WO2009039281A2

WO2009039281A2 - Particle drying apparatus and methods for forming dry particles

Info

Publication number: WO2009039281A2
Application number: PCT/US2008/076863
Authority: WO
Inventors: Willard Foss; Paul Burke; Robert Platz; Michael Kennedy
Original assignee: Amgen Inc.
Priority date: 2007-09-19
Filing date: 2008-09-18
Publication date: 2009-03-26
Also published as: WO2009039281A3

Abstract

A novel multistage particle dryer is disclosed for producing dry particles. The dryer is capable of forming particles with a low residual content of volatile material, suitable particle sizes and a solid, spherical morphology. The disclosed methods and equipment can be used to generate microparticles in an enclosed sanitizable environment with desirable product attributes in a rapid single-step operation, obviating the need for secondary drying.

Description

TITLE OF THE INVENTION

PARTICLE DRYING APPARATUS AND METHODS FOR FORMING DRY

PARTICLES

BACKGROUND

[0001] Small particles containing a mixture of chemical components are widely useful in a variety of industries. In fact, any industry producing dry powdered material as an end-product or intermediate could potentially be served by new particle compositions and/or methods for producing them.

[0002] In the pharmaceutical industry for example, small particulate compositions can be components of active pharmaceutical ingredients (APIs) that can be included in a wide variety of dosage forms. Particles containing active agents can also make up the entire formulation, such as in formulations for sustained or controlled release or for pulmonary delivery.

[0003] Small particles frequently find use in controlled release formulations. These formulations have been developed in response to the need for treating diseases with a constant level of medicament over sustained time periods. This generally results in more effective prophylactic, therapeutic or diagnostic results. Medicaments that are given in more traditional formulations generally result in fluctuating medication levels despite efforts to exert control over the doses and time intervals of their administration.

[0004] In addition, microparticles suitable for systemic delivery of medicaments have the benefit of being injectable either sub-cutaneously or intramuscularly, generally with a small gauge needle and without the need for incisions or implantation. The inherent biodegradability of certain polymers can also be used in such compositions to improve or modulate the release of the medicament and provide additional control over consistent and even concentrations of medicaments in the body.

[0005] Spray drying can be an effective and efficient method for manufacture of small polymeric particles. However, one difficulty associated with this technique is the removal of the potentially harmful formulating solvent(s) to safe levels. In addition, although the formation of a spherical and solid particle morphology can be highly desirable for evenly controlled drug release, such particle morphologies can be difficult to obtain using traditional spray drying techniques.

[0006] Traditional spray drying equipment generally consists of a single drying chamber that is generally operated at a single drying temperature. The drying temperature must be kept low enough, and certainly below the glass transition temperature (Tg) of the particles, to avoid particle agglomeration and the adhesion of particles to the chamber surfaces. Polymeric microparticles prepared with such equipment using traditional methodologies often contain undesirably high levels of residual solvents and can require lengthy secondary drying steps to reduce their concentrations to acceptable levels. Moreover, most known spray dryers are unsuitable for aseptic processing, as they generally do not provide for complete drying of particles in a sanitizable, aseptic, closed system.

SUMMARY

[0007] Multistage spray drying apparatus and spray drying methods are disclosed for the manufacture of dry particles. Particles having surprisingly low residual content of volatile materials can be prepared by the disclosed equipment and methods. In addition, substantially homogeneous and solid particles can be made having a substantially spherical morphology. Other morphologies can also be made. The disclosed equipment also can be configured as a closed sanitizable environment which can be used to produce particles in a pharmaceutically acceptable manner.

[0008] To these ends a spray drying apparatus is disclosed that includes a chamber through which particles and a gas can be passed. In an embodiment, the gas can have a temperature above the glass transition temperature of a polymer in the particles. At such temperatures the evaporation of volatile material from the particle occurs more quickly and the amount of residual volatile material in the particles can be reduced to lower concentrations. Preferably, the drying particles are entrained in the gas and pass through the center of the chamber without contacting the walls of the chamber to any appreciable extent. More preferably, the gas and the drying particles pass through the system in a laminar flow. Advantageously, no extra-particulate excipients are required to obtain the drying levels achievable with the disclosed apparatus and methods. Moreover, these drying levels can be achieved without agglomeration.

