Solid forms of a pharmaceutically active compound

Abstract

The present application discloses solid forms of compound (1), methods for making them, as well as compositions said solid forms.

Description

[0001] SOLID FORMS OF A PHARMACEUTICALLY ACTIVE COMPOUND

[0002] Field of the Invention

[0003] The present invention relates to various solid forms of compounds, for example, compounds which are small molecules and have use in pharmaceutical applications.

[0004] Background of the Invention

[0005] The compound (4S)-7-chloro-6-(2,6-difluorophenyl)-l,4-dimethyl-8-(trifluoromethyl)-4H- [l,2,4]triazolo[4,3-a][l,4]benzodiazepine is represented by formula (1).

[0006] The compound of formula (1), or compound (1), as well as methods for making it, are disclosed in WO 2021 / 198124. Compound (1) is selective GABAA yl receptor positive allosteric modulators (PAMs). It is thus useful in the treatment or prevention of diseases related to GABAA yl receptor dysfunction and diseases or conditions which can be treated by the enhancement of GABAA yl receptor activity, such as autism spectrum disorders (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, fragile-X disorder, schizophrenia, tardive dyskinesia, anxiety, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, disruptive, impulse-control and conduct disorders, Tourette’s syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders including narcolepsy-cataplexy, neurodegenerative conditions including Parkinson’s disease (PD), Huntington’s chorea, Alzheimer’s disease (AD), mild cognitive impairment (MCI) dementia, behavioral and psychological symptoms (BPS) in neurodegenerative conditions, multi-infarct dementia, psychosis and aggression, eating disorders including anorexia nervosa, bullimia nervosa, binge eating disorder, depression and related conditions including treatment-resistant depression (TRD), chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, drowsiness, sexual dysfunction, bipolar disorders, epilepsy and pain.

[0007] Active pharmaceutical ingredients (API’s), such as e.g. compound (1), may be prepared in a variety of different forms, such as for example salts, solvates, hydrates, co-crystals. API’s may also be in their amorphous state or one or several crystalline forms (polymorphs). Depending on the form, the physicochemical properties of an API may change, leading to e.g. different solubility, thermodynamic stability, density or melting point of different forms. Such physicochemical properties therefore may have significant influence of the efficacy or bioavailability of a known API.

[0008] Summary of the Invention

[0009] The present invention provides solid forms of the compound of formula (1) selected from the group consisting of, a) a substantially amorphous form of compound (1); or b) a polymorph designated Pattern 1, 2, 2’, 3, 4 (also “Form 1”) or 5 of compound (1).

[0010] In another particularly preferred embodiment, said solid form is the polymorph designated Pattern 4 ( or Form 1) of compound (1).

[0011] In yet another preferred embodiment, said solid form is selected from the substantially amorphous form of compound 1.

[0012] In another embodiment, the invention provides a method of for treating a disease or condition in a patient in need thereof. The method includes administering to said patient an effective amount of a composition comprising a solid form of compound (1) as described herein.

[0013] The solid forms disclosed herein may be further processed into any type of solid pharmaceutical preparations or dosage forms, which are known to the person of skill in the art. Particularly preferred are oral dosage forms such as tablets, capsules, pills, powders, suspensions, pasts and the like. Detailed descriptions of suitable excipients as well as methods for making such pharmaceutical preparations can for example be found in: Raymond C. Rowe et al, Handbook of Pharmaceutical Excipients, 6thedition, 2009, Pharmaceutical Press (Publ.); ISBN-10: 0853697922.

[0014] Consequently, so obtained pharmaceutical preparations form further embodiments provided herein.

