Patent Application
20090192311
The present invention is directed to crystal and amorphous forms of the 5-HT1A receptor antagonist 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride, as well as compositions thereof and methods of using the same.
Certain N-aryl-piperazine derivatives act on the central nervous system (CNS) by binding to 5-HT receptors. In pharmacological testing, it has been shown that these derivatives can bind to receptors of the 5-HT1A type and exhibit activity as 5-HT1A antagonists. See, for example, U.S. Pat. Nos. 6,127,357; 6,469,007; and 6,586,436, as well as WO 97/03982, the disclosures of each of which are incorporated herein by reference.
An example N-aryl-piperazine, having 5-HT1A antagonist activity, is 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide, the structure of which (as the HCl salt) is shown below in Formula I.
This compound is useful in treating patients suffering from central nervous system (CNS) disorders such as schizophrenia, (and other psychotic disorders such as paranoia and mano-depressive illness), Parkinson's disease and other motor disorders, anxiety (e.g., generalized anxiety disorders, panic attacks, and obsessive compulsive disorders), depression (such as by the potentiation of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors), Tourette's syndrome, migraine, autism, attention deficit disorders and hyperactivity disorders. This compound can also be useful for the treatment of sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, eating disorders such as for example obesity, anorexia and bulimia, sexual dysfunction, and the treatment of alcohol, drug and nicotine withdrawal. Additionally, this compound is useful for the treatment of cognitive dysfunction and may be useful for the treatment of cognitive dysfunction associated with mild cognitive impairment (MCI)) Alzheimer's disease and other dementias, including Lewy Body, vascular, and post stroke dementias. Cognitive dysfunction associated with surgical procedures, traumatic brain injury or stroke may also be treated with the compound of Formula I. Further, this compound can be useful for the treatment of diseases in which cognitive dysfunction is a co-morbidity such as, for example, Parkinson's disease, autism, and attention deficit disorders.
The compound of Formula I and related compounds can be prepared according to known procedures such as those described in U.S. Pat. Nos. 6,713,626 and 6,469,007 as well as U.S. App. Ser. No. 60/554,666 and U.S. application Ser. No. 11/082,510 (published as US 2005/0209245A1), each of which is incorporated herein by reference it its entirety. Additionally, pharmaceutical dosage forms and compositions containing the compound of Formula I are described in U.S. App. Ser. No. 60/554,622 and U.S. application Ser. No. 11/082,548 (published as US 2005/0215561A1), which is incorporated herein by reference in its entirety.
Improved drug formulations, showing, for example, better bioavailability or better stability, are consistently sought. There is an ongoing need for new or purer crystalline forms of existing drug molecules. Accordingly, crystalline 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride (I) described herein is directed toward this and other ends.
The present invention provides crystal and amorphous forms of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride (I) characterized according to the X-ray powder diffraction, single crystal X-ray diffraction, differential scanning calorimetry (DSC), therogravimetric analysis (TGA) and other techniques described herein.
The present invention further provides compositions containing the crystal form of the invention.
The present invention further provides processes for preparing crystal forms of the invention.
The present invention further provides methods of antagonizing a 5-HT1A receptor by contacting the receptor with a crystal form of the invention.
The present invention further provides methods of treating CNS disorders and cognitive dysfunction by administering a therapeutically effective amount of a crystal form of the invention to a patient in need of the treatment.