[0009] Methods for preparing dry solid particles are also disclosed. In a method, a droplet containing a particle-forming material in a volatile material, such as a dissolved polymer in a solvent, can be passed through a chamber containing a drying gas. The volatile material can be evaporated from the particle until a particle having about three (3) percent, more preferably about two (2) percent, even more preferably about one (1) percent, more preferably about 0.75 percent and yet more preferably about 0.66 percent or about 0.5% or less of residual volatile material, by mass, is formed, as desired. The droplet containing the particle-forming material can contain various other components including active agents, such as peptides, proteins, vitamins, or small molecules; excipients; fillers; encapsulated particulates or stabilizers, for example. Alternatively, the particle-forming material or one or more of the other components can be suspended or emulsified in a non-solvent. The method can be used to prepared particles such that the majority of particles are in a nonagglomerated state, termed for purposes of this application a substantially nonagglomerated state.

[0010] In an embodiment, a spray drying apparatus is disclosed that has a drying chamber that contains a mixture of a gas and particles that contain both a particle-forming material and a volatile material, such as a solvent, for that particle-forming material. The gas can have a temperature above the glass transition temperature of the particle-forming material. The gas and particle mixture can flow through the drying chamber from an inlet port to an exit port, preferably without contacting the walls of the chamber. The exit port of the drying chamber can be fluidly connected to another chamber such that particles and gas exiting the drying chamber enter the second chamber. The second chamber can contain a gas below the glass transition temperature of the particle-forming material such that the particles dried in the drying chamber can be cooled to below their glass transition temperature.

[0011] In an embodiment a spray drying apparatus is disclosed that contains a first chamber configured with an atomizer for atomizing a solution containing a particle-forming material into liquid particles. The atomizer can be surrounded by an annular gas inlet that can introduce a gas into the chamber. Preferably, the gas has a temperature below the boiling point of a volatile material in the particles. The first chamber can have an exit port that can be fluidly connected to an inlet of a second chamber. Particles and gas from the first chamber can flow into the second chamber through this inlet port. The inlet port in the second chamber can be surrounded by an annular gas inlet through which a gas, which preferably has a temperature above the temperature of the gas in the first chamber, can flow. Preferably, the temperature of the gas entering the second chamber, when mixed with the gas from the first chamber, is above the glass transition temperature of a component in the particle. Preferably, the gas and particles travel through one or both chambers in a laminar flow.

[0012] The drying chambers can be of any suitable shape that allows drying without a substantial quantity of particles contacting the chamber walls while they are in a state that would cause them to adhere or be destroyed by that contact. Suitable chamber shapes include cylindrical shapes or partially or completely tapered such as cones. Thus, chambers that are slightly divergent or convergent towards their outlet end could be used.

[0013] The drying chambers in the aforementioned devices can be cylindrical and vertically elongated. The chambers can have exit ports and inlet ports at opposite ends of the extended chamber such that the gas particle mixtures can flow through the chambers without contacting the chamber walls.

BRIEF DESCRIPTION OF THE FIGURES

[0014] Figure 1 provides a schematic diagram of a three stage spray dryer.

[0015] Figure 2 provides a graphical analysis of particle size distribution for runs where the temperature of the gas exiting chamber 2 was fixed at 100 ⁰C.

[0016] Figure 3 provides a scanning electron micrograph of particles generated from runs where the gas exiting chamber 2 was fixed at 20 ⁰C, 65 ⁰C and 100 ⁰C.

[0017] Figure 4 provides a graphical analysis of residual solvent content as a function of outlet temperature from chamber 2.

DETAILED DESCRIPTION

[0018] The term "particle," as used herein, refers to either liquid, partially dried or solid particles which can be formed from an atomizer or by other known processes.

[0019] The term "about," as used with a number in this application, refers to the range of numbers that are within experimental error of the number at the 66% confidence level but at least encompasses a range of ±10% of the referenced number.

[0020] At constant temperatures and pressures the rate of evaporation of volatile material in a droplet of a polymer solution varies widely over the course of drying. Initially, when the concentration of the volatile material is high the evaporation occurs relatively quickly as if the droplet was pure solvent. Pure solvent droplets evaporate according to the diameter-squared law wherein the square of the droplet diameter decreases linearly with time and the constant of proportionality between the square of the diameter and time is the evaporation rate constant. The evaporation rate constant is a function of gas temperature and composition, and the properties of the volatile material. The solvent evaporation rate is relatively rapid in the initial stages of droplet drying.

[0021] Subsequently, as solvent evaporation proceeds, evaporation can slow as the polymer concentration increases near surface of a droplet and reduces the vapor pressure of volatile material. In this intermediate drying stage, polymer can begin to accumulate near the particle surface as the droplet surface recedes and a polymer skin can begin to form.

