Residual solvent extraction method and microparticles produced thereby
Methods for preparing microparticles having reduced residual solvent levels. Microparticles are contacted with a non-aqueous washing system to reduce the level of residual solvent in the microparticles. Preferred non-aqueous washing systems include 100% ethanol and a blend of ethanol and heptane. A solvent blend of a hardening solvent and a washing solvent can be used to harden and wash microparticles in a single step, thereby eliminating the need for a post-hardening wash step.
1 . A method for preparing microparticles, comprising:
preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent;
combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;
extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;
drying the precipitated microparticles to form finished microparticles; and
after said drying step, washing the finished microparticles in a non-aqueous washing system that is either (1) 100% ethanol or (2) a blend of ethanol and heptane to thereby reduce a level of residual halogenated solvent.
2 . The method of claim 1 , wherein the peptide is a luteinizing-hormone-releasing hormone (LHRH) analogue.
3 . The method of claim 2 , wherein the halogenated solvent is methylene chloride.
4 . The method of claim 1 , wherein the blend is a 3:1 ratio of ethanol to heptane.
5 . The method of claim 1 , wherein the blend is a 1:1 ratio of ethanol to heptane.
6 . The method of claim 1 , wherein a temperature of the washing system is between about 10° and about 26° C.
7 . The method of claim 3 , wherein the coacervating agent is silicone oil.
8 . The method of claim 1 , wherein the halogenated solvent is methylene chloride.
9 . The method of claim 1 , wherein the coacervating agent is silicone oil.
10 . The method of claim 7 , wherein the extraction medium is heptane.
11 . The method of claim 1 , wherein the extraction medium is heptane.
12 . The method of claim 1 , wherein the biodegradable, biocompatible polymer is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.
13 . The method of claim 3 , wherein the biodegradable, biocompatible polymer is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.
14 . The method of claim 1 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.
15 . The method of claim 3 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.
16 . The method of claim 1 , further comprising after said washing step:
final drying the washed microparticles.
17 . A method for processing microparticles, comprising:
contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix comprising a peptide and a halogenated solvent with a non-aqueous washing system to thereby reduce a level of residual halogenated solvent in the dried, finished microparticles to form washed microparticles, wherein the washing system is either (1) 100% ethanol or (2) a blend of ethanol and heptane; and
recovering the washed microparticles from the washing system.
18 . The method of claim 17 , wherein the peptide is a luteinizing-hormone-releasing hormone (LHRH) analogue.
19 . The method of claim 18 , wherein the halogenated solvent is methylene chloride.
20 . The method of claim 17 , wherein the blend is a 3:1 ratio of ethanol to heptane.
21 . The method of claim 17 , wherein the blend is a 1:1 ratio of ethanol to heptane.
22 . The method of claim 17 , wherein a temperature of the washing system is between about 10° and 26° C.
23 . The method of claim 17 , wherein the contacting step is carried out until the level of residual halogenated solvent in the recovered microparticles is less than about 0.06% by weight.
24 . Microparticles prepared by the method of claim 1 .
25 . The microparticles of claim 24 , wherein the peptide is a luteinizing-hormone-releasing hormone (LHRH) analogue.
26 . A method for processing microparticles, comprising:
contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix comprising goserelin and a halogenated solvent with a non-aqueous washing system to thereby reduce a level of residual halogenated solvent to less than about 0.06% by weight of the dried, finished microparticles to form washed microparticles, wherein the washing system is either (1) 100% ethanol or (2) a blend of ethanol and heptane; and
recovering the washed microparticles from the washing system.
27 . A method for preparing microparticles, comprising:
preparing a first phase comprising a biodegradable, biocompatible polymer and a halogenated solvent;
preparing an aqueous second phase comprising a peptide;
combining the first phase and the second phase under the influence of a mixer to form an emulsion;
combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;
extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;
drying the precipitated microparticles to form finished microparticles; and
after said drying step, washing the finished microparticles in a non-aqueous washing system that is either (1) 100% ethanol or (2) a blend of ethanol and heptane to thereby reduce a level of residual halogenated solvent.
28 . The method of claim 27 , wherein the mixer is a static mixer.
29 . The method of claim 27 , wherein the peptide is a luteinizing-hormone-releasing hormone analogue.
30 . The method of claim 29 , wherein the halogenated solvent is methylene chloride.
31 . The method of claim 27 , wherein the blend is a 3:1 ratio of ethanol to heptane.
32 . The method of claim 27 , wherein the blend is a 1:1 ratio of ethanol to heptane.
33 . The method of claim 27 , wherein a temperature of the washing system is between about 10° and about 26° C.
34 . The method of claim 30 , wherein the coacervating agent is silicone oil.
35 . The method of claim 27 , wherein the halogenated solvent is methylene chloride.
36 . The method of claim 27 , wherein the coacervating agent is silicone oil.
