CN1688288A - Preparation of submicron sized particles with polymorph control and new polymorph of itraconazole - Google Patents

Abstract

This invention provides a method for preparing pharmaceutical compound particles with polymorphism and particle size control, comprising the following steps: (1) providing a pharmaceutical compound of a first phase; (2) introducing a seed compound; (3) transforming the phase of the pharmaceutical compound into a second phase of the desired polymorphism; and (4) wherein the average particle size is less than 7 μm. This invention further provides polymorphic itraconazole.

Description

Preparation of submicron-sized particles with polymorph control and novel polymorphic forms of itraconazole

Cross Reference to Related Applications

The present application claims the benefit of co-pending U.S. patent application 10/246,802 filed on 9/17/2002 and 10/213,352 filed on 8/5/2002, both of which are filed as part of a continuation application No.10/035,821 filed on 19/10/2001, which is a continuation application No.09/953,979 filed on 17/2001, and No.09/953,979 is a continuation application No.09/874,637 filed on 5/6/2001, which claims priority to a provisional application 60/258,160 filed on 22/12/2000, each of which is incorporated herein by reference and made a part hereof.

Background

Increasingly, drugs that are poorly soluble or insoluble in aqueous solutions are formulated. These drugs create problems with administering the drugs via injectable forms such as parenteral administration. For drugs that are not soluble in water, it would be of significant benefit to formulate them as stable suspensions of particles smaller than 3 microns in diameter. Precise control of particle size is important for safe and effective use of the present formulations. Particles must be less than 7 microns in diameter in order to safely pass through capillaries without causing embolization (Allen et al, 1987; Davis and Taube, 1978; Schroeder et al, 1978; Yokel et al, 1981).

Us patent 2,745,785 discloses a method of administering an insoluble drug. This patent discloses a process for the preparation of penicillin G crystals suitable for parenteral administration. The process comprises the step of recrystallizing penicillin G from a formamide solution by reducing the solubility of penicillin G by adding water. The' 785 patent further provides penicillin G particles which may be coated with a wetting agent such as lecithin, or an emulsifier, a surface active and antifoaming agent, or a sorbitan incomplete higher fatty acid ester or polyoxyalkylene derivative thereof, or an aromatic hydrocarbon based polyether alcohol or salt thereof. The' 785 patent further discloses a process for micronization of penicillin G under pressure with air jets to form crystals of about 5 to 20 microns.

Another method is disclosed in us patent 5,118,528, which discloses a method of making nanoparticles. The method comprises the following steps: (1) preparing a liquid phase of the material in a solvent or solvent mixture to which one or more surfactants may be added; (2) preparing a second liquid phase of a non-solvent or mixture of non-solvents, which may be mixed with a solvent or mixture of solvents for the substance; (3) adding the solutions of (1) and (2) together by stirring; and (4) removing the unwanted solvent to produce a colloidal suspension of nanoparticles. The' 528 patent discloses a method of generating particles of less than 500 nanometers without the need for a supply of energy. In particular, the' 528 patent indicates that high energy rate equipment, such as sonicators and homogenizers, need not be used.

U.S. Pat. No. 4,826,689 discloses a process for making uniform size particles from water insoluble drugs or other organic compounds. First, a suitable solid organic compound is dissolved in an organic solvent, and the solution is diluted with a non-solvent. Then, an aqueous precipitation liquid is injected to precipitate non-polymeric particles of substantially uniform average diameter. The particles are then isolated from the organic solvent. Depending on the organic compound and the particle size of interest, parameters such as temperature, ratio of non-solvent to organic solvent, injection rate, agitation rate, and volume may be varied in accordance with the present invention. The method disclosed in the' 689 patent produces a thermodynamically unstable metastable state of the drug which eventually transforms into a more stable crystalline state. This' 689 discloses the collection of drugs having free energies in a metastable state between the starting drug solution and the stable crystalline form. The' 689 patent discloses the use of crystallization inhibitors (e.g., polypropylene pyrrolidone) and surfactants (e.g., a copolymer of polyethylene oxide and propylene oxide) to stabilize the precipitate sufficiently to enable separation by centrifugation, membrane filtration, or reverse osmosis.

U.S. Pat. nos. 5,091,188; 5,091,187 and 4,725,442 disclose: (a) coating small drug particles with natural or synthetic phospholipids or (b) dissolving the drug with a suitable lipophilic carrier and forming an emulsion stabilized with natural or semi-synthetic phospholipids. One disadvantage of these formulations is that the particular drug in suspension tends to grow over time due to the dissolution and re-precipitation phenomenon known as "Oswald ripening".

U.S. Pat. No. 5,145,684 discloses another method of parenteral administration of insoluble drugs. The 684 patent discloses wet milling an insoluble drug in the presence of a surface modifier to produce drug particles having an average effective particle size of less than 400 nm. The 684 patent discloses that the surface modifying agent is adsorbed onto the surface of the drug particles in a sufficient amount to prevent agglomeration into large particle masses.

U.S. Pat. No. 5,922,355 discloses another method for parenteral administration of insoluble drugs. The 355 patent discloses the use of a surface modifier and phospholipid combination followed by particle size reduction using techniques such as sonication, homogenization, milling, microfluidization, precipitation or recrystallization to obtain particles of submicron fine particle size.

U.S. patent 5,780,062 discloses a method for preparing small particles of an insoluble drug by: (1) dissolving the drug in a water-miscible first solvent, (2) preparing a second solution of the polymer and amphiphilic molecules in an aqueous second solvent in which the drug is substantially insoluble, wherein a polymer/amphiphilic molecule complex is formed, and (3) mixing the solutions obtained in the first and second steps and precipitating the drug and polymer/amphiphilic molecule complex polymer.

U.S. Pat. No. 5,858,410 discloses nanosuspensions suitable for parenteral administration. The' 410 patent discloses dispersing at least one solid therapeutically active compound in a solvent by high pressure homogenization with a piston-opening homogenizer to form particles having an average diameter of 40nm to 100nm as determined by Photon Correlation Spectroscopy (PCS), the number distribution being determined by a Coulter counter, all particles not previously dissolved and the proportion of particles greater than 5um being less than 0.1%, wherein the active compound is solid and insoluble at room temperature and only sparingly or moderately soluble in water, an aqueous medium and/or an organic solvent. Jet milling prior to homogenization is disclosed in the examples of the' 410 patent.

Us patent 4,997,454 discloses a method of producing uniform particle size particles from a solid compound. The steps of the method of this patent 454 include dissolving the solid compound in a suitable solvent and then injecting a precipitation solution, thereby precipitating non-polymeric particles of substantially uniform average diameter. The particles are then separated from the solvent.

One method aims to prepare protein coated suspension particles. U.S. patent 5,916,596 to Desai et al discloses a high shear flow of a mixture of an organic phase having dispersed therein a pharmacologically active agent and an aqueous medium containing a biocompatible polymer. The mixture is subjected to shear flow with a high pressure homogenizer at a pressure of about 3,000 to 30,000 psi. The' 596 patent states that the mixture must be substantially free of surfactant because the mixing of surfactant with protein can result in the formation of large acicular crystal particles that increase in volume during storage. See columns 17-18, example 4. Example 2 discloses that emulsified crude oil can be sonicated to produce nanoparticles of 350-420 nm.

Et al, Soon-Shiong, U.S. patent 5,560,933, discloses coating a water-insoluble drug to form a polymeric shell for in vivo delivery. The method discloses sonicating a mixture comprising a polymer-aqueous medium and a dispersing agent having dispersed therein a substantially water-insoluble drug. In these references, sonication is used to drive the disulfide bonds that form the polymers, cross-linking them to create a polymeric shell around the drug. Sonication is carried out for a period of time to form disulfide bonds.

In us patent 5,665,383, Grinstaff et al disclose the application of ultrasound to a single phase, i.e., an aqueous medium, to encapsulate an immune-activating agent within a polymeric shell for in vivo release. The ultrasound induces cross-linking of the encapsulant by disulfide bonds to form the shell.

Another approach to preparing water-insoluble drugs for in vivo delivery has focused on reducing the particle size of the drug-releasing particles. In us patent 6,228,399; 6,086,376, respectively; 5,922,355; and 5,660,858 et al, Parikh et al disclose that sonication can be used to prepare microparticles of water-insoluble compounds. Of these, U.S. Pat. No. 5,922,355 discloses an improved method for preparing smaller particles using sonication. The improvement comprises mixing the active pharmaceutical agent with a phospholipid and a surfactant in a single phase aqueous system and applying energy to the system to produce smaller particles.

U.S. patent No. 5,091,188 to Haynes also discloses reducing the particle size of a pharmacologically active water-insoluble drug and coating the particles with a lipid to impart a solid form. The' 188 patent is directed to pharmaceutical compositions having aqueous suspensions of solid particles of the drug having a diameter of about 0.05 to about 10 microns. The lipid coating attached to the surface of the particles helps them to form a solid form. The composition is produced by adding the drug to water and then reducing the particle size in the aqueous suspension. Example 6 of this reference discloses the use of a medicinal oil selected for its inability to dissolve crystalline drugs. See column 16, lines 8-12.

Another method of preparing microparticles of a pharmaceutical agent is directed to studying the application of the inverse principle. U.S. Pat. Nos. 6,235,224B1 and 6,143,211, owned by Mathiowitz et al, disclose the precipitation of microencapsulated particles by exploiting the reverse phase phenomenon. The method includes mixing the polymer and the drug with a solvent. The mixture is introduced into an effective amount of a miscible non-solvent, thereby causing the spontaneous formation of a microencapsulated product.

Another technique for preparing nanoparticle agent suspensions is by micro-precipitation by pH change. See, for example, U.S. patents 5,665,331 and 5,662,883. This technique involves dissolving the pharmaceutical agent in an aqueous matrix followed by neutralization to form a suspension.

In another method, such as disclosed in U.S. patent 5,766,635 owned by Spenlnhauer et al, nanoparticles are prepared by dissolving poly (ethylene) oxide and/or poly (propylene) oxide in an organic solvent, mixing the organic solution so formed with an aqueous solution to precipitate the nanoparticles out of solution, and micro-liquefying the precipitated solution without the use of a surfactant.

Summary of The Invention

The present invention relates to a process for preparing submicron-sized particles of a pharmaceutical compound. The process includes the additional step of controlling the polymorphic formation of the pharmaceutical compound to ultimately produce submicron-sized particles of the desired particle size range and polymorph. The methods can be divided into two broad categories. The first category involves the use of seeding techniques during the preparation of nanoparticles to produce sub-micron sized particles of a pharmaceutical compound by applying energy to the compound. The second category involves the use of seeding techniques during precipitation to produce sub-micron sized particles of the compound.

The present invention provides a process for preparing polymorphic and controlled size submicron particles of a pharmaceutical compound. The steps of the method include providing a pharmaceutical compound in a first phase; introducing a seed compound; phase-changing the pharmaceutical compound into a desired polymorphic second phase; and wherein the particles have an average particle size of less than 7 μm. The term "phase" as used herein refers to the state of the compound and includes gases, supercooled liquids, semicrystalline states, crystalline states, and other phases and combinations of phases known in the art. The phase change includes a transition of the compound from, for example, a supercooled liquid to a crystalline state, a transition of a crystalline material having a first polymorphic form to a crystalline material having a second polymorphic form different from the first polymorphic form. The term "phase" is also used to refer to emulsion components such as aqueous phases as well as organic phases.

The invention further provides a process for preparing submicron-sized particles of a pharmaceutical compound. The method comprises the following steps: (1) dissolving a pharmaceutical compound in a first solvent to form a first solution, (2) precipitating the pharmaceutical compound to form a pre-suspension, and (3) seeding the first solution or the pre-suspension.

The invention further provides a process for preparing submicron-sized particles of a pharmaceutical compound. The method comprises the following steps: (1) dissolving a drug compound in a first solvent to form a first solution; (2) mixing the first solution with a second solvent to precipitate particles of the pharmaceutical compound to form a pre-suspension, wherein the pharmaceutical compound has a greater solubility in the first solvent than in the second solvent; (3) seeding a seed compound into the first solution or the second solvent or the pre-suspension; (4) adding energy to the pre-suspension; and (5) wherein the particles have an average particle size of less than 500 nm.

The invention further provides a process for preparing submicron-sized particles of a pharmaceutical compound. The method comprises the following steps: (1) adding a sufficient amount of a pharmaceutical compound to the first solvent to produce a supersaturated solution; (2) aging the supersaturated solution to form detectable crystals to produce a seeding mixture, and (3) mixing the seeding mixture with a second solvent to precipitate the pharmaceutical compound to form a pre-suspension, wherein the pharmaceutical compound has greater solubility in the first solvent than in the second solvent.

The invention further provides a process for preparing sub-micron sized suspensions of pharmaceutical compounds having the polymorphic form of interest. The method comprises the following steps: (1) providing a carrier for the suitable pharmaceutical compound; (2) dispersing the pharmaceutical compound in a carrier to produce a pre-suspension; (3) applying energy to the pre-suspension; and (4) seeding the pre-suspension to provide particles of the pharmaceutical compound having an average effective particle size of less than 500nm and having the polymorph of interest.

The present invention further provides a polymorph of itraconazole having an X-ray diffraction pattern substantially as shown in fig. 10b, characterized by powder X-ray diffraction 2-theta peaks at about 7.3 degrees, 19.9 degrees, 21.9 degrees, 26.1 degrees, and 32.2 degrees. The itraconazole polymorph is further characterized as having an infrared Fourier Transform (FTIR) spectrum substantially as shown in fig. 16 b. The itraconazole polymorph is further characterized as having a DSC profile substantially identical to that shown in figure 11 b.

