaks at 1.41-1.93 (m, 8H), 1.51 (d, J=7
Hz, 6H), 2.13 (m, 1H), 2.52 (m, 7H), 2.87 (dd, J=9 Hz, J=13 Hz,
1H), 3.35 (2.times.MeOH), 3.77 (q, J=7 Hz, 2H), 3.79 (s, 3H), 3.88
(s, 6H), 6.81 (dd, J=2 Hz, J=8 Hz, 1H), 7.02 (d, J=7 Hz, 1H), 7.09
(m, 3H), 7.18 (d, J=2 Hz, 2H), 7.27 (t, J=8 Hz, 1H), 7.45 (dd, J=1
Hz, J=8 Hz, 2H), 7.66-7.74 (m, 6H).
FT-IR Spectrum of a (+)-Tramadol-(R)-Naproxen Methanol Solvate
(1:2) Co-Crystal:
[0300] The FTIR spectra (ATR) of the (+)-tramadol-(R)-naproxen
methanol solvate (1:2) co-crystal were recorded using a Bruker
Tensor 27, equipped with a MKII golden gate single reflection ATR
system, a mid-infrared source as the excitation source and a DTGS
detector. The spectra were acquired in 32 scans at a resolution of
4 cm.sup.-1. The sample of (+)-tramadol-(R)-naproxen methanol
solvate (1:2) co-crystal shows a Fourier Transform Infra Red
spectrum (ATR) with absorption bands .nu..sub.max at 3523, 3151,
2928, 2861, 2465, 1706, 1632, 1603, 1567, 1485, 1461, 1445, 1417,
1388 and 1362 cm.sup.-1.
DSC Analysis of a (+)-Tramadol-(R)-Naproxen Methanol Solvate (1:2)
Co-Crystal (See FIG. 6):
[0301] DSC analyses were recorded in a Mettler Toledo DSC822e.
Samples of 1-2 mg were weighted into 40 .mu.L aluminium crucibles
with a pinhole lid, and were heated, under nitrogen (50 mL/min), at
10.degree. C./min from 30 to 300.degree. C. The endothermic peaks
of the (+)-tramadol-(R)-naproxen methanol solvate co-crystal (1:2)
measured had onsets at 44.degree. C. and 60.degree. C., see FIG.
6.
TG Analysis of a Co-Crystal of (+)-Tramadol-(R)-Naproxen Methanol
Solvate (1:2) Co-Crystal (see FIG. 7):
[0302] Thermogravimetric analyses were recorded in a Mettler Toledo
SDTA851e. Samples of 3-4 mg were weighted into 40 .mu.L aluminium
crucibles with a pinhole lid, and heated at 10.degree. C./min from
30 to 500.degree. C., under nitrogen (80 mL/min). The TG analysis
of the (+)-tramadol-(R)-naproxen methanol solvate (1:2) co-crystal
according to the invention does show weight loss of 7.2% between 40
and 140.degree. C. followed by decomposition starting at
160.degree. C. (see FIG. 7).
Example 4
(rac)-tramadol.HCl--celecoxib (1:1) Co-Crystal
[0303] Process to Obtain (rac)-Tramadol.HCl--Celecoxib (1:1)
Co-Crystal:
Example 4a
Preparation Via Solvent-Assisted Grinding
[0304] A 5 mL stainless steel ball-mill reactor was charged with
two 7 mm steel balls, (rac)-tramadol hydrochloride (48 mg, 0.16
mmol), celecoxib (61 mg, 0.16 mmol, 1 eq) and 1 drop of methyl
isobutyl ketone. The reactor was agitated at 30 Hz for 45 minutes.
Traces of solvent were removed in vacuo affording
(rac)-tramadol.HCl--celecoxib (1:1) co-crystal as a white solid
(109 mg, quantitative yield).
Example 4b
Large Scale Via Crystallization
[0305] To a 1 L three necked flask equipped with mechanical
stirrer, addition funnel and cooler containing tramadol.HCl (26.54
g, 88.5 mmol) and celecoxib (33.74 g, 88.5 mmol, 1 eq.), was added
122 mL ethanol. The resultant suspension was heated to reflux
(complete dissolution). Cyclohexane (203 mL) was added slowly to
the solution maintaining the reflux (addition time 20 min) and
then, the solution was cooled slowly to room temperature with
stirring. The solution was seeded at 55.degree. C. with form
obtained in Example 4a and the crystallization started). The
mixture was cooled 2 h at 0.degree. C.
[0306] The white solid was filtered with a sintered funnel
n.degree. 3 and washed with a solvent mixture at 0-5.degree. C. (1
vol., 60 mL, (0.6:1) EtOH/cyclohexane). After drying 2 days at room
temperature under vacuum, (rac)-tramadol.HCl--celecoxib (1:1)
co-crystal was obtained as a white solid (54.6 g, 91% yield).