The present invention provides, inter alia, an anhydrous, non-solvated crystal form of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride (I) having an X-ray powder diffraction pattern substantially as depicted in
In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 20, at about 16.8° and about 21.8°. In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2θ, at about 14.3°, about 16.8°, about 21.8°, and about 22.3°. In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2θ, at about 14.3°, about 16.14°, about 16.8°, about 19.0°, about 21.8°, and about 22.3°. In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern comprising at least 3 characteristic peaks, in terms of 2θ, selected from about 5.3°, about 10.6°, about 11.6°, about 12.3°, about 14.3°, about 15.0°, about 16.14°, about 16.8°, about 19.0°, about 21.8°, about 22.3°, and about 23.4°. In some embodiments, the crystal form exhibits an X-ray powder diffraction pattern substantially as shown in
The crystal form having the XPRD pattern of
The crystal form having the XPRD pattern of
The crystal form of the invention having, for example, an XRPD pattern according to
Suitable crystallizing solvents include any solvent in which the compound of Formula I is partially or fully soluble. Example solvents include protic solvents such as water or alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, etc.), other polar solvents such as dimethylsulfoxide, acetonitrile, propionitrile, ethyl acetate, dimethylformamide, dichloromethane, and the like. Other suitable solvents include tetrahydrofuran, toluene, and acetone. In some embodiments, the crystallizing solvent is an alcohol. In further embodiments, the crystallizing solvent is ethanol.
Suitable antisolvents include any solvent in which the compound of Formula I is poorly soluble. Example antisolvents include non-polar or weakly polar solvents such as ethers (diethyl ether, t-butylmethyl ether, etc.) and hydrocarbons (pentane, hexanes, etc.).
The present invention further provides a crystal form of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride (I) having single crystal X-ray diffraction parameters as shown below in Table 2. Additional parameters, atomic coordinates and other data are provided in Example 7.
A crystal form of the invention having one or more of the single crystal parameters recited herein can be prepared according to routine methods. In an example method, the crystal form of the invention can be prepared by precipitating the crystal form from a solution of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride in a crystallizing solvent by addition of antisolvent. The addition of antisolvent can be carried out by any suitable method such as by direct addition or by vapor diffusion. Suitable antisolvents include ethers (such as diethyl ether or t-butylmethyl ether) and hydrocarbons (such as pentane, hexanes, etc.), and other low boiling solvents. In some embodiments, the antisolvent contains hexanes. The crystallizing solvent can be any of the crystallizing solvent recited hereinbefore. In some embodiments, the crystallizing solvent contains an alcohol. In some embodiments, the crystallizing solvent is ethanol.
The present invention further provides an amorphous form of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride (I). As can be seen from
Compositions, Formulations, and Dosage Forms
The present invention further provides a composition containing a crystal form of the invention. In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of total 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride in the composition is present as the crystal form. In some of each such embodiments, less than about 10%, less than about 5%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% by weight of total 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride in the composition is present as the amorphous form. In further embodiments, the composition is substantially free of the amorphous form of the hydrochloride. In further embodiments, the composition is a pharmaceutical composition containing a crystal form of the invention and a pharmaceutically acceptable carrier.
The present invention further provides a composition containing the amorphous form of the invention. In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of total 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride in the composition is present as the amorphous form. In further embodiments, the composition is a pharmaceutical composition containing the amorphous form of the invention and a pharmaceutically acceptable carrier.
The crystal and amorphous forms of the present invention can be administered orally or parentally, neat or in combination or association with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either in liquid or solid composition form. Preferably, the pharmaceutical compositions containing the present crystal forms are in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dosages containing appropriate quantities of the active ingredients. The unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The therapeutically effective dosage to be used may be varied or adjusted by the physician and generally ranges from 0.5 mg to 750 mg, according to the specific condition(s) being treated and the size, age and response pattern of the patient.
Further example dosage forms and compositions are described in U.S. App. Ser. No. 60/554,622 and U.S. application Ser. No. 11/082,548 (published as US 2005/0215561A1), which is incorporated herein by reference in its entirety.
