Example 1

Twenty-one 50 mg portions of compound 1 were charged to separate scintillation vials. To each vial was added the appropriate solvent and the suspensions were heated until full dissolution occurred. Stirring was suspended and the solutions were removed from the heat, allowed to cool slowly and left to stand undisturbed. Any solids that crystallized were isolated by filtration, de-liquored under a stream of nitrogen and dried at 40° C. under reduced pressure over ca 20 h (refer to Table 1).

TABLE 1
SolventSolvent
component A (20Solventcomponent BObservationYield % th.,Input formOutput form
vol, 1000 μl)component B(μl)t = 24 hnot corr.(XRPD)(XRPD)
AcetoneWater1000solid86%AA
AcetonitrileWater1020solid73%AA
AnisoleHexafluoropropan-260solution—AN/A
2-ol
ButanolWater1000solid90%AA + B
tert-ButylmethylHexafluoropropan-1250solution—AN/A
ether2-ol
ChlorobenzeneHexafluoropropan-120solution—AN/A
2-ol
CumeneHexafluoropropan-220solution—AN/A
2-ol
1,4-dioxaneWater190solid89%AA + B
EthanolWater1000solid94%AA
Ethyl acetateHexafluoropropan-1750solution—AN/A
2-ol
Isopropyl acetateHexafluoropropan-1650solution—AN/A
2-ol
MethanolWater1000solid98%AD
Methyl acetateWater1000solid93%AA
Methylethyl ketoneWater1000solid89%AA
NitromethaneHexafluoropropan-1000solution—AN/A
2-ol
2-PropanolWater1000solid94%AA
PropionitrileWater1000solid79%AA
TetrahydrofuranWater210solid74%AA + B
TolueneHexafluoropropan-170solution—AN/A
2-ol
2,2,2-Water10solution—AN/A
trifluoroethanol
TrifluorotolueneHexafluoropropan-180solution—AN/A
2-ol

Conclusions: Crystalline solids were obtained only in the presence of water. Single Form B and single Form C were not observed. A new hydrate form, designated Form D (a hemi-hydrate) was generated by crystallization from methanol/water. This was in contrast to the outcome from suspension equilibration that gave Form C (mono-hydrate), under the same solvent conditions (vide infra)

FIG. 1A provides the XRPD pattern of Form A. FIG. 1B provides the table of values for the XRPD pattern reflections of Form A. FIG. 4A provides the XRPD pattern of Form B. FIG. 4B provides the table of values for the XRPD pattern reflections of Form B.

Table 2 shows a general trend that crystallizations carried out under conditions of high water activity tend to favor the formation of hydrate forms, whilst solvent treatments at low water activity (i.e. under anhydrous conditions), promote the slow conversion of Form A into Form B (anhydrous). Table 2 shows Output Form from crystallization screen and anhydrous suspension equilibration study.

TABLE 2
Output fromSolvents
Output fromanhydrousAnhydrous
crystallizationmaturationssuspension
Aqueous crystallization systems(XRPD)(XRPD)equilibration
Acetone/water (1/1 v/v, 40 vol)AA + BAcetone
Acetonitrile/water (50/51 v/v, 40.4 vol)ABAcetonitrile
Butanol/water (1/1 v/v, 40 vol)A + BA + BButanol
1,4-dioxane/water (100/19 v/v,A + BA + B1,4-dioxane
23.8 vol)
Ethanol/water (1/1 v/v, 40 vol)ABEthanol
Methanol/water (1/1 v/v, 40 vol)DCMethanol
Methyl acetate/water (1/1 v/v, 40 vol)AA + BMethyl acetate
Methylethyl ketone/water (1/1 v/v,AAMethylethyl
40 vol)ketone
2-Propanol/water (1/1 v/v, 40 vol)AA + B2-Propanol
Propionitrile/water (1/1 v/v, 40 vol)AA + BPropionitrile
Tetrahydrofuran/water (100/21 v/v,A + BA + BTetrahydrofuran
24.2 vol)

Capsules, 5 mg, were manufactured according to cGMP using standard processes in premises suitable for the manufacture of pharmaceutical products. Table 12 provides a batch formula for preparing 5 mg capsules.

TABLE 12
ComponentAmount (g)%
Compound 11134.02.50
Silicified Microcrystalline 4841.097.00
Cellulose (Prosolv HD90)
Sodium Stearyl Fumarate25.00.50
TOTAL5000.0100.0
Gelatin Capsules, Size 2, 1525.0—
White Opaque2
TOTAL6525.0—
1Actual amount is corrected for drug substance purity (CoA)
2Based on average capsule weight provided by manufacturer

Mixing of the dry blend was conducted on five approximately equal-sized portions as follows. Compound 1 drug substance, Prosolv HD90 (silicified microcrystalline cellulose) and sodium stearyl fumarate were individually passed through 30-mesh screens to remove and break down any lumps that might be present. Approximately half of the Prosolv HD90 for each portion (10% of total amount for the batch) was added to a 4-L GMX-LAB Micro high-shear mixer, followed by compound 1 and sodium stearyl fumarate (each 20% of total amount for batch). The remainder of the Prosolv HD90 for the portion was then added to the mixer bowl.

The dry blend was mixed at 950±50 rpm for 20±1 minutes, and then the blend was transferred to a Bohle LM-40 blender with 20-L bin. Once all five of the blend portions had been processed and loaded into the Bohle blender, the final blend was mixed at 25 rpm for 20±1 minutes. Samples are taken with a sample thief and submitted for blend uniformity (BU) testing.

The final blend was filled into Size 2, white opaque, hard gelatin capsule shells using a Torpac Profill capsule filler. The capsules are polished/dedusted using a Key TD101-EWD deduster, then weighed using a Sade SP checkweigher. Capsules outside of the target weight action limits were rejected and discarded. Acceptable capsules were collected in bulk into double-layer plastic bags inside of rigid containers.

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