[0015] Brief description of the Figures

[0016] Fig- 1 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern 1

[0017] Fig- 2 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern 2

[0018] Fig- 3 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern 2'

[0019] Fig. 4 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern 3

[0020] Fig. 5 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern 4 (Form 1)

[0021] Fig. 6 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern 5

[0022] Fig. 7 : X-ray diffractogram (Relative Intensity (%) over 2Theta) of Pattern amorph (amorphous compound (1))

[0023] Detailed Description of the Invention

[0024] As used herein, the general term “amorphous forms” denote a material that lacks long range order and as such does not show sharp X-ray peaks. The X-Ray Powder Diffraction (XRPD) pattern of an amorphous material is characterized by one or more amorphous halos. More specifically, the term “amorphous form” as used herein refers to the amorphous form of (4S)-7-chloro-6-(2,6-difluorophenyl)-l,4-dimethyl-8-(trifluoromethyl)-4H-[l,2,4]triazolo[4,3- a][l,4]benzodiazepine as such.

[0025] The amorphous form of the invention is preferentially substantially pure, meaning the amorphous form includes less than about 15%, preferably less than about 10%, preferably less than about 5%, preferably less than about 1%, even more preferably less than 0.1% by weight of impurities, including other polymorph forms of compound (1). In some embodiments, at least about 30-99% by weight of the total of compound (1) in the composition is present as the amorphous form. In further embodiments, at least about 70%, at least about 80%, at least about 90%, at least about 99% or at least about 99.9% by weight of the total of compound (1) in the composition is present as the amorphous form. Also provided by the invention are compositions consisting essentially of compound (1) wherein at least about 97-99% by weight of the compound (1) is present in the composition as an amorphous form, a polymorph form, a solvate form as described herein or combinations thereof.

[0026] The term “polymorph” as used herein means one of the different crystal structures in which a compound can crystallize. Polymorphs are best characterized by their space group and unit-cell parameters. This term is reserved for materials with the same elemental analysis.

[0027] “Ambient temperature” means any temperature in the range of 18 to 28 °C, preferably 20 to 24 °C.

[0028] The term “composition” refers to a pharmaceutical preparation suitable for administration to an intended animal - or human subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof. The composition may include at least one additional pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.

[0029] The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectable preparations.

[0030] X-ray powder diffraction (XRPD) patterns (or X-ray diffractograms) were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu Ka radiation, primary Ge-monochromator, Mythen IK silicon strip detector, angular range 3° to 42° 2Theta, 0.02° 2Theta step width, 20 seconds measurement time per step). The samples were prepared and analyzed without further processing (e.g. grinding or sieving) of the substance. Measurement and evaluation of the X-ray diffraction data is done using WinXPOW software (Stoe & Cie GmbH, Darmstadt, Germany). The unique peaks of the different crystalline forms (polymorphs) of compound (1) in accordance with the present invention are presented in Table 1 and Table 2. Characteristic XRPD diffractograms for the individual forms are shown in Figure 1 to Figure 6. Table 3 presents the most important X-ray diffraction peaks for each of the crystalline patterns.

[0031] Table 1: XRPD peaks typical for Pattern 1, 2 and 2’ Table 2: XRPD peaks typical for Pattern 3, 4 and 5 Therefore, in on embodiment the present invention provides a solid form of compound (1) as defined herein, characterized in that said solid form is a polymorph, hydrate, hemi-hydrate, solvate, hemi-solvate or pharmaceutically acceptable salt. In one preferred embodiment, said solid form is a polymorph.

[0032] In one embodiement the present invention provides a solid form of compound (1), characterized by the XRPD patterns according to Table 1, 2 and / or 3.

[0033] In another embodiment, the present invention provides a solid form of compound (1), characterized in that it is the amorphous form.

[0034] In another embodiment, the present invention provides a solid form of compound (1), characterized in that it is a polymorph. In another embodiment, the present invention provides a solid form of compound (1), wherein the XRPD patterns at 2-theta values of 5.78, 10.00, 15.86, 20.07, 21.57 represent the most significant peaks. In another embodiment, the present invention provides a solid form of compound (1), wherein the XRPD patterns at 2-theta values of 6.33, 9.74, 10.13, 10.94, 12.37 represent the most significant peaks.

[0035] In another embodiment, the present invention provides a solid form of compound (1), wherein the XRPD patterns at 2-theta values of 6.23, 9.58, 9.99, 12.21, 19.75 represent the most significant peaks.

