TERTIARY AMINE PHARMACEUTICAL COMPOSITION AND INDUSTRIALIZED BATCH PREPARATION METHOD THEREOF

Abstract

A tertiary amine pharmaceutical composition includes a drug having a tertiary amine structure, a biocompatible polymer material, and a quaternary ammonium salt impurity. The pharmaceutical composition is obtained by dissolving or dispersing the drug in a halogenated hydrocarbon or a mixed solvent mainly containing halogenated hydrocarbon or a solution containing halogenated hydrocarbon. The quaternary ammonium salt impurity is generated from reacting the drug having the tertiary amine structure with the halogenated hydrocarbon. The pharmaceutical composition comprises 40 wt % to 80 wt % of the biocompatible polymer material, and 20 wt % to 60 wt % of the drug with the tertiary amine structure. The content of the quaternary ammonium salt impurity is less than 0.05 wt %, the content of the halogenated hydrocarbon in the composition is less than 1.5 wt %, and the quaternary ammonium salt impurity does not increase or increases slowly during storage, which complies with requirements of pharmaceutical regulations.

Claims

1. A tertiary amine pharmaceutical composition, comprising: a drug with tertiary amine structure, a biocompatible polymer material, and a quaternary ammonium salt impurity, wherein the pharmaceutical composition being obtained by dissolving or dispersing the drug in a halogenated hydrocarbon or a mixed solvent mainly containing halogenated hydrocarbon or a solution containing halogenated hydrocarbon, and the quaternary ammonium salt impurities being generated from a reaction of the drug with tertiary amine structure and the halogenated hydrocarbon, wherein, the pharmaceutical composition comprises 40 wt % to 80 wt/o of the biocompatible polymer material, and 20 wt % to 60 wt % of the drug with tertiary amine structure; a content of the quaternary ammonium salt impurities is less than 0.05 wt %; and a content of the halogenated hydrocarbon in the tertiary amine pharmaceutical composition is less than 1.5 wt %.

2. The tertiary amine pharmaceutical composition as claimed of claim 1, wherein the drug with tertiary amine structure comprises any one of entecavir, oxybutynin, raloxifene, rivastigmine, naloxone, naltrexone, buprenorphine, selegiline, buspirone, blonanserin, asenapine, olanzapine, lurasidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyridine[1,2-α]pyrimidine-4-keton, 6,7,8,9-tetrahydro-3-(2-(4-(6-fluoro-1,2- benzisoxazole-3-yl)-1-piperidinyl)ethyl)-9-hydroxy-2-methyl-4H-pyridine[2, 1-a]pyrimidine-4-one and (±)-3-[2-[4-[6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidine]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyridine[1,2-a]pyrimidine-9-yl palmitate.

3. The tertiary amine pharmaceutical composition of claim 1, wherein the biocompatible polymer material is PLGA, a ratio of LA to GA of the PLGA is 100/0 to 50/50, a molecular weight of the PLGA is 20 kDa to 60 kDa, and an intrinsic viscosity of the PLGA is 0.2 dL/g to 0.65 dL/g.

4. The tertiary amine pharmaceutical composition of claim 1, wherein the drug with tertiary amine structure is any one of 3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyridine[1,2-α]pyrimidine-4-keton, 6,7,8,9-tetrahydro-3-(2-(4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl)ethyl)-9-hydroxy-2-methyl-4H-pyridine[2,1-a]pyrimidine-4-one and (±)-3-[2-[4-[6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidine]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyridine[1,2-a]pyrimidine-9-yl palmitate, and the biocompatible polymer material is at least one of PLGA, chloroform or dichloromethane; and the content of the quaternary ammonium salt impurities is less than 0.04 wt %.

5. The tertiary amine pharmaceutical composition of claim 3, wherein the biocompatible polymer material is PLGA, the ratio of LA to GA of the PLGA is 100/0 to 70/30, the molecular weight of the PLGA is 20 kDa to 55 kDa, and the intrinsic viscosity of the PLGA is 0.2 dL/g to 0.57 dL/g.