[0022] As particle drying nears completion the polymer skin can begin to solidify into a film with a very low permeability. The skin effectively entraps the remaining volatile material in the particle core. At this stage evaporation can be very slow and is generally thought to be controlled by diffusion through the skin.

[0023] A multi-staged spray dryer is disclosed that can be used to provide distinct temperatures within the different drying stages. Suitable temperatures can be selected to promote more complete particle drying. The drying stages can be carried out in individual chambers which can be connected in series. Such an embodiment can include a first drying chamber which can be used to evaporate the majority of the solvent from newly formed, solvent laden particles. Any desired temperature can be used in the first drying chamber. Generally, when solid spherical particles are desired, the temperature will be below the boiling temperature of the volatile material. This avoids inflation or explosion of particles.

[0024] In order to maintain high particle yields, it is preferred that contact of the drying particles with the sides of the drying chamber be avoided. In a method the particles are entrained in the gas as they pass through the central space of the chamber. A laminar flow of particles and gas through the chamber is preferred. To accomplish this the structure of the chamber is designed to avoid eddys.

[0025] The first drying chamber can be designed using the diameter-squared law to estimate the proper length, gas flow rate and gas temperature so that any level of drying can be achieved. For example, drying of about 50% or more, preferably about 75% or more, even more preferably about 80% or more, yet more preferably about 85% or more and even more preferably about 90% or more of the volatile material by mass from the largest drying droplets can be obtained from drying chambers manufactured and operated according to pure solvent evaporation characteristics. With reference to Figure 1, the chamber length for the first drying chamber, stage 1 , can be determined empirically or estimated from the product of the particle velocity and the droplet evaporation time. The particle velocity can be estimated as the sum of the gas velocity and the settling velocity of the particles. As can be appreciated, the velocity of the gas is a function of the gas flow rate, chamber shape and volume. Centerline velocity can be used. The evaporation time can be estimated for the diameter-squared law.

[0026] In an embodiment, the dryer can have a second chamber, stage 2, that facilitates faster or more complete drying as compared to the drying that occurs in the first chamber. Faster more complete drying in the second chamber can be accomplished by heating the particles to a higher temperature than in the first chamber. At such temperatures, the diffusion of the volatile material through the particles is thought to be increased resulting in more rapid transport of a volatile material out of the particles. The diffusivity for a given polymer in a volatile material, such as a solvent, generally has an Arrhenius temperature dependence above the glass transition temperature of the mixture. This is also true for the amorphous component in mixtures having both crystalline and amorphous components.

[0027] With reference again to Figure 1 , the second drying chamber can be designed with sufficient length, drying gas temperature and drying gas velocity to assure that the volatile material can be removed to any desired level, including down to about 0.5% by mass before particles pass from this drying stage. Suitable lengths can be determined empirically or by using the product of the particle velocity and the particle drying time.

[0028] The time for drying can be calculated using a theoretical estimate of the time dependence for the mass of a diffusing substance leaving a sphere given by J. Crank, The Mathematics of Diffusion, 2nd Ed., Oxford University Press., (1995).

[0029] The velocity of the particles through the chamber is the sum of the gas velocity and the particle terminal velocity. The velocity of the gas is a function of the gas flow rate, chamber shape and volume. Centerline velocity can be used.

[0030] In an embodiment, a third chamber, stage 3, can be included in the particle drying apparatus. A third chamber could be used for a variety of purposes. For example, a third stage could be used to quench the gas temperature of the gas exiting the second stage to a temperature below the glass transition of the particles such that the particles are cooled to below their glass transition temperature in preparation for particle collection. In such an embodiment, the particles and hot gas exiting the second chamber can be cooled with large amounts of cold gas. The third chamber or additional chambers can be used for a variety of additional purposes including additional temperatures for particle curing or stabilization of the active pharmaceutical ingredient.

[0031] A schematic diagram of an embodiment of a three stage spray dryer 10 is provided in Figure 1. The apparatus of Figure 1 is generally arranged with a vertical orientation such that gas and particles can flow concurrently and generally from top to bottom of the figure in a vertical direction. Stage 1 drying can occur in a first chamber 110 which can be located atop the apparatus. Stage 2 drying can occur in a second chamber 210 after the first chamber 110 in the particle flow path and a stage 3 chamber 310 can be located after the second chamber 210 toward the bottom of the apparatus illustrated in Figure 1. In some cases, the apparatus can be oriented in a horizontal direction. A horizontal orientation can be used when the gas flow through the device is sufficient to keep the particles suspended in air with little or no contact with the walls of the device.