[0036] In another embodiment, the present invention provides a solid form of compound (1), wherein the XRPD patterns at 2-theta values of 9.72, 9.94, 11.93, 15.69, 19.83 represent the most significant peaks.

[0037] In another embodiment, the present invention provides a solid form of compound (1), wherein the XRPD patterns at 2-theta values of 5.75, 10.01, 10.64, 13.59, 19.77 represent the most significant peaks.

[0038] In another embodiment, the present invention provides a solid form of compound (1), wherein the XRPD patterns at 2-theta values of 9.72, 11.85, 15.69, 16.73, 20.00 represent the most significant peaks.

[0039] The present solid forms of compound (1) can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topical ocularly (e.g. in the form of solutions, ointments, gels or water soluble polymeric inserts). However, the administration can also be effected parenterally, such as intramuscularly, intravenously, or intraocularly (e.g. in the form of sterile injection solutions).

[0040] The present solid forms of compound (1) can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0041] Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0042] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0043] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0044] Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0045] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0046] In addition to the above additives or excipients, use of any conventional materials and procedures for formulation and preparation of oral dosage forms using the compositions disclosed herein known by those skilled in the art are potentially useful. For example, the skilled artisans may formulate the compositions in an appropriate manner, and in accordance with accepted practices, such as e.g. those described in Remington's Pharmaceutical Sciences (Gennaro, Ed., Mack Publishing Co., Pa. 1990).

[0047] The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should it be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of medicament and the required dose, which can be between 0.1 and 25 mg in can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated. Consequently, a further embodiment of the present invention includes a pharmaceutical preparation containing the solid forms of compound (1) as obtained by a method as described herein.

[0048] In one embodiment, there is provided a pharmaceutical composition comprising one or several solid forms of compound (1) as disclosed herein together with pharmaceutically acceptable adjuvants or excipients. In another embodiment, said solid form of compound (1) is characterized by 2-theta values of 5.78, 10.00, 15.86, 20.07, 21.57 as the most significant peaks; or

[0049] 2-theta values of 6.33, 9.74, 10.13, 10.94, 12.37 as the most significant peaks; or

[0050] 2-theta values of 6.23, 9.58, 9.99, 12.21, 19.75 as the most significant peaks; or

[0051] 2-theta values of 9.72, 9.94, 11.93, 15.69, 19.83 as the most significant peaks; or

[0052] 2-theta values of 5.75, 10.01, 10.64, 13.59, 19.77 as the most significant peaks; or

[0053] 2-theta values of 9.72, 11.85, 15.69, 16.73, 20.00 as the most significant peaks in the X-ray diffractogram.

[0054] In yet another embodiment, there is provided a pharmaceutical composition comprising one or several solid forms of compound (1) as characterized by the XRPD peaks presented in Table 1 and / or Table 2; or as shown in Figure 1 to Figure 6.

[0055] In another embodiment, the present invention provides one or several solid forms as disclosed herein for use as medicaments.

[0056] In another embodiment, the present invention provides one or several solid forms as disclosed herein for the use as medicaments for the treatment or prevention of diseases related to GABAA yl receptor dysfunction. In one embodiment the term “diseases related to GABAA yl receptor dysfunction” means a disease or disorder selected from acute neurological disorders, chronic neurological disorders, cognitive disorders, autism spectrum disorders (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, fragile-X disorder, schizophrenia, tardive dyskinesia, anxiety, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, disruptive, impulse-control and conduct disorders, Tourette’s syndrome (TS), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), sleep disorders, Parkinson’s disease (PD), Huntington’s chorea, Alzheimer’s disease (AD), mild cognitive impairment (MCI), dementia, behavioral and psychological symptoms (BPS) in neurodegenerative conditions, multi-infarct dementia, agitation, psychosis, substance-induced psychotic disorder, aggression, eating disorders, depression, chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, postpartum depression, drowsiness, sexual dysfunction, bipolar disorders, epilepsy and pain. In another embodiment the term “diseases related to GABAA yl receptor dysfunction” means a disease or disorder selected from anxiety, targeting social anxiety disorder (social phobia) and generalized anxiety disorder, and autism spectrum disorder (ASD), targeting core symptoms and associated comorbidities including anxiety and irritability. In yet another embodiment, the present invention provides a method of preventing or treating a disease related to GABAA yl receptor dysfunction, as defined above, wherein said methods involves administering to a patient in need a pharmaceutical preparation comprising one or several of the solid forms of compound (1) as defined herein.

