Methylethyl ketone

Example 7

Preparation of Carbon Black Pigment Containing Polymer Particulate Dispersion Element

Preparation of Polymer Solution A

After sufficient replacement with nitrogen gas in a flask equipped with a mechanical stirrer, a thermometer, a nitrogen gas introducing tube, a reflux tube, and a dripping funnel, Mix 11.2 g of styrene, 2.8 g of acrylic acid, 12.0 g of lauryl methacrylate, 4.0 g of polyethylene glycol methacrylate, 4.0 g of styrene macromer, and 0.4 g of mercapto ethanol followed by heating the system to 65° C. Next, drip a liquid mixture of 100.8 g of styrene, 25.2 g of acrylic acid, 108.0 g of lauryl methacrylate, 36.0 g of polyethylene glycol methacrylate, 60.0 g of hydroxyethyl methacrylate, 36.0 g of styrene macromer, 3.6 g of mercapto ethanol, 2.4 g of azobisdimethyl valeronitrile, and 18 g of methylethyl ketone into the flask in two and a half hours. Subsequent to dripping, drip a liquid mixture of 0.8 g of azobis methyl valeronitrile and 18 g of methylethyl ketone into the flask in half an hour. After one-hour aging at 65° C., add 0.8 g of azobismethyl valeronitrile followed by another one-hour aging. After the reaction, add 364 g of methylethyl ketone to the flask to obtain 800 g of a polymer solution A having a concentration of 50% percent weight.

Preparation of Carbon Black Pigment Containing Polymer Particulate Dispersion Element

Sufficiently stir 28 g of the polymer solution A, 42 g of C.I. carbon black (FW100, manufactured by Degussa AG), 13.6 g of 1 mol/1 potassium hydroxide solution, 20 g of methylethyl ketone, and 13.6 g of deionized water followed by mixing and kneading with a roll mill. Place the obtained paste in 200 g of deionized water followed by sufficient stirring. Distill away methylethyl ketone and water using an evaporator and remove coarse particles by filtrating the thus-obtained liquid dispersion with a polyvinylidene fluoride membrane filter having an average hole diameter of 5.0 μm under pressure to obtain a carbon black pigment containing polymer particulate liquid dispersion containing a solid pigment portion in an amount of 15 percent by weight with a solid portion concentration of 20 percent by weight.

The volume average particle diameter (D50) of the polymer particulate in the liquid dispersion measured by a particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.) is 104 nm.

Example 29

A dispersion was prepared of polyacrylic acid hydroxyethyl acrylate copolymer 95:5, 40%, silver behenate 56% and IR dye ADS 830A 4% in methylethyl ketone to give a solids content of 4%. The mixture was ball-milled using glass marbles overnight. A solution of hexamethylene diisocyanate in methylethyl ketone was added to the dispersion so that equimolar isocyanate function to hydroxyl function was obtained and the mixture was knife-coated onto a grained, anodized aluminum sheet. After the solvent had dried, the coating was imaged using an infrared laser with an energy of 400 mJ at 10 Watts. The coating was not removed using 50 double wipes with fountain solution and 5% isopropanol. An inked image was formed when wiped with lithographic ink. The non-image areas did not take ink.

Example 1

Preparation of Surface Reformed Black Pigment Dispersion

A total of 100 g of Black Pearls® 1000 (carbon black having a BET specific surface area of 343 m²/g and an amount of absorbing dibutylphthalate (DBPA) of 105 ml/100 g, manufactured by Cabot Corporation), 100 milimole of sulfanilic acid, and 1 litter of highly deionized water were mixed by a Silverson Mixer at 6,000 rpm in a room temperature environment.

Thereafter, 100 milimole of nitric acid was added to the thus-obtained slurry. Thirty minutes later, 100 milimole of sodium nitrite dissolved in a 10 mL of highly deionized water was gradually added. Furthermore, the resulting material was heated to 60 degrees C. while being stirred to conduct reaction for one hour to obtain a reformed pigment in which sulfanilic acid was added to carbon black.

Next, pH of the product was adjusted to 9 with tetrabutyl ammonium hydroxide solution (methanol solution) at 10 percent to obtain a reformed pigment dispersion in 30 minutes. Thereafter, subsequent to ultrafiltering by dialysis membrane using the dispersion and highly deionized water followed by ultrasonic dispersion, surface reformed pigment dispersion having a solid portion accounting for 20 percent was obtained.