Brief description of the drawings

FIG. 1 is a photomicrograph of the amorphous particles of example 1 prior to homogenization;

FIG. 2 is a photomicrograph of the particles of example 1 after annealing by homogenization;

FIG. 3 is an X-ray diffraction pattern of itraconazole microprecipitated with PEG-66012-hydroxystearic acid before and after homogenization in example 5;

FIG. 4 is a photomicrograph of carbamazepine crystals of example 6 prior to homogenization;

FIG. 5 is a photomicrograph of carbamazepine microparticles after homogenization (Avestin C-50);

FIG. 6 is a schematic representation of the microprecipitation method of prednisolone used in examples 9-12;

FIG. 7 is a photomicrograph of a prednisolone suspension prior to homogenization (Hoffman transform phase contrast, 1250 magnification);

FIG. 8 is a photomicrograph of the prednisolone suspension after homogenization (Hoffman transform phase contrast, 1250 magnification);

FIG. 9 is a comparison of the particle size distribution of nanosuspensions and commercial fat emulsions (inventive example 13);

figure 10a is the X-ray powder diffraction pattern of the starting material itraconazole. FIG. 10b is the X-ray powder diffraction pattern of SMP-2-PRE (example 16);

figure 11a is a DSC trace of the starting material itraconazole (example 16). FIG. 11b is a DSC trace of SMP-2-PRE (example 16);

FIG. 12 is a DSC trace (example 16) illustrating dissolution of the less stable polymorph upon heating above 160 ℃, a recrystallization event upon cooling, and subsequent dissolution of more polymorph upon reheating to 180 ℃;

FIG. 13 is a DSC trace of an SMP-2-PRE sample after homogenization. Solid line is a sample seeded with itraconazole, a starting material. Dotted line-unseeded sample. The 1W/g shift has been made for the transparent solid line (example 16);

fig. 14 is a DSC trace illustrating seeding effect during precipitation. The dotted line is an unseeded sample, and the solid line is a sample seeded with itraconazole, a raw material. The unseeded trace (dashed line) has been shifted by 1.5W/g for clarity (example 17).

Figure 15 is a DSC trace illustrating the effect of seeding a drug concentrate by aging. The top X-ray diffraction pattern is that of the crystals prepared from the fresh drug concentrate, corresponding to the stable polymorph (see fig. 10 a). The bottom pattern is of crystals prepared from aged (seeded) drug concentrate, corresponding to metastable polymorph (see fig. 10 b). The top pattern has been shifted up for clarity (example 18);

FIG. 16a is the FTIR spectrum of itraconazole, a starting material, and FIG. 16b is the FTIR spectrum of SMP-2-PRE (example 16);

figure 17a illustrates a DSC trace of itraconazole having two endotherms showing the presence of two polymorphs (example 22); and

figure 17b illustrates DSC traces of itraconazole after seeding and after grinding with a mortar and pestle (example 22).

Detailed description of the invention

It will be apparent to those skilled in the art that various changes and modifications can be made to the presently preferred embodiments described herein. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be included within the scope of the appended claims.

The present invention relates to a process for the preparation of submicron fine particle size particles of a pharmaceutical compound. The method includes the additional step or steps of controlling the crystalline structure of the pharmaceutical compound to ultimately produce submicron fine particle size particles of the desired particle size range and the desired crystalline structure. Additional steps may be used in conjunction with any method of producing nanoparticles, including methods of producing nanoparticles using mechanical energy to reduce particle size and methods of producing nanoparticles by precipitation techniques.

The pharmaceutical compound is preferably insoluble or sparingly soluble in water. The term "water-insoluble" means that the compound has a solubility in water of less than 10mg/mL, preferably less than 1mg/mL in water. The term "pharmaceutical compound" means a pharmaceutically active compound and a pharmaceutically acceptable excipient. The pharmaceutically active compound may be selected from such as, but not limited to: antihyperlipidemic agents, antimicrobial agents, such as antibacterial agents like sulfadiazine, antifungal agents like itraconazole; nonsteroidal anti-inflammatory drugs, such as indomethacin; anti-high cholesterol agents, such as bis-thiopropane; and steroid compounds, such as dexamethasone; immunosuppressants such as cyclosporin a, tacrolimus, and mycophenolate mofetil.

Energy addition techniques to form nanoparticles

Generally, the method of preparing nanoparticles using energy addition techniques includes the steps of adding a pharmaceutical compound, sometimes referred to as a drug, in a quantity to form a suitable carrier such as water or an aqueous solution containing one or more excipients set forth below, or other liquid, to form a pre-suspension of the drug in which the pharmaceutical compound is insoluble, adding energy to the pre-suspension to form a post-suspension of drug particles having an average effective particle size of less than about 500nm, more preferably less than about 400nm, more preferably less than about 300nm or from about 50nm to about 500nm or any range or combination or sub-combination of ranges. The determination of particle size can be performed using techniques known in the art, such as dynamic light scattering methods (e.g., light correlation spectroscopy, laser diffraction, low depression angle laser scattering (LALLS), medium angle laser scattering (MALLS), light obscuration methods (e.g., Coulter method), rheology, or microscopy (light or electron) within the ranges described above).

The drug compound has a preferred polymorphic form and a portion of the drug particles will be the polymorphic form of interest after the seeding step. The polymorph of interest may be the same as or different from most drugs. In a preferred form of the invention, greater than 50% of the particles of the post-suspension are of the polymorphic form of interest, more preferably greater than 70%, more preferably greater than 90%.

The step of adding energy includes mechanical milling techniques such as ball milling, pearl milling, hammer milling, hydraulic ore mills or wet milling techniques such as those disclosed in U.S. patent No. 5,145,684, which is incorporated herein by reference and made a part hereof. The seed introduction step, discussed in detail below, may be performed at any point during milling.

The technique of adding energy further includes subjecting the drug containing suspension to high shear conditions including cavitation, shear flow or impact forces, which may be generated using a microfluidizer, piston orifice homogenizer or counter-flow homogenizer, such as those disclosed in U.S. Pat. No. 5,091,188, which is incorporated herein by reference and made a part hereof. Suitable piston opening homogenizers are commercially available, such as those sold by Avestin under the product name EMULSIFLEX, and by Spectronic instruments, Inc. of French Pressure Cells. Suitable microfluidic dispersers (microfluidizers) are available from Microfluidics corporation. The seed introduction step described below may be performed at any time while the solution is subjected to high shear conditions, and most preferably is performed before the energy addition step.

The step of adding energy may also be accomplished using sonication techniques. The sonication step may be performed using any suitable sonication device such as Branson model S-450A or Cole-Parmer model 500/750 Watt. Such devices are well known in the industry. Typically the sonication device has a sonication horn or probe inserted into the drug-containing solution to emit ultrasonic energy into the solution. Preferred ultrasonic treatment devices of the present invention operate at frequencies of from about 1kHz to about 90kHz, more preferably from about 20kHz to about 40kHz, or any range or combination of ranges therein. The probe size may vary, preferably 1/2 inches or 1/4 inches, etc. It may also be desirable to cool the solution to a temperature below room temperature during sonication. The seed introduction step described below may be carried out at any time while the solution is subjected to high shear conditions, very preferably before the energy addition step.

Precipitation process for preparing submicron sized particles

Any precipitation method known in the art for producing submicron-sized particles may be used in combination with the seed introduction step of the present invention. The following is a description of the precipitation method examples. The examples are intended to illustrate, but not to limit the scope of the invention.

Micro precipitation method

One example is the microprecipitation method disclosed in U.S. patent 5,780,062, which is incorporated herein by reference and made a part hereof. The' 062 patent discloses an organic compound precipitation process comprising: (i) dissolving an organic compound with a water-miscible first solvent; (ii) preparing a solution of the polymer and the amphiphilic molecule in a second solvent comprising water, the organic compound being substantially insoluble in the second solvent, wherein a polymer/amphiphilic molecule complex is formed; and (iii) mixing the solutions of steps (i) and (ii) to precipitate the organic compound and the polymer/amphiphile complex polymer. The polymorph control step discussed in detail below can be performed at any time during these steps. In a preferred form of the invention, the polymorph control step is carried out while the solution (iii) is mixed.

Disclosed in co-filed and concurrently-approved U.S. patent 09/874,499; 09/874,799, respectively; 09/874,637, respectively; and 10/021,692, which are incorporated herein by reference and made a part hereof. The disclosed method comprises the following steps: (1) dissolving an organic compound in a water-soluble first organic solvent to produce a first solution; (2) mixing the first solution with a second solvent or water to precipitate an organic compound to produce a pre-suspension; and (3) adding energy to the pre-suspension in the form of high shear mixing or heating to form a stable morphology organic compound having a desired particle size range. One or more optional surface modifying agents may be added to the first organic solvent or the second aqueous solution. The polymorph control step discussed in detail below can be performed during any of the steps.

Emulsion precipitation method

One suitable creamy precipitation technique is disclosed in co-pending and commonly assigned U.S. patent application 09/964,273, which is incorporated herein by reference and made a part hereof. In this method, the method comprises the steps of: (1) forming a multiphase system having an organic phase and an aqueous phase, wherein the organic phase has a pharmaceutically effective compound; and (2) sonicating the system to evaporate a portion of the organic phase to precipitate a compound having an average effective particle size of less than about 2 μm in the aqueous phase. The step of forming a multiphase system comprises: (1) mixing a water-insoluble solvent with a pharmaceutically effective compound to produce an organic solution, (2) preparing an aqueous solution containing one or more surface active compounds, and (3) mixing the organic solution with an aqueous solution to form a multiphase system. The step of creating high shear conditions to mix the organic and aqueous phases may be performed using a process comprising a piston-opening homogenizer, colloid mill, high speed stirring device, extrusion device, manual agitation or shaking device, microfluidizer, or other device or technique. The emulsified crude oil has oil mist droplets having a particle size of less than about 1 μm diameter in water. The crude oil is emulsified by sonication to create a microemulsion and ultimately a particle suspension of submicron particle size.

The polymorph control step discussed in detail below can be performed during any of the steps. The polymorph control step can be performed before or after the sonication system. In a very preferred form of the invention, the polymorph control step is carried out during sonication.

Another method for producing submicron-sized particles is disclosed in co-pending and commonly assigned U.S. patent application 10/183,035, which is incorporated herein by reference and made a part hereof. The method comprises the following steps: (1) forming a crude suspension of the multiphase system having an organic phase and an aqueous phase, wherein the organic phase has the pharmaceutical compound; (2) energizing the raw suspension to form a micro-dispersion; (3) freezing the microdispersion; and (4) lyophilizing the microdispersion to obtain submicron fine-particle-size particles of the pharmaceutical compound. The step of forming a multiphase system comprises: (1) mixing a water-insoluble solvent with a pharmaceutically effective compound to produce an organic solution; (2) preparing an aqueous-based solution containing one or more surface-active compounds; and (3) mixing the organic solution with the aqueous solution to form a multiphase system. The step of mixing the organic and aqueous phases includes the use of piston-ported homogenizers, colloid mills, high speed stirring equipment, extrusion equipment, manual agitation or shaking equipment, microfluidics, or other equipment or techniques that provide high shear conditions.

The polymorph control step discussed in detail below can be performed during any of the steps. In the most preferred form of the invention, the polymorph control step is carried out in a mixing step (3) which is a step of forming a multiphase system.

Solvent anti-solvent precipitation process

Suitable solvent anti-solvent precipitation techniques are disclosed in U.S. Pat. Nos. 5,118,528 and 5,100,591, which are incorporated herein by reference and made a part hereof. The method comprises the following steps: (1) preparing a liquid phase of the biologically active substance in a solvent or solvent mixture, to which one or more surfactants may be added; (2) preparing a second liquid phase of a non-solvent or a mixture of solvents, the non-solvent being miscible with the solvent or mixture of solvents for the biologically active substance; (3) adding the solutions of (1) and (2) together by stirring; and (4) removing the unwanted solvent to produce a colloidal suspension of nanoparticles. The' 528 patent discloses a method of generating particles of a substance less than 500nm without the need for a supply of energy.

The polymorph control step discussed in detail below can be performed at any step. In the most preferred form of the invention, a polymorph control step is carried out before the solutions (1) and (2) are combined and mixed in step (3).

Reverse phase precipitation

Us patent 6,235,224; 6,143,211 and U.S. patent application 6,235,224; one suitable reverse phase precipitation method is disclosed in U.S. Pat. No. 6,143,211 and U.S. patent application 2001/0042932, which are incorporated herein by reference and made a part hereof. Inversion is a term used to describe the physical phenomenon by inverting the polymer dissolved in the continuous phase solvent system into a solid macromolecular network in which the polymer is the continuous phase. One method of inducing reverse phase is to add a non-solvent to the continuous phase. The polymer undergoes a transition from a single phase to an unstable biphasic mixture: a component rich in and lacking polymers. The non-solvent micelle droplets in the polymer-rich phase serve as nucleation sites and are coated with polymer. The' 224 patent discloses that under certain conditions the inverse phase of the polymer solution may spontaneously form discrete particles, including nanoparticles. The' 224 patent discloses dissolving or dispersing a polymer in a solvent. While the pharmaceutical agent is dissolved or dispersed in the solvent. In order for the seed introduction step to be effective in this process, it is desirable to dissolve the agent in a solvent. The polymer, agent and solvent together form a mixture having a continuous phase, wherein the solvent is the continuous phase. Then adding to the mixture at least a tenfold excess of the miscible non-solvent to produce spontaneously formed medicament particles having a micro-seal with an average particle size between 10nm and 10 μm. Particle size is affected by the solvent to non-solvent volume ratio, polymer concentration, viscosity of the polymer-solvent solution, molecular weight of the polymer, and solvent-non-solvent pair properties. The method eliminates the step of creating solvent droplets, such as forming an emulsion. The process also avoids agitation and/or shear forces.