[0032] The chambers can be any suitable shape that does not cause particles to contact the chamber surface or that does not disrupt a laminar flow. Generally cylindrical symmetric shapes are envisioned. Preferably, the chamber walls (120, 220) of drying chambers (110, 210) will have no convergences or divergences in the direction of flow as such formations can create eddies that disrupt the flow of the droplets and particles through the device causing them to impact the walls of the drying chambers. Furthermore, particle may impact on non-vertical surfaces by gravitational settling. The chambers can be made of any material that can withstand the temperature of the gases and particles within the chamber. As can be appreciated, this will depend upon the volatile material and particle-forming materials used to form the desired particles. Suitable materials can include glass, particularly heat resistant glass, metals, such as stainless steel or heat resistant polymers, particularly thermoplastic polymers. Each chamber in the device can be made of the same or a different material, as desired.

[0033] An atomizer 150 can be positioned in an inlet to form particles from a particle- forming material solution. While the atomizer spray could theoretically be introduced at any point in drying apparatus, it is generally envisioned that atomizer 150 will be positioned at the upper end of first drying chamber 110. Generally, atomizer 150 can be mounted near the center of the first chamber such that spray droplets enter the chamber near its center. Suitable atomizers can spray a droplet pattern such that substantially all of the particles travel down the center of the chamber and particle contact with the chamber walls is minimized or avoided. Suitable atomizers include ultrasonic, pressure, pressure swirl, two fluid, monodisperse, piezoelectric, showerhead and Raleigh jet atomizers, for example. The atomizer can be mounted to the device by any suitable means known in the art. For example, the atomizer can be clamped around a molded edge or a flange of chamber 110.

[0034] An annular gas distributor plate 140 can be mounted around atomizer 150 such that a gas can be introduced into the chamber concurrently with atomized spray droplet particles. Any gas distributor plate that can introduce gas into the chamber such that the gas and particles can travel substantially down the center of the chamber can be used. Preferably, the gas distributor plate and atomizer operate together with appropriate gas and particle flow rates so as to form a laminar flow through the first drying chamber 110. To these ends, the gas distributor plate 140 is generally mounted such that, as gas enters chamber 110, it surrounds the spray droplet stream to create the desired flow of particles entrained in gas through the chamber. Porous glass, plastic or metal distributor plates can be used so long as they can withstand the gas temperatures and provide the necessary gas flow rates. Sintered gas distributor plates are desirable. Sintered stainless steel gas distributor plates are particularly suitable.

[0035] As is known in the art, laminar flows are generally characterized by Reynolds numbers of about 2100 or less. However, the present embodiments are capable of producing flows having much lower Reynolds numbers. For example, flows having a Reynolds number of about 1500 or less, or more preferably about 1000 or less, even more preferably about 500 or less, still more preferably about 250 or less and even more preferably about 200, 150, or even about 100 or less can be created. Methods for determining the Reynolds number are known in the art and can be used.

[0036] Any suitable gas can be introduced into the chamber 110. Exemplary gases include air, nitrogen and argon. In many cases the gas will be inert with respect to the particle ingredients. Suitable gases are preferably clean such that they do not contaminate the particles and can have any suitable temperature depending on the chamber the gas is introduced into and the desired particle characteristics. With respect to the first drying chamber the gas can be below the boiling point of the volatile material or materials used to dissolve, suspend or emulsify the particle-forming material in order to make relatively spherical solid particles.

[0037] The gas flow rate through each chamber must be low enough to avoid creating turbulence in the chamber yet sufficiently fast to allow the desired evaporation of the volatile material to occur. It is well within the skill of one skilled in the art to identify and use suitable gas flow rates.

[0038] In the embodiment illustrated in Figure 1, chamber 110 is fluidly attached to a second chamber 210. Chamber 210 can be used to remove additional volatile material from the partially dried particles. In this embodiment the exit 160 of chamber 110 is directly connected to the second chamber 210, as illustrated in Figure 1. The connection can be by any suitable method, such as clamped flanges, or other fastening devices or through adhesives or welding where suitable, and can include a gasket such that the particles can enter into the second chamber without significant leaking from the apparatus and with minimal particle trapping at the interface between the chambers. Preferably exit 160 of chamber 110 is located such that the particles and gas exiting the chamber enter a central region of the second chamber 210. An annular gas distributor plate 240 is mounted in chamber 210 of the illustrated device such that a gas can be introduced into the chamber concurrently with the particles and gas exiting from chamber 110. Gas distributor plate 240 can be of any suitable construction using the same considerations described above with respect to distributor plate 140 of chamber 110, keeping in mind that the gas passing through the distributor plate 240 in second chamber 210 is likely to be substantially hotter than the gas entering the first chamber.