6. The tertiary amine pharmaceutical composition of claim 1, wherein the drug with tertiary amine structure is 3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyridine[1,2-α]pyrimidine-4-keton with a content of 30 wt % to 50 wt %; the biocompatible polymer material is PLGA with a content of 50 wt % to 70 wt %; and a structural formula of the impurity is as shown by Formula (1): ##STR00003## wherein, the content of the impurity is less than 0.03 wt %.

7. The tertiary amine pharmaceutical composition of claim 6, wherein a ratio of LA to GA of the PLGA is 95/05 to 70/30, a molecular weight of the PLGA is 25 kDa to 50 kDa, and an intrinsic viscosity of the PLGA is 0.24 dL/g to 0.52 dL/g.

8. The tertiary amine pharmaceutical composition of claim 1 wherein the tertiary amine pharmaceutical composition is a spherical or non-spherical particle with a major axis of 10 μm to 200 μm.

9. A method comprising using the tertiary amine pharmaceutical composition of claim 1 in preparing a drug for resisting anxiety and depression and treating acute and chronic schizophrenia and other obvious positive and negative symptoms of various psychotic states, wherein the drug with tertiary amine structure is any one of buspirone, blonanserin, asenapine, olanzapine, lurasidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyridine[1,2-α]pyrimidine-4-keton, 6,7,8,9-tetrahydro-3-(2-(4-(6-fluoro-1,2- benzisoxazole-3-yl)-1-piperidinyl)ethyl)-9-hydroxy-2-methyl-4H-pyridine[2, 1-a]pyrimidine-4-one and (±)-3-[2-[4-[6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidine]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyridine[1,2-a]pyrimidine-9-yl palmitate.

10. An industrialized batch preparation method for preparing the tertiary amine pharmaceutical composition of claim 1, the method being an emulsion-solvent evaporation method comprising the following steps of: (1) preparing an aqueous solution with a surfactant, and cooling the aqueous solution for later use; (2) dissolving or dispersing the drug with tertiary amine structure and the biocompatible polymer material in the halogenated hydrocarbon to form a solution or suspension, wherein a time spent is no more than 4 hours, a temperature of the solution is no more than 20° C.±5° C., and no heating step is carried out; (3) injecting the solution or suspension obtained in step (2) into the aqueous solution with the surfactant for emulsification to form 0/W or S/O/W emulsion, wherein a time spent is no more than 4 hours, an ambient temperature is no more than 25° C., and no heating or vacuum step is carried out; (4) mechanically stirring to remove the halogenated hydrocarbon in a product of step (3) to obtain solidified spherical or non-spherical particles, wherein a duration for the mechanical stirring is no less than 24 hours, an ambient temperature and a system temperature are no more than 25° C., no heating or vacuum step is carried out, and a residual amount of the halogenated hydrocarbon in the obtained particles is no more than 2.0 wt %; (5) washing the particle of step (4) to remove the surfactant on the surface of the particles; and (6) freeze-drying the particle of step (5) to obtain the tertiary amine pharmaceutical composition.

11. The method of claim 10, wherein step (2) and step (3) are continuous processes, or a time between the two steps is no more than 1 hour.

12. The method of claim 10, wherein in step (6), freeze-drying conditions are: pre-freezing at −30° C. to −45° C. for 4 hours to 6 hours; primary drying at −20° C. to −5° C. for 8 hours to 16 hours under 100 mtorr to 200 mtorr; secondary drying at 30° C. to 35° C. for 18 hours to 30 hours under 100 mtorr to 200 mtorr; and the residual amount of the halogenated hydrocarbon in the obtained particle being no more than 1.5 wt %

13. The method of claim 10, wherein the industrialized batch refers to a batch with a single batch production cycle of 1 to 2 months, and no less than 500,000 doses.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0070] FIG. 1 is the mass spectrogram of an impurity generated when N1 reacts with dichloromethane.