Methods of Use
As antagonists of the 5-HT1A receptor, the crystal forms of the invention can useful in inhibiting the activity of the receptor. The inhibiting can be carried out, for example, by contacting the crystal form with the receptor in vitro, in vivo, or ex vivo. Accordingly, the crystal or amorphous forms of the present invention can be used to treat a subject (e.g., patient, individual, etc.) suffering from CNS disorders such as schizophrenia, (and other psychotic disorders such as paranoia and mano-depressive illness), Parkinson's disease and other motor disorders, anxiety (e.g. generalized anxiety disorders, panic attacks, and obsessive compulsive disorders), depression (such as by the potentiation of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors), Tourette's syndrome, migraine, autism, attention deficit disorders and hyperactivity disorders. Crystal and amorphous forms of the present invention can also be useful for the treatment of sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, eating disorders such as for example obesity, anorexia and bulimia, sexual dysfunction, and the treatment of alcohol, drug and nicotine withdrawal.
Crystal and amorphous forms of the present invention are also useful for the treatment of cognitive dysfunction. Thus, crystal forms of the present invention may be useful for the treatment of cognitive dysfunction associated with mild cognitive impairment (MCI)) Alzheimer's disease and other dementias including Lewy Body, vascular, and post stroke dementias. Cognitive dysfunction associated with surgical procedures, traumatic brain injury or stroke may also be treated in accordance with the present invention. Further, crystal or amorphous forms of the present invention may be useful for the treatment of diseases in which cognitive dysfunction is a co-morbidity such as, for example, Parkinson's disease, autism and attention deficit disorders.
Treatment of a patient can be carried out by administering a therapeutically effective amount of a crystal or amorphous form of the compound of Formula I to a patient in need of treatment. Suitable patients are, for example, mammals, especially humans, suffering from or likely to suffer from any of the CNS disorders or cognitive dysfunctions listed above, or other 5-HT1A receptor-associated disease.
As used herein, the term “individual” or “patient” or “subject,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
(1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) such as stabilizing viral load in the case of a viral infection; and
(3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as lowering viral load in the case of a viral infection.
One or more additional pharmaceutical agents can be used in combination with the crystal forms of the present invention for treatment of 5-HT1A-associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
In some embodiments of each of the crystal forms described herein, the crystal forms are provided in a form that is substantially free of hydrocarbon solvents, such as hexane and heptane. Such solvents have been used in the later stages of preparation of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride, for example in the procedures described in U.S. Pat. Nos. 6,713,626 and 6,469,007, and U.S. App. Ser. No. 60/554,666, described supra. In such cases, it is desirable to further purify the preparations of the compound to remove traces of such solvents that may remain in the preparation. This can be accomplished by any of a variety of standard techniques, including one or more recrystallizations from a more pharmacologically acceptable solvent, such as ethanol, or by additional drying or chromatography procedures, or other procedures used for the removal of impurities from pharmaceuticals.
As used herein, the term “substantially free” as applied to a chemical species, is intended to mean that the indicated species is present in less than about 0.01% by weight, relative to the total weight of the sample.
In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.
4-Cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride (15 Kg) was combined with 105 Kg of ethanol 2B (standard commercial form of anhydrous ethanol that typically consists of 99.5% ethanol and 0.5% toluene (by weight)) and the resulting mixture was heated to reflux (approx. 78° C.). Once dissolution was complete, the mixture was cooled to 60-65° C. and clarified by filtration through a 0.2 micron cartridge filter. Additional hot (60-70° C.) ethanol 2B, 30 Kg, was used to rinse the vessel and filter cartridge. The combined filtrates were concentrated to a volume of 86 L by vacuum distillation (maximum pot temperature=40° C.). The reduced solution was then heated to reflux and held for 10 minutes. The solution was then cooled to 15-25° C. over 1 hour followed by stirring for a minimum of 2 hours. The mixture was then cooled further to −15 to −5° C. over 1 hour followed by stirring for a minimum of 2 hours. The crystallized product was filtered and then washed with two 15 Kg portions of ethanol 2B. The material thus obtained was then dried at 60° C. under vacuum. Yield: 11.3 Kg.
Micronization: The crystalline material obtained above was first comilled using a 0.094″ screen at 1200 to 1400 RPM. The resulting material was then micronized using 35 PSI nitrogen at a feed rate of 50 to 80 grams/minute with 80 CFM jets using a T-15 trost mill micronizer to yield a fine crystalline powder.