[0039] Particles passing through second chamber 210 are dried in much the same manner as chamber 110 with the exception of the hotter gas temperature. As one of skill would appreciate, ultimately the temperature in the environment of the particles will result from the combination of the new gas entering second chamber 210 with the particles and gas exiting first chamber 110. In either the first or second drying chamber, gas temperature can be actively and accurately controlled by monitoring the temperature of the gas at any point in the chamber, such as by a thermocouple at the exit of a chamber, and controlling the temperature of the gas entering the chamber. Of course, temperatures can be monitored at multiple locations in each chamber of the apparatus.

[0040] Various methods for heating gas are known in the art and can be used. Microwave heating and heating with an infrared furnace are exemplary heating methods. As indicated above, in chamber 210 particles can be heated to a temperature above the glass transition of the particle-forming material from which they are made. This is thought to facilitate evaporation at least in part because it increases the diffusivity of the volatile material through the particle. The gas used in the second chamber can be the same or different than the gas used in the first chamber.

[0041] In an embodiment, the second chamber 210 can be fluidly attached to a third chamber 310 which can be used to cool the particles to a temperature below the glass transition temperature of the polymer in the particles. Many methods for connecting such chambers are known and can be used as described for connection between the first and second chambers. The connection between chamber 210 and 310 should preferably allow for the passage of particles without leakage and with minimal accumulation at the interface between the two chambers. Chamber 310 can provide cooling in any suitable manner that allows the particles entering the chamber to be cooled to below their glass transition temperature while they are airborne. For example, chamber 310 can be cooled through jacketing or can have one or more inlets for cold gas which can be added in a manner to create turbulence with the gas and particle stream exiting chamber 210. Of course, a variety of cooling methods can be combined in any suitable manner.

[0042] In alternative embodiments, one or more of the drying chambers can have double walls to provide insulation. The space between the walls can contain heated gases or liquids. In another embodiment, the inner wall can have perforations and gas can enter the chamber through the perforations. Further, any number of additional chambers can be included such that additional drying or curing temperatures can be used.

[0043] Methods for forming dry particles using the disclosed equipment are also disclosed. A spray solution can be prepared by dissolving a solid forming material, such as a polymer, which can be used to form the bulk of the particle. Alternatively, the material can be suspended or emulsified in a non-solvent to form a suspension or emulsion.

[0044] Particle-forming materials can include any substance that can be formed into a particle using the disclosed apparatus and methods. Particle-forming materials can include amorphous polymers, crystalline polymers, or other amorphous or crystalline solids, for example. Many particle-forming materials are suitable for use in the present methods and apparatus. They include synthetic and natural polymers, non-biodegradable and biodegradable polymers, and water-soluble and water-insoluble polymers. Representative synthetic polymers include poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid) and poly(lactic acid-co-glycolic acid) polyglycolide, polylactide, poly(lactide-co-glycolide) and blends, polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides such as poly(ethylene oxide), polyalkylene terepthalates such as poly(ethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, derivativized celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, and cellulose sulfate sodium salt (jointly referred to herein as "synthetic celluloses") and derivatives thereof, polymers of acrylic acid, methacrylic acid or copolymers or derivatives thereof including esters, poly(methyl methacrylate), poly( ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate) (jointly referred to herein as "polyacrylic acids"), poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), polycaprolactone and copolymers and blends thereof.

[0045] As used herein, "derivatives" include polymers having substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications that can be made by known methods. Examples of preferred non-biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, copolymers and mixtures thereof. Examples of preferred biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid, polylactide, polyglycolide, poly(lactide- co-glycolide), and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), and derivatives of hydroxypropylmethylcellulose, such as acetate and succinate substituted derivatives. Representative natural polymers include proteins, peptides and polysaccharides.