DETAILED DESCRIPTION

[0071] The present invention provides a tertiary amine pharmaceutical composition, comprising a drug with tertiary amine structure, a biocompatible polymer material, and quaternary ammonium salt impurities. The pharmaceutical composition is obtained by dissolving or dispersing the drug in a halogenated hydrocarbon or a mixed solvent mainly containing halogenated hydrocarbon or a solution containing halogenated hydrocarbon, and the quaternary ammonium salt impurities are generated from reaction of the drug with tertiary amine structure with the halogenated hydrocarbon. Through research, it is found by the present application that, by controlling the content of the quaternary ammonium salt impurities and the content of residual halogenated hydrocarbon in the tertiary amine pharmaceutical composition, the content of the impurities cannot increase or increase slowly during storage under conventional conditions, or do not exceed ICH requirements within the validity period of identification.

[0072] In the following embodiments, N1 is used as a model drug and dichloromethane is used as a halogenated hydrocarbon to describe the solutions of the present invention in detail. When N1 reacts with the dichloromethane, a structure of an impurity generated is:

##STR00002##

[0073] The mass spectrogram of the impurity is as shown in FIG. 1, and the RRT of the impurity by liquid phase detection is 1.5, wherein detection conditions of the impurity are:

[0074] (1) chromatographic column: Agilent ZORBAX SB—C18, 150×4.60 mm, 5 μm or equivalent chromatographic column;

[0075] (2) mobile phase: acetonitrile: trifluoroacetic acid: water=20:0.15:80 (pH 3.0)

[0076] (3) flow rate: 1.5 mL/min

[0077] (4) column temperature: 35° C.

[0078] (5) detection wavelength: 275 nm

[0079] Under these detection conditions, there may also be known impurities U1, U2 and U3 in the N1 pharmaceutical composition, with RRT of 0.7, 1.6 and 1.7 respectively.

Embodiment 1 Preparation of N1-Containing Composition

[0080] A formulation process for manufacturing 100,000 to 500,000 dose batches (a specific batch quantity of each batch was determined according to test parameters) of N1 composition shown in the following table, and the preparation method was:

[0081] (1) preparing 0.1 wt % to 1.5 wt % polyvinyl alcohol aqueous solution, and cooling to 5+/−3° C. for later use;

[0082] (2) completely dissolving N1 (40 wt %) and PLGA (60 wt %) in about 4 times (V/w) of dichloromethane under mechanical stirring, and then filtering the mixture by a filter membrane with a pore diameter of 0.2 μm at a temperature not exceeding 20° C.;

[0083] (3) after the step (2) was completed, slowly injecting the solution into the solution of step (1) for high-speed homogenization to form an O/W emulsion with a flow rate ratio of 1:100, and an ambient temperature no more than 25° C.;

[0084] (4) mechanically stirring the emulsion of step(3) to remove the dichloromethane and filtering to obtain a solidified spherical or non-spherical particle, filtering and changing water(room temperature, equal volume) twice in the middle of the process for equal time;

[0085] (5) washing the particles of step (4) with water for injection at 5 times the volume not exceeding 10° C. to remove the polyvinyl alcohol on the surface of the particles;

[0086] (6) freeze-drying the particle of step (5) to obtain the composition, wherein the freeze-drying method was:

TABLE-US-00002 pre-freezing −30° C., 6 hours primary drying −20° C. to −5° C., 8 hours, 200 mtorr; secondary drying 35° C., 24 hours, 100 mtorr

[0087] (7) filling the particle of step (6) in a penicillin bottle sealed with a rubber stopper with a unit dose of 50 mg (calculated on the basis of N1), and then sealing the penicillin bottle with a moisture-proof aluminum foil bag for storage.

[0088] By adjusting the time used in step (2) and step (3) and controlling the duration of step (4), and adjusting and controlling the ambient temperature and the system temperature, drug particles with different residual amounts of halogenated hydrocarbon were obtained, and the influences of these indicators on the content control of RRT1.5 in the composition were investigated.