The polymorph control step discussed in detail below can be performed during any of the steps. In a preferred form of the invention, the polymorph control step is carried out before or during the addition of the non-solvent to the continuous phase.

precipitation with pH change

The step of pH-altering precipitation techniques generally involves dissolving the drug at a pH at which the drug is soluble in solution, followed by changing the pH to a point where the drug is no longer soluble. The pH may be acidic or basic depending on the particular pharmaceutical compound. The solution is then neutralized to form a pre-suspension of sub-micron fine particle size particles of the pharmaceutically active compound. One suitable pH-modified precipitation process is disclosed in U.S. patent 5,665,331, incorporated herein by reference and made a part hereof. The steps of the method include dissolving the pharmaceutical agent together with a Crystal Growth Modifier (CGM) in an alkaline solution and then neutralizing the solution with an acid in the presence of a suitable surface modifying surfactant or agent to form a fine particle suspension of the pharmaceutical agent. The precipitation step may be followed by a diafiltration purification step of the suspension, and the concentration of the suspension is then adjusted to the desired level. The present method reportedly produces microcrystalline particles having a Z-average diameter of less than 400nm as measured by photon correlation spectroscopy.

The polymorph control step discussed in detail below can be performed during any of the steps. In a very preferred form of the invention, the polymorph control step is carried out before or during the neutralization step.

Examples of other pH-modified precipitation methods are disclosed in us patent 5,716,642; 5,662,883, respectively; 5,560,932, respectively; and 4,608,278, incorporated herein by reference and made a part hereof.

Injection precipitation method

Suitable injection precipitation techniques are disclosed in U.S. Pat. Nos. 4,997,454 and 4,826,689, incorporated herein by reference and made a part hereof. First, a suitable solid compound is dissolved in a suitable organic solvent to form a solvent mixture. Then, the solvent mixture is infused with a precipitating non-solvent miscible with the organic solvent at a rate of from about 0.01ml per minute to about 1000ml per minute per 50ml volume at a temperature between about-10 ℃ and about 100 ℃ to produce a uniform suspension of precipitated non-polymeric solid particles having an average diameter substantially less than 10 μm. Agitation (e.g., by stirring) is preferably applied to the solution of the infused precipitating non-solvent. The non-solvent may contain a surfactant to stabilize the particles against polymerization. The particles are then separated from the organic solvent. The temperature parameters, the ratio of non-solvent to solvent, the injection rate, the agitation rate, the volume, and other parameters of the present invention can be varied depending on the solid compound and the particle size of interest. The particle size is directly proportional to the ratio of non-solvent to solvent volume and the injection temperature is inversely proportional to the injection speed and agitation speed. Depending on the relative solubilities of the compound and the desired suspending vehicle, the precipitation non-solvent may be aqueous or anhydrous.

The polymorph control step discussed in detail below can be performed during any of the steps. In a preferred form of the invention, the polymorph control step is carried out before or during the injection of the non-solvent.

Temperature change precipitation method

Temperature-shift precipitation, also known as the hot-melt technique, is disclosed in U.S. Pat. Nos. 5,188,454 and 4,826,689 to Domb, which are incorporated herein by reference and made a part hereof. In one embodiment of the present invention, the step of preparing the liposphere is: (1) melting or dissolving a substance to be administered, such as a drug, in a dissolution vehicle to form a liquid to be administered; (2) adding a phospholipid to the melted material or carrier together with an aqueous medium at a temperature above the melting temperature of the material or carrier; (3) mixing the suspension at a temperature above the melting temperature of the carrier until a homogeneous fine preparation is obtained; and then (4) rapidly cooling the preparation to room temperature or below.

The polymorph control step discussed in detail below can be performed at any time during these steps, as long as the temperature of administration does not exceed the melting point of the drug. In a most preferred form of the invention, the polymorph control step is carried out before or during the step of cooling the warm pharmaceutical suspension.

Solvent evaporation precipitation process

Solvent evaporation precipitation techniques are disclosed in U.S. patent 4,973,465, incorporated herein by reference and made a part hereof. The' 465 patent discloses a method of making microcrystals comprising the steps of: (1) preparing a pharmaceutical composition and a phospholipid solution dissolved in a common organic solvent or solvent combination, (2) evaporating the solvent or solvent(s) and (3) vigorously stirring, the suspended membrane being obtained by evaporation of the solvent or solvent(s) in an aqueous solution. The solvent is removed by adding energy to the solution for evaporation in sufficient quantity to precipitate the compound. The solvent may also be removed by other known techniques such as applying a vacuum to the solution or blowing nitrogen through the solution. The polymorph control step discussed in detail below can be performed during any of the steps. In a most preferred form of the invention, the polymorph control step is carried out prior to the evaporation step.

Reaction precipitation method

The step of the reactive precipitation method comprises dissolving the pharmaceutical compound in a suitable solvent to form a solution. The amount of compound added should be equal to or below the saturation point of the compound in the solvent. The compound is modified by reaction with a chemical agent or by modification by addition of energy such as heat or ultraviolet light, such that the modified compound has a lower solubility in the solvent and precipitates out of solution. The polymorph control step discussed in detail below can be performed at any step in between. In a most preferred form of the invention, the polymorph control step is carried out before or during the precipitation step.

Compressed fluid precipitation process

Suitable techniques for precipitation by compression of a fluid are disclosed in WO97/14407 to Johnston, which is incorporated herein by reference and made a part hereof. The steps of the method include dissolving a water-insoluble drug in a solvent to form a solution. The solution is then sprayed into a compressed fluid which may be a gas, liquid or critical fluid. The compressed fluid is added to a solute solution dissolved in a solvent such that the solute reaches or approaches a supersaturated state and the particles precipitate out. In this case, the compressed fluid acts as an anti-solvent to reduce the cohesive energy density of the solvent in which the drug is dissolved.

Alternatively, the drug may be dissolved in a compressed fluid and then sprayed into the aqueous phase. The rapid expansion of the compressed fluid reduces the dissolving capacity of the liquid, which in turn causes the solute to precipitate out of particles in the aqueous phase. In which case the compressed fluid acts as a solvent.

To stabilize the particles against polymerization, this technique uses a surface modifier such as a surfactant. The particles produced by the present technique are typically 500nm or less.

The polymorph control step discussed in detail below can be performed at any step in between. In a very preferred form of the invention, the polymorph control step is carried out before or during the particle formation step.

Polymorph control

The present invention is directed to the preparation of submicron-sized particles having a desired crystalline structure by a precipitation process such as that described above.

The term "crystal structure" refers to the arrangement and/or structure of molecules within a crystal lattice. Compounds that can crystallize into different crystal structures are referred to as polymorphs. Many of the pharmaceutical compounds and excipients used to administer drugs, as set forth in detail below, are known to be polymorphic. Since different polymorphs of the same drug may show differences in solubility, therapeutic activity, bioavailability, and suspension stability, the identification of the polymorph is an important step in the formulation of the drug. Likewise, different polymorphs of the same excipient may show differences in solubility, compatibility with drug administration, chemical stability and suspension stability. Therefore, it is important to control the polymorphism of the compound in order to ensure product purity and batch-to-batch reproducibility.

The polymorphic form of the compounds in the processes discussed above may be controlled by additional seed introduction. Seed introduction includes the use of a grain compound or the addition of energy to form a grain compound. In a preferred form of the invention, the seed compound is a pharmaceutically active compound of the polymorphic form of interest. In addition, the seed compound may also be an inert impurity or an organic compound having a structure similar to the polymorph of interest.

The seed compound may be precipitated from a solution of any of the above methods of containing the drug. The steps of the method include adding a sufficient amount of the pharmaceutically active compound to the first solution to exceed the solubility of the pharmaceutically active compound to produce a supersaturated solution. The supersaturated solution is intended to precipitate the desired polymorphic form of the pharmaceutically active compound. Treatment of the supersaturated solution involves aging the solution for a period of time until crystals form or a seeding mixture is observed to form. The treatment of the solution also includes subjecting the solution to a temperature change or a pH change. Additionally, energy may be added to the supersaturated solution to cause the pharmaceutically active compound to precipitate out of solution in the desired polymorph. The energy may be added in various ways including the energy addition step described above. Furthermore, energy can be added by heating or exposing the pre-suspension to electromagnetic energy, a particle beam or an electron beam source. The electromagnetic energy may include the use of a laser beam, dynamic electromagnetic energy, or other radiation source. Furthermore, ultrasound, electrostatic fields and static magnetic fields are conceivable as energy sources.

In a preferred form of the invention, the method of producing seed crystals from an aged supersaturated solution comprises the steps of: (i) adding a quantity of a pharmaceutically active compound to a drug solution to produce a supersaturated solution, (ii) aging the supersaturated solution to form detectable crystals, to produce a seeding mixture; and (iii) precipitating the seeding mixture to produce a pre-suspension. The pre-suspension may be further processed as described above to prepare an aqueous suspension of the pharmaceutically active compound in the polymorphic form of interest and in the particle size range of interest.

Seeding may also be performed by adding energy to the first solution or pre-suspension to form a seeding compound, so long as the contacting liquid contains the pharmaceutical compound or seeding material. Energy can be added to the supersaturated solution in the same manner as described above.

Accordingly, the present invention provides compositions of a pharmaceutical compound of a polymorph of interest that are substantially free of unspecified polymorphs. The process of the present invention can be selectively applied to produce a number of desired polymorphic forms of a pharmaceutical compound.

Optional surface active compounds and excipients

One or more optional surface active compounds, such as anionic surfactants, cationic surfactants, nonionic surfactants or biological surface active molecules, may be added thereto to prepare the drug solution or the pre-suspension or both the drug solution and the pre-suspension. Suitable ionic surfactants include, but are not limited to, potassium laurate, sodium lauryl sulfonate, sodium dodecyl sulfonate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inosine, phosphatidic acid and their salts, glyceryl esters, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and their salts (e.g., sodium deoxycholate, and the like). Suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, cetrimide, dodecyldimethylaniline chloride, esteracyl carnitine hydrochloride, or alkyl pyridinium halides. Phospholipids may be used as ionic surfactants. Suitable phospholipids include, for example, lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipid, egg or soybean phospholipid or combinations thereof. The phospholipids may be salts or desalted, hydrogenated or partially hydrogenated or natural semisynthetic or synthetic.

Suitable nonionic surfactants include: polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span), glycerol monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxomers), gyramines, methyl cellulose, oxidized cellulose, hydroxypropyl methyl cellulose, noncrystalline cellulose, polysaccharides including starch and starch derivatives such as hydroxyethyl starch (HES), polyvinyl alcohol, and polyvinylpyrrolidone. In a preferred form of the invention, the non-ionic surfactant is a copolymer of polyethylene oxide and polypropylene oxide, preferably a segmented copolymer of propylene glycol and ethylene glycol. These polymers are sold under the trade name POLOXAMER and are also sometimes referred to as PLURONIC *, sold by several suppliers including Spectrum Chemical and ruder corporation, among others. Polyoxyethylene fatty acid esters include those having short alkyl chains. An example of these surfactants is SOLUTOL * HS15, polyethylene-660-hydroxystearate, manufactured by BASF Aktiengesellschaft.

Surface active biomolecules include molecules such as albumin, casein, heparin, hirudin or other suitable proteins.

It may also be desirable to add a pH adjusting agent such as sodium hydroxide, hydrochloric acid, Tris buffer or citrate, acetate, lactate, meglumine, etc. to the second solution. The second solution should have a pH in the range of about 3 to about 11.

Excipients known to be polymorphic include animal fats, limit dextrins, aspartame, terbutaline-4-hydroxy anise ether, calcium oxalate, calcium phosphate, cellulose, chenodeoxycholic acid, cyclodextrins, fatty acids, fatty alcohols, glycerides, glyceryl monostearate, glycine hydrochloride, hydrogenated rape oil, lactose, lipids, menthol, magnesium stearate, paraffin, sucrose (sucrose), sorbitol, and suppository bases.

