Patent Application
20080051453
One aspect of the current invention relates to a pharmaceutical co-crystal comprising:
an active pharmaceutical ingredient; and
a co-crystal agent having the structure R1—C(═O)XH, wherein X is O, N(C1-6alkyl) or NH and R1 is a C3-8alkyl group containing at least one trans-oriented double bond and being substituted by 0, 1, 2, 3 or 4 groups independently selected from halo, phenyl and hydroxyl.
In another embodiment, in conjunction with any of the above or below embodiments, the R1—C(═O)XH portion of the co-crystal agent has a pKa value at least three units higher than the most basic functional group of the active pharmaceutical ingredient.
In another embodiment, in conjunction with any of the above or below embodiments, the R1—C(═O)XH portion of the co-crystal agent has a pKa value at least four units higher than the most basic functional group of the active pharmaceutical ingredient.
In another embodiment, in conjunction with any of the above or below embodiments, the R1—C(═O)XH portion of the co-crystal agent has a pKa value at least five units higher than the most basic functional group of the active pharmaceutical ingredient.
In another embodiment, in conjunction with any of the above or below embodiments, the R1—C(═O)XH portion of the co-crystal agent has a pKa value at least six units higher than the most basic functional group of the active pharmaceutical ingredient.
In another embodiment, in conjunction with any of the above or below embodiments, the R1—C(═O)XH portion of the co-crystal agent has a pKa value at least seven units higher than the most basic functional group of the active pharmaceutical ingredient.
In another embodiment, in conjunction with any of the above or below embodiments, X is O.
In another embodiment, in conjunction with any of the above or below embodiments, X is NH.
In another embodiment, in conjunction with any of the above or below embodiments, X is N(C1-6alkyl).
In another embodiment, in conjunction with any of the above or below embodiments, the co-crystal agent is selected from sorbic acid, trans-2-hexenoic acid, trans-3-hexenoic acid, trans-4-hexenoic acid, trans-2-butenoic acid, trans-2-pentenoic acid, trans-3-pentenoic acid, trans-2,4-pentadienoic acid.
In another embodiment, in conjunction with any of the above or below embodiments, the co-crystal agent is selected from sorbic acid amide, trans-2-hexenoic acid amide, trans-3-hexenoic acid amide, trans-4-hexenoic acid amide, trans-2-butenoic acid amide, trans-2-pentenoic acid amide, trans-3-pentenoic acid amide, trans-2,4-pentadienoic acid amide.
In another embodiment, in conjunction with any of the above or below embodiments, the co-crystal agent is sorbic acid.
Another aspect of the invention relates to a method of manufacturing a pharmaceutical co-crystal according any of the above and below embodiments, comprising the steps of:
contacting a co-crystal agent with an active pharmaceutical ingredient;
isolating the formed pharmaceutical co-crystal.
In another embodiment, in conjunction with any of the above or below embodiments, the contacting occurs with both the co-crystal agent and the active pharmaceutical ingredient dissolved in a solvent.
In another embodiment, in conjunction with any of the above or below embodiments, the contacting occurs in a milling device with both the co-crystal agent and the active pharmaceutical ingredient being solids.
Another aspect of the invention relates to a pharmaceutical composition comprising:
a co-crystal as described above; and
a pharmaceutically-acceptable carrier or diluent.
Another aspect of the invention relates to a method for increasing the bioavailability of an active pharmaceutical ingredient in a mammal comprising the steps of contacting the active pharmaceutical ingredient with a co-crystal agent; and forming a co-crystal comprising the active pharmaceutical ingredient and the co-crystal agent.
In another embodiment, in conjunction with any of the above or below embodiments, the bioavailability is increased at least two fold.
In another embodiment, in conjunction with any of the above or below embodiments, the bioavailability is increased at least three fold.
In another embodiment, in conjunction with any of the above or below embodiments, the bioavailability is increased at least four fold.
In another embodiment, in conjunction with any of the above or below embodiments, the bioavailability is increased at least eight fold.
Examples of how to form and test co-crystals can be found in the following publications, hereby incorporated by reference in their entirety: WO 04/064762, WO 04/078161 and WO 04/078163.
Examples of active pharmaceutical ingredients include, but are not limited to, the examples and generic descriptions found in the following publications, hereby encorporated by reference in their entirety: US 20030158188, US 20030158198, US 20030158198, US 20040157845, US 20040157849, US 20040209884, US 20050009841, US 20050080095, US 20050085512, WO 02008221, WO 02030956, WO 02072536, WO 02076946, WO 02090326, WO 03006019, WO 03014064, WO 03022809, WO 03029199, WO 03049702, WO 03053945, WO 03055484, WO 03055484, WO 03055848, WO 03062209, WO 03066595, WO 03068749, WO 03070247, WO 03074520, WO 03080578, WO 03093236, WO 03095420, WO 03097586, WO 03097670, WO 03099284, WO 04002983, WO 04007459, WO 04007495, WO 04011441, WO 04014871, WO 04024710, WO 04028440, WO 04029031, WO 04029044, WO 04033435, WO 04035533, WO 04035549, WO 04046133, WO 04052845, WO 04052846, WO 04054582, WO 04055003, WO 04055004, WO 04056774, WO 04058754, WO 04072020, WO 04072069, WO 04074290, WO 04078101, WO 04078744, WO 04078749, WO 04089877, WO 04089881, WO 04096784, WO 04099177, WO 04100865, WO 04103281, WO 04108133, WO 04110986, WO 04111009, WO 05003084, WO 05004866, WO 05007646, WO 05007648, WO 05007652, WO 05009977, WO 05009980, WO 05009982, WO 05009987, WO 05009988, WO 05012287, WO 05014580, WO 05016915, WO 05016922, WO 05030753, WO 05030766, WO 05032493, WO 05033105 and WO 05035471.