TABLE-US-00003 TABLE 1 Formulations, processes and parameters of composition Time Time Duration Ambient temperature and spent in spent in of step solution/suspension/emulsion Batch PLGA parameters step (2) step (3) (4) temperature in step (4) A1 100/0, 20 kDa, 0.20 dL/g 8 h 3 h 48 h 20° C. A2 100/0, 25 kDa, 0.24 dL/g 6 h 3 h 48 h 20° C. A3 100/0, 30 kDa, 0.29 dL/g 4 h 3 h 48 h 20° C. A4 100/0, 35 kDa, 0.34 dL/g 3 h 3 h 48 h 20° C. A5 75/25, 35 kDa, 0.34 dL/g 3 h 6 h 48 h 20° C. A6 75/25, 40 kDa, 0.41 dL/g 3 h 5 h 48 h 20° C. A7 75/25, 50 kDa, 0.52 dL/g 3 h 4 h 48 h 20° C. A8 75/25, 60 kDa, 0.63 dL/g 3 h 3 h 48 h 20° C. A9 95/5, 30 kDa, 0.29 dL/g 3 h 3 h 24 h 20° C. A10 95/5, 35 kDa, 0.34 dL/g 3 h 3 h 30 h 20° C. A11 95/5, 40 kDa, 0.41 dL/g 3 h 3 h 36 h 20° C. A12 95/5, 45 kDa, 0.46 dL/g 3 h 3 h 48 h 20° C. A13 85/15, 30 kDa, 0.31 dL/g 3 h 3 h 48 h 35° C. A14 85/15, 35 kDa, 0.35 dL/g 3 h 3 h 48 h 30° C. A15 85/15, 40 kDa, 0.40 dL/g 3 h 3 h 48 h 25° C. A16 85/15, 45 kDa, 0.45 dL/g 3 h 3 h 48 h 20° C.

Embodiment 2

[0089] By studying results of different batches of products obtained in embodiment 1, the influences of the time spent in step (2) and the time spent in step (3) on the content of RRT1.5 were discussed. The results were shown in Table 2.

TABLE-US-00004 TABLE 2 Changes of RRT1.5 impurity in different processes Content of Content of Particle RRT1.5 halogenated size Process parameters impurity/% hydrocarbon/% scope/μm Time spent A1 8 0.08 0.95 20 to 89 in step A2 6 0.04 0.91 25 to 107 (2)/h A3 4 0.01 0.90 30 to 98 A4 3 — 0.94 28 to 114 Time spent A5 6 0.03 0.96 35 to 137 in step A6 5 0.02 0.90 22 to 96 (3)/h A7 4 — 0.91 38 to 106 A8 3 — 0.93 31 to 110 “—” means no impurity was detected or the content of the impurity was lower than a quantitative limit.

[0090] It can be seen from the data in Table 2 that when other conditions are constant, the content of RRT1.5 impurity obviously decreases with the decrease of the time spent in step (2) or step (3).

Embodiment 3

[0091] Influences of the duration of step (4), the ambient environment and the system temperature on the content of RRT1.5 were further studied. The results were shown in Table 3.

TABLE-US-00005 TABLE 3 Changes of RRT1.5 impurity in different processes Content of Particle Content of halogenated size Process parameters RRT1.5 hydrocarbon scope/μm Duration A9 24 — 1.15 30 to 105 of step A10 30 0.00 0.91 32 to 94 (4)/h A11 36 — 0.70 27 to 96 A12 48 0.01 0.64 26 to 124 Ambient environment A13 35 0.13 068 20 to 85 and system A14 30 0.07 0.70 33 to 114 temperature of A15 25 0.02 0.67 39 to 107 step (4)/° C. A16 20 — 0.63 34 to 122 “—” means no impurity was detected or the content of the impurity was lower than a quantitative limit.

[0092] It can be seen from the data in Table 3 that when steps (2) and (3) are preferred conditions, the content of the RRT1.5 impurity does not change significantly with the increase of the duration of step (4), but organic solvent residues decrease obviously with the increase of time; when the durations of step (2), step (3) and step (4) are preferred conditions, the content of the RRT1.5 impurity obviously decreases with the decrease of the ambient environment and the system temperature of step (4).

Embodiment 4

[0093] Preparation of N1-Containing Composition:

[0094] A formulation process for manufacturing 100,000 to 500,000 dose batches (a specific batch quantity of each batch was determined according to test parameters) of N1 composition was shown in Table 4, wherein the preparation method was the same as that of Embodiment 1. Meanwhile, N1 compositions with different contents of RRT1.5 impurity and different contents of halogenated hydrocarbon were obtained by adjusting the process parameters.