The solubility of the compound of Formula I in a variety of solvents was measured according to routine methods at 23° C. and 50° C. Results are presented below in Table A.
The crystal form of the invention, prepared according to Example 1, was analyzed by TGA and DSC by heating a 2-10 mg sample in a platinum cup under nitrogen flow from 25 to 300° C. at a linear scan rate of 10′/min using a Q600 SDT DSC/TGA instrument (TA Instruments). A representative spectrum is provided in
The crystal form of the invention remained stable upon slurrying in a variety of different solvents at 23° C. and 50° C. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) data of products of various re-slurries are compared in Tables B and C below together with TGA/DSC data from the crystal form of the invention prepared according to Example 1. TGA/DSC data was obtained as described in Example 3. While DSC endotherms and TGA weight losses slightly differ between experiments, the variation is expected for HCl loss and decomposition of the sample. Powder X-ray diffraction data (see below Examples) of samples from each of the slurries were consistent with the diffraction pattern of
The crystal form of the invention was obtained by crystallization from various solutions. Differential scanning calorimetry (DSC) data of products of various crystallizations are compared in Tables D, E and F below. Table D contains data for crystalline material obtained by cooling solutions of the compound of Formula I in the solvents listed. For example, a saturated solution of the compound of Formula I in the specified solvent at about 50° C. was cooled to about 20-25° C. and the resulting crystalline material analyzed. Table E contains data for crystalline material obtained by evaporation of solutions of the compound of Formula I using solvents listed. For example, evaporation was carried out by gradually warming a saturated solution of the compound of Formula I or by leaving a saturated solution of the compound of Formula I in a vial (covered by Al foil or perforated paraffin) exposed to air for enough time to generate crystalline solid. Table E contains data for crystalline material obtained by antisolvent methods (e.g., adding antisolvent to a saturated solution of the compound of Formula I or adding a saturated solution of compound of Formula I to antisolvent) using the solvents listed and t-BMS as antisolvent. Use of water or ethanol in the evaporation experiments resulted only in oils. DSC data was obtained as described in Example 3. And, as with the reslurry experiments of Example 4, the DSC endotherms slightly differ between experiments, and are accounted for by HCl loss and decomposition of the sample. Powder X-ray diffraction data (see below Examples) of samples from each of the cooling, evaporation, and antisolvent experiments were consistent with
X-Ray powder diffraction (XRPD) data was collected on a sample of the compound of Formula I prepared according to Example 1 using a Rigaku Miniflex Diffractioin System (Rigaku MSC, Inc.). Powder samples were deposited on a zero-background polished silicon sample holder. A normal focus copper X-ray tube at 0.45 kW equipped with a Ni K-beta filter scanning at 1.0 degree/min from 3.00 to 40.00 degree 2-theta was used as the X-ray source. Data processing was carried out using Jade 6.0 software. Similarly, XRPD data was acquired for the samples obtained from the polymorph screens of Examples 4 and 5. One diffraction pattern was consistently observed and is provided in
The X-ray structure was determined for the compound of Formula I. The ORTEP drawing is provided in
Single crystals (colorless needles) of a compound of Formula I were obtained from EtOH/hexanes. A single needle, cut to 0.05 mm×0.10 mm×0.22 mm in size, was mounted on a glass fiber with silicone grease and transferred to a Nonius Kappa CCD diffractometer equipped with an MSC X-stream cryosystem and molybdenum K-α radiation (λ=0.71073 Å). Six hundred frames of data were collected at 200 (2) K with an omega oscillation range of 0.5 degree/frame, and an exposure time of 240 seconds/degree. A total of 10,607 reflections (θ maximum=22.50°) were indexed, integrated and corrected for Lorentz and polarization effects using DENZO-SMN and SCALEPACK. A Gaussian Face-Indexed absorption correction was then applied using SHELXTL to give 3416 unique reflections (Rint=0.0844) of which 2933 had I>2σ(I). The minimum and maximum transmission factors were 0.98135 and 0.99183, respectively. Post-refinement of the unit cell parameters gave a=8.4682(4) Å, b=9.2948(3) Å, c=33.2986(15) Å, alpha=beta=gamma=90°, and V=2620.9(2) cubic Å. Axial photographs and systematic absences were consistent with the compound having crystallized in the orthorhombic space group P2(1)2(1)2(1) (No. 19). The observed mean |E*E−1| value was 0.777 (versus the expectation values of 0.968 and 0.736 for centric and noncentric data, respectively).