Suitable pharmaceutically active compounds of known polymorphic forms include, but are not limited to, acebutolol hydrochloride, aceclidine hydrochloride, diacetyldapsone, acemetacin, acetamide, acetaminophen, acetazolamide, acetylbenzenesulfonylcyclohexane urea, 21-acetoxypregnenolone acetate, p-acedigoxin, DL-n-acetyl pantolactone, acetylsalicylic acid, acetylsulindazole, adenylic acid derivatives, spasmolytic hydrochloride, amazalin, allantoin, dipropylenebarbital, allopregnane-3 p, 20 a-diol, 5-allyl-barbituric acid derivatives, propranol hydrochloride, amcinonide, amiloride hydrochloride, amino acids, p-aminobenzoic acid, amikacin disulfate, aminopenicillanic acid derivatives, amiperone, amiloride, amisomepiride, amitriptyline hydrochloride, amoebastal, amoxicillin, amphetamine sulfate, ampicillin, amilocaine hydrochloride, amrinone, androstane-diol derivatives, androstane-dione derivatives, androsterone, anileride, anthranilic acid, anthraquinone carboxylic acid, aprepidine hydrochloride, 5-propenyl-5-isopropylbarbituric acid, valylurea, arecoline hydrochloride, asparaginase, auranofin, azaperone hydrochloride, azelastine, azinamide, aztreonam, amazoneptanide, beta-p-chlorophenyl-gamma-aminobutyric acid, buthanol sulfate, pamipramine hydrochloride, barbiturate azo derivatives, benoxastill, benflumethiazide, benoxaprofen, phentolamine, benzamide, benzidine, benzocaine, benzoylbenzoglitazone, benzopyran derivatives, phenoxyethanethiol, berberine hydrochloride, betamethasone acetate, bimagride, anorthite, biperiden, dithiocyanbenzene, boandrostanediol dipropionate, bromoisovaleryl urea, brompipitol, brompheniramine maleate, brotizolam, strychnine, buclizamide, bumetanide, butylpyramide, bicaine hydrochloride, blanolol hydrochloride, busulfan, buspirone hydrochloride, butacaine hydrochloride, butobarbital, butoxylin, buthionol sodium, butobarbital, butambenzyl hydrochloride, butozanium, caffeine, calcium glucoheptonate, calcium lactate, calcium pantothenate, camphoric acid derivatives, captopril, caramiphene hydrochloride, caramipramine, carbamazepine, carbopol hydrochloride, carbazoluron, carbobromurea, cofactors, ceftiodine, ceftiofur-thiin, cefamandole, cefazolin, cefixime, celecoxol hydrochloride, chenodeoxycholic acid, chloral hydrate, chloramphenicol derivatives, chloramphenicol palmitate, chlorobenzamide hydrochloride, chlordiazepoxide hydrochloride, domperidone, clomidazole hydrochloride, chloroacetamide, chlorophenoxyamine hydrochloride, chlorpropamide, chlorpromazine hydrochloride, chloroquine diphosphate, chloroquinate, chlorotestosterone, chlortestosterone hydrochloride, chlortetracycline hydrochloride, chlorthalidone, cholesterol and its esters, choline chloride, quinazoline hydrochloride, cimetidine, cinnamic acid, clenbuterol hydrochloride, chlordantoin, clofenamide, loratadine hydrochloride, clomipramine hydrochloride, clonidine hydrochloride, clidanol, clidanazol, codeine, adrenaline, cortisone acetate, heptanoate, coumarol, cresol, cromolyn disodium salt, cyclanoate, cycloparbital, sodium cyclobarbital, cyclobutamol, cyclopenthiazide, cyclophosphamide, cycloheptatrine hydrochloride, danthrone, dapsone, dihydroketonic acid, epiandrosterone dihydropropionate, desoxyadrenaline propionate, dexrazidine, dexamethasone acetate, dexamethasone palmitate, diamorphine, diatrizoic acid, diazepam, dibromosol, diclofenac aminosalicylate, dipentyl, diethylamine salicylate, diethylstilbestrol, diphenoxylate hydrochloride, docusate sodium, benzindenone, difenidol, diphenylamine, phenytoin, diphenylmethane, disulfofuramine, diphenylallylamine, diprophylline, dipyridamole, dobutamine hydrochloride, domethat, antiminer, droloxifene, flupiride, enbramine hydrochloride, emedastine difumarate, imidilantine hydrochloride, enalapril maleate, inolamine, ephedrine, epiandrosterone, eplerenone hydrochloride, ergometridine tartrate, ergotamine tartrate, erythritol, erythromycin and erythromycin, estradiol and salts, estradiol esters, estrone, ethacrynic acid, efaviride hydrochloride, isabiturate, ethambutol dihydrochloride, ethionamide, ethinylestradiol, dicumarol ethyl acetate, pekinetin hydrochloride, etidocaine hydrochloride, the present cholane derivatives, etoxytheophylline, etoposide, famotidine, felodipine, phenylbutyric acid, phenylethene diphenylpropylamine hydrochloride, phentermine sulfate, fenoterol hydrobromide, fenpride, fenretinide, fluanidone, flecainide, flucloxacillin, fludrocortisone acetate, flufenamic acid, flumorphone, flucyclocortolone and salts, fludrocortisone acetate, fluprednisone, flugestrol acetate, fluspirilene, fosinopril, furazolidone, furinamide (furosemide), gepirone hydrochloride, glafenine, phenylurea, glibenclamide, gliadin (glycodiamine), glucose, glutethimide, gramicidin, griseofulvin, guaifenesin, guanoxaxifene sulfate, lipoamide, haloperidol, cycloheptbital, methotrexate hydrochloride, cetnurone, heroin (diacetylmorphine), hexachlorophene, hexobarbital, histamine, histidine salts, homalopine hydrochloride, hydrochlorothiazide, hydrocortisone and salts, hydroflumethiazide, hydroxyvemethanamine, hydroxypropyl theophylline, scopolamine hydrochloride, bromobutyl scopolamine, hyoscyamine sulfate, ibuprofen, lysyl ibuprofen, imidazopyridine derivatives, midazoline hydrochloride, imipramine hydrochloride, indapapine, indocyanine, indomethacin, inositol nicotinate, iopromide, iopanoic acid, iprindole hydrochloride, isoimazaline hydrochloride, isometholone hydrochloride, isoniazid, isoproterenol sulfate, isothiourea derivatives, ketoconazole, methylpiperizone hydrobromide, dexrazoxane, delavay, lobunox, levodopa, levomipramine hydrochloride, lidocaine hydrochloride, lisinopril, loperamide, lorazepam hydrochloride, losartan hydrochloride, mafenide hydrochloride, mebendazole, medroxyprogesterone, medetomidine hydrochloride, mefenamic acid, mefenrex hydrochloride, doxycycline, vitamin K, menthol, mibexaline hydrochloride, mefenfenacin, mefenamide sulfate, mefenamic acid, carbocaine hydrochloride, annine, mercaptopurine, mesterol, metahexedrea, maytansazone, methamphetamine, metaxyline bitartrate, metaxalone hydrochloride, metformin hydrochloride, methadone, estramic acid, methamphetamine hydrochloride, methandrostaphylol and mefenadine hydrochloride, methidathiozone, mexone, 8-methoxine, methotrexate, methothrexafen, methyl androstenediol, methyl estradiol, methyldopa, methyl nitrovinyl imidazole, methylphenylbarbituric acid, methylprednisolone and acetate, methylsulfosfamide, methyltestosterone, metoclopramide and hydrochloride, metoclopramide hydrochloride, metolazone, metronidazole benzoate, methyl linac acid, bradycardia hydrochloride, miconazole, midodrine hydrochloride, minoxidil hydrochloride, micafomycin, moclobemide, mefenozole, moperone, mopidanol, morphine, mupirocin, nabilone, nafagrel hydrochloride, nafcillin, nafoxidine hydrochloride, naftifine hydrochloride, nalidixic acid, nimodipine, nitrofluoromethane, nitrofuratoin, desmetamine, nososterone, norphenylephrine hydrochloride, norpiperacillin, norleucine, norpseudoephedrine hydrochloride, nortriptyline hydrochloride, kekelin hydrochloride, novobiocin, noxitilin, nystatin, ouabain G, oxacerone, oxaniquine, nordroxydiazepam, oxiradine citrate, oxicaine, oxyhexyltheobromine, propacetam hydrochloride, hydroxychlorosalicylanilide, oxyphenbutazone hydrochloride, oxyphenbutazone, oxytetracycline, pantolactone, paracetamol, praTOXENE, parsol 1789, paroxetine hydrochloride, penbutolol sulfate, N-penicillamine, penicillin G, pentamidine isethionate, pentazocine, pentobarbital, pentostatin, erucamonium bromide, pethidine hydrochloride, halocaine, N-acetyl paraethoxyaniline, fenoxathine hydrochloride, phenazine, phenazopyridine, phenelzine dihydrosulfate, bromoxyethyl hydrazine, bromophenylethylamine, norglycopyrrolate, phenmetrazine hydrochloride and salts, phenobarbital, methylphenethylamine hydrochloride, phensuamine, phentermine hydrochloride, phenylbutazone, demethylephedrine hydrochloride, phenytoin, phthalylthiazole, pilocarpine nitrate, pimeltin, pimozide, proparazine, piprazine, piperazine, piperazone, dibromopropyl piperazine, piribedil, piroxicam, pyrrollol, priocaine hydrochloride, prometone, propadifen hydrochloride, bis-thiopropane, progesterone, proline, promethazine, profarbital, propantheline bromide, naphthylisopropamide hydrochloride, phenoxazine, prothionamide, prothiocypodol hydrochloride, propoxyphylline, pseudoephedrine hydrochloride, dimethyl-4-hydroxytryptamine, Gymnolen, Piramide, pyrazinamide, pyrantel tartrate, pyridine derivatives, pyrimidines, pyrimidone derivatives, Podocosan hydrochloride, Pirazolone, Quercolone, quinine salts, Raclepride tartrate, Ramantadine, Renitorine hydrochloride, reserpine, Bromoninolanilide, resorcinol, riboflavin, Rifampicin, rotenone, salbutamol, salicylic acid, Hyoscyamine hydrochloride, Sesbitudin, ampicillin sodium, disodium Tryperidone, spironolactone, Spiromycin, eliminate Daxin, Conlimone, steroid hormones, streptomycin sulfate, Setepentanol, Succinimidyl, Sulfanamide, Sulfamidoyl, Sulfamidourea, Sulfamidoacetic acid, Sulfamethoxazine, sulfadiazine, pentene, Sulfadimidine, Sulfamethoxazole, Sulfanimisoxazole, Sulfalin, Sulfamethoxazine, methylene hydrochloride, Sulfamethoxazole, Sulfamethoxazine, sulfamethoxyzine, sulfamethylthiazole, sulfamonomethoxine, sulfamethoxazole, sulfambisaminoazobenzene, sulfanilamide, sulfamethamide methoxypyrimidine, sulfamonomethoxide, sulfamazole, sulfapyridine, sulfamoproline, sulfathiazole, sulfathiourea, sulfatriazine, sulfapyrazole, sulfisoxazole, sulfonamide, sulfadoxine, sulindac, suloctidil, sulpiride, tamoxifen citrate, terconazole, temazepam, terfenadine, terpineol, testosterone and salts, tetracaine hydrochloride, tetracycline, tetrazolium derivatives, hydroxolone hydrochloride, cocoa butter, theophylline, thiobarbital, vitamin B1 salts, thiamphenicol and salts, thiopental, allylthiourea, sulfometone, thiamethoxide, ticlopidine hydrochloride, telidine hydrochloride, timolol maleate, tinidazole, thiocoramide, tobramycin, tobucaine hydrochloride, tolbutadine, topiramine hydrochloride, tramazoline hydrochloride, tranilast, trazodone hydrochloride, triamcinolone diacetate, trimethoprim, trimetazidine, triperazine, tripareol, triamantane hydrochloride, trospium hydrochloride, tyramine, uracil, urapidil, usnic acid, verapamil hydrochloride, visotron, pentenbitol, retinoic acid, and tolbutal.

Examples

Example 1: preparation of itraconazole suspension by homogenization

To a 3 liter flask was added 1680mL of water, the liquid was heated to 60 c-65 c, and 44 grams of pullulan F-68 (poloxamer 188), and 12 grams of sodium deoxycholate were slowly added, with stirring after each addition of the solids. After complete addition of the solid, stir at 60 ℃ to 65 ℃ for 15 minutes to ensure complete dissolution. 50mM Tris (trimethylaminomethane) buffer was prepared for addition by dissolving 6.06 grams of Tris in 800mL of water. The solution was titrated with 0.1M hydrochloric acid to pH 8.0. The resulting solution was diluted to 1 liter with additional water. 200mL of Tris buffer was added to the poloxamer/deoxycholic acid solution. Thoroughly stirred to mix the solution.

To a 150mL beaker were added 20g of itraconazole and 120mL of N-methyl-2-pyrrolidone. The mixture was heated to 50-60 ℃ and stirred to dissolve the solids. After complete dissolution was visible, stirring was continued for 15 minutes to ensure complete dissolution. The itraconazole-NMP solution was cooled to room temperature.

The syringe pump (two 60-mL glass syringes) was filled with 120mL of the previously prepared itraconazole solution. All surfactant solutions were simultaneously poured into the homogenizer cylinder (jacketed cylinder through which a refrigerant was circulated, or cooled around the cylinder with ice) which had been cooled to 0-5 ℃. A mechanical stirrer was placed into the surfactant solution to completely wet the blades. The entire itraconazole solution was slowly (1-3mL/min) added to the stirred, cooled surfactant solution using a syringe pump. The stirring speed is preferably at least 700 rpm. The resulting suspension samples were analyzed by optical microscopy (Hoffman transform phase contrast) and laser diffraction (Horiba). The suspension was observed by light microscopy to contain roughly spherical amorphous particles (less than 1 micron), either bound to each other as aggregates or free to move by brownian motion. See fig. 1. Dynamic light scattering measurements typically provide a bimodal distribution pattern (10-100 micron particle size) indicative of the presence of polymer and amorphous particles in the medium particle size 200-700nm range.