TABLE-US-00006 TABLE 4 Formulation and parameters of composition Rate of Rate of Content of Content of Particle charge of charge of RRT1.5 halogenated size Batch PLGA parameters PLGA N1 impurity hydrocarbon scope/μm B1 100/0, 20 kDa, 0.2 dL/g 40% 60% 0.10% 0.98%  23 to 115 B2  95/5, 25 kDa, 0.24 dL/g 80% 20% 0.07% 1.03%  32 to 110 B3  85/15, 30 kDa, 0.29 dL/g 60% 40% 0.05% 1.00% 20 to 95 B4  85/15, 35 kDa, 0.34 dL/g 65% 35% 0.04% 1.07%  35 to 123 B5  85/15, 40 kDa, 0.40 dL/g 60% 40% 0.03% 1.15%  40 to 137 B6  75/25, 50 kDa, 0.52 dL/g 65% 35% 0.02% 1.05%  28 to 106 B7  70/30, 55 kDa, 0.57 dL/g 50% 50% 0.01% 0.92% 22 to 89 B8  85/15, 35 kDa, 0.34 dL/g 65% 35% 0.04% 2.01%  30 to 104 B9  85/15, 35 kDa, 0.34 dL/g 65% 35% 0.04% 1.53%  37 to 131 B10  85/15, 35 kDa, 0.34 dL/g 65% 35% 0.04% 1.25%  30 to 118 B11  85/15, 35 kDa, 0.34 dL/g 65% 35% 0.04% 0.71%  26 to 104 B12  85/15, 35 kDa, 0.34 dL/g 65% 35% 0.04% 0.60% 31 to 98

Embodiment 5

[0095] Under a storage condition of 5° C.±3° C., a residual amount of a halogenated hydrocarbon was about 1%, and influences of the residual amount of the halogenated hydrocarbon on a content change of an RRT1.5 impurity during storage were shown in Table 5.

TABLE-US-00007 TABLE 5 Changes of RRT1.5 impurity during storage at 5° C. ± 3° C. Storage time/month B1 B2 B3 B4 B5 B6 B7 0 0.10% 0.07% 0.05% 0.04% 0.03% 0.02% 0.01% 1 0.11% 0.09% 0.06% 0.04% 0.03% 0.02% 0.01% 3 0.15% 0.12% 0.08% 0.06% 0.04% 0.02% 0.01% 6 0.19% 0.15% 0.10% 0.08% 0.06% 0.03% 0.02% 12 0.22% 0.19% 0.13% 0.11% 0.07% 0.04% 0.02% 18 0.29% 0.24% 0.15% 0.13% 0.09% 0.06% 0.02% 24 0.35% 0.29% 0.19% 0.16% 0.13% 0.08% 0.02%

[0096] According to the changes of the RRT1.5 impurity in Table 5, when the initial content of the RRT1.5 impurity is higher than 0.05%, the contents increase to more than 0.2% after 18 months of storage, and when the initial content of the RRT1.5 impurity is less than 0.05%, all the contents are lower than 0.2% after 24 months of storage, and the smaller the initial content of the RRT1.5 impurity is, the slower the increase is. When the initial content of the RRT1.5 impurity is less than 0.02%, there is no obvious increase within 24 months.

Embodiment 6

[0097] Under a storage condition of 20° C.±5° C., a residual amount of a halogenated hydrocarbon was about 1%, and influences of the residual amount of the halogenated hydrocarbon on a content change of the RRT1.5 impurity during storage were shown in Table 6.

TABLE-US-00008 TABLE 6 Changes of RRT1.5 impurity during storage at 20° C. ± 5° C. Storage time/month B1 B2 B3 B4 B5 B6 B7 0 0.10% 0.07% 0.05% 0.04% 0.03% 0.02% 0.01% 1 0.15% 0.11% 0.06% 0.05% 0.04% 0.02% 0.01% 3 0.19% 0.16% 0.08% 0.07% 0.05% 0.03% 0.02% 6 0.25% 0.21% 0.10% 0.09% 0.08% 0.05% 0.03% 12 0.30% 0.24% 0.13% 0.11% 0.11% 0.07% 0.05% 18 0.36% 0.29% 0.16% 0.14% 0.13% 0.08% 0.06% 24 0.42% 0.34% 0.20% 0.18% 0.16% 0.11% 0.08%