Characterisation of the Co-Crystal:
[0307] (rac)-tramadol.HCl--celecoxib (1:1) co-crystal obtained
according to example 4 was fully characterised by .sup.1H-NMR,
FTIR, powder X-Ray diffraction, DSC and TG (see FIGS. 8 to 10).
Powder X-Ray Diffraction (PXRD) Pattern of a
(rac)-Tramadol.HCl--Celecoxib (1:1) Co-Crystal: (See FIG. 8):
[0308] PXRD analysis was performed using a Philips X'Pert
diffractometer with Cu K.sub..alpha. radiation in Bragg-Brentano
geometry. The system is equipped with a mono-dimensional, real time
multiple strip detector. The measurement parameters were as
follows: the range of 2.theta. was 3.degree. to 40.degree. at a
scan rate of 8.8.degree. per minute (see FIG. 8). The peaks
expressed in angles 2.theta. and d-values are described in detail
in table 4:
TABLE-US-00005 TABLE 4 List of selected peaks obtained by powder
X-Ray diffraction of (rac)-tramadol.cndot.HCl-celecoxib (1:1)
co-crystal. Angle Relative Angle Relative 2.theta..sup.1 d-Value
(.ANG.) Intensity % 2.theta..sup.1 d-Value (.ANG.) Intensity % 7.06
12.52 29 23.57 3.78 15 9.32 9.49 1 24.11 3.69 13 10.21 8.67 5 24.36
3.65 10 10.69 8.27 2 25.20 3.53 6 13.64 6.49 10 26.12 3.41 11 13.86
6.39 14 26.58 3.35 2 14.13 6.27 100 26.77 3.33 2 15.53 5.71 3 27.45
3.25 5 16.10 5.51 6 27.94 3.19 4 16.25 5.45 5 28.13 3.17 3 16.85
5.26 44 29.07 3.07 9 17.50 5.07 12 29.91 2.99 3 18.00 4.93 11 30.15
2.96 3 19.05 4.66 38 31.11 2.88 3 19.48 4.56 11 31.34 2.85 5 19.91
4.46 25 31.74 2.82 1 20.48 4.34 25 32.49 2.76 3 21.18 4.19 11 32.83
2.73 2 21.27 4.18 11 34.42 2.61 1 21.44 4.14 8 35.04 2.56 2 21.80
4.08 18 35.76 2.51 1 22.14 4.02 3 36.24 2.48 2 22.56 3.94 14 37.19
2.42 1 22.73 3.91 32 .sup.1The 2.theta. values were obtained using
cupper radiation (Cu.sub.K.alpha. 1.54060.ANG.)
.sup.1H-NMR Spectrum of a Co-Crystal of (rac)-Tramadol.HCl and
Celecoxib (1:1):
[0309] Proton nuclear magnetic resonance analyses were recorded in
methanol-d.sub.4 in a Varian Mercury 400 spectrometer, equipped
with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired
dissolving 5-10 mg of sample in 0.6 mL of deuterated solvent.
[0310] .sup.1H NMR spectrum (in d4-methanol at 400 MHz) .delta.
shows peaks at 7.97-7.90 (m, 2H); 7.53-7.46 (m, 2H); 7.30 (t, J=8.0
Hz, 1H); 7.22-7.14 (m, 4H); 7.12-7.09 (m, 1H); 7.07 (d, J=7.8 Hz,
1H); 6.90 (s, 1H); 6.83 (dd, J=2.7 Hz, J=8.2 Hz, 1H); 3.80 (s, 3H);
2.98 (dd, J=9.0 Hz, J=13.3 Hz, 1H); 2.75-2.60 (m, 8H); 2.35 (s,
3H); 2.28-2.18 (m, 1H); 2.00-1.46 (m, 8H) ppm.
FT-IR Spectrum of a Co-Crystal of (rac)-Tramadol.HCl and Celecoxib
(1:1):
[0311] FTIR spectra were recorded using a Thermo Nicolet Nexus 870
FT-IR, equipped with a beamsplitter KBr system, a 35 mW He--Ne
laser as the excitation source and a DTGS KBr detector. The spectra
were acquired in 32 scans at a resolution of 4 cm.sup.1.
[0312] The sample (KBr pellet) shows a Fourier Transform Infra Red
spectrum with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0
(m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1(m),
1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6
(s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1(m), 786.5
(m) 625.9 (m) cm.sup.-1.
DSC Analysis of a Co-Crystal of (rac)-Tramadol.HCl and Celecoxib
(1:1) (See FIG. 9):
[0313] DSC analyses were recorded with a Mettler DSC822.sup.e. A
sample of 1.6230 mg was weighed into 40 .mu.L aluminium crucible
with a pinhole lid and was heated, under nitrogen (50 mL/min), at
10.degree. C./min from 30 to 200.degree. C.