The surface reforming level of the thus-obtained surface reformed pigment dispersion was 0.75 milimole/g and the 50 percent cumulative volume particle diameter (D₅₀) was 120 nm as measured by a particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

Preparation of Water-Dispersible Polyurethane Resin A

Preparation of Polyester Polyol P-1

A total of 830 parts of terephthalic acid, 830 parts of isophthalic acid, 374 parts of ethylene glycol, 598 parts of neopentyl glycol, and 0.5 parts of dibutyltin oxide were loaded in a reaction container equipped with a thermometer, a nitrogen gas introducing tube, and a stirrer and allowed to conduct polycondensation reaction at 230 degrees C. for 15 hours while introducing nitrogen gas into the reaction container until the acid value was 1 or less at 180 to 230 degrees C. to obtain a polyester polyol P-1 having a hydroxyl value of 74.5 mgKOH/g, an acid value of 0.2 mgKOH/g, and an average molecular weight of 1500.

Preparation of Hydrophobic Polyester Polyol Q-1

A total of 1,660 parts of orthophthalic acid, 1,637 parts of diethylene glycol, and 0.5 parts of dibutyltin oxide were charged in a container equipped with a thermometer, a nitrogen gas introducing tube, and a stirrer and allowed to conduct polycondensation reaction at 230 degrees C. for 15 hours while introducing nitrogen gas into the reaction container until the acid value was 1 or less at 180 to 230 degrees C. to obtain a polyester polyol Q-1 having an aromatic ring structure with a hydroxyl value of 190 mgKOH/g and an acid value of 0.3 mgKOH/g.

Preparation of Water-Dispersible Polyurethane Resin A

A thousand parts of polyester polyol P-1 was subjected to dehydration at 100 degrees with a reduced pressure. Subsequent to cooling down to 80 degrees C., 907 parts of methylethyl ketone was added followed by sufficient stirring to obtain a solution. Thereafter, 80 parts of 2,2′-dimethylol propionic acid was added to the solution.

Next, 281 parts of isophorone diisocyanate was added to allow reaction at 75 degrees C. for eight hours to complete urethanation. After the isocyanate value became 0.1 percent or less, the mixture was cooled down to 50 degrees C. and 340 parts of the polyester polyol Q-1 was added to obtain a homogeneous solution. After 60 parts of triethyl amine was added for neutralization, 7000 parts of water was added to obtain an aqueous solution.

After removing methyl ethyl ketone from the obtained transparent reaction product under a reduced pressure at a temperature range of from 40 to 60 degrees C., water was added to adjust the concentration to obtain a stable translucent colloidal water dispersion having a nonvolatile content of 25 percent.

Preparation of Ink

A total of 65.00 parts of 3-methoxy-N,N-dimethyl propane amide, 2.00 parts of 2-ethyl-1,3-hexane diol, 5.00 parts of propylene glycol, 0.40 parts of 2,5,8,11-tetramethyl decane-5,8-diol, 1.00 part of polyether-modified siloxane compound represented by Chemical Formula 8 illustrated above, and 1.00 part of photoacid generator represented by Chemical Formula 1 illustrated above were mixed and stirred in a vessel equipped with a stirrer for 30 minutes.

Next, 0.10 parts of polyoxyethylene perfluoroalkyl ether (UNIDYNE™ DSN403N, effective component of 100 percent, manufactured by DAIKIN INDUSTRIES, LTD.), 0.05 parts of preservatives and fungicides (Proxel GXL, manufactured by Avecia Inkjet Limited), 0.30 parts of 2-amino-2-ethyl-1,3-propane diol, 20.00 parts of the liquid dispersion of polymer particulate containing carbon black pigment of Preparation Example 8, and a balance of pure water to make the total 100 percent were added followed by mixing and stirring for 60 minutes.

Thereafter, the thus-obtained mixture was filtered with a polyvinilydene fluoride membrane filter having an average hole diameter of 1.2 μm under pressure to remove coarse particles and dust. Thus, ink of Example 1 was obtained.

Example 2

Preparation of Surface Reformed Magenta Pigment Dispersion

One kg of SMART Magenta 3122BA (Pigment Red 122 surface treated dispersion, solid portion: 14.5 percent by mass, manufactured by SENSIENT Corporation) was subjected to acid deposition with 0.1 normal HCL aqueous solution.

