Claims
- 1. A method of preparing particles with polymorph and size control of a pharmaceutical compound, the method comprising the steps of:
providing a pharmaceutical compound in a first phase; seeding the compound; causing a phase change in the pharmaceutical compound to a second phase of a desired polymorphic form; and wherein the mean particle size of the particles is less than 7 μm.
- 2. The method of claim 1, wherein the pharmaceutical compound is selected from the group consisting of pharmaceutically active compounds and pharmaceutical excipients.
- 3. The method of claim 2, wherein the first phase is selected from the group consisting of a supercooled liquid, amorphous, semi-crystalline, and a first polymorphic crystalline form.
- 4. The method of claim 1, wherein the step of providing a pharmaceutical compound comprises the steps of adding the pharmaceutical compound to a diluent.
- 5. The method of claim 4, wherein the pharmaceutical compound is soluble in the diluent.
- 6. The method of claim 4, wherein the pharmaceutical compound is insoluble in the diluent.
- 7. The method of claim 4, wherein the diluent is a solid a liquid or a compressed gas.
- 8. The method of claim 4, wherein the step of causing a phase change includes one step selected from the group consisting of precipitating the first compound from the diluent and adding energy to the diluent.
- 9. The method of claim 5, wherein the step of causing a phase change includes the step of precipitating the pharmaceutical compound from the diluent.
- 10. The method of claim 9, wherein the step of precipitating the compound is accomplished by a process selected from the group consisting of: microprecipitation, emulsion precipitation, solvent anti-solvent precipitation, phase inversion precipitation, pH shift precipitation, infusion precipitation, temperature shift precipitation, solvent evaporation precipitation, reaction precipitation, and compressed fluid precipitation.
- 11. The method of claim 10, wherein the diluent is an organic solvent.
- 12. The method of claim 11, wherein the diluent is water miscible.
- 13. The method of claim 12, further comprising the step of providing a solution that is aqueous and wherein the step of precipitating the pharmaceutical compound comprises the step of mixing the diluent and pharmaceutical compound with the aqueous solution to form a presuspension.
- 14. The method of claim 13, wherein the step of seeding comprises the step of seeding at least one of the liquids selected from the group consisting of: the diluent, the aqueous solution and the presuspension.
- 15. The method of claim 14, wherein the step of mixing comprises the step of adding the diluent and pharmaceutical compound to the aqueous solution.
- 16. The method of claim 15, further comprising the step of removing the diluent.
- 17. The method of claim 15, further comprising the step of subjecting the presuspension to high shear mixing.
- 18. The method of claim 10, wherein the diluent is water immiscible and further comprising the step of providing an aqueous solution.
- 19. The method of claim 18, further comprising the step of mixing the water immiscible diluent and pharmaceutical compound with the aqueous solution to form an emulsion.
- 20. The method of claim 19, further comprising the step of removing a portion of the water immiscible diluent from the emulsion to precipitate the pharmaceutical compound.
- 21. The method of claim 20, wherein the step of seeding comprises the step of seeding a liquid selected from the group consisting of the diluent, the aqueous solution and the emulsion.
- 22. The method of claim 5, wherein the diluent has a first pH wherein the pharmaceutical compound has a first solubility such that the compound is dissolved in the diluent and wherein the step of precipitating comprises the step of changing the pH of the diluent to a second pH wherein the compound has a second solubility lower than the first solubility and the compound precipitates from the diluent.
- 23. The method of claim 5, wherein the diluent has a first temperature wherein the pharmaceutical compound has a first solubility such that the compound is dissolved in the diluent and wherein the step of precipitating comprises the step of lowering the temperature of the diluent to a second temperature wherein the compound has a second solubility lower than the first solubility and the compound precipitates from the diluent.
- 24. The method of claim 5, wherein the step of precipitating comprises the step of removing a portion of the diluent.
- 25. The method of claim 5, wherein the compound is dissolved in the diluent to form a first solution and wherein the step of precipitating the compound comprises the step of combining the first solution with a compressed fluid.
- 26. The method of claim 25, wherein the compressed fluid is selected from the group consisting of gas, liquid, or supercritical fluid.
- 27. The method of claim 1, wherein the step of causing a phase change is by mechanically grinding the compound.