[0057] The invention is now further described by the following specific working, which are not meant to limit in any way the scope of the present invention.

[0058] Examples

[0059] Experimental

[0060] Pattern 1, 2, 2’, 3 and 5 have been recorded using a Panalytical Empyrean powder diffractometer and Pattern 4 and the amorphous Pattern (amorph) have been recorded using a Stoe Stadi P powder diffractometer.

[0061] Panalytical Empyrean

[0062] XRPD diffractograms were collected on a Panalytical Empyrean powder diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Seller slits with a focusing mirror were used on the incident beam. A Pixcel 3D detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Seller slits. The software used for data collection was X’Pert Data Collector using X’Pert Operator Interface.

[0063] Samples were prepared and analyzed in either a metal 96 well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 - 2 mg) were used as received.

[0064] The details of the standard screening data collection method are:

[0065] • Angular range: 2.5 to 32.0° 2Theta

[0066] • Step size: 0.0130° 2Theta

[0067] • Collection time: 12.75 s / step (total collection time of 2.07 min)

[0068] Stoe Stadi P

[0069] X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a Stoe Stadi P powder diffractometer (Cu Ka radiation, primary Ge-monochromator, Mythen IK silicon strip detector, angular range 3° to 42° 2Theta, 0.02° 2Theta step width, 20 seconds measurement time per step). The samples are prepared and analyzed without further processing (e.g. grinding or sieving) of the substance.

[0070] Measurement and evaluation of the X-ray diffraction data is done using WinXPOW software (Stoe & Cie GmbH, Darmstadt, Germany). Example 1: Pattern 1 (Polymorph)

[0071] Compound (1) (150 mg, amorphous) was dispensed to HPLC vials and suspended in heptane / di chloromethane mixture (1 : 1; v / v) (750 pL, 5 volumes). The suspension was subjected to maturation cycles (4 hours at RT, 4 hours at 50 °C) with shaking for 4 days. Solids were analysed by XRPD.

[0072] Example 2: Pattern 2 (Polymorph)

[0073] Compound (1) (20 mg, amorphous) was dispensed to HPLC vials with a small magnetic stirrer bar. A 9:1 heptane / THF (v / v) (5 volumes) was added and stirred (500 rpm) at 5 °C for 7 days. Solids were isolated under positive pressure with SPE cartridge and frit and analyzed by XRPD.

[0074] Example 3: Pattern 2 ’ (Polymorph)

[0075] Compound (1) (20 mg, amorphous) was dispensed to HPLC vials with a small magnetic stirrer bar. A 9:1 heptane / 2-methyl-THF (v / v) (5 volumes) was added and stirred (500 rpm) at 5 °C for 7 days. Solids were isolated under positive pressure with SPE cartridge and frit and analysed by XRPD

[0076] Example 4: Pattern 3 (Polymorph)

[0077] Compound (1) (20 mg, amorphous) was dispensed to HPLC vials with a small magnetic stirrer bar. A 9:1 heptane / dichloromethane (v / v) (5 volumes) was added and stirred (500 rpm) at 5 °C for 7 days. Solids were isolated under positive pressure with SPE cartridge and frit and analysed by XRPD.

[0078] Example 5: Pattern 4 (also designated “Form 1 ”) (Polymorph)

[0079] After the initial difficulties to isolate crystalline solids, Form 1 eventually became a predominant form that was found across many samples. The following are some example situations where Form 1 was isolated with no seeding undertaken.

[0080] Liquid -assisted grinding followed by ambient evaporation: Compound (1) (25 mg, amorphous) was dispensed to HPLC vials and two stainless steel grinding balls added (3 mm diameter). A drop aliquot of 1 -propanol (5 pL) was added and the mixture ground at 500 rpm for 2 hours on a planetary mill. A viscous liquid resulted. The vial was uncapped and evaporated over 25 days. The resulting white solid was analysed by XRPD.