Next, pH of the product was adjusted to 9 with tetraethyl ammonium hydroxide aqueous solution at 10 percent to obtain a reformed pigment dispersion in 30 minutes. The thus-obtained reformed pigment dispersion including a pigment bonded to at least one amino benzoate group or amino benzoate tetraethyl ammonium salt was subjected to ultrafiltering by dialysis membrane with highly deionized water, followed by ultrasonic dispersion to obtain a surface reformed magenta pigment dispersion having a pigment solid portion of 20 percent by mass.

The surface reformed magenta pigment dispersion had a 50 percent cumulative volume particle diameter (D₅₀) of 104 nm as measured by a particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

Preparation of Water-Dispersible Polyurethane Resin B

A thousand parts of polyester polyol P-1 was subjected to dehydration at 100 degrees with a reduced pressure. Subsequent to cooling down to 80 degrees C., 907 parts of methylethyl ketone was added followed by sufficient stirring to obtain a solution. Thereafter, 80 parts of 2,2′-dimethylol propionic acid was added to the solution.

Next, 281 parts of isophorone diisocyanate was added to allow reaction at 75 degrees C. for eight hours to complete urethanation. After the isocyanate value became 0.1 percent or less, the mixture was cooled down to 50 degrees C. After 60 parts of triethyl amine was added for neutralization, 7,000 parts of water was added to obtain an aqueous solution. After removing methyl ethyl ketone from the obtained transparent reaction product under a reduced pressure at a temperature range of from 40 to 60 degrees C., water was added to adjust the concentration to obtain a stable translucent colloidal aqueous dispersion having a nonvolatile content of 25 percent by mass.

Preparation of Ink

A total of 7.50 parts of 3-methoxy-N,N-dimethyl propane amide, 5.00 parts of propylene glycol monopropyl ether, 22.00 parts of propylene glycol, 2.00 parts of 2-ethyl-1,3-hexane diol, 0.50 parts of 2,4,7,9-tetramethyl decane-4,7-diol, 1.50 parts of polyether-modified siloxane compound represented by Chemical Formula 8 illustrated above, and 1.50 parts of photoacid generator represented by Chemical Formula 2 illustrated above were mixed and stirred in a vessel equipped with a stirrer for 30 minutes.

Thereafter, 0.05 parts of preservatives and fungicides (Proxel GXL, manufactured by Avecia Inkjet Limited), 0.30 parts of 2-amino-2-ethyl-1,3-propane diol, 24.00 parts of the prepared water-dispersible polyurethane resin A, 1.62 parts of polyurethane dispersion (TAKELAC™ W-6110, manufactured by Mitsui Chemicals, Inc.), 15.00 parts of surface-modified black pigment dispersion of Preparation Example 1, and a balance of pure water to make the total 100 parts were added to the mixture followed by mixing and stirring for 60 minutes.

Thereafter, the thus-obtained mixture was filtered with a polyvinilydene fluoride membrane filter having an average hole diameter of 1.2 μm with a reduced pressure to remove coarse particles and dust. The ink of Example 2 was thus obtained.

Example 5

Preparation of Polymer Solution A

After sufficient replacement with nitrogen gas in a flask equipped with a mechanical stirrer, a thermometer, a nitrogen gas introducing tube, a reflux tube, and a dripping funnel, 11.2 g of styrene, 2.8 g of acrylic acid, 12.0 g of lauryl methacrylate, 4.0 g of polyethylene glycol methacrylate, 4.0 g of styrene macromer, and 0.4 g of mercapto ethanol were mixed in the flask and heated to 65 degrees C. Next, a liquid mixture of 100.8 g of styrene, 25.2 g of acrylic acid, 108.0 g of lauryl methacrylate, 36.0 g of polyethylene glycol methacrylate, 60.0 g of hydroxyethyl methacrylate, 36.0 g of styrene macromer, 3.6 g of mercapto ethanol, 2.4 g of azobismethyl valeronitrile, and 18 g of methylethyl ketone was dripped into the flask in two and a half hours. Subsequently, a liquid mixture of 0.8 g of azobismethyl valeronitrile and 18 g of methyl ethyl ketone was added dropwise to the flask in half an hour.