[0046] Volatile materials, include solvents that can dissolve the particle-forming material, or materials that can be used to suspend or emulsify the particle-forming material such that it can be sprayed using a spray atomizer. Volatile materials that can dissolve, disperse or form an emulsion with the chosen polymer mixture such that the mixture forms a solid particle when passed through the spray drying equipment can be used in the present apparatus. Suitable volatile materials that may find use include organic solvents that have a relatively low boiling point and that are acceptable for administration to humans in trace amounts. Representative volatile materials include acetic acid, acetaldehyde dimethyl acetal, acetone, acetonitrile, butynol, chloroform, chlorofluorocarbons, dichloromethane, dipropyl ether, diisopropyl ether, N,N-dimethlyformamide (DMF), dimethyl sulfoxide (DMSO), dioxane, ethanol, ethyl acetate, ethyl formate, ethyl vinyl ether, glycerol, heptane, hexane, isopropanol, methanol, nitromethane, octane, pentane, tetrahydrofuran (THF), toluene, 1,1,1- trichloroethane, 1,1,2-trichloroethylene, water, xylene, and combinations thereof. In general, the particle-forming material can be dissolved, emulsified or suspended in the volatile material to form a solution having a concentration of between 0.1 and 75% weight to volume (w/v), more preferably between 0.5 and 30% (w/v)of the particle-forming material.

[0047] Components, such as active pharmaceutical ingredients or drugs, including chemotherapeutics, vaccines, peptides and protein drugs; diagnostic agents, such as imaging agents and contrast agents; nanoparticulates; nucleic acids; gene therapy vectors; radionucleotides; siRNAs; growth factors; antigens surfactants; bulking agents; stabilizers; lubricants or pore forming agents can also be added. The disclosed apparatus and methods are particularly useful with peptide drugs.

[0048] The solution can then be introduced into spray atomizer 150 by methods well known in the art. A pump or pressurized feed system can be run at any suitable rate, typically these are operated at rates that range from about 0.25 to about 10 ml/min. As one of skill in the art could appreciate, operation outside this range would depend on feed solution properties and the scale of the system. Any pumping or pressurized feed system that can be used to supply feed solution to the nozzle of the atomizer in present apparatus can be used, for example, the solution can be drawn into a glass syringe and placed on a syringe pump. Droplets of the particle-forming material solution can then be generated and ejected into the top and center of drying chamber 110. The flow rate of the solution fed to the atomizer can be controlled by any suitable method many of which are commonly known in the art.

[0049] In a method, a drying gas having a suitable temperature below the boiling point of the volatile material also enters chamber 110 through annular distributor plate 140 surrounding atomizer 150. The gas can entrain particles carrying the drying particles downward through the center of chamber 110. The gas and particles can form a laminar flow through chamber 110.

[0050] The gas with entrained partially dried particles exiting chamber 110 flows into the top center of chamber 210. Here, additional heated drying gas can be introduced through annular distributor plate 240 around the stream entering from chamber 110. Optionally, additional drying gas can be introduced through perforated walls in this chamber to provide sheath flow and to prevent particles from depositing on the walls 220.

[0051] The second chamber 210 can be operated at higher temperatures than chamber 110 to facilitate additional drying. In this manner the residual content volatile material in the particles passing through chamber 210 can be reduced to surprisingly low levels. To achieve such drying, the particles can be heated to temperatures well above their glass transition temperature. At these temperatures, the diffusivity of the volatile material through the particles is thought to be increased, allowing for more rapid transport of volatile material to the particle surface where it can evaporate. Chamber 210 can be designed with sufficient length and drying gas temperature and particle velocity to assure that volatile material can be removed from the particles to the desired levels before exiting to the third chamber 310. This can be determined empirically or through the methodology described above. Using such an approach, systems and methods can be designed that produce particles having a volatile material content of about 5%, 4%, 3% by weight or less. More preferably, particles having residual contents of about 2%, about 1.5%, about 1% or about 0.9%, about 0.8%, about 0.7%, about 0.6% and most preferably about 0.5% or less can be obtained. Lower residual solvent contents are generally preferred.

[0052] A third chamber 310 can be used to quench the gas temperature to below the glass transition of the particles to prepare the particles for collection. In chamber 310, the particles and hot gas exiting chamber 210 can be cooled with large amounts of a cold gas. The temperature of the mixed gas and the walls of the vessel are preferably below the glass transition temperature of the particles to prevent particle adhesion on the walls. The particle laden gas flow from chamber 210 can be introduced at the top center of chamber 310 and the quenching gas can be introduced through any number of entry points at any number of positions to create a turbulent cooling environment within the chamber. A number of suitable cooling chambers that are capable of carrying out turbulent mixing are known in the art and can be used so that rapid heat transfer can occur. Once cooled to about the glass transition temperature of the polymer or lower, the particles can contact the walls of the chamber and can be collected. The particles can then be collected from the quenched gas and particle mixture by a standard particle separator, such as a cyclone or a filter, which can be fluidly connected to the outlet of the cooling chamber.