The suspension is then homogenized (10,000 to 30,000psi) for 10-30 minutes. At the end of the homogenization, the temperature of the suspension in the vat does not exceed 75 ℃. The homogenized suspension was collected in a 500mL bottle and immediately cooled in a refrigerator (2 deg.C-8 deg.C). Suspension (suspension B) was analyzed by light microscopy and found to contain small elongated flakes having a length in the range of 0.5 to 2 microns and a width in the range of 0.2 to 1 micron. See fig. 2. Dynamic light scattering measurements generally represent a median particle size of 200-700 nm.

Stability of suspension A ("Pre-suspension") (example 1)

Upon microscopic examination of an aliquot of suspension a, crystallization of the amorphous solid was directly observed. Suspension A was stored at 2 deg.C-8 deg.C for 12 hours and examined by light microscopy. Gross visual inspection showed severe flocculation of the sample with some content settling to the bottom of the container. Microscopic examination revealed the presence of large, elongated plate-like crystals over 10 microns long.

Stability of suspension B

In contrast to the instability of suspension a, suspension B was stable at 2-8 ℃ during the primary stability study (1 month). Microscopy of the aged samples clearly showed no significant change in the morphology or particle size of the particles. This was confirmed by light scattering measurements.

Example 2: itraconazole suspensions were prepared using ultrasonication.

To a 500mL stainless steel container was added 252mL of water for injection. The liquid was heated to 60-65 deg.C, then 6.6 grams of Pluronic F-68 (Poloxamer 188), and 0.9 grams of sodium deoxycholate were slowly added, with stirring after each addition to dissolve the solids. After complete addition of the solid phase, it was stirred at 60-65 ℃ for 15 minutes to ensure complete dissolution. 50mM tris (tris) buffer was prepared by dissolving 6.06 g of tris in 800ml of water for injection. The solution was titrated with 0.1M hydrochloric acid to pH 8.0. The resulting solution was diluted to 1 liter with additional water for injection. To the poloxamer/deoxycholate solution was added 30ml of tris buffer. Stirring was sufficient to mix the solution.

In a 30mL vessel, 3 grams of itraconazole and 18mL of N-methyl-2-pyrrolidone were added. The mixture was heated to 50-60 ℃ and stirred to dissolve the solids. After complete dissolution was visible to the naked eye, stirring was continued for 15 minutes to ensure complete dissolution. The itraconazole-NMP solution was cooled to room temperature.

The syringe pump was filled with 18mL of itraconazole solution prepared previously. The mechanical stirrer was fixed to the surfactant solution so that the paddle was fully submerged. The vessel was cooled to 0-5 ℃ by immersion in an ice bath. The entire itraconazole solution was slowly (1-3mL/min) added to the stirred, cooled surfactant solution using a syringe pump. The stirring speed is preferably at least 700 rpm. The sonicator probe was immersed in the resulting suspension so that the probe was approximately 1cm above the bottom of the stainless steel vessel. Sonication (10,000 to 25,000Hz, at least 400W) is carried out for 15 to 20 minutes at 5 minute intervals. After 5-minutes sonication, the ice bath was removed and the subsequent sonication continued. At the end of the ultrasonication, the temperature of the suspension in the vessel did not exceed 75 ℃.

The homogenized suspension was collected in a 500mLI glass bottle and immediately cooled in a refrigerator (2 ℃ -8 ℃). The particle morphology characteristics of the suspension before and after sonication were similar to those before and after homogenization in example 1, respectively.

Example 3: itraconazole suspensions were prepared by homogenization.

50mM tris (tris) buffer was prepared by dissolving 6.06 g of tris in 800ml of water for injection. The solution was titrated with 0.1M hydrochloric acid to pH 8.0. The resulting solution was diluted to 1 liter with additional water for injection. 1680mL of water for injection was added to a 3L flask. 200mL of tris buffer were added to 1680mL of water. Stirring was sufficient to mix the solution.

44 grams of Pluronic F-68 (Poloxamer 188) was added to a 150mL beaker, and 12 grams of sodium deoxycholate was added to 120mL of N-methyl-2-pyrrolidone. The mixture was heated to 50-60 ℃ and stirred to dissolve the solids. After complete dissolution was visible to the naked eye, stirring was continued for 15 minutes to ensure complete dissolution. To the solution was added 20g of itraconazole and stirred until completely dissolved. The itraconazole-NMP solution was cooled to room temperature.

The syringe pump (two 60mL glass syringes) was filled with 120mL of the previously prepared concentrated itraconazole solution. The previously prepared diluted tris buffer solution was simultaneously added to the homogenizer cylinder (which may be by circulation of a refrigerant therethrough, or a jacketed water tank with ice surrounding the cylinder) which had been cooled to 0-5 ℃. The mechanical stirrer was fixed to the buffer solution so that the paddle was fully submerged. The entire itraconazole-surfactant concentrate was added slowly (1-3mL/min) to the already stirred, cooled buffer solution using a syringe pump. The stirring speed is preferably at least 700 rpm. The resulting cooled suspension is then homogenized (10,000 to 30,000psi) for 10-30 minutes. At the end of the homogenization, the temperature of the suspension in the vat does not exceed 75 ℃.

The homogenized suspension was collected in a 500mL bottle and immediately cooled in a refrigerator (2 deg.C-8 deg.C). The morphology of the suspension particles before and after homogenization was very similar to that of example 1, except that during this process the pre-homogenized material tended to form fewer and smaller aggregates, which resulted in smaller particle sizes as determined by laser diffraction. After homogenization, the dynamic light scattering results are typically the same as in example 1.

Example 4: itraconazole suspensions were prepared using ultrasonication.

To a 500mL flask was added 252mL of water for injection. 50mM tris (tris) buffer was prepared by dissolving 6.06 g of tris in 800ml of water for injection. The solution was titrated with 0.1M hydrochloric acid to pH 8.0. The resulting solution was diluted to 1 liter with additional water for injection. To 1680mL of water was added 30mL of tris buffer. Stirring was sufficient to mix the solution.

To a 30mL beaker was added 6.6 g of Pluronic F-68 (Poloxamer 188), and to 18mL of N-methyl-2-pyrrolidone was added 0.9 g of sodium deoxycholate. The mixture was heated to 50-60 ℃ and stirred to dissolve the solids. After complete dissolution was visible to the naked eye, stirring was continued for 15 minutes to ensure complete dissolution. To the solution was added 3.0g of itraconazole and stirred until completely dissolved. The itraconazole-NMP solution was cooled to room temperature.

The syringe pump (a 30mL glass syringe) was filled with 18mL of the previously prepared concentrated itraconazole solution. The mechanical stirrer was fixed to the buffer solution so that the paddle was fully submerged. The vessel was cooled to 0-5 ℃ by immersion in an ice bath. Using a syringe pump, the entire itraconazole-surfactant concentrate was slowly (1-3mL/min) added to the already stirred, cooled buffer solution. It is recommended that the stirring speed be at least 700 rpm. The resulting cooled suspension was immediately sonicated (10,000 to 25,000Hz, at least 400W) at 5 minute intervals for 15 to 20 minutes. After 5-minutes sonication, the ice bath was removed and the subsequent sonication continued. At the end of the sonication, the temperature of the suspension in the tank did not exceed 75 ℃.

The resulting suspension was collected in a 500mL bottle and immediately cooled in a refrigerator (2 deg.C-8 deg.C). The morphology of the suspension particles before and after sonication was very similar to that of example 1, except that during this process the pre-sonicated material tended to form fewer and smaller aggregates, as determined by laser diffraction, which produced smaller particle sizes. After sonication, the dynamic light scattering results are typically the same as in example 1.

Example 5: preparation of Ipomoea from 0.75% Solutol * HR (PEG-66012-hydroxystearic acid) Troconazole suspension (1%).

Solutol (2.25g) and itraconazole (3.0 g) were weighed into a beaker and 36mL of filtered N-methyl-2-pyrrolidone (NMP) was added. The mixture was stirred at low heat for approximately 15 minutes until the solution components dissolved. The solution was cooled to room temperature and filtered through a 0.2 micron filter under vacuum. Two 60ml syringes were filled with the filtered drug concentrate and placed in the syringe pump. The pump was set to deliver the concentrate to a rapidly stirred (400rpm) aqueous buffer solution at approximately 1 mL/min. The buffer solution contained 22g/L glycerol in 5mM tris buffer. The buffer solution was kept in an ice bath at 2-3 ℃ throughout the addition of the concentrate. At the end of the precipitation, after complete addition of the concentrate to the buffer solution, approximately 100mL of the suspension was centrifuged for 1 hour and the supernatant discarded. The pellet was resuspended in 20% aqueous NMP and centrifuged again for 1 hour. The material was dried in a vacuum oven at 25 ℃ overnight. The dried material was transferred into a vial and analyzed by X-ray diffractometry using chromium radiation (see figure 3).

20000Hz, 80% full-amplitude (600 w) sonicates an additional 100mL sample of the microprecipitation suspension for 30 minutes. 3 aliquots of the sample were sonicated for homogenization for 45 minutes (AvestinC5, 2 deg.C-5 deg.C, 15,000-. The composition components were centrifuged for about 3 hours, the supernatant removed and the pellet resuspended in 20% NMP. The resuspended mixture was centrifuged again (5 ℃, 15,000 rpm). The supernatant was discarded and the pellet was dried under vacuum at 25 ℃ overnight. The obtained precipitate was examined by X-ray diffractometry (see FIG. 3). As shown in fig. 3, the X-ray diffraction patterns of the samples treated before and after homogenization were substantially the same, while showing a significantly different pattern compared to the starting raw material. The unplasmified suspension is unstable and agglomerates when stored at room temperature. The stability resulting from homogenization is believed to result from surfactant rearrangement on the particle surface. Rearrangement results in a reduced tendency for particle polymerization.

Example 6: carbamazepine suspensions were prepared by homogenization.

2.08 grams of carbamazepine was dissolved in 10mL of NMP, and then 1.0mL of the concentrate was added dropwise at 0.1mL/min to a stirred 20mL of a 1.2% lecithin and 2.25% glycerol solution. The temperature of the lecithin system was maintained at 2-5 ℃ throughout the addition. The predispersion was then homogenized at 15,000psi low temperature (5-15 ℃) for 35 minutes. The pressure was increased to 23,000psi and homogenization continued for 20 minutes. The process produced particles having an average diameter of 0.881 μm, 99% of the particles being less than 2.44 μm.

Example 7: a 1% carbamazepine suspension was prepared by homogenization.

A 20% carbamazepine and 5% glycodeoxycholic acid (Sigma chemical) drug concentrate in N-methyl-2-pyrrolidone was prepared. The microprecipitation step involves the addition of drug concentrate to the receiving solution (distilled water) at a rate of 0.1 ml/min. The receiving solution was stirred and maintained at about 5 ℃ during precipitation. After precipitation, the final components were carbamazepine at a concentration of 1% and Solutol * at a concentration of 0.125%. The drug crystals were examined under an optical microscope using positive phase contrast (400X). The precipitate comprises fine needle-like crystals having a diameter of about 2 microns and a length of from 50 to 150 microns.

Homogenization (Avestin C-50 piston-open homogenizer) at about 20,000psi produced small particles that were less than 1 micron in size and substantially non-agglomerated for about 15 minutes. Laser diffraction analysis (Horiba) of the homogenized material showed an average particle size of 0.4 microns with 99% of the particles being less than 0.8 microns. Low energy sonication of the samples suitable for disrupting agglomerated particles without sufficient energy to produce a single particle unit had no effect on the results (with or without sonication in the same amount) prior to the Horiba analysis. The results were consistent with no particle agglomeration.

The sample prepared by the above procedure was centrifuged and the supernatant replaced with a displacement solution containing 0.125% Solutol *. After centrifugation and displacement of the supernatant, the suspension components were at 1% carbamazepine and 0.125% Solutol *. The samples were re-homogenized with a piston-open homogenizer and stored at 5 ℃. After 4 weeks storage, the suspension had an average particle size of 0.751, with 99% less than 1.729. The digital report is from a Horiba analysis of the non-sonicated sample.

Example 8: preparation of a solution in 0.06% sodium glycodeoxycholate and 0.06% poloxolate by homogenization A 1% carbamazepine suspension of xamm 188.

A drug concentrate containing 20% carbamazepine and 5% glycodeoxycholic acid (Sigma chemical) in N-methyl-2-pyrrolidone was prepared. The microprecipitation step involves the addition of drug concentrate to the receiving solution (distilled water) at a rate of 0.1 ml/min. Thus, this example and the examples below show that the above-described methods a and B can be selected to add surfactants or other excipients to the aqueous precipitation solution. The receiving solution was stirred and maintained at about 5 ℃ during precipitation. After precipitation, the final component concentrations were 1% carbamazepine and 0.125% Solutol *. The drug crystals were examined under an optical microscope using positive phase contrast (400X). The precipitate comprises fine needle-like crystals having a diameter of about 2 microns and a length of 50-150 microns. Comparison of the precipitated and pre-precipitated starting materials showed that the precipitation step in the presence of the surface modifier (glycodeoxycholic acid) produced very fine crystals, which were much finer than the starting material (see fig. 4).

Homogenization (Avestin C-50 piston-open homogenizer) at about 20,000psi produced small particles that were less than 1 micron in size and substantially non-agglomerated for about 15 minutes. See fig. 5. Laser diffraction analysis (Horiba) of the homogenized material showed that the particles had an average particle size of 0.4 microns with 99% of the particles being less than 0.8 microns. Sonication of the samples prior to Horiba analysis had no effect on the results (same values with and without sonication). The results were consistent with no particle agglomeration.