[0081] Liquid -assisted grinding followed by ambient evaporation and then sonication in heptane:

[0082] Compound (1) (25 mg, amorphous) was dispensed to HPLC vials and two stainless steel grinding balls added (3 mm diameter). A drop aliquot of ethanol (5 pL) was added and the mixture ground at 500 rpm for 2 hours on a planetary mill. A viscous liquid resulted. The vial was uncapped and evaporated over 25 days. The resulting white solid was analysed by XRPD.

[0083] This procedure can be replicated for a significant number of different solvents. In summary, Form 1 was the most prevalent crystalline form. It could be isolated from multiple viscous liquids following sonication in n-heptane and by multiple slurry conversion experiments in different n-heptane / solvent mixtures. Form 1 was successfully reproduced in larger scale and characterized as a slightly hygroscopic non-solvated form that was stable upon storage at 25 °C / 97 %-RH and 40 °C / 75 %-RH for 7 days.

[0084] Example 6: Pattern 5 (Polymorph)

[0085] Compound (1) (25 mg, amorphous) was dispensed to HPLC vials and two stainless steel grinding balls added (3 mm diameter). A drop aliquot of acetone (5 pL) was added and the mixture ground at 500 rpm for 2 hours on a planetary mill. A viscous liquid resulted. The vial was uncapped and evaporated over 25 days. The resulting white solid was analyzed by XRPD.

[0086] Example 7: Amorphous Form

[0087] Ca. 50 L solution (ELN027349-056-HF) (isopropanol / heptane) from prep. HPLC [CHIRAL] were concentrated at 55 °C. The wet residue was azeotroped with ca 3000 mL ethanol abs. and the light brown foamy solid was dried at 55 °C / 10 mbar / 6 h. Obtained: 249.2 g

[0088] The residue was dissolved in ethanol p.a (395 g, 500 mL). A yellow solution was obtained and dropped on water (7.5 kg, 7.50 L) at RT within 20 min (Stirring vigorously ! 300 rpm). A white suspension was observed. After 45 min, it was filtered off and the residue was washed with 5.0 L water WBI and 2 x with 500 mL n-pentane. The white powder was dried at 55 °C / 10 mbar / 10 h. Sample Pl (ELN027901-124-P1)

Claims

Claims1. A solid form of compound (1)2. A solid form according to claim 1, characterized in that said solid form is a polymorph, hydrate, hemi-hydrate, solvate, hemi-solvate or pharmaceutically acceptable salt.

3. A solid form according to claim 1, characterized in that it is the amorphous form.

4. A solid form according to claim 1 or 2, characterized in that it is a polymorph.

5. A solid form according to claim 1, 2 or 4, wherein the XRPD patterns at 2-theta values of 5.78, 10.00, 15.86, 20.07, 21.57 represent the most significant peaks.

6. A solid form according to claim 1, 2 or 4, wherein the XRPD patterns at 2-theta values of 6.33, 9.74, 10.13, 10.94, 12.37 represent the most significant peaks.

7. A solid form according to claim 1, 2 or 4, wherein the XRPD patterns at 2-theta values of 6.23, 9.58, 9.99, 12.21, 19.75 represent the most significant peaks.

8. A solid form according to claim 1, 2 or 4, wherein the XRPD patterns at 2-theta values of 9.72, 9.94, 11.93, 15.69, 19.83 represent the most significant peaks.

9. A solid form according to claim 1, 2 or 4, wherein the XRPD patterns at 2-theta values of 5.75, 10.01, 10.64, 13.59, 19.77 represent the most significant peaks.

10. A solid form according to claim 1, 2 or 4, wherein the XRPD patterns at 2-theta values of 9.72, 11.85, 15.69, 16.73, 20.00 represent the most significant peaks.

11. A pharmaceutical composition comprising one ore several solid forms according to any one of claims 1 to 10, together with pharmaceutically acceptable adjuvants or excipients.

12. The novel compounds, methods, compositions and uses substantially as described herein.***

Images