Unless otherwise specified, the following definitions apply to terms found in the specification and claims:
“Cα-βalkyl” means an alkyl group comprising a minimum of a and a maximum of β carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein α and β represent integers. The alkyl groups described in this section may also contain one or two double or triple bonds. Examples of C1-6alkyl include, but are not limited to the following:
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups (Y′=O, S, NR), and the like, which are illustrated in the following examples:
and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.
The specification and claims contain listing of species using the language “selected from . . . and . . . ” and “is . . . or . . . ” (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise stated it is meant to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this language is merely for shorthand purposes and is not meant in any way to limit the removal of individual elements or subgroups as needed.
Generally, co-crystals may be formed as follows:
1 eq drug
1.05 eq co-crystal former (for 1:1 ratio) or 2.10 eq (for 1:2 ratio)
Liquid formulation vehicle with other necessary inert excipients added such as surfactants for wetting
Slurry Method: Add co-crystal former and drug to the formulation vehicle and provide the necessary energy to mediate conversion. For some drugs, sonication with a sonicating probe will be needed. For others sonicating on a water bath or even light stirring will be sufficient. The conversion should be follow by a suitable solid-state characterization technique such as X-ray powder diffraction.
Co-crystal formers were purchased from Sigma-Aldrich, Fluka, TCI, EM Science, Alfa Aesar and EMD Chemicals (source of sorbic acid).
API and co-crystal former were ball milled with or without approximately 20 μL of isopropyl alcohol, acetone, methanol, ethyl acetate or 2-butanol in a mixer mill MM301 (Retsch Inc., Newton, Pa.) at a 1:1.2 ratio of API to co-crystal former in a 1.5 mL stainless steel grinding jar containing a 5 mm stainless steel grinding ball for 2 min.
Crystallizations were accomplished by slow cooling a saturated solution. API and co-crystal former were dissolved in a 1:1.2 ratio in isopropyl alcohol, isopropyl acetate, acetone, methanol, ethyl acetate, dichloromethane, 1,2-dichloroethane or 2-butanol at 50° C. (or less depending on boiling point) then cooled at 2° C./min in an Imperial V oven (Lab-Line Instruments Inc., Melrose Park, Ill.). If crystallization did not occur within 48-72 hrs, slow evaporation was also utilized.
Differential scanning calorimetry was performed on a Q100 (TA Instruments, New Castle, Del.) at 2 or 10° C./min from 30-250° C. in an open, aluminum pan. Thermal gravimetric analysis was performed on a Q500 (TA Instruments) at 2 or 10° C./min from 30-300° C. in a platinum pan.
X-ray diffraction patterns were obtained on an X'Pert PRO x-ray diffraction system (PANalytical, Almelo, the Netherlands). Samples were scanned in continuous mode from 5-45° (2θ) step size 0.0334 on a spinning stage at 45 kV and 40 mA with CuKα radiation (1.54 Å). The incident beam path was equipped with a 0.02 rad solar slit, 15 mm mask, 4° fixed anti-scatter slit and a programmable divergence slit. The diffracted beam was equipped with a 0.02 rad solar slit, programmable anti-scatter slit and a 0.02 mm nickel filter. Detection was accomplished with an RTMS detector (X'Cellerator).
Microscopy was obtained on an Eclipse E600 POL (Nikon Inc., Melville, N.Y.) equipped with an LTS 350 heating/freezing stage (Linkam Scientific Instruments Ltd., England). Samples were analyzed from 25-300° C. at 10° C./min at 100× magnification.
1H NMR analysis was performed on a Bruker 400 MHz NMR (Bruker BioSpin GmbH, Germany) in DMSO-d6 or chloroform-d at 25° C.
Hygroscopicity was determined by dynamic vapor sorption on the DVS Advantage (Surface Measurement Systems Ltd, London). Measurements were taken from 0-90-0% RH at 25° C. with equilibration set to dm/dt+0.002%/min for 5 min or 120 min/step (min. 10 min/step).