The sample prepared by the above procedure was centrifuged and the supernatant was replaced with a displacement solution containing 0.06% glycodeoxycholic acid (Sigma chemical) and 0.06% poloxamer 188. The samples were re-homogenized with a piston-open homogenizer and stored at 5 ℃. After 2 weeks of storage, the suspension had an average particle size of 0.531 microns with 99% less than 1.14 microns. The digital report is from a Horiba analysis of the non-sonicated sample.

Mathematical analysis of the pressure required to break down the precipitated particles compared to the pressure required to break down the starting raw material (carbamazepine) particles (example 8):

the width of the largest crystals seen in the carbamazepine starting material (fig. 4, left panel) was approximately 10 times greater than the width of the crystals in the microprecipitated material (fig. 4, right panel). Assuming that the ratio of crystal thickness (1: 10) is directly proportional to the ratio of crystal width (1: 10), the pressure required for large crystals in the cracking raw material should be about 1,000 times the pressure required to destroy the microprecipitated material, since:

e_L＝6PL/(Ewx²) Equation 1

Wherein,

e_Lthe longitudinal strain required to break the crystal ("yield value")

P-beam load

Distance between load and torsion point

E ═ elastic modulus

w is the crystal width

x is the crystal thickness

It is assumed that L and E are equal for the starting material and the precipitated precipitate. In addition, assume w/w₀＝x/x₀10. Then it is determined that,

(eL)₀＝6P₀L/(EW₀x₀ ²) Where the "0" subscript refers to the starting material

e_L＝6P_L/(Ewx²) For micro-precipitates

(e_L)₀And e_LAnd the identity of the two is identical,

6PL/(Ewx²)＝6P₀L/(Ew₀x₀ ²)

after the simplification, the operation is finished,

P＝P₀(w/w₀)(x/x₀)²＝P₀(0.1)(0.1)²＝0.001P₀

thus, the yield force, P, required to break the micro-precipitated solid is one thousandth of the force required to break the initial crystalline solid. If lattice defects or amorphous features are generated due to rapid precipitation, the modulus (E) should be reduced to make the microprecipitates more susceptible to cleavage.

Example 9: preparation 1.6% with 0.05% sodium deoxycholate and 3% N-methyl-2-pyrrolidone (w/v) prednisolone suspension

A schematic of the overall production process is shown in FIG. 6. A concentrated solution of prednisolone and sodium deoxycholate was prepared. To a sufficient volume of 1-methyl-2-pyrrolidone (NMP) was added prednisolone (32 g) and sodium deoxycholate (1 g). The resulting prednisolone concentration was approximately 533.3mg/mL, while the sodium deoxycholate concentration was approximately 16.67 mg/mL. 60mL of NMP concentrate was added to 2L of water cooled to 5 ℃ at an addition rate of 2.5mL/min with stirring at about 400 rpm. The obtained suspension contained elongated needle-like crystals with a width of less than 2pm (fig. 7). The precipitation suspension contained a concentrate of 1.6% (w/v) prednisolone, 0.05% sodium deoxycholate, and 3% NMP.

The precipitation suspension was adjusted to pH 7.5-8.5 with sodium hydroxide and hydrochloric acid and then homogenized 10 times at 10,000psi (Avestin C-50 piston-open homogenizer). NMP was removed by 2 successive centrifugation steps, each time replacing the supernatant with fresh surfactant solution containing the surfactant concentrate of interest to stabilize the suspension (see table 1). The suspension was homogenized 10 more times at 10,000 psi. The final suspension contained particles having an average particle size of less than 1 μm, 99% of the particles being less than 2 μm. Figure 8 is a photomicrograph of the final prednisolone suspension after homogenization.

Various concentrations of surfactant were used in the centrifugation/surfactant displacement step (see table 1). Table 1 lists combinations of surfactants whose particle size (average < 1 μm, 99% < 2 μm), drug concentration (less than 2% loss) and resuspendability (resuspend in 60 seconds or less) are stable.

In particular, the process allows the addition of the active compound to an aqueous diluent without surfactants or other additives.

Table 1: list of stable prednisolone suspensions prepared by the procedure of FIG. 6 (example 9)

			2 weeks		2 month
													Initiation of		40℃		5℃		25℃		40℃
Preparation	Average	＞99％	Average	＞99％	Average	＞99％	Average	＞99％	Average	＞99％	% loss*
												6% prednisolone, 0.6% phospholipid, 0.5% sodium deoxycholate, 5mM Tris, 2.2% glycerol**	0.79	1.65	0.84	1.79	0.83	1.86	0.82	1.78	0.82	1.93	2％
1.6% prednisolone, 0.6% solutol *, sodium deoxycholate, 2.2% glycerol	0.77	1.52	0.79	1.67	0.805	1.763	0.796	1.693	0.81	1.633	2％
												1.6% of prednisolone, 0.1% of poloxamer 188, 0.5% of sodium deoxycholate and 2.2% of glycerol	0.64	1.16	0.82	1.78	0.696	1.385	0.758	1.698	0.719	1.473	2％
1.6% prednisolone, 5% phospholipid, 5mM Tris, 2.2% glycerol	0.824	1.77	0.87	1.93	0.88	1.95	0.869	1.778	0.909	1.993	2％

^*Difference in itraconazole concentration between samples stored at 5 ℃ and 25 ℃ for 2 months.

^**Is stable for at least 6 months.

Particle size (measured by laser light scattering), expressed in microns:

5 ℃ of: 0.80 (average), 1.7 (99%)

25 ℃ of: 0.90 (average); 2.51 (99%)

40 ℃ C: 0.99 (average); 2.03 (99%)

Difference in itraconazole concentration between samples stored for 2 months at 5 and 25 ℃: is less than 2 percent.

Example 10: prednisolone suspensions are prepared using homogenization.

32 grams of prednisolone were dissolved in 40mL of NMP. Gentle heating at 40-50 ℃ is required for effective dissolution. The pharmaceutical NMP concentrate was then dropped at 2.5mL/min into 2 liters of a stirred solution containing 0.12% lecithin and 2.2% glycerol. No other surface modifier was added. The active agent system was buffered at pH 8.0 with 5mM tris buffer and the temperature was controlled at 0 ℃ to 5 ℃ throughout the precipitation. The post-precipitation suspension was homogenized 20 times at 10,000psi at low temperature (5-15 ℃). After homogenization, NMP is removed by centrifuging the suspension, removing the supernatant, and replacing the supernatant with fresh surfactant. The suspension was then centrifuged and re-homogenized at 10,000psi for 20 times at low temperature (5 ℃ -15 ℃). This procedure resulted in particles having an average diameter of 0.927 μm, with 99% of the particles being smaller than 2.36 μm.

Example 11: the nabumetone suspension was prepared by homogenization.

The surfactant (2.2 grams of poloxamer 188) was dissolved in 6mL of N-methyl-2-pyrrolidone. The solution was stirred at 45 ℃ for 15 minutes, then 1.0 g of nabumetone was added. The drug dissolves rapidly. A diluent containing 5mM tris buffer 2.2% glycerol was prepared and the pH adjusted to 8. 100mL of diluent was cooled in an ice bath. The drug concentrate was slowly (approximately 0.8mL/min) added to the diluent while stirring vigorously. The crude suspension was homogenized at 15,000psi for 30 minutes, then at 20,000psi for 30 minutes (temperature 5 ℃). The final nanosuspension had an effective average diameter of 930nm (as analyzed by laser diffraction). 99% of the particles are less than about 2.6 microns.

Example 12: preparation of naphthalene by homogenization and Solutol * HS15 as surfactant A suspension of bupropion. The supernatant was replaced with phospholipid medium.

Nabumetone (0.987 g) was dissolved in 8mL of N-methyl-2-pyrrolidone. To the solution was added 2.2 grams of Solutol * HS 15. The mixture is stirred until the surfactant is completely dissolved in the drug concentrate. A diluent containing 5mM tris buffer 2.2% glycerol was prepared and the pH adjusted to 8. The diluent was cooled in an ice bath and the drug concentrate was added slowly (approximately 0.5mL/min) to the diluent while stirring vigorously. The crude suspension was homogenized at 15,000psi for 20 minutes, and then at 20,000psi for 30 minutes.

The suspension was centrifuged at 15,000rpm for 15 minutes, and the supernatant removed and discarded. The remaining solid particles were resuspended in a diluent containing 1.2% phospholipids. The medium is the same volume as the amount of supernatant removed in the previous step. The resulting suspension was then homogenized at about 21,000psi for 30 minutes. The final suspension was analysed by laser diffraction and found to contain particles with an average diameter of 542nm and a 99% cumulative particle distribution of less than 1 micron.

Example 13: preparation of 1% Etqu soluble in poloxamer with a mean particle diameter of about 220nm And (3) a suspension of the conazole.

Itraconazole concentrate was prepared by dissolving 10.02 g of itraconazole concentrate in 60mL of N-methyl-2-pyrrolidone. Heating to 70 ℃ is required to dissolve the drug. The solution was then cooled to room temperature. 50mM tris (hydroxymethyl) aminomethane buffer (tris buffer) was prepared and the pH was adjusted to 8.0 with 5M hydrochloric acid. An aqueous surfactant solution containing 22g/L poloxamer 407, 3.0g/L lecithin, 22g/L glycerin, and 3.0g/L sodium cholate dihydrate was prepared. 900mL of the surfactant solution was mixed with 100mL of tris buffer to prepare 1000mL of aqueous diluent.

The aqueous diluent was added to the cylinder of the homogenizer (APV Gaulin model 15MR-8TA) and cooled using an ice jacket. The solution was stirred rapidly (4700rpm) and the temperature was monitored. Itraconazole concentrate was slowly added at a rate of about 2mL/min using a syringe pump. The addition was completed after about 30 minutes. The resulting suspension was stirred for an additional 30 minutes while cooling the cylinder with an ice jacket and aliquots were removed to examine dynamic light scattering by optical microscopy. The remaining suspension was then homogenized at 10,000psi for a further 15 minutes. At the end of the homogenization the temperature rose to 74 ℃. The homogenized suspension was collected in a 1L glass type I bottle and closed with a rubber stopper. The bottles containing the suspension were stored in a 5 ℃ refrigerator.

Suspension samples prior to homogenization showed that the samples contained free particles, particulate clumps, and multiple layers of lipid. Free particles cannot be clearly seen due to brownian motion; however, many polymers appear to be composed of amorphous, non-crystalline materials.

The homogenized sample contained free submicron fine particles with excellent size uniformity, with no visible lipid vesicles. Dynamic light scattering showed a monodisperse logarithmic particle size distribution with a median particle size of about 220 nm. The upper 99% cumulative size threshold is about 500 nm. Fig. 9 shows a comparison of particle size distribution of nanosuspensions prepared with a typical parenteral fat emulsion product (10% Intralipid *, Pharmacia).

Example 14: preparation of 1% itraconazole nano suspension by using hydroxyethyl starch

Preparation of solution a: hydroxyethyl starch (1 g, Ajinomoto Co.) was dissolved in 3mL of N-methyl-2-pyrrolidone (NMP). The solution was heated in a water bath at 70-80 ℃ for 1 hour. To a separate container was added 1 gram of itraconazole (Wyckoff corporation). 3mL of NMP was added and the mixture was heated (approximately 30 minutes) to 70-80 ℃ for efficient dissolution. Phospholipid (lipid S-100) was added to the hot solution. Heating at 70-90 deg.C for 30 min is continued until all phospholipids are dissolved. The hydroxyethyl starch solution was combined with the itraconazole/phospholipid solution. The mixture was dissolved by heating at 80-95 ℃ for an additional 30 minutes.

Solution a was added to tris buffer: 94mL of 50mM Tris buffer was cooled in an ice bath. The tris solution was stirred rapidly and the hot solution A (see above) was added slowly dropwise (less than 2 cc/min).

After the addition was complete, the suspension cooled in an ice bath was sonicated (Cole-Parmer sonicator, 20,000Hz, 80% amplitude modulation). A 1 inch solid probe was used. Sonication continued for a period of 5 minutes. The ice bath was removed, the probe removed and readjusted, and the probe again immersed in the suspension. The suspension was sonicated again for 5 minutes without an ice bath. The sonicator probe was removed again and readjusted and the sample sonicated for an additional 5 minutes after probe immersion. At this point, the suspension temperature rose to 82 ℃. The suspension was again rapidly cooled in an ice bath, poured into a type I glass bottle when below room temperature and closed. Microscopic examination of the particles revealed individual particle sizes of 1 micron or less.

After storage at room temperature for one year, the suspension particle size was re-checked and found to have an average diameter of about 300 nm.

Example 15: prophetic example of preparation of a 1% itraconazole suspension by adding HES to an aqueous solution For example.

The present invention followed the procedure of example 14, using hydroxymethyl starch to prepare a 1% itraconazole nanosuspension, except that HES was added to tris buffer instead of NMP solution. The aqueous solution was heated to dissolve the HES.

Example 16: seeding during homogenization to convert unstable polymorph to more A stable polymorph.