37 . The method of claim 34 , wherein the extraction medium is heptane.
38 . The method of claim 27 , wherein the extraction medium is heptane.
39 . The method of claim 27 , wherein the biodegradable, biocompatible polymer is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.
40 . The method of claim 30 , wherein the biodegradable, biocompatible polymer is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.
41 . The method of claim 27 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.
42 . The method of claim 30 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.
43 . The method of claim 2 , wherein the LHRH analogue is goserelin.
44 . The method of claim 18 , wherein the LHRH analogue is goserelin.
45 . The method of claim 29 , wherein the LHRH analogue is goserelin.
46 . A method for preparing microparticles, comprising:
preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent;
combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;
extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;
drying the precipitated microparticles to form finished microparticles; and
after said drying step, washing the finished microparticles in a non-aqueous washing system that comprises ethanol.
47 . A method for processing microparticles, comprising:
contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix containing an active agent and an organic solvent with a non-aqueous washing system to thereby reduce a level of residual organic solvent in the dried, finished microparticles to form washed microparticles, wherein the non-aqueous washing system is either (1) 100% ethanol or (2) a blend of ethanol and heptane; and
recovering the washed microparticles from the non-aqueous washing system.
48 . The method of claim 47 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
49 . The method of claim 47 , wherein the active agent is a peptide.
50 . The method of claim 48 , wherein the organic solvent is a solvent blend comprising ethyl acetate and benzyl alcohol.
51 . The method of claim 49 , wherein the non-aqueous washing system is 100% ethanol.
52 . The method of claim 47 , further comprising prior to said contacting step:
preparing an emulsion that comprises the active agent, the biodegradable, biocompatible polymer, and the organic solvent; and
extracting the organic solvent from the emulsion using an extraction liquid to thereby form microparticles containing the active agent.
53 . The method of claim 47 , further comprising prior to said contacting step:
preparing a first phase that comprises the active agent, the biodegradable, biocompatible polymer, and the organic solvent, wherein the organic solvent is a solvent for the biodegradable, biocompatible polymer;
preparing a second phase that is free from solvents for the biodegradable, biocompatible polymer;
combining the first phase and the second phase to form an emulsion;
extracting the organic solvent from the emulsion using an extraction medium, whereby microparticles precipitate out of the extraction medium.
54 . The method of claim 53 , wherein the extraction medium is a non-solvent for the biodegradable, biocompatible polymer and a solvent for the organic solvent.
55 . The method of claim 49 , wherein the peptide is goserelin.
56 . The method of claim 53 , wherein the second phase comprises silicone oil.
57 . A method for preparing microparticles, comprising:
preparing a first phase, the first phase comprising an active agent, a biodegradable, biocompatible polymer, and a solvent;
preparing a second phase, wherein the first phase is substantially immiscible with the second phase;
combining the first phase and the second phase to form an emulsion;
extracting solvent from the emulsion using an extraction liquid to thereby form microparticles containing the active agent;
drying the microparticles to form finished microparticles; and
after said drying step, washing the finished microparticles with a non-aqueous washing system to thereby reduce the level of residual solvent in the microparticles, wherein the non-aqueous washing system comprises ethanol.
58 . The method of claim 57 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
59 . The method of claim 58 , wherein the solvent is a solvent blend comprising ethyl acetate and benzyl alcohol.
60 . A method for preparing microparticles, comprising:
preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a solvent;
combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;
extracting solvent from the combined phase in an extraction medium that is a non-solvent for the polymer and a solvent for the solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;
drying the precipitated microparticles to form finished microparticles; and
after said drying step, washing the finished microparticles in 100% ethanol.
61 . The method of claim 60 , wherein the peptide is goserelin.
62 . The method of claim 60 , wherein the coacervating agent is silicone oil.
63 . The method of claim 60 , wherein the extraction medium is heptane.
64 . The method of claim 60 , wherein the washing step is carried out until the level of solvent in the microparticles is less than about 0.06% by weight.
65 . The method of claim 57 , wherein the non-aqueous washing system is 100% ethanol.
66 . The method of claim 47 , wherein the contacting step is carried out until the level of residual organic solvent is less than about 0.2% by weight.
67 . The method of claim 50 , wherein the contacting step is carried out until the level of ethyl acetate is less than about 0.2% by weight and the level of benzyl alcohol is less than about 0.2% by weight.
68 . A method for processing microparticles, comprising:
contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix containing an active agent and an organic solvent with a non-aqueous washing system to thereby reduce a level of residual organic solvent in the dried, finished microparticles to form washed microparticles, wherein the non-aqueous washing system is either (1) 100% alcohol or (2) a blend of alcohol and a liquid alkane; and
recovering the washed microparticles from the non-aqueous washing system.
69 . The method of claim 68 , wherein the active agent is a peptide.
70 . The method of claim 69 , wherein the non-aqueous washing system is the blend of alcohol and a liquid alkane.