[0098] According to the changes of the RRT1.5 impurity in Table 6, compared with the storage condition of 5° C.±3° C., when the initial content of the RRT1.5 impurity is higher than 0.05%, the content increases more obviously during the storage at 20° C.±5° C., and the content exceeds 0.2% after 6 months; when the initial content of the RT1.5 impurity is less than 0.03%, the content is still less than 0.2% within 24 months, and when the initial content of the RRT1.5 impurity is less than 0.02%, the increase rate is relatively slow within 24 months.

Embodiment 7

[0099] Under a storage condition of 20° C.±5° C., an initial content of the RRT1.5 impurity was 0.04%, and influences of a residual amount of a halogenated hydrocarbon on a content change of the impurity were shown in Table 7.

TABLE-US-00009 TABLE 7 Changes of RRT1.5 impurity during storage at 20° C. ± 5° C. Storage time/month B4 B8 B9 B10 B11 B12 0 0.04% 0.04% 0.04% 0.04% 0.04% 0.04% 1 0.05% 0.08% 0.07% 0.05% 0.05% 0.04% 3 0.07% 0.15% 0.13% 0.07% 0.06% 0.05% 6 0.09% 0.23% 0.20% 0.11% 0.08% 0.05% 12 0.11% 0.27% 0.25% 0.14% 0.10% 0.06% 18 0.14% 0.33% 0.29% 0.17% 0.13% 0.07% 24 0.18% 0.38% 0.34% 0.20% 0.15% 0.08%

[0100] According to the changes of the RRT1.5 impurity in Table 7, when the content of the halogenated hydrocarbon is higher than 1.5%, the RRT1.5 impurity increases more obviously during the storage at 20° C.±5° C., and the content exceeds 0.2% after 9 months; when the initial content of the RT1.5 impurity is less than 1.1%, the content is still less than 0.2% within 24 months, and when the initial content of the RRT1.5 impurity is less than 0.70%, the increase rate is not obvious within 24 months.

Embodiment 8

[0101] Under a storage conditions of 5° C.±3° C. and 20° C.±5° C., influences of a content of a halogenated hydrocarbon on U1, U2 and U3 impurities were shown in Table 8.

TABLE-US-00010 TABLE 8 Changes of U1, U2 and U3 impurities during storage Content of impurity/% Batch of 5° C. ± 3° C. 20° C. ± 5° C. Impurity composition 0 month 12 months 24 months 36 months 12 months 24 months 36 months U1 B1 — — — — — — — B8 — — — — — — — B9 0.02 0.01 0.01 0.02 0.01 0.01 0.01 B10 — — — — — — — B11 — — — — — — — B12 0.03 0.03 0.03 0.03 0.04 0.03 0.03 U2 B1 0.01 — 0.01 0.01 0.01 0.01 0.01 B8 0.02 0.01 0.02 0.02 0.01 0.01 0.02 B9 — — — — — — — B10 — — — — — — — B11 — — — — — — — B12 — — — — — — — U3 B1 — — — — — — — B8 — — — — — — — B9 0.01 0.01 0.01 0.01 — 0.01 0.02 B10 — — — — — — — B11 — — — — — — — B12 — — — — — — — ″—″ means no impurity was detected or the content of the impurity was lower than a quantitative limit.

[0102] It can be seen from the data in Table 8 that in the N1 composition, three impurities, U1, U2 and U3, have almost no change during storage, and have no visible relationship with the content of the halogenated hydrocarbon in the composition.

Embodiment 9

[0103] According to the preparation method of Embodiment 1, sustained-release microspheres of entecavir, oxybutynin, raloxifene, rivastigmine, naloxone, naltrexone, buprenorphine, selegiline, buspirone, blonanserin, asenapine, olanzapine, lurasidone, N2 and N3 were prepared. The compositions were shown in Table 9. The particle size scope of the microspheres was controlled to be 30 μm to 120 μm, the content of a quaternary ammonium salt impurities was less than 0.05%, and the content of a halogenated hydrocarbon was about 0.69 to 0.9%. Changes of the quaternary ammonium salt impurities stored at 5° C.±3° C. and 20° C.±5° C. for 12 months, 24 months and 36 months were investigated. The results were shown in Table 9.