[0053] The disclosed drying method and apparatus can also be used to dry preformed solid particles, such as solid particles prepared by prior art methods. Such particles contain higher concentrations of residual volatile materials than if they had been prepared using the disclosed apparatus and method. Solid particles can be introduced into either the first or second chamber by any suitable manner that disperses the particles as they enter the center of the chamber, such as through a sieve. The sieve can be surrounded by a gas distributor plate such that the particles travel through the device in a laminar flow with the gas and are dried. Suitable gas temperatures for such applications can raise the temperature of the particles to above the glass transition temperature of a polymer in the particle. Such drying of preformed particles could be accomplished using a three chamber embodiment as described above with the exception of a particle delivery device such as a sieve in place of the atomizer. Alternatively, preformed particles could be introduced directly into a second chamber adapted with a sieve.

EXAMPLE

[0054] In the following example particles of poly^actide-co-glycolide), also known as Resomer RG502H (lot# 1009848 from Boehringer Ingelheim Pharma, Ingelheim am Pvhein, Germany) were prepared by dissolving the polymer in analytical grade dichloromethane and drying according to disclosed methods.

[0055] Dry particle batches were prepared in spray drying runs performed by varying the outlet temperature as measured at the bottom of drying chamber 210 to study the effect of the drying temperature on the residual solvent levels in particles. Temperatures ranging from about 20 ⁰C to about 100 ⁰C were used. The yield of each spray drying batch was determined and the resulting microparticles were characterized. Particle size distribution was determined using low angle laser light scattering. Residual solvent was measured using headspace gas chromatography. Particle morphology was determined by scanning Electron Microscopy (SEM).

[0056] The particle yield was observed to increase with increasing temperature from about 20 ⁰C to about 65 ⁰C. Surprisingly, no drop in particle yield was observed with outlet temperatures from chamber 210 were up to about 100 ⁰C. Figure 2 shows the particle size distribution (PSD) range for particles prepared with an outlet temperature from chamber 210 of about 100 ⁰C. Figure 3 shows that solid spherical particles were obtained at higher temperatures.

[0057] Figure 4 shows the surprising reduction in residual solvent that was obtained when elevated temperatures (above the glass transition temperature of the polymer) were used as in chamber 210. The high residual solvent in particles obtained using lower temperatures was comparable to the residual solvent content in particles prepared from known spray dryers. At higher temperatures much lower levels of residual solvent were present in particles. For example, at an outlet temperature of 100 ⁰C when measured at the bottom of the second chamber, the residual solvent level was measured at less than 1% and was very close to about 0.5%.

[0058] This example demonstrates that a multi-stage spray dryer can be used to generate microparticles with solvent content less then 1% and close to 0.5% with desired product morphology in a single step fabrication process. This process eliminates the need for lengthy secondary drying procedures. [0059] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Claims

CLAIMSThe invention is claimed as follows:

1. A particle drying apparatus comprising: a chamber having at least one inlet and at least one outlet containing particles comprising a particle-forming material and a volatile material and further comprising a gas having a temperature at the outlet above the glass transition temperature of the material, wherein the particles and gas flow from an inlet to an outlet in the chamber.

2. The particle drying apparatus of Claim 1, further comprising a heater for heating the gas.

3. The particle drying apparatus of Claim 1, further comprising particles exiting the outlet having an average of about three (3) percent or less of the volatile material by mass.

4. The particle drying apparatus of Claim 1, wherein at least a portion of the particles and the gas are in a laminar flow.

5. The particle drying apparatus of Claim 1, wherein the particles at the chamber outlet are substantially nonagglomerated.

6. The particle drying apparatus of Claim 1, wherein the particles in the chamber lack an additional excipient apart from the particles.

7. The particle drying apparatus of Claim 1, wherein a portion of the chamber is cylindrical.

8. The particle drying apparatus of Claim 1, wherein a portion of the chamber is vertically elongated.

9. The particle drying apparatus of Claim 1, wherein a portion of the chamber is vertically elongated and an outlet is positioned in the vicinity of the bottom of the chamber.

10. The particle drying apparatus of Claim 1, wherein the chamber is vertically elongated and the inlet is positioned in the vicinity of the top of the chamber.

11. The particle drying apparatus of Claim 1 , wherein the chamber inlet comprises an annular ring through which gas above the glass transition temperature of the particle- forming material is introduced.

12. The particle drying apparatus of Claim 1, further comprising a second chamber, wherein the outlet from the chamber is joined to the inlet of the second chamber.