The starting material was prepared.Itraconazole nanosuspensions were prepared by a microprecipitation-homogenization method as follows. Itraconazole (3g) and Solutol * HS15(2.25g) were dissolved with stirring and heating at low temperature36mL of N-methyl-2-pyrrolidone (NMP) to form a drug concentrate. The solution was cooled to room temperature and the insoluble drug or particulate matter was removed under vacuum through a 0.2 μm nylon filter. The solution was observed under polarized light to ensure that no crystalline material was present after filtration. The drug concentrate was then added to approximately 264mL of aqueous buffer solution (22 g/L glycerol in 5mM buffer) at 1.0 mL/min. The aqueous solution was maintained at 2-3 deg.C and was continuously stirred at approximately 400rpm during the addition of the drug concentrate. Approximately 100mL of the resulting suspension was centrifuged and the solid particles were resuspended in a pre-filtered 20% aqueous NMP solution. The suspension was recentrifuged and the solid particles were transferred to a vacuum oven for overnight drying at 25 ℃. The resulting solid sample was labeled SMP 2 PRE.

Identification of the starting material.The SMP 2 PRE sample and the raw material itraconazole sample were analyzed using X-ray powder diffraction method. Measurements were performed using a Rigaku MiniFlex + instrument with a copper target, K β filter, at a voltage of 30 kv and a current of 40 ma. Data was collected using a 0.02 ° 2-theta step between 5 ° and 38 ° 2-theta and a scan speed of 0.25 ° 2-theta/min. The powder diffraction pattern obtained is shown in fig. 10. This pattern shows that SMP-2-PRE (fig. 10b) is significantly different from the starting material (fig. 10a), indicating the presence of a different polymorph or pseudopolymorph. The X-ray powder diffraction pattern of SMP-2-PRE showed peaks expressed in degrees 2-theta consistent with those in Table 2.

Table 2: peaks in degrees 2-theta of 2-theta X-ray powder diffraction pattern of SMP-2-PRE

2-θ	d(A)	I％
			7.3108.88010.38610.58911.21012.27613.21013.61814.14814.60015.77316.52917.68218.72219.10019.93120.91021.29021.87023.10024.05024.60024.94026.14027.08027.49028.50028.88029.27129.59930.24132.21032.91934.740	12.08299.94978.51008.34757.88647.20386.69676.49686.25496.06205.61385.35875.01184.73584.64294.45104.24484.17004.06063.84723.69733.61593.56733.40623.29003.24203.12933.08893.04863.01552.95302.77682.71862.5801	16.44.01.12.46.73.82.66.115.73.56.46.1100.037.817.532.43.34.034.013.213.714.42.517.614.46.96.64.63.84.63.210.41.63.3

Fourier Transform Infrared (FTIR) spectra of itraconazole polymorphs are shown in fig. 16a and 16 b. FIG. 16a is a Fourier Transform Infrared (FTIR) spectrum of itraconazole starting material and FIG. 16b is a Fourier Transform Infrared (FTIR) spectrum of SMP-2-PRE.

Differential Scanning Calorimetry (DSC) traces of the samples are shown in fig. 11a and 11 b. Both samples were heated to 180 ℃ in sealed aluminum cans at 2 °/min.

The trace of the starting material itraconazole (fig. 11a) shows a sharp endotherm at about 165 ℃ and a melting enthalpy of about 87J/g.

The trace for SMP 2 PRE (FIG. 11b) shows an endotherm at about 153 ℃ and a melting enthalpy of about 68J/g. This result, combined with the powder X-ray diffraction pattern and FTIR spectra, suggests that SMP 2 PRE is a new polymorph that is less stable than the polymorph present in the starting material.

Evidence of this conclusion is further provided by the DSC trace of fig. 12, which indicates that upon heating the SMP 2 PRE through a first transformation, followed by cooling and reheating, the less stable polymorph melts and recrystallizes to form a more stable polymorph.

The conversion of the starting material to a more stable polymorph.0.2g of solid SMP 2 PRE and 0.2g of the starting material itraconazole were dissolved with distilled water to a final volume of 20mL (inoculated sample)Thereby preparing a suspension. The suspension was stirred until all solid particles were wetted. A second suspension was prepared in the same manner, but without the addition of itraconazole starting material (unseeded sample). The resulting suspension was then homogenized at approximately 18,000psi for 30 minutes. The final temperature of the suspension after homogenization was about 30 ℃. The approximate particle size of the particles in both suspensions ranged from 0.5 to 2.5 microns as determined by light microscopy. The suspension was then centrifuged and the solid particles were dried at 30 ℃ for approximately 16 hours.

Figure 13 shows DSC traces for seeded and unseeded samples. In a sealed aluminum can, both samples were heated to 180 ℃ at a heating rate of 2 °/min. The trace of the unseeded sample shows two endotherms, indicating that unstable polymorph remains after homogenization. The traces of the seeded samples show that seeding and homogenization results in the transition of the solid particles to a stable polymorph. Thus, seeding appears to affect the transition from the unstable to the more stable polymorph.

Example 17: seeding during precipitation preferentially forms stable polymorphs

And (4) preparing a sample. itraconazole-NMP drug concentrate was prepared by dissolving 1.67g of itraconazole in 10mL of NMP with stirring and mild heating. The solution was filtered twice using a 0.2 μm syringe filter. To 20mL of the aqueous receiving solution, 1.2mL of the drug concentrate was added with stirring at about 500rpm at about 3 ℃ to prepare an itraconazole nanosuspension. A seeded nanosuspension was prepared using approximately 0.02g of the starting material itraconazole and a mixture with distilled water as a receiving solution. Unseeded nanosuspensions were prepared using distilled water alone as the receiving solution. Both suspensions were centrifuged, the supernatant discarded, and the solid particles were dried in a vacuum oven at 30 ℃ for approximately 16 hours.

And (5) identifying the sample.Figure 14 shows a comparison of DSC traces of solid particles from seeded and unseeded suspensions. The sample was heated to 180 ℃ in a sealed aluminum can at 2 °/min. The dotted line represents unseededThe sample of (2), showing two endotherms, indicates the presence of a mixture of polymorphs.

The solid line represents the seeded sample, showing a single endotherm near the expected melting temperature of the starting material, indicating that the seeded material induces the exclusive formation of a more stable polymorph.

Example 18: polymorph control by seeding with drug concentrate

And (4) preparing a sample.Itraconazole solubility in NMP at room temperature (about 22 ℃) was determined experimentally to be 0.16 g/mL. A0.20 g/mL drug concentrate was prepared by dissolving 2.0g of itraconazole and 0.2g of poloxamer 188 in 10mL of NMP with heating and stirring. The solution was then cooled to room temperature to obtain a supersaturated solution. A micro-precipitation experiment was immediately performed by adding 1.5mL of the drug concentrate to 30mL of an aqueous solution containing 0.1% deoxycholate and 2.2% glycerol. The aqueous solution was maintained at-2 ℃ during the addition and a stirring speed of 350 rpm. The resulting pre-suspension was homogenized at about 13,000psi for about 10 minutes at 50 ℃. Most of the suspended particles were smaller than 1 micron as determined by optical microscopy. The suspension was then centrifuged, the supernatant discarded, and the solid crystals were dried in a vacuum oven at 30 ℃ for 135 hours.

The supersaturated drug concentrate is then aged by storage at room temperature to induce crystallization. After 12 days, the drug concentrate became turbid, indicating that crystal growth had occurred. An itraconazole suspension was prepared from the drug concentrate by adding 1.5mL of the drug concentrate to 30mL of an aqueous solution containing 0.1% deoxycholate and 2.2% glycerol in the same manner as in the first experiment. The aqueous solution was maintained at-5 ℃ and a stirring speed of 350rpm during the addition. The resulting pre-suspension was homogenized at 13,000psi for approximately 10 minutes at 50 ℃. The suspension was then centrifuged, the supernatant discarded, and the solid crystals were dried in a vacuum oven at 30 ℃ for 135 hours.

And (5) identifying the sample.The morphology of the dried crystals was determined by X-ray powder diffraction inspection. The powder diffraction pattern obtained is shown in fig. 15. From the first oneThe crystals of the experiment (using fresh drug concentrate) were determined to contain the more stable polymorph. In contrast, the crystals from the second experiment (aged drug concentrate) consisted primarily of the less stable polymorph, also with a small amount of the more stable polymorph.

Example 19: prophetic examples of seeding by emulsion precipitation to form stable polymorphs.

The present invention contemplates the preparation of submicron sized particles of water insoluble compounds with stable polymorphic forms. The process uses the steps of first dissolving a starting compound material in an organic solvent that is immiscible with water to form a solution at or near the saturation point of the compound. The solution is then mixed with an excess of aqueous solution containing a surface active modifier and a small amount of a stable polymorph of the compound to form a multiphase suspension of the organic solvent in aqueous solution. Freezing and lyophilizing the multiphase suspension to remove the liquid phase of the suspension to form submicron particulates of the stable polymorph of the compound. Alternatively, a small amount of the stable polymorph of the compound can be added to an organic solvent solution of the compound, either before the mixing step or after mixing but before the freezing step, so that the amount in the original solution exceeds the solubility of the polymorph.

Example 20: seeding during microprecipitation-homogenization to preferentially form stabilization Of (2) a polymorph of

A 2-liter batch of itraconazole nanosuspension was prepared as follows. A drug concentrate containing 20g of itraconazole and 2g of poloxamer 188 in 120mL of N-methyl-2-pyrrolidone (NMP) was added to an aqueous solution containing 2% mannitol and 0.1% sodium deoxycholate. The pre-suspension was then re-homogenized 15 times at 10,000 psi. The suspension was centrifuged to remove NMP and the supernatant was replaced with a fresh solution containing 0.1% poloxamer 188, 0.1% sodium deoxycholate, and 2% mannitol. The suspension was then re-homogenized 15 additional times at 10,000 psi. The nanosuspension samples were tested by X-ray powder diffraction and were found to contain a mixture of polymorphs. Laser diffraction analysis gave the suspension an average particle size of 0.43 microns with 99% of the particles being less than 0.81 microns.

The above process was repeated except for seeding. Approximately 20mL of the existing nanosuspension was added to the aqueous solution prior to the precipitation step to seed. Existing nanosuspensions have previously been characterized by X-ray powder diffraction to contain only stable polymorphic forms. The subsequent steps are performed as above. Existing nanosuspension samples previously contained only stable polymorphic forms as measured by X-ray powder diffraction. Laser diffraction analysis gave the suspension an average particle size of 0.35 microns with 99% of the particles being less than 0.63 microns.

Example 21: seeding during microprecipitation-homogenization to preferentially form metastable state Of (2) a polymorph of

A 10 liter batch of itraconazole nanosuspension was prepared as follows. An aqueous solution was prepared containing 2.2% glycerol, 0.1% sodium deoxycholate, and approximately 80mL of an existing nanosuspension previously identified by X-ray powder diffraction to contain metastable polymorph. 1200mL of N-methyl-2-pyrrolidone drug concentrate containing 100g of itraconazole and 10g of poloxamer 188 was added to the aqueous solution to form a pre-suspension. The pre-suspension was then re-homogenized 15 times at 10,000 psi. The suspension was centrifuged to remove NMP and the supernatant was replaced with a fresh solution containing 0.1% poloxamer 188, 0.1% sodium deoxycholate, and 2.2% glycerol. The suspension was then re-homogenized for an additional 15 times at 10,000 psi. Prior nanosuspension samples previously tested by X-ray powder diffraction contained only metastable polymorphs. Laser diffraction analysis gave the suspension an average particle size of 0.20 microns with 99% of the particles being less than 0.39 microns.

Example 22: by milling the conversion of the metastable polymorph to the stable polymorph.

Itraconazole nanosuspensions were prepared as follows. A drug concentrate was prepared by dissolving 0.625g of Solutol HS and 0.833g of itraconazole in 10mL of N-methyl-2-pyrrolidone (NMP) with heating at low temperature and stirring. The drug concentrate was filtered using a 0.2 micron syringe filter. The suspension was then prepared by adding 7.2mL of the filtered drug concentrate to 52.8mL of an aqueous buffer solution containing 2.2% glycerol and 5mM Tris. The mixture was kept at 5 ℃ and stirred at 400rpm during the addition. The resulting suspension was centrifuged and the supernatant was replaced with 20% aqueous NMP. The solid particles were resuspended by shaking and then recentrifugation. The supernatant was then discarded and the solid particles were dried in a vacuum oven at 25 ℃. A sample of the powder obtained was analyzed by Differential Scanning Calorimetry (DSC) and found to contain a mixture of polymorphs. Figure 17a shows the DSC trace for the sample. The second powder sample was ground using a mortar and pestle and then subjected to DSC analysis. As shown in fig. 17b, the DSC trace of the sample showed that most samples were more stable polymorphic. It is therefore concluded that stable form components are present in the powder before it is used as a seeding material by milling to promote the transition of the metastable material to a stable form.

While particular embodiments have been illustrated and described, numerous modifications come to mind without departing from the spirit of the invention and the scope of protection is only limited by the scope of the accompanying claims.

Claims (111)

1. A process for preparing particles of a pharmaceutical compound having polymorphic form and particle size control comprising the steps of:

providing a drug compound in a first phase;

introducing a seed compound;

(ii) phase transformation of the pharmaceutical compound into a second phase of the polymorph of interest; and

wherein the particles have an average particle size of less than 7 μm.

2. The method according to claim 1, wherein the pharmaceutical compound is selected from the group consisting of pharmaceutically active compounds and pharmaceutical excipients.

3. The process according to claim 2, wherein the first phase is selected from the group consisting of ultra-cold liquid, amorphous, semi-crystalline and first polymorphic crystalline forms.