- 28. The method of claim 27, wherein the step of mechanically grinding is a method selected from the group consisting of: ball milling, pearl milling, hammer milling, fluid energy mills and using a mortar and pestle.
- 29. The method of claim 6, wherein the pharmaceutical compound is insoluble in the diluent and wherein the step of causing a phase change is by adding energy to the diluent.
- 30. The method of claim 29, wherein the step of adding energy is accomplished by a process selected from the group consisting of mechanical grinding and high shear mixing.
- 31. The method of claim 30, wherein the step of mechanical grinding is a process selected from the group consisting of ball milling, pearl milling, dry grinding and wet grinding.
- 32. The method of claim 30, wherein the step of high shear mixing is carried out using a device selected from the group consisting of a homogenizer, piston gap homogenizer, counter current flow homogenizer, microfluidizer, and sonicator.
- 33. The method of claim 1, wherein the mean particle size of the compound is less than 3 μm.
- 34. The method of claim 1, wherein the mean particle size of the compound is less than 1 μm.
- 35. The method of claim 1, wherein the mean particle size of the compound is less than 500 nm.
- 36. A method for preparing submicron sized particles of a pharmaceutical compound, the method comprising the steps of:
dissolving the pharmaceutical compound in a first solvent to form a first solution; precipitating the pharmaceutical compound to form a presuspension; seeding the first solution or the presuspension; and wherein the compound in the presuspension is in the form of particles having a mean particle size of less than 7μm and the particles are in a desired polymorphic form.
- 37. The method of claim 36, wherein the step of precipitating the pharmaceutical compound is by mixing the first solution with a second solvent to precipitate the compound to form the presuspension, and wherein the solubility of the compound is greater in the first solvent than the second solvent.
- 38. The method of claim 36, further comprising the step of causing a phase change in the pharmaceutical compound from a first phase selected from the group consisting of a supercooled liquid, an amorphous particle, a semicrystalline particle, and a crystalline particle having a first polymorphic form to a second phase of the desired polymorphic form.
- 39. The method of claim 38, further comprising the step of adding energy to the presuspension.
- 40. The method of claim 39, wherein the adding-energy step comprises the step of subjecting the presuspension to high shear conditions selected from the group consisting of cavitation, shearing or impact forces utilizing a microfluidizer, piston gap homogenizer or counter current flow homogenizer high energy agitation.
- 41. The method of claim 39, wherein the adding-energy step comprises the step of adding heat to the presuspension.
- 42. The method of claim 39, wherein the adding-energy step comprises the step of exposing the presuspension to electromagnetic energy.
- 43. The method of claim 42, wherein the step of exposing the presuspension to electomagnetic energy comprises the step of exposing the presuspension to a laser beam.
- 44. The method of claim 38, wherein the step of seeding comprises the step of using a seed compound.
- 45. The method of claim 44, wherein the seed compound is of the desired polymorphic form of the pharmaceutical compound.
- 46. The method of claim 44, wherein the seed compound is a compound other than the desired polymorphic form of the pharmaceutical compound.
- 47. The method of claim 46, wherein the seed compound is selected from the group consisting of: an inert impurity; and an organic compound with a structure similar to that of the desired polymorphic form.
- 48. The method of claim 44, wherein the seed compound is added to the first solution.
- 49. The method of claim 44, wherein the seed compound is added to the second solvent.
- 50. The method of claim 44, wherein the seed compound is added to the presuspension.
- 51. The method of claim 44, wherein the step of forming a desired polymorph comprises the step of forming a seed compound in the first solution.
- 52. The method of claim 51, wherein the step of forming the seed compound in the first solution comprises the step of adding the pharmaceutical compound in sufficient quantity to exceed the solubility of the pharmaceutical compound in the first solvent to create a supersaturated solution.
- 53. The method of claim 51, wherein the step of forming the seed compound in the first solution further comprises the step of treating the first solution.
- 54. The method of claim 53, wherein the step of treating the supersaturated solution comprises the step of a process selected from the group of aging the supersaturated solution, temperature shifting the solution and pH shifting of the solution.
- 55. The method of claim 36, wherein the seeding step comprises the step of using electromagnetic energy to form a seed compound.
- 56. The method of claim 55, wherein the electromagnetic energy is dynamic electromagnetic energy.
- 57. The method of claim 55, wherein the electromagnetic energy is a laser beam.