The structure was solved by direct methods and refined by full-matrix least-squares on F2 using SHELXTL The coordinates and anisotropic displacement coefficients for the nonhydrogen atoms were free to vary. The coordinates for the piperazinium hydrogen H(4) were also refined, while those for the remaining hydrogens were allowed to ride on their respective carbons. The hydrogen atoms were assigned isotropic displacement coefficients U(H)=1.2U(C), 1.5U(Cmethyl) or 1.5U(N), and the weighting scheme employed was w=1/[\s2(Fo2)+(0.0209P)2+0.5003P] where P=(Fo2+2Fc2)/3. The refinement converged to R(F)=0.0518, wR(F2)=0.0944, and S=1.118 for 2933 reflections with I>2sigma(I), and R(F)=0.0665, wR(F2)=0.1027, and S=1.118 for 3416 unique reflections and 338 parameters. The maximum |delta/sigma| in the final cycle of least-squares was less than 0.001, and the residual peaks on the final difference-Fourier map ranged from −0.178 to 0.234 electrons/cubic Angstroms. Scattering factors were taken from the International Tables for Crystallography, Volume C.
The Flack parameter refined to −0.11(10) [versus the expectation values of 0 for the correct hand and 1 for the wrong hand] indicating that the hand of the molecule can be unequivocally assigned as (1R).
For comparison, a refinement of the inverted molecule having the wrong absolute structure, i.e., (1S), gave R(F)=0.0526, wR(F2)=0.0972, and S=1.114 for 2933 reflections with I>2σ(I), and R(F)=0.0673, wR(F2)=0.1057, and S=1.113 for 3416 unique reflections and 338 parameters. The Flack parameter based on the wrong absolute structure was 1.10(10).
The amorphous form of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride was prepared by adding abot 100 mg of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride to 1 ml of water in a vial. The suspension was heated to about 40° C. and stirred until all solids were dissolved. The solution was placed in an oven set to 50° C., and the pressure was gradually reduced to −20 inch of Hg. After 24 hours, the vial was removed, yielding the amorphous material. The X-ray powder diffraction pattern of the amorphous form is shown in
Other Crystal Forms
A screen was performed to determine the existence of additional crystal forms of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride.
Reslurry Experiments:
4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride was reslurried in about 1-2 ml of ethanol, IPA, ethyl acetate, acetone, THF, acetonitrile, toluene, iso-propyl acetate, and water. The suspensions were stirred in 5 ml vials for 12 days at RT. The suspension samples were withdrawn at days 6 and 12, filtered, and analyzed via XRD while wet. No transformation was noticed, all XRD scans showed Form A (see Table M).
Form Screening by Crystallization
Three sets of crystallization experiments were carried out to investigate polymorphism of this compound. In the first set, the compound was recrystallized from conventional solvents using different techniques. In the second set, solids were generated from the reslurry of amorphous material in different solvents including some non-conventional solvents. In the third set, solids were generated through reactive crystallization of HCl and the free base in different solvents.
First Set of Form Screening
4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride was crystallized from different solvents by cooling, antisolvent, and evaporative crystallization. Excess API solid was added to different solvents, the suspension stirred for 2 hrs at 60° C., and the undissolved solids were filtered off. About 1.5 ml of each solution was obtained for each experiment.