TABLE-US-00011 TABLE 9 Parameters of pharmaceutical composition containing drug with tertiary amine structure Drug Content of the containing a quaternary Content of tertiary amine Content ammonium salt halogenated Batch structure of drug PLGA impurities hydrocarbon C1 Entecavir 28.5%.sup.  85/15, 33 kDa, 0.32 dL/g — 0.70% C2 Oxybutynin 30% 95/5, 25 kDa, 0.24 dL/g 0.02% 0.69% C3 Raloxifene 35% 85/15, 30 kDa, 0.29 dL/g — 0.75% C4 Rivastigmine 40% 85/15, 40 kDa, 0.41 dL/g — 0.80% C5 Naloxone 25% 75/25, 45 kDa, 0.46 dL/g 0.01% 0.85% C6 Naltrexone 42% 75/25, 50 kDa, 0.52 dL/g 0.02% 0.84% C7 Buprenorphine 36% 70/30, 55 kDa, 0.57 dL/g 0.03% 0.86% C8 Selegiline 30% 85/15, 35 kDa, 0.34 dL/g — 0.85% C9 Buspirone 20% 85/15, 35 kDa, 0.34 dL/g 0.01% 0.78% C10 Blonanserin 40% 80/20, 35 kDa, 0.34 dL/g 0.04% 0.90% C11 Asenapine 25% 80/20, 35 kDa, 0.34 dL/g — 0.82% C12 Olanzapine 55% 85/15, 30 kDa, 0.30 dL/g — 0.90% C13 Lurasidone 45% 90/10, 25 kDa, 0.24 dL/g — 0.73% C14 N2 50% 95/5, 25 kDa, 0.24 dL/g 0.03% 0.90% C15 N3 60% 100/0, 20 kDa, 0.2 dL/g 0.04% 0.70% “—” means no impurity was detected or the content of the impurity was lower than a quantitative limit.

TABLE-US-00012 TABLE 10 Changes of the quaternary ammonium salt impurities in compositions of batches C1 to C15 during storage at 20° C. ± 5° C. Content of the quaternary ammonium salt impurities/% Batch of 5° C. ± ° C. 20° C. ± ° C. composition 0 month 12 months 24 months 36 months 12 months 24 months 36 months C1 — — 0.01 0.2 0.01 0.3 0.05 C2 0.02 0.02 0.03 0.04 0.03 0.05 0.08 C3 — — 0.01 0.03 0.02 0.05 0.07 C4 — — 0.02 0.05 0.02 0.04 0.08 C5 0.01 0.02 0.04 0.08 0.03 0.07 0.10 C6 0.02 0.03 0.07 0.09 0.05 0.08 0.12 C7 0.03 0.03 0.06 0.09 0.08 0.13 0.17 C8 — — 0.02 0.05 0.01 0.04 0.10 C9 0.01 0.01 0.03 0.06 0.02 0.05 0.09 C10 0.04 0.05 0.07 0.08 0.08 0.12 0.16 C11 — — 0.01 0.03 0.02 0.05 0.08 C12 — — 0.01 0.05 0.02 0.08 0.15 C13 — — — 0.02 — 0.03 0.07 C14 0.03 0.04 0.07 0.11 0.06 0.11 0.19 C15 0.04 0.04 0.05 0.07 0.07 0.10 0.14 ″—″ means no impurity was detected or the content of the impurity was lower than a quantitative limit.

[0104] It can be seen from the changes of the quaternary ammonium salt impurities of each composition in Table 9 that when the content of the halogenated hydrocarbon content does not exceed 0.9% and the initial value of the quaternary ammonium impurities does not exceed 0.04%, the quaternary ammonium impurities of the composition is still less than 0.2% during storage at two temperatures. Meanwhile, when the content of the halogenated hydrocarbon is larger or the initial value of the quaternary ammonium salt impurities is higher, the increase of the quaternary ammonium salt impurities is larger during storage at two temperatures.