4. The method according to claim 1, wherein the step of providing the pharmaceutical compound comprises the step of adding the pharmaceutical compound to a diluent.

5. The method according to claim 4, wherein the pharmaceutical compound is soluble in a diluent.

6. The method according to claim 4, wherein the pharmaceutical compound is insoluble in the diluent.

7. A process according to claim 4 wherein the diluent is a solid, liquid or compressed gas.

8. The method of claim 4, wherein the step of inducing a phase change comprises a 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 inducing a phase change comprises the step of precipitating the pharmaceutical compound from a diluent.

10. The method according to claim 9, wherein the step of precipitating the compound is accomplished by a method selected from the group consisting of: micro-precipitation, emulsion precipitation, solvent anti-solvent precipitation, phase inversion precipitation, pH shift precipitation, infusion precipitation, temperature change precipitation, solvent evaporation precipitation, reaction precipitation, and compressed fluid precipitation.

11. The method according to claim 10, wherein the diluent is an organic solvent.

12. The method according to claim 11, wherein the diluent is water-miscible.

13. The method according to claim 12, further comprising the step of providing an aqueous solution and wherein the step of precipitating the pharmaceutical compound comprises the step of mixing the diluent and the pharmaceutical compound with the aqueous solution to form a pre-suspension.

14. The method of claim 13, wherein the seeding step comprises the step of seeding at least one liquid selected from the group consisting of: diluent, aqueous solution and pre-suspension.

15. The method according to claim 14, wherein the step of mixing comprises the step of adding a diluent and the pharmaceutical compound to the aqueous solution.

16. The method according to claim 15, further comprising the step of removing the diluent.

17. The method according to claim 15, further comprising the step of subjecting the pre-suspension to high shear mixing.

18. The method according to claim 10, wherein the diluent is water-immiscible, and further comprising the step of providing an aqueous solution.

19. The method according to claim 18, further comprising the step of mixing the water-immiscible diluent and the pharmaceutical compound with an aqueous solution to form an emulsion.

20. The method according to 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 seeding step comprises the step of seeding a liquid selected from the group consisting of: diluents, aqueous solutions and emulsions.

22. The method according to claim 5, wherein the diluent has a first pH, wherein the pharmaceutical compound has a first solubility such that the compound is soluble in the diluent, and wherein the precipitating step comprises the step of changing the pH of the diluent to a second pH, wherein the compound has a second solubility that is lower than the first solubility, and precipitating the compound 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 soluble in the diluent, and wherein the precipitating step comprises the step of lowering the temperature of the diluent to a second temperature, wherein the compound has a second solubility that is lower than the first solubility, and precipitating the compound from the diluent.

24. The method according to claim 5, wherein the precipitating step comprises the step of removing a portion of the diluent.

25. The method according to claim 5, wherein the compound is dissolved in a diluent to form a first solution and wherein the step of precipitating the compound comprises the step of mixing the first solution with a compressed liquid.

26. The method of claim 25, wherein the compressed liquid is selected from the group consisting of a gas, a liquid, or a supercritical liquid.

27. The method of claim 1, wherein the step of inducing a phase change is performed by mechanically abrading the compound.

28. The method of claim 27, wherein the step of mechanically milling is selected from the group consisting of: ball milling, pearl milling, hammer milling, hydraulic milling and grinding with a mortar and pestle.

29. The method according to claim 6, wherein the pharmaceutical compound is insoluble in the diluent and wherein the step of inducing a phase change is adding energy to the diluent.

30. The method according to claim 29, wherein the step of adding energy is accomplished by a method selected from the group consisting of mechanical milling and high shear mixing.

31. The method of claim 30, wherein the step of mechanically milling is a method selected from the group consisting of ball milling, pearl milling, dry milling and wet milling.

32. The method of claim 30 wherein the high shear mixing step is performed using a device selected from the group consisting of: a homogenizer, a piston gap homogenizer, a counter-flow homogenizer, a microfluidization bed device, and an ultrasonograph.

33. The method according to claim 1, wherein the average particle size of the compound is less than 3 μm.

34. The method according to claim 1, wherein the average particle size of the compound is less than 1 μm.

35. The method of claim 1, wherein the average particle size of the compound is less than 500 nm.

36. A method of preparing submicron-sized particles of a pharmaceutical compound, comprising the steps of:

dissolving a pharmaceutical compound in a first solvent to form a first solution;

precipitating the drug compound to form a pre-suspension;

seeding the first solution or pre-suspension; and

wherein the compound in the pre-suspension is in the form of particles having an average particle size of less than 7 μm and the particles are of the desired polymorph.

37. The method according to 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 a pre-suspension, and wherein the compound has a greater solubility in the first solvent than in the second solvent.

38. The method according to claim 36, further comprising the step of converting a first phase of the pharmaceutical compound selected from the group consisting of an ultra-cold liquid having a first polymorphic form, amorphous particles, semi-crystalline particles and crystalline particles to a second phase having a desired polymorphic form.

39. The method of claim 38, further comprising the step of adding energy to the pre-suspension.

40. The method according to claim 39, wherein the adding-energy step comprises the step of subjecting the pre-suspension to high shear conditions selected from the group consisting of: cavitation, shearing or impact with high energy agitation using microfluidizer, piston gap homogenizer or counter current homogenizer.

41. The method according to claim 39, wherein the adding-energy step comprises the step of heating the pre-suspension.

42. The method according to claim 39, wherein the step of adding-energy comprises the step of exposing the pre-suspension to electromagnetic energy.

43. A method according to claim 42 wherein the step of exposing the pre-suspension to electrical energy comprises the step of exposing the pre-suspension to a laser beam.

44. The method of claim 38 wherein the seeding step comprises the step of utilizing a seeding compound.

45. The process according to claim 44, wherein the seed compound is the polymorph of interest of a pharmaceutical compound.

46. A process according to claim 44, wherein the seed compound is a compound other than the polymorph of interest of the pharmaceutical compound.

47. The method according to claim 46, wherein the seed compound is selected from the group consisting of: inert impurities; and organic compounds having a structure similar to the polymorph of interest.

48. The method of claim 44, wherein a seed compound is added to the first solution.

49. The method of claim 44, wherein a seed compound is added to the second solvent.

50. The method according to claim 44, wherein a seed compound is added to the pre-suspension.

51. A process according to claim 44, wherein the step of forming the polymorph of interest comprises the step of forming a seed compound in the first solution.

52. A method according to claim 51, wherein the step of forming the seed compound in the first solution comprises the step of adding a sufficient amount of the drug compound to exceed the solubility of the drug compound in the first solvent to produce a supersaturated solution.

53. The method of claim 51 wherein the step of forming a 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 a step of a method selected from the group consisting of: aging the supersaturated solution, changing the solution temperature, and changing the solution pH.

55. The method according to claim 36, wherein the seeding step comprises the step of forming the seeding compound using electromagnetic energy.

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 seeding step comprises the step of forming a seeding compound using a particle beam.

60. The method according to claim 36, wherein the seeding step comprises the step of forming a seeding compound using an electron beam.

61. The method of claim 36, wherein the seeding step comprises the step of forming a seeding compound using ultrasound.

62. The method of claim 36, wherein the seeding step comprises the step of forming the seeding compound using an electrostatic field.

63. The method of claim 36, wherein the seeding step comprises the step of forming a seeding compound using a static magnetic field.

64. The method of claim 36, wherein the particles have an average particle size of less than about 2 μm.

65. The method of claim 36, wherein the particles have an average particle size of less than about 500 nm.

66. The method of claim 36, wherein the particles have an average particle size of less than 200 nm.

67. The method of claim 37, further comprising a surface active compound in the pre-suspension.

68. The method of claim 36, further comprising the steps of providing a second solvent and mixing the first solvent and the second solvent.

69. The method according to claim 68, wherein the second solvent is selected from the group consisting of: a solvent miscible with the first solvent and a solvent 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 the 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 precipitate the compound in the aqueous phase to form a pre-suspension.

72. The method of claim 70, wherein the seeding step comprises the step of seeding the first solution, the second solvent, or the pre-suspension.

73. The method according to claim 70, wherein the step of mixing the water-immiscible organic solvent and the aqueous solution to form a multiphase system comprises using a piston gap homogenizer, colloid milling, high speed stirring, extrusion, manual agitation or shaking, microfluidization, or other high shear conditions.

74. The method of claim 71, wherein the aqueous phase is substantially free of organic solvent after the sonication.

75. The method according to claim 70, further comprising the step of evaporating the organic solvent by a method selected from the group consisting of: freeze drying, rotary evaporation and spray drying.

76. The method according to claim 36, wherein the precipitating step is by changing the pH of the first solvent.

77. The method according to claim 36, wherein the step of dissolving the drug compound in the first solvent comprises bringing the first solvent to a first temperature to form a first solution and then 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 first solvent is mixed with the second solvent by injecting 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 liquid.

83. The method of claim 82, wherein the compressed liquid is a supercritical liquid.

84. The method according to claim 36, wherein the precipitating step comprises the step of reacting the compound to form a modified compound, wherein the modified compound has less solubility in the first solvent than the compound.

85. A method according to claim 84, wherein the step of causing the first compound to react comprises the step of adding a drug to chemically react with the first compound or adding energy to cause modification of the first compound.

86. The method according to claim 36, wherein the precipitating step comprises the step of evaporating a portion of the volume of the first solvent.

87. A method of preparing submicron-sized particles of a pharmaceutical compound, comprising the steps of:

dissolving a pharmaceutical compound in a first solvent to form a first solution;

mixing the first solution with a second solvent to precipitate particles of the pharmaceutical compound to form a pre-suspension, wherein the solubility of the pharmaceutical compound in the first solvent is greater than the solubility in the second solvent;

introducing a seeding compound into the first solution or the second solvent or the pre-suspension;

adding energy to the pre-suspension; and

wherein the particles have an average particle size of less than 500 nm.

88. The method according to claim 87, further comprising the step of forming the polymorphic pharmaceutical compound of interest.

89. A process according to claim 88, wherein the seed compound is a pharmaceutical compound of the polymorphic form of interest.

90. A process according to claim 88, wherein the seed compound is a compound other than the pharmaceutical compound of the polymorphic form of interest.

91. The method of claim 90, wherein the seed compound is selected from the group consisting of: inert impurities; and organic compounds having a structure similar to the polymorph of interest.

92. The method of claim 87, wherein a seed compound is added to the first solution.

93. The method of claim 87, wherein a seed compound is added to the second solvent.

94. The method of claim 87, wherein a seed compound is added to the pre-suspension.

95. A method according to claim 87, wherein the step of forming the polymorph of interest comprises the step of forming a seed compound in the first solution.

96. A method according to claim 95, wherein the step of forming the seed compound in the first solution comprises the step of adding a sufficient amount of the drug compound to exceed the solubility of the drug compound in the first solvent to produce 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. A method according to claim 97 wherein the step of treating the supersaturated solution comprises the step of a method selected from the group consisting of: aging the supersaturated solution, changing the temperature of the solution, or changing the pH of the solution.

99. The method of claim 87, wherein the energy adding step comprises the step of using a device selected from the group consisting of: homogenizer, piston gap homogenizer, countercurrent homogenizer, microfluidization bed ware, milling device and ultrasonograph.

100. A method of preparing submicron-sized particles of a pharmaceutical compound, comprising the steps of:

adding a sufficient amount of the drug compound to the first solvent to produce a supersaturated solution;

aging the supersaturated solution to form detectable crystals to produce a seeding mixture; and

the crystallization mixture is mixed with a second solvent to precipitate the drug compound to form a pre-suspension, wherein the drug compound has a greater solubility in the first solvent than in the second solvent.

101. The method according to claim 100, further comprising the step of converting the compound in the pre-suspension from a first phase selected from the group consisting of: ultra-cold liquids, amorphous particles, semi-crystalline particles, and crystalline particles.

102. The method of claim 101, wherein the step of converting the compound comprises the step of adding energy to the pre-suspension.

103. The method of claim 102, wherein the adding-energy step comprises the step of heating the pre-suspension.

104. The method of claim 102, wherein the step of adding-energy comprises the step of exposing the pre-suspension to electromagnetic energy.

105. The method of claim 104, wherein the step of exposing the pre-suspension to electromagnetic energy comprises the step of exposing the pre-suspension 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: homogenizer, piston gap homogenizer, countercurrent homogenizer, microfluidizer, milling device and ultrasonoscope.

107. A process for preparing a sub-micron particle size suspension of a pharmaceutical compound having a desired polymorphic form, comprising the steps of:

providing a suitable carrier for the pharmaceutical compound;

dispersing a pharmaceutical compound in a carrier to form a pre-suspension;

applying energy to the pre-suspension; and

seeding the pre-suspension produces particles of the pharmaceutical compound having an average effective particle size of less than 500nm and having the polymorph of interest.

108. The method of claim 107, wherein the applying energy step is performed using a technique selected from the group consisting of: mechanical milling, microfluidization, homogenization and ultrasonication.

109. A polymorphic crystalline form of itraconazole having substantially the same X-ray diffraction pattern as shown in figure 10b, characterized by peaks with 2-theta values of about 7.3 °, 19.9 °, 21.9 °, 26.1 °, and 32.2 °.

110. The polymorphic form of itraconazole according to claim 109 further having an FTIR spectrum substantially the same as shown in figure 16 b.

111. The polymorphic itraconazole according to claim 109, further having a DSC pattern substantially the same as shown in figure 11 b.

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