After one-hour aging at 65 degrees C., 0.8 g of azobismethyl valeronitrile was added followed by aging for another hour. After the reaction was complete, 364 g of methylethyl ketone was added to the flask to obtain 800 g of a polymer solution A having a concentration of 50 percent.

Preparation of Liquid Dispersion of Polymer Particulate Containing Magenta Pigment

After 28 g of the polymer solution A, 42 g of C.I. Pigment Red 122, 13.6 g of 1 mol/L potassium hydroxide solution, 20 g of methylethyl ketone, and 13.6 g of deionized water were sufficiently stirred, the mixture was mixed and kneaded using a roll mill. The obtained paste was placed in 200 g of pure water followed by sufficient stirring. Methylethyl ketone and water were distilled away using an evaporator. Furthermore, this liquid dispersion was filtered under pressure by a polyvinylidene fluoride membrane filter having an average hole diameter of 5.0 μm to remove coarse particles. Consequently, a liquid dispersion of polymer particulates containing a magenta pigment was obtained, which contained the pigment in an amount of 15 percent by mass and a solid content of 20 percent by mass.

The liquid dispersion of polymer particulates containing a magenta pigment had a 50 percent cumulative volume particle diameter (D₅₀) of 127 nm as measured by a particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

Preparation of Acrylic-Silicone Polymer Particulate A

After sufficient replacement with nitrogen gas in a flask (1 L) equipped with a mechanical stirrer, a thermometer, a nitrogen gas introducing tube, a reflux tube, and a dripping funnel, 8.0 g of LATEMUL S-180 (reactive anionic surfactant, manufactured by Kao Corporation) was admixed with 350 g of deionized water and heated to 65 degrees C.

Thereafter, 3.0 g of t-butylperoxy benzoate serving as reaction initiator and 1.0 g of sodium isoascorbiate were added to the mixture. Five minutes later, a mixture of 45 g of methylmethacrylate, 160 g of methacrylic acid-2-ethylhexyl, 5 g of acrylic acid, 45 g of butylmethacrylate, 30 g of cyclohexyl methacrylate, 15 g of vinyltriethoxysilane, 8.0 g of LATEMUL S-180, and 340 g of deionized water were dripped in the flask in three hours.

Subsequent to heating at 80 degrees C. for two-hour aging, the resulting aged matter was cooled down to room temperature. pH of the resulting matter was adjusted to 7 to 8 by sodium hydroxide.

Thereafter, ethanol was distilled away by an evaporator followed by moisture adjustment to obtain 730 g of acrylic-silicone polymer particulate having a solid portion of 40 percent by mass. In addition, the 50 percent cumulative volume particle diameter (D₅₀) of the polymer particulate in the dispersion was 125 nm as measured by a particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

Example 6

Preparation of Liquid Dispersion of Polymer Particulate Containing Cyan Pigment

Liquid dispersion of polymer particulate containing a cyan pigment was prepared in the same manner as in Preparation Example 5 except that C.I. Pigment red 122 serving as pigment was changed to a phthalocyanine pigment (C.I. Pigment Blue 15:3).

The cumulative average particle diameter (D₅₀) of the polymer particulates in the liquid dispersion of polymer particulates containing a cyan pigment was 93 nm as measured by particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

Example 7

Preparation of Liquid Dispersion of Polymer Particulate Containing Yellow Pigment

A liquid dispersion of polymer particulates containing a yellow pigment was prepared in the same manner as in Preparation Example 5 except that C.I. Pigment Red 122 was replaced with bisazo yellow pigment (C.I. Pigment Yellow 155).

The liquid dispersion of polymer particulates containing a yellow pigment had a 50 percent cumulative volume particle diameter (D₅₀) of 76 nm as measured by a particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

Example 8

Preparation of Liquid Dispersion of Polymer Particulate Containing Carbon Black Pigment

A liquid dispersion of polymer particulates containing a black pigment was prepared in the same manner as in Preparation Example 5 except that C.I. Pigment Red 122 serving as pigment was changed to carbon black (FW100, manufactured by Degussa AG).

The cumulative average particle diameter (D₅₀) of the polymer particulates in the liquid dispersion of polymer particulates containing a black pigment was 104 nm as measured by particle size distribution measuring instrument (NANOTRAC UPA-EX150, manufactured by NIKKISO CO., LTD.).

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).

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.

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.

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.