- 58. The method of claim 55, wherein the electromagnetic energy is radiation.
- 59. The method of claim 36, wherein the step of seeding comprises the step of using a particle beam to form a seed compound.
- 60. The method of claim 36, wherein the step of seeding comprises the step of using an electron beam to form a seed compound.
- 61. The method of claim 36, wherein the step of seeding comprises the step of using ultrasound to form a seed compound.
- 62. The method of claim 36, wherein the step of seeding comprises using a static electric field to form a seed compound.
- 63. The method of claim 36, wherein the step of seeding comprises using a static magnetic field to form a seed compound.
- 64. The method of claim 36, wherein the particle has a mean particle size of less than about 2 μm.
- 65. The method of claim 36, wherein the particle has a mean particle size of less than about 500 nm.
- 66. The method of claim 36, wherein the particle has a mean particle size of less than 200 nm.
- 67. The method of claim 37, further including a surface active compound in the presuspension.
- 68. The method of claim 36, further comprising the step of providing a second solvent and combining the first solvent and the second solvent.
- 69. The method of claim 68, wherein the second solvent is selected from the group consisting of solvents miscible with the first solvent, and solvents immiscible with the first solvent.
- 70. The method of claim 69, wherein the first solvent is a water immiscible organic solvent, and the second solvent is an aqueous solution, wherein a multiphase system having an organic phase and an aqueous phase is formed by mixing the organic solvent and the aqueous solution.
- 71. The method of claim 70, further comprising the step of sonicating the multiphase system to evaporate a portion of the organic phase to cause precipitation of the compound in the aqueous phase to form the presuspension.
- 72. The method of claim 70, wherein the step of seeding comprises the step of seeding the first solution, the second solvent or the presuspension.
- 73. The method of claim 70, wherein the step of mixing the water immiscible organic solvent and the aqueous solution to form the multiphase system comprises the use of a piston gap homogenizer, a colloidal mill, high speed stirring, extrusion, manual agitation or shaking, microfluidization, or other high shear conditions.
- 74. The method of claim 71, wherein the aqueous phase after sonication is essentially free of the organic solvent.
- 75. The method of claim 70, further comprises the step of evaporating the organic solvent by a method selected from the group consisting of lyophilization, rotary evaporation, and spray drying.
- 76. The method of claim 36, wherein the step of precipitating is by changing the pH of the first solvent.
- 77. The method of claim 36, wherein the step of dissolving the compound in the first solvent comprises the steps of bringing the first solvent to a first temperature to form the first solution followed by cooling the first solution to a second temperature to precipitate the compound, wherein the compound is soluble in the first solvent at the first temperature.
- 78. The method of claim 77, wherein the second temperature is below the melting point of the compound.
- 79. The method of claim 79, wherein the second temperature is above the melting point of the compound.
- 80. The method of claim 37, wherein the method of mixing the first solvent with the second solvent is by infusing the second solvent into the first solution to precipitate the compound.
- 81. The method of claim 80, wherein the first solvent is an organic solvent, and the second solvent is an aqueous solution.
- 82. The method of claim 37, wherein the second solvent is a compressed fluid.
- 83. The method of claim 82, wherein the compressed fluid is a supercritical fluid.
- 84. The method of claim 36, wherein the step of precipitating comprises the steps of causing a reaction of the compound to form a modified compound wherein the modified compound has less solubility in the first solvent than the compound.
- 85. The method of claim 84, wherein the step of causing a reaction of the first compound comprises the step of adding an agent to chemically react with the first compound or adding energy to cause the first compound to become modified.
- 86. The method of claim 36, wherein the step of precipitating comprises the step of evaporating a portion of the volume of the first solvent.
- 87. A method for preparing submicron sized particles of a pharmaceutical compound, the method comprising the steps of:
dissolving the pharmaceutical compound in a first solvent to form a first solution; mixing the first solution with a second solvent to precipitate the pharmaceutical compound as particles to form a presuspension, wherein the solubility of the pharmaceutical compound is greater in the first solvent than in the second solvent; providing a seed compound to the first solution or the second solvent or the presuspension; adding energy to the presuspension; and wherein the particles have an average particle size of less than 500 nm.
- 88. The method of claim 87, further comprising the step of forming a desired polymorph of the pharmaceutical compound.