Solubility was measured from a slurry (3.33 mg/mL) in FaSIF (5 mM taurocholic acid sodium and 1.5 mM lecithin in pH 6.8 phosphate buffer) with measurements taken at 1, 15, 30, 45, 60, 90, 120, 240 and 1440 min. Samples were filtered through a 0.2μ PTFE syringe filter. Analysis by HPLC-UV on an Agilent 1100 series HPLC (Agilent Technologies, Palo Alto, Calif.) equipped with a binary pump (G1312A), DAD detector (G1315B), autosampler (G1329A) and a 4.5×150 mm YMC ProC18 column (Waters Corporation, Milford, Mass.). Gradient method run from 10-95% acetonitrile 0.1% triflouroacetic acid at 1 mL/min for 15 min. Standards were prepared in 50% acetonitrile at 0.05 mg/mL and injected at 1, 5, 10 and 15 μL.
Particle size was determined by laser diffraction on the HELOS/BF with a CUVETTE disperser (Sympatec GmbH, Clausthal-Zellerfeld). Samples were suspended in 2% Hydroxypropyl methylcellulose 1% Tween 80 by vortex. The suspension was then added drop wise to the 50 mL cuvette containing water until a 5-15% optical concentration was achieved. Measurements were taken for 10 s on the R3 or R5 lens with mixing at 500 rpm.
Elemental analysis was performed at Galbraith Laboratories (Knoxville, Tenn.).
Single crystal structures for N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide trans-cinnamic acid co-crystal (Example 1) and N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide trans-2-hexanoic acid co-crystal (Example 2) were determined as follows for Example 3:
4-(6-(4-(Trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine sorbic acid co-crystal (Example 3): The colorless block crystal with dimensions 0.20×0.18×0.18 mm was mounted on a glass fiber using very small amount of paratone oil. Data were collected using a Bruker SMART CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream low-temperature apparatus operating at 193 K. A suitable crystal was chosen and mounted on a glass fiber using grease. Data were measured using omega scans of 0.3° per frame for 30 seconds, such that a hemisphere was collected. A total of 1850 frames were collected with a maximum resolution of 0.76 Å. The first 50 frames were recollected at the end of data collection to monitor for decay. Cell parameters were retrieved using SMART software and refined using SAINT on all observed reflections (SMART V 5.625 (NT) Software for the CCD Detector System; Bruker Analytical X-ray Systems, Madison, Wis. (2001)). Data reduction was performed using the SAINT software (SAINT V 6.22 (NT) Software for the CCD Detector System Bruker Analytical X-ray Systems, Madison, Wis. (2001)) which corrects for Lp and decay. Absorption corrections were applied using SADABS (Program for absorption corrections using Siemens CCD based on the method of Robert Blessing; Blessing, R. H. Acta Cryst. A51 1995, 33-38) multiscan technique, supplied by George Sheldrick. The structures are solved by the direct method using the SHELXS-97 (Sheldrick, G. M. SHELXS-90, Program for the Solution of Crystal Structure, University of Göttingen, Germany, 1990) program and refined by least squares method on F2, SHELXL-97 (Sheldrick, G. M. SHELXL-97, Program for the Refinement of Crystal Structure, University of Göttingen, Germany, 1997), incorporated in SHELXTL-PC V 6.10 (SHELXTL 6.1 (PC-Version), Program library for Structure Solution and Molecular Graphics; Bruker Analytical X-ray Systems, Madison, Wis. (2000)). The structure was solved in the space group P
Single crystal structure of the N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide freebase (Example 4) was determined on a Rigaku AFC7R diffractometer with graphite monochromated Cu-Ka radiation. Data was collected at 20° C., to a maximum 2Θ value of 120.1°.
The single crystal structure of N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide sorbic acid co-crystal (Example 5) was determined on a Rigaku FR-E SuperBright rotating copper anode generator equipped with a Rigaku Saturn 92 CCD area detector, AFC11 goniostat, and the Varimax optics. Data was collected at −160° C., to a maximum 2Θ value of 108.5°, refined to 0.95 Å, and processed using CrystalClear (Rigaku). Both structures were solved by direct methods and expanded using Fourier techniques. The position of the hydrogen bonds was determined using the Mercury 1.4 software using standard settings.
aPresented as median and range.
Oral administration of the Example 4 in tablet form yielded mean Cmax and AUC values approximately 17-19% those of the suspension formulation of Example 4, with relatively low inter-animal variability in exposure (% CV 5-17). Oral administration of the Example 5 “in situ” sorbic acid cocrystal/physical blend tablet yielded mean Cmax and AUC values approximately 52-63% those of the suspension formulation, with higher inter-animal variability in exposure (% CV˜50-60). Oral administration of the Example 5 “in situ” sorbic acid cocrystal/physical blend tablet yielded mean Cmax and AUC values approximately 65% those of the suspension formulation, with comparable or somewhat lower inter-animal variability in exposure (% CV˜30-45) relative to the “in situ” sorbic acid co-crystal formulation.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, which are defined, in the appended claims.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
This application claims the benefit of U.S. Provisional Application No. 60/839,581, filed Aug. 22, 2006, which is hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60839581 | Aug 2006 | US |