[0314] The novel type of crystal of the present invention is
characterized in that the endothermic sharp peak corresponding to
the melting point has an onset at 164.44.degree. C. (fusion
enthalpy -93.56 J/g), measured by DSC analysis (10.degree. C./min)
(see FIG. 9).
TG Analysis of a Co-Crystal of (rac)-Tramadol.HCl and Celecoxib
(1:1) (See FIG. 10):
[0315] Thermogravimetric analyses were recorded in a
thermogravimetric analyzer Mettler TGA/SDTA851.sup.e. A sample of
3.0560 mg was weighed into a 70 .mu.L alumina crucible with a
pinhole lid and was heated at 10.degree. C./min from 30 to
200.degree. C., under nitrogen (50 mL/min).
[0316] The TG analysis of the crystalline form according to the
invention shows insignificant weight loss between 30 and
200.degree. C.
Single Crystal XRD Analysis of a Single Crystal of a Co-Crystal of
(Rac)-Tramadol.HCl and Celecoxib (1:1) (see FIG. 11):
[0317] The crystal structure was determined from single crystal
X-ray diffraction data. The colourless prism used
(0.33.times.0.16.times.0.11 mm) was obtained from the
crystallization of a seeded solution in heptane and IPA of
equimolar amounts of (rac)-tramadol hydrochloride and
celecoxib.
[0318] Analysis was performed at room temperature using a Bruker
Smart Apex diffractometer with graphite monochromatic Mo
K.sub..alpha. radiation equipped with a CCD detector. Data were
collected using phi and omega scans (program used: SMART 5.6). No
significant decay of standard intensities was observed. Data
reduction (Lorentz and polarization corrections) and absorption
correction were applied (program used: SAINT 5.0).
[0319] The structure was solved with direct methods and
least-squares refinement of F.sub.o.sup.2 against all measured
intensities was carried out (program used: SHELXTL-NT 6.1). All
non-hydrogen atoms were refined with anisotropic displacement
parameters. Crystal data and structure refinement for
(rac)-tramadol-celecoxib (1:1) co-crystal is given in the following
table 5.
TABLE-US-00006 TABLE 5 Most relevant structural dataof the SCXRD
analysis of a co- crystal of (rac)-tramadol.cndot.HCl-celecoxib
(1:1). Crystal system Orthorhombic Space group Pna2.sub.1 a (.ANG.)
11.0323(7) b (.ANG.) 18.1095(12) c (.ANG.) 17.3206(12) Volume
(.ANG..sup.3) 3460.5(4) Z 4 D calc. (Mg/m.sup.3) 1.308 N. of refl.
8336 Refl. with I > 2.sigma.(I) 5240 R (I > 2.sigma.(I))
0.0584
[0320] The crystal structure is depicted in FIG. 12 (only half of
the unitcell contents is shown, hydrogen atoms have been omitted
for clarity; program used: Mercury 2.2, C. F. Macrae, I. J. Bruno,
J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L.
Rodriguez-Monge, R. Taylor, J. van de Streek and P. A. Wood, J.
Appl. Cryst., 41, 2008, 466-470).
[0321] Simulation of XRPD diffractogram from single crystal data
gives an almost identical diagram to the experimental one presented
above.
Example 4c
Determination of the Bioavailability of Co-Crystal of
(rac)-tramadol.HCl--celecoxib (1:1)
[0322] The objective is to measure plasma exposure in rat of
(rac)-tramadol.HCl and celecoxib by means of AUC determination of
the co-crystal of (rac)-tramadol.HCl--celecoxib (1:1) of the
present invention, and comparing it with each active principle of
the co-crystal and the fixed combination of the two active
principles.
[0323] Bioavailability of (rac)-tramadol.HCl--celecoxib co-crystal
is compared to those obtained after administration of tramadol.HCl
plus celecoxib, combined and separately, to rats by oral route.
Products with an equivalent particle size are orally administered
by means of rodent capsules at a dose level of 25 mg/kg of
co-crystal and at an equivalent dose level of comparators (11 mg
tramadol.HCl/kg, 14 mg celecoxib/kg). Blood from rats is extracted
at the following time points: predose, 15, 30, 45 min, 1, 1.5, 2,
3, 4, 5, 6, 8 and 24 h. Plasma is isolated by centrifugation,
purified by SPE and plasma levels are determined by LC-MS-MS.
Pharmacokinetic parameters are calculated using non-compartmental
pharmacokinetic analysis.
[0324] The results show an increase exposure of celecoxib when the
co-crystal (rac)-tramadol.HCl--celecoxib is administered compared
to celecoxib alone and to the combination of both API's (the
mixture of tramadol and celecoxib).
* * * * *