13. The particle drying apparatus of Claim 1, further comprising a second chamber, wherein the outlet from the first chamber is joined to the inlet of the second chamber, the second chamber containing a gas below the glass transition temperature of the particle-forming material.

14. A method for preparing a particle comprising: obtaining a solid particle containing a particle-forming material and a volatile material, passing the particle through a chamber containing a drying gas and evaporating the solvent until a particle having about three (3) percent or less of the volatile material, by mass, is formed and collecting the particle.

15. The method of Claim 14, wherein the particle comprises an amorphous glass.

16. The method of Claim 14, wherein the particle comprises a polymer.

17. The method of Claim 14, wherein the particle comprises a protein.

18. The method of Claim 14, wherein the particle comprises an amorphous small molecule.

19. The method of Claim 14, further comprising evaporating the volatile material from the particle until a particle having about two (2) percent or less of the volatile material, by mass, is formed.

20. The method of Claim 14, further comprising evaporating the volatile material from the particle until a particle having about one (1) percent or less of the volatile material, by mass, is formed.

21. The method of Claim 14, further comprising evaporating the volatile material from the particle until a particle having about 0.75 percent or less of the volatile material, by mass, is formed.

22. The method of Claim 14, further comprising evaporating the volatile material from the particle until a particle having about 0.66 percent or less of the volatile material, by mass, is formed.

23. A method for preparing a particle comprising: introducing a droplet containing a polymeric particle-forming material and a volatile material into a chamber containing a drying gas and evaporating the solvent until a particle having about three (3) percent or less of the volatile material, by mass, is formed and collecting a solid nonagglomerated polymeric particle.

24. A particle drying apparatus comprising: an drying chamber comprising an inlet and an opposing outlet and a flow from the inlet to the outlet of a mixture of a gas and particles containing a particle-forming material, wherein the gas has a temperature above the glass transition temperature of the particle-forming material; and further comprising, a second chamber fluidly connected to the exit of the drying chamber such that particles and gas exiting the drying chamber enter the second chamber through an inlet, wherein the second chamber further comprises a gas below the glass transition temperature of the particle-forming material to cool particles in the second chamber.

25. The particle drying apparatus of Claim 24, wherein the flow of the mixture of gas and particles in the drying chamber is a laminar flow.

26. The particle drying apparatus of Claim 24, wherein the particles flowing into the inlet of the drying chamber are partially dried.

27. A particle drying apparatus comprising: a first chamber comprising an atomizer, atomizing a solution comprising a particle-forming material into liquid particles, surrounded by an annular gas inlet introducing a gas having a temperature below the boiling point of a volatile material in the particles, the first chamber having an outlet fluidly connected to an inlet of a second chamber through which particles and gas from the first chamber flow into the second chamber, wherein the inlet to the second chamber is surrounded by an annular gas inlet through which a gas having a temperature above the temperature of the gas in the first chamber flows such that the particles become entrained in the gas in the second chamber.

28. The particle drying apparatus of Claim 27, wherein the temperature of the gas in the second chamber is above the glass transition temperature of a particle-forming material in particles.

29. The particle drying apparatus of Claim 27, further comprising a third chamber, wherein an outlet from the second chamber is joined to the inlet of the third chamber.

30. The spray drying apparatus of Claim 27, further comprising a third chamber, wherein the outlet from the second chamber is joined to the inlet of the third chamber, the third chamber containing a gas below the glass transition temperature of the particle-forming material.

31. A particle drying apparatus comprising: a first chamber comprising an atomizer, atomizing a solution comprising a particle-forming material into liquid particles, surrounded by an annular gas distributor introducing into the first chamber a gas having a temperature below the boiling point of a volatile material in the particles, the first chamber having an outlet fluidly connected to an inlet of a second chamber, the second chamber comprising an inlet and an opposing outlet and a flow from the inlet to the outlet of a mixture of a gas and particles containing a particle- forming material, wherein the gas has a temperature above the glass transition temperature of the particle-forming material; and further comprising, a third chamber fluidly connected to the exit of the second chamber such that particles and gas exiting the second chamber enter the third chamber through an inlet, wherein the third chamber further comprises a gas below the glass transition temperature of the particle-forming material to cool particles received from the second chamber.

32. A particle drying apparatus comprising: a chamber having at least one inlet and at least one outlet containing particles comprising a particle-forming material that crystallizes to form a substantially crystalline solid and a volatile material and further comprising a gas having a temperature in the chamber that is sufficient to melt a crystalline particle-forming material in the chamber, wherein the particles and gas flow from an inlet to an outlet in the chamber.