- 89. The method of claim 88, wherein the seed compound is the desired polymorph of the pharmaceutical compound.
- 90. The method of claim 88, wherein the seed compound is a compound other than the desired polymorph of the pharmaceutical compound.
- 91. The method of claim 90, wherein the seed compound is selected from the group consisting of: an inert impurity; and an organic compound with a structure similar to that of the desired polymorph.
- 92. The method of claim 87, wherein the seed compound is added to the first solution.
- 93. The method of claim 87, wherein the seed compound is added to the second solvent.
- 94. The method of claim 87, wherein the seed compound is added to the presuspension.
- 95. The method of claim 87, wherein the step of forming the desired polymorph comprises the step of forming a seed compound in the first solution.
- 96. The method of claim 95, wherein the step of forming the seed compound in the first solution comprises the step of adding the pharmaceutical compound in sufficient quantity to exceed the solubility of the pharmaceutical compound in the first solvent to create a supersaturated solution.
- 97. The method of claim 95, wherein the step of forming the seed compound in the first solution further comprises the step of treating the first solution.
- 98. The method of claim 97, wherein the step of treating the supersaturated solution comprises the step selected from the group consisting of aging the supersaturated solution, temperature shifting the solution or pH shifting the solution.
- 99. The method of claim 87 wherein the energy addition step comprises the step of using a device selected from the group consisting of a homogenizer, piston gap homogenizer, counter current flow homogenizer, microfluidizer, milling device and sonicator.
- 100. A method for preparing submicron sized particles of a pharmaceutical compound, the method comprising the steps of:
adding a sufficient quantity of the pharmaceutical compound to a first solvent to create a supersaturated solution; aging the supersaturated solution to form detectable crystals to create a seeding mixture; and mixing the seeding mixture with a second solvent to precipitate the pharmaceutical compound to form a presuspension, wherein the pharmaceutical compound has a greater solubility in the first solvent than in the second solvent.
- 101. The method of claim 100, further comprising the step of converting the compound in the presuspension to a desired polymorphic form from a first phase selected from the group consisting of a supercooled liquid, an amorphous particle, a semicrystalline particle, and a crystalline particle.
- 102. The method of claim 101, wherein the step of converting the compound comprises the step of adding energy to the presuspension.
- 103. The method of claim 102, wherein the adding-energy step comprises the step of adding heat to the presuspension.
- 104. The method of claim 102, wherein the adding-energy step comprises the step of exposing the presuspension to electromagnetic energy.
- 105. The method of claim 104, wherein the step of exposing the presuspension to electromagnetic energy comprises the step of exposing the presuspension to a laser beam.
- 106. The method of claim 102 wherein the step of adding energy comprises the step of using a device selected from the group consisting of a homogenizer, piston gap homogenizer, counter current flow homogenizer, microfluidizer, and sonicator.
- 107. A method for preparing a submicron sized suspension of a pharmaceutical compound having a desired polymorphic form, the method comprising the steps of:
providing a suitable carrier for the pharmaceutical compound; dispersing the pharmaceutical compound in the carrier to define a presuspension; applying energy to the presuspension; and seeding the presuspension to provide particles of the pharmaceutical compound having an average effective particle size of less than 500 nm and having the desired polymorphic form.
- 108. The method of claim 107, wherein the applying energy step can be conducted using techniques selected from the group consisting of: mechanical grinding, microfluidization, homogenization and ultrasonication.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation in part of application Ser. No. 10/035,821 filed Oct. 19, 2001, which is a continuation in part of application Ser. No. 09/953,979 filed Sep. 17, 2001 which is a continuation in part of application Ser. No. 09/874,637 filed Jun. 5, 2001, which claims priority from provisional application Ser. No. 60/258,160 filed Dec. 22, 2000, each of which is incorporated herein by reference and made a part hereof.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60258160 |
Dec 2000 |
US |
Continuation in Parts (3)
|
Number |
Date |
Country |
Parent |
10035821 |
Oct 2001 |
US |
Child |
10246802 |
Sep 2002 |
US |
Parent |
09953979 |
Sep 2001 |
US |
Child |
10035821 |
Oct 2001 |
US |
Parent |
09874637 |
Jun 2001 |
US |
Child |
09953979 |
Sep 2001 |
US |