For fast cooling crystallization, the temperature of the solution was either reduced to room temperature in about 10 minutes, or crash cooled to −15° C. in ice/methanol. Slow cooling was carried out in around 1 hour. Fast antisolvent crystallization was performed by immediately adding several volumes of heptane to the solution at 60° C.; slow addition was carried out in around 30 minutes. In evaporative crystallization, vials containing unsaturated solutions were stirred open-cap for two days (slow evaporation) and placed in an oven at 50° C. and gradually vacuum applied until all solvents evaporated (fast evaporation). Some vials did not generate solids due to very low solubility. In slow cooling with water, the solution oiled out and XRD showed amorphous material. The oiling out in water is associated with the compound's very high solubility in this solvent. Based on XRD scans, Forms A and an amorphous material were generated in these experiments. The results are summarized on Table N.
To further investigate the possibility of a hydrate form, saturated solutions of the compound in ethanol, IPA, acetone, THF, and acetonitrile containing 5% water were prepared. The solutions were both crash-cooled and slow-cooled. In these experiments also, only Form A was observed (see Table O).
Form Screening Starting from Amorphous API
In these experiments, amorphous API was reslurried in different solvents at room temperature. To prepare amorphous API, around 100 mg of the API was added to about 1 ml of water in 22 vials. The suspension heated to about 40° C. and stirred until all solids dissolved. The solutions were placed in an oven and the temperature was set to 50° C.; the pressure was gradually reduced to −20 inch of Hg. After 24 hours, the vials were removed while the solids in the vials were glassy and amorphous. To each vial, between 0.25 to 1 ml of different solvents (see Table P) were added, after 30 minutes to 1 hour stirring at room temperature, some vials contained white suspension indicating potential form transformation. Some vials stirred overnight and the same color change (glassy to white) observed. In some vials, the solids remained glassy, for others the solids fully dissolved due to the high solubility of solids in the solvents. In cases where color change was observed, the suspension was filtered and analyzed by XRD without drying in the oven. According to XRD results, the solids were all Form A (see Table P).
Form Screening by Salt Formation Via Reactive Crystallization
Salt was produced from the free base and HCl solution in both pure and mixed solvents.
Salt formation in pure solvents: HCl solutions in ethanol, ethyl acetate, t-BME, IPA, and methanol were made. See Table Q for the concentration of HCl in each solvent. Amorphous free base was made by evaporation of the solvent from a free base-ethanol solution. Evaporation was performed by placing the solution in an oven at room temperature under full vacuum for three days.
Salt generation in mixed solvents: In these experiments salt was generated from free base dissolved in different solvents (see Table R) and HCl solution in either methanol or IPA. The concentration of HCl in methanol and IPA were 15% and 29%, respectively. Results are shown in Table R. No new form was generated in the experiments. Table S shows the onset temperature of thermal events of Form A and amorphous salt.
Polymorph Search by Thermal Operation
Since the amorphous salt undergoes a glass transition, crystallization, and melting events, the existence of a possible new form after crystallization and before melting was investigated. Accordingly, a sample was heated to 188° C. and then cooled and analyzed by XRD. The analysis showed that the amorphous had converted to Form A before melting.
Acquisition of Analytical Data
Differential scanning calorimetry data were collected using a DSC (TA instrument, model Q1000) under the following parameters: 50 mL/min purge gas(N2); scan range 37 to 300° C., scan rate 10° C./min. X-Ray data was acquired using an X-ray powder diffractometer (Bruker-axs, model D8 advance) having the following parameters: voltage 40 kV, current 40.0 mA, scan range (2θ) 5 to 30°, total scan time 20 minutes, with Ni filter, Vantec-1 detector, 1 mm divergence slit.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety.
This application is a divisional application of U.S. patent application Ser. No. 11/364,902, which claims priority benefit of U.S. Provisional Application Ser. No. 60/657,575, filed Mar. 1, 2005. The contents of both applications are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60657575 | Mar 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11364902 | Feb 2006 | US |
| Child | 12365156 | US |
